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Body Worlds Vital visits Rhode Island, page 66 R SPECIAL SECTION Advances in Autoimmune Diseases Guest editor: Edward V. Lally, MD

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18 Newer Treatment Strategies for Autoimmune Diseases Edward V. Lally, MD Guest Editor

E. Lally, MD

19 Targeted Immunomodulatory Therapy: An Overview Ashley L. Lefebvre, PharmD, CDOE Laura McAuliffe, PharmD: PGY2

23 Systemic Lupus Erythematosus: A. Lefebvre, PharmD A Review of the Clinical Approach to Diagnosis and Update on Current Targeted Therapies Joanne Szczygiel Cunha, MD Katarzyna Gilek-SEIbert, MD J. Cunha, MD

28 Pemphigus: Pathogenesis to Treatment K. Gilek-Siebert, MD Christopher DiMarco, MD

32 Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP): C. DiMarco, MD Clinical Features, Diagnosis, and Current Treatment Strategies Jacques Reynolds, DO George Sachs, MD, PhD G. Sachs, MD, PhD Kara Stavros, MD

36 Autoimmune Cytopenias: Diagnosis & Management Christian P. Nixon, MD, PhD Joseph D. Sweeney, MD

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8 COMMENTARY Medical Tourism Joseph H. Friedman, MD

Dickensian Diagnostics: The Diseases of Christmas Past What ailed Scrooge and Tiny Tim? Herbert Rakatansky, MD

reconnecting with my Purpose in the Kingdom of Bhutan Eric Cohen, MD

17 RIMJ Around the World New York, New York

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66 Spotlight body Worlds Exhibit: Anatomy Up Close & Personal Mary Korr

78 heritage Dec. 7, 1941: 75 years ago, Japan attacks Pearl Harbor RIMJ launches special features: Doctors at War & Calling All Battle Stations Mary Korr RHODE ISLAND M EDICAl J ournal

In the news

ALPERT FOUNDATION 68 72 WOMEN & INFANTS awards Brown medical school $27M files letter of intent for renovation of labor and delivery suite AMA ADOPTS NEW POLICIES 68 to support student wellness and mental health 72 STOICO/FIRSTFED FOUNDATION TEXTBOOK 70 donates $1.1M for maternity care trains physicians on ‘third science’ at St. Luke’s Hospital

BRADLEY HASBRO CHILDREN’S RESEARCH CENTER 70 73 DRS. GRUPPUSO, ADASHI awarded $3.3M NIH grant to study effects of trauma question ‘residency placement fever’ on teens and value of social media in recovery

People/PLACES

PHYLLIS A. DENNERY, MD 75 76 ROGER WILLIAMS CANCER CENTER named president-elect recognized at American Cancer of Society for Redox Society’s RI research breakfast Biology and Medicine 78 GAURAV GUPTA, MD, DEMETRA C. OUELLETTE 75 graduates from AAO leadership named president of Roger development program Williams Medical Center 78 MEMORIAL HOSPITAL LAWRENCE T. SAULNIER, RN, BSN 75 School of Nurse Anesthesia joins Visiting Nurse of HopeHealth graduates 9 as director of nursing 80 ROBERT J. WESTLAKE, MD, EDEN CARDOZO, MD 76 honored by Butler Hospital joins W&I to oversee fertility preservation 80 KENT’S WOMEN’S CARE CENTER program receives Baby-Friendly designation DECEMBER 2016 VOLUME 99 • NUMBER 12 RHODE ISLAND Rhode Island Medical Society R I Med J (2013) 2327-2228 M EDICAl J ournal 99 publisher Rhode Island Medical Society 12 president 2016 RUSSELL A. SEttipane, MD

December president-elect 1 Sarah J. fessler, MD vice president Bradley J. Collins, MD CONTRIBUTION secretary Christine Brousseeau, MD 41 Fibromyalgia Syndrome, A Geriatric Challenge treasurer Julio C. DeFillo-Draiby, MD Jose r. Polanco, MD John S. Page immediate past president Peter Karczmar, MD Executive Director CASE REPORTS Newell E. warde, PhD 45 Fournier’s gangrene of the penis in a Editor-in-Chief 12-year-old patient secondary to phimosis Joseph H. Friedman, MD Luther Ward, MD, MPH, FACS associate editor Daniel Eisenson, BA Sun Ho Ahn, MD Jean-Louis Fils, MD

Publication Staff managing editor 47 Right in Front of Our Eyes: Mary Korr Evolution of Streptococcal Toxic Shock Syndrome [email protected] with Ischemic Optic Neuropathy graphic designer Salaheldin M. Elhamamsy, MD Marianne Migliori Mazen O. Al-Qadi, MD advertising Steven DeToy Taro Minami, MD Sarah Stevens Marguerite Neill, MD [email protected]

Editorial board PUBLIC HEALTH John J. Cronan, MD James P. Crowley, MD 50 PUBLIC HEALTH BRIEFING Edward R. Feller, MD Ten Years and Growing: John P. Fulton, PhD Peter A. Hollmann, MD Medical Marijuana in Rhode Island – Where Are We Now? Kenneth S. Korr, MD James V. McDonald, MD, MPH Marguerite A. Neill, MD Mike Simoli Frank J. Schaberg, Jr., MD Lawrence W. Vernaglia, JD, MPH 53 HEALTH BY NUMBERS Newell E. Warde, PhD Surveillance of Suicide and Suicide Attempts Among Rhode Island Youth Using Multiple Data Sources

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Medical Tourism

Joseph H. Friedman, MD [email protected] 8 9 EN

This column is about a I am monolingual, which might be wise advice for any different sort of medi- a major drawback, I teacher, especially one from New York. cal tourism. The term believe, in life. I find There are two questions to consider “medical tourism” gen- the experiences always about this type of medical tourism. erally refers to patients enriching. Now that I am What are the benefits for the tourist and who travel outside their an experienced, old-hand what are the benefits for the recipient? country to seek medical at this, or, simply, just The hosts always act grateful, although, care, usually because of old, and a professor at to be honest, cultural insensitivity expense. There are places Brown, I have taken on from both ends, may undercut this. that may be tourist des- the title of the visiting My colleagues at home rarely appear to tinations, with nice cli- professor. Since I have comprehend, however, how much the mates, beautiful beaches, visited places that are tourist receives in exchange. cheap hotels and good food, where the greatly deficient in neurology, I think Each medical trip I’ve made has staff may be first rate, often Ameri- I can make a difference, albeit a small always increased my gratefulness for can- or European-trained, who practice one, in helping general internists under- being born when and where I was, for medicine at a high level, with excellent stand and evaluate neurological prob- not being poor, for not having limited nursing care, air-conditioned, hotel-like lems better. There is, of course, a limit possibilities. But I’ve always been premises, and solicitous VIP treatment. on how much one can accomplish in any impressed with the resourcefulness of The cost may be less than the co-pay period of time, and shorter, obviously, the local doctors, and for the patients’ for some insurance plans, or the treat- means less. However, some government tolerance of their limited medical pos- ment may not be covered by insurance ministries are loath to consider an ex- sibilities. It is a harsh and awful fact in the U.S. or may be performed much patriot for a stay of less than 2 or 3 that a family in most of Africa will sooner than can be provided by national months, assuming, correctly, I think, in accept as an unfortunate fate that they insurers, as in Canada or England. most cases, that it takes several weeks for lack the money to pay for the tests or I have been a different kind of med- a newcomer to get his “sea legs.” It often treatment for a loved one. It contrasts ical tourist. I spent time in Tanzania takes some weeks to both understand with the railing against the unfairness of (3 months as a graduating medical English with a novel accent, especially fate I sometimes see from the children student), working in or teaching in when spoken softly, as is the norm in of the 88-year-old person with one of hospitals in Zambia (4 weeks), Kenya some places, and, perhaps more impor- the dread neurological disorders of the (2 weeks), Rwanda (10 weeks), Malawi tantly for a teacher, to be understood. elderly. Seeing medicine in different (4 weeks) and Ghana (2 weeks). I cannot When I was a Peace Corps teacher cultures teaches us about life, how each account for my focus on African coun- in Ghana, several decades ago, I some- of us lives our lives as constrained by tries, other than, perhaps, the fact that times would translate from English our cultures. I have only gone to places where the into English, for new American I do not believe that I have developed national language, the language in which arrivals who were not understood any greater insights than anyone else school is taught, medicine is taught by Ghanaians, or vice versa. Since who visits a hospital for short periods. and often communicated, is English. then I have always taught at a slower I am not an anthropologist, and, since Unlike all of my African colleagues, pace, with attention to articulation, I mostly have visited places only once,

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I’ve, unfortunately, made no real friends than may be the norm. Some hospitals this is a great experience that I recom- to provide insights that I could not have preserved the pedantic style of mend for doctors at all levels of prac- perceive on my own. the colonial UK, where professors were tice, I am hopeful that poor countries What the hosts get is extra education. never wrong and certainly never to be can harness the expertise and attitudes In the places I’ve been there has been lit- challenged. Junior faculty are window of the increasing numbers of retired tle neurology teaching available. There dressing even when more knowledge- American physicians, who now have the was one neurologist in Zambia, four in able than the senior doctor. time to continue making contributions Ghana, one in Malawi, none in my area Cultural insensitivity may undermine they were unable to make before. v of Kenya. Neurological problems affect the hosts’ feeling of gratefulness. This over a third of patients on the medical is usually due to the guest, but this has Author wards. If one learns neurology from been rare, as best I can tell (but I am Joseph H. Friedman, MD, is Editor-in-chief someone who learned neurology from unlikely to be a sensitive guide, I admit). of the Rhode Island Medical Journal, someone…who was not a neurologist, Some problems develop, I believe, from Professor and the Chief of the Division who did not know how to perform a having too many ex-patriots, creating a of Movement Disorders, Department of neurological exam…you get the pic- two-tier system of doctors. The ex-pats Neurology at the Alpert Medical School of ture. I can help change that a little bit. become the “experts” and the nice guys, Brown University, chief of Butler Hospital’s Hopefully that makes a difference. I try never disciplining the laggard students Movement Disorders Program and first to convey the excitement I feel about and house officers, while the local recipient of the Stanley Aronson Chair in neurological disorders, perhaps inspir- attending physicians are relegated to the Neurodegenerative Disorders. ing someone to become a neurologist. shadows and to playing the “heavies.” It also brings a different teaching style The experience is unparalleled. While Disclosures on website

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Dickensian Diagnostics: The Diseases of Christmas Past What ailed Scrooge and Tiny Tim?

Herbert Rakatansky, MD 11 12 EN

Wh e n w e f i r s t m e e t psyche to lie dormant could be raised whether his behavior the Ebenezer Scrooge (A until the “first spirit” next day was manic and today would be Christmas Carol by revives them. treated, perhaps with drugs. Charles Dickens), he is Did Scrooge have an Brief psychotic episodes (1 full day–1 miserable and friendless. underlying obsessive- month) may be spontaneous or precipi- He had been distanced compulsive personality tated by factors such as drugs, emotional from his father and sent disorder? He certainly trauma, etc. Bipolar disease may present to a boarding school. He had a long-standing, fixed with grandiose delusions, but there were was allowed to return pattern of behavior that no antecedent episodes. In some cultures home only at the urging was outside the spectrum and religions such behavioral episodes of his sister, who reas- of “normal” and had neg- may be considered as “normal.” But sured Scrooge, “Father is ative consequences for Scrooge had no such affiliations. Some so much kinder than he him and others. These speculate that a brief psychotic episode used to be.” We are not disorders are resistant to can change one’s self-image, usually for told what happened at home and we treatment and generally do not change the worse. Scrooge’s self-image, how- know little else of his father (his mother easily, if at all. ever, changed for the better. And the is not mentioned) but it is not a stretch One night Scrooge described hearing hallucinations were limited to only one to conclude that Scrooge was emotion- voices and seeing “ghosts.” The next night, thus not fitting the criteria for a ally deprived as a child. day, unexpectedly, and without apparent brief psychotic episode. His only sister, who was caring and for cause, he suddenly began giving away Perhaps his hallucinations really were whom he cared, died in childbirth. He substantial sums of money and exhibit- just vivid dreams. He recalled the visual never forgave his nephew for this loss ing a markedly aberrant mood (friendly and auditory sensations as if he had been and was estranged from him. and exuberant). His visual and auditory awake. We all have had dreams like that. A planned marriage was cancelled by hallucinations might be diagnosed as a They seem very real, but they do not his fiancée, discouraged by Scrooge’s brief psychotic disorder and the question change our lives. total devotion to his business and making money. His only friend had been his business partner, Jacob Marley, who had a similar temperament, but was now deceased. His considerable wealth bought him neither comfort nor happi- ness. Scrooge lived very modestly and disavowed material pleasures. If this all sounds authentic, it is. Dick- ens was brought up in poverty in London and knew of what he wrote. Mr. Fezziwig, his first employer, was remembered as a caring and kind person. One might surmise that Dickens planted this memory and the memory of the affection of his sister in Scrooge’s

Charles Dickens, full-length portrait, seated at desk, facing left, in his study at Gad’s Hill Place.

Created by Samuel Hollyer, circa 1875. of Co ng r ess Libr a ry

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The original illustration It is estimated that 60% of children of Marley’s Ghost visiting in London at that time had rickets. The Ebenezer Scrooge by John first evidence that lack of an essential Leech appeared in the nutrient was the cause of rickets was 1843 publication of noted in 1899. After multiple litters of A Christmas Carol. lion cubs died of rickets at the London Zoo, survival was achieved with a diet prudent dose of alka- that included cod liver oil. Subsequent line carbonates.” If investigations led to the discovery of Tiny Tim received this Vitamin D and its structure, for which treatment, his meta- Adolph Windaus won the Nobel Prize bolic acidosis might in 1928. have improved and Thus the improved nutrition, the also the osteomala- Vitamin D in the cod liver oil and the cia and propensity for exposure to sunlight at country sanatoria fractures. Of course if would have been appropriate treatment ry of Co ng r ess Libr a ry he received fish liver for Tiny Tim’s rickets. oil he would be getting Additionally, in Dickens’ era, fully Vitamin D as well. 50% of London children had TB. The The theory at that etiology of TB was unknown. Proof of time was that disease its infectious etiology (Koch) appeared Tiny Tim and 19th-Century London transmission was due to “miasmas,” only in 1882. The major illness in A Christmas Carol, a mysterious property of the air. To If Tiny Tim had TB, why did it get however, is the crippling disease suf- protect them, children were kept fully better? Macrophages take up Vitamin D fered by Tiny Tim, who needed a crutch clothed, including their arms and legs, and this activates a series of intracellular and metal braces. Many orthopedic, and kept indoors, a certain impediment processes resulting in the production infectious, neurologic, congenital and to achieving adequate Vitamin D levels. of cathelicidin, a molecule that is bac- other conditions could be the culprit. At that time London industry was tericidal, especially to M tuberculosis. Dickens’ books were illustrated, but no fueled by coal and the pollution was This also helps explain the success of visual clue about Tiny Tim is available, profound. The sky was “blackened with treatment for TB with rest, adequate as he was not pictured in illustrations soot and particles.” And there were high nutrition and sunlight in the pre-anti- during Dickens’ lifetime. concentrations of sulfur dioxide which biotic era. We know that Tiny Tim survives after block UV light. Type 1 RTN is a rare genetic disease. the latest and best treatment is financed The diet of Londoners, especially the Rickets and TB were ubiquitous. Tiny by Scrooge after his “transformation” poor, was mostly carbohydrates and Tim’s response to treatment and the (from whatever cause). So the disease deficient in Vitamin D. Commercial prevalence of rickets and TB suggest that must be amenable to treatment available bread from small bakeries was adulter- these were his afflictions. in 1843. ated with alum and aluminum salts, All this clinical retrospection is inter- One proposed theory suggests that that precipitate phosphates leading to esting. But the power of this tale, as an type 1 renal tubular acidosis (RTN) hypophosphatemia, which worsened the allegory, is greater than its physiology. might be the culprit. Treatment for rickets. This was illegal. The inspectors, Perhaps the story of Scrooge’s “brief psy- symptoms such as weakness and failure however, concentrated on large flour chotic episode” or dreams (if you prefer), to thrive (after all, he was called Tiny wholesalers so that flour for home- and Tiny Tim’s recovery, can ”trans- Tim) might have included rest, nutri- baking was not adulterated. Did Tiny Tim form” the reader and lead to a better tion, trips to the country to rest, etc. eat commercial or home baked bread? world. Thanks be to Charles Dickens. v Cod and halibut liver oil were common We know that Mrs. Cratchit, Tiny Tim’s remedies for various afflictions. Dickens mother, cooked “pudding” but there is himself describes taking cod liver oil. no mention of her baking bread. In 1857, Author Various “tonics” and mineral waters John Snow first suggested the associa- Herbert Rakatansky, MD, FACP, FACG, generally were advised. Some of these tion of adulterated bread with rickets. is Clinical Professor of Medicine Emeritus, contained bicarbonate that might have The diet and lack of sunlight com- The Warren Alpert Medical School of served to ameliorate the acidosis. Scrof- bined to produce profound Vitamin D Brown University. ula (TB) and rickets were treated with “a deficiency and rickets.

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Reconnecting with my Purpose in the Kingdom of Bhutan

Eric Cohen, MD 13 15 EN [Editor’s note: To get to Bhutan, Dr. Cohen immersing myself in the flew from Boston to Dubai to Bangkok and Bhutanese culture with a then took a flight to Paro, Bhutan on Druk Air. goal of applying western From Paro, it is an hour drive to the capital of medicine best practices Thimphu, Bhutan and the hospital where he to have an impact on the The entrance gates to Jigme Doriji Wangchuck National Re- worked. It takes about 24 hours of traveling to patient community served ferral Hospital in Thimphu, Bhutan. The hospital was created get there. Prior to departure, volunteers must by the Jigme Dorji Wang- in 1972 and named after the Third King of Bhutan. It functions have updated vaccinations for yellow fever chuck National Referral as the main referral hospital for the country with 350 hospital and hepatitis.] Hospital in Thimphu, Bhu- beds. Bhutan has a nationalized healthcare system and ba- tan. But, I returned to the sic healthcare is provided for all citizens by the government.

Keywords: Heath Volunteers states five weeks later with Oversees (HVO), international a newfound connection to several core the western world, this may seem obvi- volunteer, medical mission, medical principles that will undoubtedly be ous and easy to do. But, when you strip education, Bhutan invaluable to my future practice as an out luxuries like access to the latest orthopaedic surgeon. literature, high-speed communication The first core principle I reconnected platforms and exposure to the most On March 11, 2016, I began my jour- with was the importance of continuing sophisticated experts in a given field, ney to the Kingdom of Bhutan, a small medical education across all disciplines. the value you place on medical educa- Buddhist country nestled in the Hima- To medical and surgical practitioners in tion expands exponentially. Within my layans, on a volunteer medical mission through Heath Volunteers Oversees (HVO) with support from the Caroll M. Silver Traveling Fellowship. For me, volunteering abroad was more than just wanting to satisfy my need for an adven- ture or the need to conquer something new. If that were the case, I would have left on this mission at least five years earlier. Timing was critical to my plan; I finally had medical knowledge to share. My mission to Bhutan was rooted in my need to show gratitude for all that has been given to me over the course of my medical school and residency career to date. As a chief orthopaedic surgery res- Dr. Eric Cohen presenting Grand Rounds on pediatric septic arthritis of the hip to the Bhutanese ident at Rhode Island Hospital, I left orthopaedic surgeons, fellow (Heath Volunteers Oversees) HVO volunteers, fourth-year medical Rhode Island with the intention of students, orthopaedic technicians and orthopaedic nurses.

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Dr. Cohen teaching one of for the patient’s environment, culture the Bhutanese orthopaedic and values. It would have been easy for technicians a splinting technique me to approach each patient with the for lower-extremity fractures. authoritative “surgeon-knows-best” persona that comes all too naturally for fractures and general trauma those of us in the field. But, that persona and spine evaluation, cir- is lost on the 80-year-old Buddhist monk culated through the ortho- who just walked 20 miles from a rural paedic technicians to rural village while clutching his prayer beads village clinics. I didn’t come with a chronic infected lateral malleolar back from Bhutan having bursitis – a condition he developed due to treated every patient – I prolonged meditation in the cross-legged returned knowing I was able position. Advising a monk to undergo a to share my knowledge with surgery that will take him away from the staff so that they could his monastery for several weeks is not help more patients by avoid- a conversation that has much room for first few days in Bhutan, I encountered ing missteps in the future. I was touched the surgical super ego. Instead, I learned a pediatric patient who came into the to hear from one of my orthopaedic tech- to approach this consult and others with hospital from one of the smaller villages nicians recently, now a valued friend, a different style altogether. By mirroring with an undiagnosed septic hip for two that the orthopaedic team is continuing the bedside manner of my attendings, weeks. He presented with the classic to apply some of the educational content one a Bhutanese native, and the other signs of pediatric septic hip arthritis – and knowledge-sharing high fevers, refusal to bear weight, and techniques I left them external rotation of the hip; however, he with a few months ago, was referred for evaluation of shoulder like implementing daily and knee pain. I addressed this patient’s review of all new con- medical needs and also took the critical sults and admissions and next step of hosting a Grand Rounds preoperative planning for an audience of attendings, nurses discussions. and orthopaedic technicians to educate Another key princi- them on this topic. Utilizing this pedi- ple that emerged during atric patient as a classic case study, I my trip was approach- am positive that future cases such as ing patient care with an this will be diagnosed and treated in a appreciation and respect timely manner. This experience made me realize that Dr. Cohen and Wangchuk while I now had the necessary technical Dorji, a senior orthopaedic skills, the most significant impact I technician, at the Ortho- could make over my five weeks was not paedic Clinic. Orthopaedic through patient care – it was through technicians function as phy- education and mentorship. My Grand sician assistants providing Rounds lecture as well as a dozen other orthopaedic care throughout seminars on the topics of midfoot and Bhutan and assisting the forefoot fractures, lower extremity Bhutanese orthopaedic casting and splinting, pediatric elbow surgeons in surgery.

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The Taktsang Palphug Monastery, also known as the Tiger’s nest, is a sacred Buddhist temple located on the side of a cliff in Paro, Bhutan. In the eighth century, Guru Rinpoche, who is credited with bringing Buddhism to Bhutan, is said to have flown from Tibet on a flying tigress and stayed and meditat- ed in a cave at this location. This breathtaking monastery is the most popular tourist attraction in Bhutan. two seasoned HVO volunteers, I began this technology. is an invaluable resource with volunteer to relax my body language, slow down I have been back in the United States opportunities throughout the world. For the cadence of my speech and demon- for several months and returned to a more information regarding interna- strate active listening through playback fast-paced orthopaedic trauma fellow- tional volunteer projects, visit the HVO techniques. I was surprised how quickly ship. But, amidst the fast-paced speed of website at www.hvousa.org. I settled into this new style and saw the play in a level-one trauma hospital in a positive impact it had on my patients country with seemingly infinite access Acknowledgments and their families almost immediately. and resources, Bhutan is imprinted I am truly thankful for the Brown Orthopae- dic Surgery Residency Program for the sup- Finding creative and sustainable in my memory and is an experience I port and encouragement I received to pursue solutions was a final theme threaded reflect on frequently. This experience this opportunity. I would also like to thank throughout my trip. Orthopaedic inju- has truly enhanced my five years of the Caroll Silver Family Trust for their in- spiration and continued financial support of ries are the same in any country, but orthopaedic surgery residency training international volunteer experiences across their presentations and how you treat and was essential to my development as the Brown Orthopaedic Surgery Residency program. Lastly, I would like to thank my them can be different and are contin- a caring, thoughtful physician. Recon- orthopaedic attending HVO volunteers, Dr. gent on environmental circumstances. I necting with one’s purpose through Bill Lehman and Dr. Lawrence Freedman, worked at the main referral hospital for volunteerism can be a profound expe- for their advice, support and guidance throughout our time together in Bhutan. the entire country and the infrastructure rience. The purpose of HVO is medical getting to this hospital was very poor, education of physicians and ancillary Author Eric Cohen, MD, Orthopaedic Trauma Fel- which meant we were often seeing open staff in developing nations to enact low, Department of Orthopaedic Surgery, fractures that were several days old, long-term change and improvement in Warren Alpert Medical School of Brown University, Providence, RI. increasing the risk of infection. While patient care. Ironically, I think I learned the injuries were the same as those I more from my patients and fellow Bhu- Correspondence dealt with domestically, my approach tanese orthopaedic surgeons than they Eric Cohen, MD 2 Dudley St., Suite 200 to treatment was limited. I learned did from me. Providence, RI 02905 to operate with limited fluoroscopy, For fellow residents and professionals 401-626-3870 which increased my appreciation for considering volunteering abroad, HVO [email protected]

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www.rimed.org | rimj archives | DECEMBER webpage DECEMBER 2016 Rhode Island medical journal 17 Advances in Autoimmune Diseases

Newer Treatment Strategies for Autoimmune Diseases

Edward V. Lally, MD Guest Editor

18 18 EN In contemporary parlance, autoimmune disease has been syndromes and can more readily allow for immunotherapy used as a designation for a variety of chronic inflammatory directed at specific pathways (“targeted therapies”). disorders that are characterized by the presence of auto- In this issue of the Rhode Island Medical Journal, we antibodies. This rubric has been applied to diseases whose review four inflammatory syndromes traditionally consid- etiologies are not infectious, neoplastic or degenerative in ered to be autoimmune in nature. By the above definition, nature. The autoantibody profile may simply include a pos- two of these (SLE, pemphigus) would be viewed as auto- itive antinuclear antibody (ANA) test or it may be further antibody-mediated but the other two (cytopenias, CIDP) defined by autoantibodies with specific identifiable auto- both likely fit the criteria even though the demonstration antigens. By this description, autoimmune disease encom- of specific autoantibodies in these disorders has been elu- passes a wide variety of disorders manifesting as chronic sive. Other immunologically-mediated diseases (rheumatoid inflammation confined to a tissue or organ or as a systemic arthritis, multiple sclerosis, inflammatory bowel disease, inflammatory disease. Although, this nosology may serve myasthenia gravis, and autoimmune thyroid and liver dis- to define syndromes that may be amenable to specific anti- ease) should also be viewed as autoimmune in nature. There inflammatory or immunosuppressive treatments, it has not have been significant developments in immunomodulatory served to advance our understanding of the etiology of these therapy as reviewed in the introductory article by Lefebvre diseases, nor does it imply that the autoantibodies them- and McAuliffe. There is convincing evidence that the dis- selves directly participate in the pathogenesis of the disease. eases listed in this review article are characterized by While these diseases may be “immunologically-mediated”, antigen-driven T-Cell activation and subsequent pro-inflam- there is often very little evidence that these autoantibodies matory cytokine generation. However, effective strategies actually are involved in the disease pathogenesis. to abrogate T-cell activation and block resultant cytokines A stricter definition of autoimmune disease would or cytokine receptors have outpaced the ability to identify include the stipulation, that not only should autoantibodies specific triggering antigens or subsequent autoantibodies be present, but that there is evidence to support the notion that are pathogenic. Nonetheless, the advent of such sophis- that they actually participate in the etiopathogenesis of the ticated targeted therapies will undoubtedly improve man- disorder. This definition adds a more rational framework agement and outcomes for immunologically-mediated for understanding autoimmune disease. It also allows for a diseases, some, but not all, of which should be considered better characterizing of the immunopathogenesis of these auto-immune in nature.

Author Edward V. Lally, MD, is Professor of Medicine, and Director, Division of Rheumatology, Rhode Island Hospital and The Alpert Medical School of Brown University.

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Targeted Immunomodulatory Therapy: An Overview

Ashley L. Lefebvre, PharmD, CDOE; Laura McAuliffe, PharmD

19 22 EN ABSTRACT species of the mAB (i.e. human, mouse, chimeric, etc.). The Monoclonal antibodies and other biologic response mod- suffix “-mab” is common to most mABs.3 ifiers have allowed for targeted drug therapy in managing various autoimmune diseases. A number of immune pathways have been exploited in the development of CYTOKINE-DIRECTED THERAPIES targeted immunomodulatory therapies, including cyto- TNFα Inhibitors kine-directed therapies such as tumor necrosis factor-al- Tumor necrosis factor-alpha (TNFα) is a cell-signaling pro- pha and interleukins, integrins, B-cells, and co-stimulation tein, or cytokine, that induces cell proliferation and differ- modulators. With new targeted therapies in the pipe- entiation through its interaction with TNF receptors on cell line, more options are becoming available for treatment surfaces. TNFα plays a role early in many inflammatory of autoimmune diseases. immune processes. It is produced primarily by macrophages, KEYWORDS: monoclonal antibodies, biologic response but also by monocytes, B-cells, and other tissues. Activa- modifiers, immunomodulatory therapy tion of TNFα also leads to the secretion of interleukin (IL)-1 and IL-6, both proinflammatory cytokines.D ysregulation of TNFα can lead to the development of various autoimmune diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), ankylosing spondilitis, and psoriasis.4 For INTRODUCTION instance, in IBD, TNFα secretion leads to the stimulation of With major advances in genetic sequencing and biomedi- endothelial cells to express adhesion molecules, facilitating cal research, targeted therapy with monoclonal antibodies migration of various white blood cells into inflamed tissue.5 (mABs) has emerged as a successful strategy for managing TNFα inhibitor therapies are recombinant IgG mABs that autoimmune diseases. Treatment with mABs has the advan- essentially serve as decoy TNF receptors. They bind to TNFα tage of modifying specific immune pathways as opposed to molecules and prevent their interaction with TNF receptors, other non-specific therapies. The first mAB (muromonab ultimately leading to suppression of the immune system and CD3) was developed from mice and approved in 1986 to inflammatory responses. Examples of TNFα inhibitors are prevent rejection of a kidney transplant.1 However, this adalimumab and etanercept, with the latter possessing a lon- first generation of mABs was not well-tolerated due to for- ger half-life due to its dimeric nature. The goal of treatment eign recognition of the murine components by the patient’s with TNFα inhibitor therapy is to reduce inflammation and immune system.2 severity of symptoms, with the hope of achieving improved Since then, different approaches to producing chimeric quality of life. (part mouse, part human) and fully humanized mABs have been discovered, rendering mABs less immunogenic. One Interleukins such approach to producing mABs is from hybridomas, Interleukins are a large class of cytokines responsible for var- formed from the fusion of B-lymphocytes and immortal ious immune responses, including inflammatory response myeloma cells.1 The B-lymphocytes are obtained from the mediation, lymphocyte growth and differentiation, and spleens of mice after they have been immunized against a immune cell chemotaxis, which can be implicated in auto- specific antigenic determinant, or epitope.1 The hybridomas immune diseases. Interleukin-17A (IL-17A), produced largely are cultured, leading to the generation of polyclonal antibod- by T-helper 17 cells (Th17), acts directly on keratinocytes ies. The polyclonal culture is screened for the desired anti- to stimulate various pro-inflammatory processes in plaque body activity and then cloned.1 psoriasis.6 Interleukin-12 (IL-12) and interleukin-23 (IL-23) The World Health Organization has policies for nomen- have been implicated in the production and development of clature of mABs.3 The structure is composed of four parts: Th17 cells, leading to psoriatic plaques and joint inflamma- the prefix, substem-A, substem-B, and suffix. Substem-A tion in psoriatic arthritis.7 In RA, IL-6 is released directly by indicates the nature of the target of the mAB, such as tumor synovial cells and macrophages into the synovium causing or cardiovascular. Substem-B indicates the originating inflammation and destruction.8

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Monoclonal antibodies targeting interleukins are directed notice and produce antibodies, present “self” antigens, and at cytokines involved in the production of interleukin, the produce various cytokines implicated in the disease process. interleukin itself, or receptors at which interleukin exerts Monoclonal antibodies directed at B-cells are generally its effect. Ustekinumab was developed against the p40 sub- focused at B-cell depletion. The primary agent used for unit of both IL-12 and -23, both important in differentiation B-cell depletion in autoimmune diseases is rituximab, a of naïve T-cells to Th17 cells that produce IL-17A. Usteki- mAB directed against the CD-20 antigen on B-lympho- numab binds the p40 subunit of IL-12 and -23, resulting in cytes. CD-20 is present on more than 95% of B-cells and reduced levels of Th17 cells.9 Secukinumab, an anti-IL-17A plays a part in B-cell activation and cell-cycle progression. mAB, has been approved for treatment of plaque psoriasis. When rituximab binds to CD-20, it activates complement- Inhibition of IL-17A prevents triggering of signaling and dependent and antibody-dependent B-cell cytotoxicity, and recruitment of numerous innate immune cells such as mast B-cell apoptosis.13 cells, neutrophils, and macrophages to psoriatic plaques.10 Tocilizumab, an anti-IL-6 receptor (IL-6R) recombinant mAB, blocks IL-6 signal transduction by binding to IL-6R OTHER BIOLOGIC RESPONSE MODIFIERS (BRMS) embedded in the cell membrane and floating in soluble form Co-stimulation Modulators in the blood. It also can dissociate already formed IL-6/IL-6R T-cells require two signals from antigen-presenting cells complexes, thereby effectively halting downstream signal (APCs) to undergo activation: antigen presentation by his- transduction pathways that lead to joint inflammation and tocompatibility molecules and a co-stimulatory signal pro- destruction in RA.11 vided by molecules on the APCs. In the CD80/86-CD28 co-stimulatory pathway, CD80 or CD86 on APCs binds with CD28 on the surface of T-cells and causes T-cell acti- SELECTIVE ADHESION MOLECULE INHIBITORS/ vation, proliferation, and cytokine production. Co-stimula- INTEGRIN RECEPTOR ANTAGONISTS tory pathways may also be inhibitory, as seen with cytotoxic Integrin molecules are conducive to lymphocyte trafficking T-lymphocyte antigen-4 (CTLA-4). CTLA-4 binds to CD80 by facilitating adhesion and migration from the vascula- or CD86, resulting in inhibition of T-cell responses by ture into inflamed tissue. Integrin molecules are expressed preventing release of interleukins and blocking cell-cycle on the surface of activated lymphocytes. Integrins interact progression.14 This pathway is important in the pathogen- with their receptors, which are the cell-adhesion molecules esis of RA, where activated T-cells are present in inflamed (CAMs) present on vascular endothelium. This interaction synovium. enables lymphocytes to migrate across the endothelium into Co-stimulation modulator antibodies target the signals tissues such as the brain and gut.12 Integrins α4β1 and α4β7 required for co-stimulation of the T-cells to occur. Abata- are implicated in multiple sclerosis and IBD, respectively. cept, a fusion protein used in the treatment of RA, consists Integrin receptor antagonist therapies are mABs that serve of the extracellular domain of human CTLA-4 protein and as decoys for the CAM receptors. They bind to integrin mol- the modified Fc region of human IgG1. The CTLA-4 por- ecules to prevent interaction with CAMs, ultimately block- tion of abatacept binds CD80/86 on APCs, thereby blocking migration of the activated T-lymphocytes into inflamed ing the interaction between CD28 and APCs required for tissues. Selectivity of adhesion-molecule inhibitors can vary; T-cell activation. The result of this blockade is a long-lasting for instance, natalizumab modulates lymphocyte trafficking attenuation of T-cell response.15 Belimumab, a human IgG1ʎ in both the central nervous system and gut, while vedoli- recombinant mAB used in the treatment of systemic lupus zumab is specific to the gut. Increased specificity is advan- erythematosus, targets B-lymphocyte stimulator (BLyS), the tageous for targeting desired tissues and limiting adverse co-stimulator for B-cell survival and function. BLyS binds effects, such as progressive multifocal leukoencephalop- to BLyS receptors and promotes the survival of autoanti- athy, which is a Black Box Warning for natalizumab. The body-producing B-cells by preventing their selection and currently available integrin receptor antagonist therapies apoptosis. Belimumab binds to soluble BLyS, preventing are humanized mABs. Overall, the goal of integrin receptor interaction with BLyS receptors and thereby decreasing antagonist therapy is to reduce migration of activated T-cells B-cell survival and production of autoantibodies.16 and limit progression of chronic inflammation. Interleukin BRMs IL-1 is a system consisting of two pro-inflammatory ligands B-CELL DEPLETING THERAPIES and the naturally occurring antagonist IL-1Ra. In RA, levels B-cells play an important role in numerous autoimmune of IL-1 are elevated in plasma and synovial fluid.17 Anakinra, diseases. In healthy individuals, auto-reactive B-cells are a recombinant human IL-1Ra, binds to IL-1 receptors to pre- removed from both the bone marrow and peripheral circu- vent intracellular signaling leading to cell activation and lation prior to causing significant harm. In autoimmune dis- biological responses.18 eases, a defect causes these auto-reactive B-cells to escape

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Table 1. Currently Approved Monoclonal Antibodies and Biologic Response Modifiers

Generic Name Brand Name Class Clinical Uses Adalimumab Humira® TNF inhibitor Rheumatoid arthritis, Psoriatic arthritis, Plaque psoriasis, Etanercept Enbrel® Crohn’s disease, Ulcerative colitis, Ankylosing spondylitis, Juvenile idiopathic arthritis Certolizumab pegol Cimzia® Golimumab Simponi® Infliximab Remicade® Anakinra Kineret® IL-1 antagonist Rheumatoid arthritis Canakinumab Ilaris® IL-1 inhibitor Juvenile idiopathic arthritis Tocilizumab Actemra® IL-6 antagonist Rheumatoid arthritis, Juvenile idiopathic arthritis Ustekinumab Stelara® IL-12 and IL-23 inhibitor Psoriatic arthritis, Plaque psoriasis Secukinumab Cosentyx® IL-17A receptor antagonist Plaque psoriasis, Ankylosing spondylitis, Psoriatic arthritis Ixekizumab Taltz® IL-17A receptor antagonist Plaque psoriasis Abatacept Orencia® Co-stimulation blocker of CD-28 Rheumatoid arthritis, Juvenile idiopathic arthritis Belimumab Benlysta® BLyS inhibitor Systemic lupus erythematosus Vedolizumab Entyvio® Integrin receptor antagonist Crohn’s disease, Ulcerative colitis Natalizumab Tysabri® Anti-integrin antibody Crohn’s disease, Ulcerative colitis, Multiple sclerosis Rheumatoid arthritis, Lupus nephritis, Idiopathic thrombocytopenic Rituximab Rituxan® Anti-CD20 antibody purpura, Graft-versus-host disease

Table 2. Monoclonal Antibodies and Biologic Response Modifiers in the Pipeline Generic Name Stage in Trial Names Class Clinical Uses Development Plaque psoriasis, Psoriatis Brodalumab Phase III clinical trials AMAGINE and AMVISION IL-17A receptor monoclonal antibody arthritis, Ankylosing spondylitis Guselkumab Phase II clinical trials X-PLORE IL-23 monoclonal antibody Plaque psoriasis Tildrakizumab Phase III clinical trials - IL-23 p19 subunit monoclonal antibody Plaque psoriasis Anifrolumab Phase III clinical trials - IFN Type I receptor monoclonal antibody Systemic lupus erythematosus Ozoralizumab Phase II clinical trials - Anti-TNFα Nanobody Rheumatoid arthritis Etrolizumab Phase III clinical trials - Integrin inhibitor Crohn’s disease

CONCLUSION Monoclonal antibodies and other BRMs have allowed for 4. Rutgeerts P, Vermeire S, Van Assche G. Biological therapies targeted drug therapy in managing various autoimmune dis- for inflammatory bowel disease. Gastroenterology. 2009;136: 1182-1197. eases. A number of immune pathways have been exploited in 5. Yuvienco C and Schwartz S. Monoclonal antibodies in rheumat- the development of mABs by targeting cytokines, cell-adhe- ic disease. Med Health RI. 2011;94(11):320-324. sion molecules, co-stimulation signals, and B-cells (Table 1). 6. Martin DA, Towne JE, Russell CB. The emerging role of inter- Promising new agents are in the pipeline (Table 2), providing leukin-17 in the pathogenesis of psoriasis: preclinical and clinical findings. J Invest Dermatol 2013; 133(1):17-26. additional options for managing autoimmune conditions. 7. Johnsson HJ, McInnes IB. Interleukin-12 and interleukin-23 inhibition in psoriatic arthritis. Clin Exp Rheumatol 2015; 33(Suppl. 93):S115-8. References 8. Srirangan S, Choy DH. The role of interleukin 6 in the patho- 1. Liu, JKH. The history of monoclonal antibody development – physiology of rheumatoid arthritis. The Adv Musculoskelet Dis Progress, remaining challenges and future innovations. Ann 2010; 2(5):247-58. Med Surg. 2014;3(4):113-116. 9. Koutruba N, Emer J, Lebwohl M. Review of ustekinumab, an in- 2. Chames, P, Regenmortel MV, Weiss E, et al. Therapeutic an- terleukin-12 and interleukin-23 inhibitor used for the treatment tibodies: successes, limitations and hopes for the future. Br J of plaque psoriasis. Ther Clin Risk Manag 2010; 6:123-141. Pharmacol. 2009;157(2):220-233. 10. Patel DD, et al. Effect of IL-17A blockade with secukinumab 3. World Health Organization. International Nonproprietary in autoimmune diseases. Ann Rheum Dis 2013; 72:ii116-ii123. Names (INN) Working Group: General policies for monoclonal 11. Okuda Y. Review of tocilizumab in the treatment of rheumatoid antibodies. INN Working Document 09.251, update June 2009. arthritis. Biologics 2008; 2(1):75-82.

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12. Gendron V and Rizvi S. The role of monoclonal antibodies in Authors neurological disorders. Med Health RI. 2011:94(11):333-336. Ashley L. Lefebvre, PharmD, CDOE, Clinical Pharmacist 13. Cohen MD, Keystone E. Rituximab for rheumatoid arthritis. Specialist, Ambulatory Care, Department of Pharmacy, Rhode Rheumatol Ther 2015; 2(2):99-111. Island Hospital, Providence, RI. 14. Sharpe AH, Abbas AK. T-cell costimulation – biology, therapeu- Laura McAuliffe, PharmD, Ambulatory Care Pharmacy Resident, tic potential, and challenges. N Engl J Med 2006; 355:973-75. Department of Pharmacy, Rhode Island Hospital, Providence, 15. Korhonen R, Moilanen E. Abatacept, a novel CD80/86-CD28 T RI. cell co-stimulation modulator, in the treatment of rheumatoid Basic Clin Pharmacol Toxicol arthritis. 2009; 104:276-84. Correspondence 16. Dubey AK, et al. Belimumab: first targeted biological treatment Ashley L. Lefebvre, PharmD for systemic lupus erythematosus. J Pharmacol Pharmacother 2011; 2(4):317-19. Department of Pharmacy 17. Kay J, Calabrese L. The role of interleukin-1 in the pathogenesis Rhode Island Hospital of rheumatoid arthritis. Rheumatology (Oxford) 2004; 43(Suppl. 593 Eddy Street 3):iii2-iii9. Providence RI, 02903 18. Arend WP. The mode of action of cytokine inhibitors. J Rheu- [email protected] matol 2002; 65:16-21.

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Systemic Lupus Erythematosus: A Review of the Clinical Approach to Diagnosis and Update on Current Targeted Therapies

Joanne Szczygiel Cunha, MD; Katarzyna Gilek-SEibert, MD

23 27 EN Abstract general population. For newly diagnosed patients, the 5-year Systemic lupus erythematosus (SLE) is a chronic, compli- survival rate is over 90% and the 15 to 20 year survival rate is cated and challenging disease to diagnose and treat. The about 80%.1 Worse outcomes and higher mortality risk cor- etiology of SLE is unknown, but certain risk factors have related with this ethnic disparity, which may be influenced been identified that lead to immune system dysfunction by a lower socioeconomic status as well.4 with antibody formation and immune complex deposi- tion. This immune system dysregulation causes organ injury, contributing to the variable manifestations and SLE Pathogenesis relapsing-remitting course of the disease. Criteria were The etiology of SLE is unknown. Certain risk factors have created to aide in the diagnosis, focusing on clinical man- been identified and shown to contribute to disease suscepti- ifestations and antibody profiles specific to SLE. Treat- bility or activate the immune system causing an inflamma- ment options are limited to a few medications to control tory response, ultimately leading to the development of the the inflammation and decrease organ damage. Continu- disease. Predisposition to SLE is influenced by genetic facing investigations into the pathogenesis of SLE has led to tors. The female predominance in SLE, may be explained, in new discoveries, making more medications available to part, by the contribution of certain hormones.5 Environmen- treat this difficult disease. tal factors, such as smoking, exposure to ultraviolet light, Keywords: systemic lupus erythematosus, antibodies, viral infections, and specific medications (e.g. sulfonamide 5,6 autoimmunity, treat to target, B-cell depletion and antibiotics) are known to trigger SLE. The pathogenesis of modulation, interferon blocking agents SLE is complex with contribution from many components of the immune system. With the underlying genetic predisposition and in response to various triggers, the balance of the immune system shifts towards reacting against itself, rather than self-tolerance. T and B cells become activated, SLE Epidemiology leading to antibody production and eventual immune com- SLE is seen worldwide, with incidence and prevalence plex formation. These complexes circulate and deposit in rates differing geographically. Studies have shown that the critical tissues causing organ injury. incidence rate of SLE around the world is about 1 to 10 per 100,000 person-years, while the prevalence rates range from 20–70 per 100,000 person-years.1 In the United States SLE Diagnosis (US), the all race incidence was found to be 5.1 per 100,000 Classification criteria have been derived for SLE, mainly person-years2 and the prevalence was estimated to be over for research purposes, to achieve population homogeneity 300,000 persons.3 SLE predominantly affects women, with among research studies. The American College of Rheuma- a reported peak female-to-male ratio of 12:1 during the tology (ACR) published criteria in 1982, which were revised childbearing years.2 The disease can also be seen in children in 1997 (Table 1). The Systemic Lupus Collaborating Clin- and the elderly with a narrower gender distribution. Stud- ics (SLICC) international group undertook the evaluation ies have shown racial/ethnic variations, with SLE being and further revision of the above criteria resulting in a new more common in non-Caucasian persons, occurring three classification system that is based on clinical and immuno- to four times more often in African-Americans.2 In addition logic manifestations (Table 1). In an actual clinical practice to African-Americans, Hispanics and Asians develop SLE setting, both criteria were analyzed; it was determined that more frequently than Caucasians.2 In these populations, SLE the SLICC 2012 criteria were more sensitive and may allow tends to be more active and severe, with a higher risk of patients to be classified with SLE earlier in the disease course.7 relapses and organ system involvement or damage.4 Even In the clinical setting, these criteria can be used as an aid in with advances in diagnosis and treatment of the disease, the diagnosis, but formal diagnostic criteria for SLE are lacking. mortality risk in patients with SLE is higher than that of the

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Table 1. Classification Criteria for Systemic Lupus Erythematosusa

ACR 1997 b SLICC 2012 c Cutaneous 1. Malar Rash 1. Acute cutaneous lupus (including malar rash, photosensitive 2. Discoid Rash lupus rash) OR 3. Photosensitivity Subacute cutaneous lupus 4. Oral or Nasopharyngeal ulceration 2. Chronic cutaneous lupus (including discoid rash) 3. Oral or nasal ulcers 4. Nonscarring alopecia Joints 5. Nonerosive arthritis 5. Synovitis - involving ≥ 2 peripheral joints characterized by pain, - involving ≥ 2 peripheral joints characterized by swelling or swelling or effusion effusion or tenderness and ≥ 30 minutes of morning stiffness Serositis 6A. Pleuritis 6. Serositis (any of the following) (pleuritic pain/rub or pleural effusion) - pleurisy OR - pleural effusions 6B. Pericarditis - pleural rub (by EKG, rub, or pericardial effusion) - pericardial pain - pericardial rub - pericardial effusion - pericarditis by EKG Renal 7A. Persistent proteinuria ( > 0.5g/day or > 3+ dipstick) 7. Renal (any of the following) OR - urine protein/creatinine (or 24 hour urine protein) > 0.5g/24hr 7B. Cellular casts - red blood cell casts Neurologic 8A. Seizures 8. Neurologic (any of the following) OR - seizures 8B. Psychosis - psychosis - mononeuritis multiplex - myelitis - peripheral or cranial neuropathy - acute confusional state Hematologic 9A. Hemolytic anemia 9. Hemolytic anemia OR 10. Leukopenia (<4,000/mm3 at least once) 9B. Leukopenia (<4,000/mm3 on ≥ 2 occasions) OR OR Lymphopenia (<1,000/mm3 at least once) 9C. Lymphopenia (<1,500/mm3 on 2 occasions) 11. Thrombocytopenia (<100,000/mm3 at least once) OR 9D. Thrombocytopenia (<100,000/mm3) Immunologic 10A. Anti-dsDNA 1. Antinuclear antibody OR 2. Anti-dsDNA 10B. Anti-Sm 3. Anti-Sm OR 4. Antiphospholipid antibody (any of the following) 10C. Antiphospholipid Antibody (any of the following) - lupus anticoagulant - anticardiolipin antibodies (IgG or IgM) - false-positive RPR - lupus anticoagulant - medium or high titer anticardiolipin (IgA, IgG, or IgM) - false positive syphilis test or > 6 months - anti-β2 glycoprotein I (IgA, IgG, or IgM) (confirmed by Treponema pallidum immobilization or 5. Low complement fluorescent treponemal antibody absorption test) - low C3, C4, CH50 11. Positive antinuclear antibody 6. Direct Coombs test Classification of SLE - Satisfy four out of the 11 criteria - Satisfy four of the criteria, including one clinical criterion and one immunologic criterion OR - biopsy-proven nephritis compatible with SLE and with ANA or anti-dsDNA antibodies Sensitivity12 83% 97% Specificity12 96% 84% Abbreviations: SLICC = Systemic Lupus International Collaborating Clinics; ACR = American College of Rheumatology; SLE = systemic lupus erythematosus; Anti-dsDNA = anti-double-stranded DNA; Anti-Sm = anti-smith antibody; EKG = electrocardiogram; RPR = rapid plasma regain; CH50 = 50% hemolyzing dose of complement a. Adapted from Epidemiology and Classification of Systemic Lupus Erythematosus. In: Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH, eds. Rheumatology. 6th ed. Philadelphia, PA: Mosby/Elsevier; 2015:1021-1025 b. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. [letter].Arthritis Rheum. 1997; 40-1725 c. Petri M, et al. Derivation and validation of Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012; 64(8):2677-2686

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SLE Clinical and Laboratory Manifestations Treat to target SLE has a variable, relapsing-remitting course and clini- Utilization of corticosteroids (CS) in SLE management cal symptoms vary between patients, depending on which began in the 1950s and was a major important therapeutic organ systems are affected. The above criteria incorporate milestone. However, challenges in SLE treatment remain to the major and common organ systems that can be affected this day. Retrospective studies have provided evidence that in SLE including skin, mucus membranes, joints, kidneys, increased disease activity in rheumatologic or autoimmune brain, lungs, heart and hematologic system (Table 1). Clin- disorders is related to future organ damage and death.10 In ical and laboratory surveillance is also important to assess response to this finding, the “treat to target’’ strategy to and monitor for the development of any new symptoms achieve disease remission was established and attainable in or findings. A serious manifestation of SLE, with resultant rheumatoid arthritis. This concept is gaining momentum in increased morbidity and mortality, is lupus nephritis (LN). the care of SLE patients with new treatment options avail- Treatment is based on the findings on a kidney biopsy. Neu- able and/or emerging medications in the research pipeline. 11 ropsychiatric involvement is rare but difficult to diagnose. It Currently there are only three agents, in addition to CS, that may not correspond to overall SLE activity. SLE patients may are FDA approved for SLE treatment. The challenge has been also have comorbidities, further complicating their disease. to create guidelines for the management and treatment of Atherosclerosis is common, presenting as coronary artery SLE due to the lack of quality evidence for almost all aspects disease (CAD), or cerebral or peripheral vascular diseases. of SLE, except lupus nephritis. CAD is linked to increased morbidity and mortality, with SLE women aged 35-44 years old being more than 50 times more likely to have a myocardial infarction than women Basic Therapy of a similar age without SLE.8 Even though traditional Management of SLE patients begins with basic recommen- cardiovascular risk factors do not fully explain the accel- dations including avoidance of sunlight and use of high-SPF erated rate of atherosclerosis in SLE patients, they should sunscreen (> 35), with screening and counseling for modi- be addressed routinely and modified to prevent further fiable cardiovascular risk factors such as cigarette smoking morbidity or mortality. and uncontrolled HTN. Family planning discussions should Autoantibody production is fundamental to the patho- be considered with SLE patients of reproductive age. Sup- genesis of SLE. These autoantibodies are directed against plementation of calcium and vitamin D is recommended. nuclear or cytoplasmic antigens and are known as antinu- The general approach to the use of pharmacological agents clear antibodies (ANA). ANA’s are included in the diag- depends on specific organ involvement and is tailored to nostic criteria (Table 1) and are seen in more than 95% of other SLE patient characteristics, such as ethnicity and SLE patients. Other antibodies have been identified that are comorbid conditions. recognized based on their targeted autoantigens and are col- lectively known as anti-extractable nuclear antigens (ENA). Anti-double stranded DNA antibody (anti-dsDNA) is highly Antimalarials specific (95% specific) for SLE, especially with renal disease. Antimalarial medications, such as hydroxychloroquine Anti-Sm antibodies (antibodies against Sm core particles) (HCQ), have proved useful in treating milder manifestations are unique and highly specific for SLE with renal disease, of lupus including dermatitis, arthritis and constitutional although seen in only about 20-30% of SLE patients over- symptoms. The exact mechanism of action of antimalarials all. Other antibodies may be seen in SLE, but are not spe- is unknown. Support for the use of HCQ as background ther- cific for the disease and can be seen in other autoimmune apy in patients with SLE emerged after a pivotal Canadian conditions. For example, anti-ribonucleoprotein (anti-RNP) study found that HCQ reduced flares in SLE patients com- is seen in 30-40% of SLE patients, but is highly associated pared to subjects in whom the medicine was withdrawn.12 with mixed connective tissue disease. Anti-Ro (anti-SSA) Subsequent analysis linked HCQ to the reduction of organ and anti-La (anti-SSB) are seen in 40% of SLE patients, but damage, thrombosis and improvement in survival. HCQ has have a stronger association with Sjogren’s syndrome. Anti- been shown to favorably modulate lipid profiles in patients ENA antibodies are used as serologic markers for SLE. receiving CS. 13 Anti-dsDNA antibodies and complement components (C3 and C4) may be used to monitor SLE activity, especially in the setting of lupus nephritis.9 Another set of antibodies Corticosteroid treatment in SLE seen in 30-40% of SLE patients are the antiphosphoslipid Considered the cornerstone of SLE treatment, CS have the antibodies, which are lupus anticoagulant, anticardiolipin major advantage of rapid control of SLE activity, from con- antibodies, and anti-β2-glycoprotein 1 antibodies. About trolling skin or joint disease, to severe and life threatening 10-15% SLE patients can have antiphospholipid syndrome, complications such as vasculitis and nephritis. CS are often manifested by recurrent venous or arterial thrombosis or given orally, but for severe life-threatening complications, pregnancy morbidity.8 intravenous forms of CS are usually administered.14 Short

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term use of CS may be necessary and often convenient to statistical significance. Further, the suboptimal response to control SLE flares, but long-term use is related to signifi- RTX may be related to immune complex-mediated advanced cant side effects. Doses of prednisone greater than 10–19 mg kidney injury rather than antibody production related dam- a day increase the risk of cardiovascular events 2.4 times age. Still, “off label” RTX is used as a second-line agent in compared to daily doses below 9 mg. 15 The risk of long term lupus complications like neuropsychiatric SLE and vasculi- CS use on skeletal health is well established and will not be tis in addition to its proven efficacy in idiopathic thrombo- addressed here. cytopenic purpura (ITP) and autoimmune hemolytic anemia (AHA). The most common side effects of RTX are related to post infusion complete blood count (CBC) abnormalities. From OTCs to chemotherapy Epratuzumab is another B cell therapy targeting the CD22 In addition to antimalarials, non-steroidal anti-inflamma- molecule on B cells. CD22 is responsible for B cell activa- tory drugs (NSAIDs) and traditional agents used for rheu- tion and function. This anti-CD 22 agent, that modulates matoid arthritis, such as methotrexate, have been used to B cell response, has entered late phases of clinical trials control mild to severe arthralgias and arthritis. Immuno- with promising preliminary data.20 Epratuzumab was first suppressive drugs such as azathioprine (AZA) in doses of studied in trials which ended prematurely due to shortage 2-2.5mg/kg/d may be used as steroid sparing agents to treat of the drug. Data analysis showed that epratuzumab may the various manifestations of SLE. For the most life threat- decrease disease activity in SLE, but the authors were unable ening SLE organ manifestations such as neuropsychiatric, to draw definitive conclusions. Another trial, studying the LN, pulmonary hemorrhage and systemic vasculitis, high- same molecule, showed improvement in most areas of SLE dose or pulse steroids as the initial treatment are being used, activity, from mucocutaneous to renal and neuropsychi- usually followed by high potency steroid sparing agents. atric manifestations. Headache and nausea were the most Cyclophosphomide (CYC), an alkalizing agent, has emerged common side effects. 21 as the gold standard medication for the management of lupus nephritis after an NIH study which showed that SLE patients on CYC had better renal survival than patients on Targeted therapies CS alone.16 The dose and regimen for CYC was standard- BLyS (a B lymphocyte stimulator) is responsible for B cell ized since the NIH experience, but based on the Euro-lupus survival in some SLE patients and is targeted by belimumab, trial, the lower dose of CYC can be safely used in selected a new FDA-approved drug. This fully human mAb binds to populations, without compromising its efficacy.17 CYC is BAFF (B-cell activating factor) receptor on mature B cells used as induction therapy to further decrease inflammation decreasing their activation, antibody secretion and possibly and decrease disease activity. Due to its significant toxicity, preventing T cell activation as well. Belimumab was found to most SLE patients are managed with maintenance medica- be beneficial in patients with SLE-related dermatitis, muco- tions that include AZA or mycophenolate mofetil (MMF) sitis and arthritis, but was not specifically studied in LN. In to reduce the frequencies of flares. 14 Nearly 25 years since one clinical trial, a subgroup of patients with elevated dsDNA the publication of the pivotal NIH study of the use of CYC and low C3 and C4, benefited from this medication the for the management of LN, MMF proved to be non-inferior most.22 Belimumab may constitute a viable, but expensive, and for some populations, non-Caucasians, even superior to option to treat SLE patients who are not responding or intol- CYC as an agent for induction of remission of LN. 18 erant to first line therapies. It has an acceptable safety profile.

B-Cell Depletion or Modulation Interferon blocking agents B cells play a central role in the pathogenesis of active lupus Interferon α (INF) has been linked to accelerated disease through cytokine production, presentation of self anti- activity and is the main target of antimalarial therapy in gens, activation of T cells and antibody production. Better SLE.23 INFα blocking therapies entered phase II clinical tri- understanding of B cell function in SLE pathology directed als and show promising results in moderate to severe SLE.24 investigators to conduct trials of rituximab (RTX) for the Preliminary data presented in abstract form in 2014 showed treatment of severe SLE. RTX is a chimeric mouse/human promising results with sifalimumab, mAb against INFα. monoclonal antibody (mAb) against the CD20 antigen on B This INF inhibitor reduced baseline moderate to severe SLE cells, rapidly decreasing B cells, hence reducing inflamma- mucocutaneous involvement, as well as decreased arthritis tion. The important study of the utilization of RTX in lupus and fatigue scores. It did not improve serological markers of nephritis did not meet the primary end point of reduction active disease, such as dsDNA and complement levels. For in proteinuria; despite reducing the level of complements this medication, the overall safety data was acceptable, with and dsDNA.19 Critics of the study point to possible faulty infections and headache as the most commonly reported study design (small number of patients, use of high dose adverse effects. Novel studies capitalize on INFɣ with INFɣ of steroids, short study time) as a reason for not reaching gene expression seen in peripheral blood of subjects with

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autoimmune disorders, such as SLE. A recent randomized 15. Magder LS, Petri M. Incidence of and risk factors for adverse controlled trial of a mAb against INFɣ (molecule AMG 811) cardiovascular events among patients with systemic lupus erythematosus. AM J Epidemiology 2012;176:708-719 used in subjects with mild to moderate SLE showed dose 16. Austin A, Klippel J. Therapy of lupus nephritis: controlled trial dependent modulation of INF gene expression and reduc- of prednisone and cytotoxic drugs. NEJM. 1986;314:614-619 tion of the inflammatory protein linked to the prediction of 17. Houssiau FA. Immunosuppressive therapy in lupus nephritis: future flares and level of disease activity.25 the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum. 2002;46(8):2121 18. Appel GB. and co. for ALMS Study Group. Mycophenolate Conclusion mofetil versus cyclophosphamide for induction treatment of lu- SLE remains a challenging disorder that requires an interdis- pus nephritis. J Am Soc Nephrol 2009 May;20(5):1103-12 19. Rovin B. (LUNAR Investigator Group), Efficacy and safety of ciplinary approach with a team of health-care providers to rituximab in patients with active proliferative lupus nephritis: diagnose, manage and tailor treatment to individual patient the Lupus Nephritis Assessment with Rituximab study. Arthri- needs. Continued dedication and research into the patho- tis Rheum. 2012; 64(4) 1215-1226 genesis of SLE to identify specific immunologic targets for 20. Wallace D. Efficacy and safety of epratuzumab in patients with moderate/sever flaring SLE: results from two randomized, dou- potential therapies, will bring more exciting new medica- ble blind controlled, multicentre studies (AALEVIATE) and fol- tions and hope to SLE patients to better control this difficult low up, Rheumatology 2013;52;1313-1322 and unique disease. 21. Wallace D. Efficacy and safety of epratuzumab in patients with moderate/severe flaring SLE: results from EMBLEM, a phase IIb, randomized, double blind controlled, multicentre study. Ann Rheum Dis 2014; 73:183-190 References 22. VanVollenhoven R. Belimumab, a BLyS-specific inhibitor, re- duces disease activity and severe flares in seropositive SLE pa- 1. Pons-Estel, GJ et al. Understanding the epidemiology and pro- tients: BLISS-76 study. Ann Rheum Dis 69(Suppl. 3): 74 gression of systemic lupus erythematosus. Semin Arthritis Rheum. 2008;39:257-268 23. Sacre K. Hydroxychloroquine is associated with impaired interferon-alpha and tumor necrosis factor-alpha production by 2. Danchenko, N, Satia JA, Anthony MS. Epidemiology of system- plasmacytoid dendritic cells in SLE. Arthritis Res Ther 2012; ic lupus erythematosus: a comparison of worldwide disease bur- 14(3):R155 den. Lupus. 2006;15:308-318 24. Khamashta M. Safety and Efficacy of Sifalimumab, an Anti 3. Helmick CG et al. Estimates of the prevalence of arthritis and IFN-Alpha Monoclonal Antibody in a Phase 2b Study of Moder- other rheumatic conditions in the United States Part I. Arthritis ate to Severe Systemic Lupus Erythematosus (SLE); [late break- Rheum. 2008; 58(1):15-25 ing abstract no14]; 2014 ACR/AHRP Annual Meeting 4. Gonzalez LA, Toloza SM, Alarcon GS. Impact of race and eth- 25. Welcher A. Blockade of INFg normalizes INF-regulated gene ex- nicity in the course and outcome of systemic lupus erythemato- pression and serum CXCL10 levels in patients with SLE. Arthri- sus. Rheum Dis Clin N Am. 2014; 433-454 tis Rheum. 2015;67(10):2713-2722 5. Tsokos, GC. Systemic Lupus Erythematosus. NEJM. 2011; 365:2110-21 Authors 6. Petri M, Allbritton J. Antibiotic allergy in systemic lupus ery- Joanne Szczygiel Cunha, MD; Division of Rheumatology, The thematosus: a case-control study. J Rheumatol. 1992;19:265-9 Warren Alpert Medical School of Brown University, Rhode 7. Ines L et al. Classification of systemic lupus erythematosus: Island Hospital and the Providence Veterans Affairs Medical systemic lupus international collaborating clinics versus Amer- Center. ican college of Rheumatology criteria. A comparative study of 2,055 patients from a real-life, international systemic lupus er- Katarzyna Gilek-Seibert, MD, Division of Rheumatology, Roger ythematosus cohort. Arthritis Care Res. 2015; 67(8):1180-1185 Williams Medical Center, Providence, RI; Boston University 8. Lisnevskaia L, Murphy G, Isenberg D. Systemic lupus erythe- School of Medicine. matosus. Lancet. 2014; 384:1878-88 9. Leffler J, Bengtsson AA, Blom AM. The complement system Disclosures in systemic lupus erythematosus: an update. Ann Rheum Dis. The authors, Drs. Cunha and Gilek-Siebert, have no financial 2014; 73:1601-1606 disclosures pertinent to this article. 10. Lopez R, Isenberg D, et al. Lupus disease activity and the risk of subsequent organ damage in a large patient cohort. Rheumatol- Correspondence ogy (Oxford) 2012;51 (3):491-498 Joanne Szczygiel Cunha, MD 11. VanVollenhoven RF, et al. Treat-to-target in systemic lupus ery- 830 Chalkstone Ave thematosus: recommendations from an international task force. Providence, RI 02908 Ann Rheum Dis 2014;00:1–10 401-273-7100 12. Canadian Hydroqychloroquine Study Group. A randomized [email protected] study of the effect of withdrawing hydroxychloroquine sulfate in SLE. NEJM 1991; 324:150-154 13. Petri M. Hydroxychloroquine use in the Baltimore Lupus Co- hort: effects on lipids, glucose and thrombosis. Lupus 1996 (5) Suppl. 1 S16-S22 14. Hahn B, Grossman J. American College of Rheumatology Guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res 2012, (6) 64;797-808

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Pemphigus: Pathogenesis to Treatment

Christopher DiMarco, MD

28 31 EN Abstract proteins, which can be found in many areas of the body, Pemphigus vulgaris (PV), pemphigus foliaceus (PF), and but which play a major role in the epidermal layers of the paraneoplastic pemphigus (PNP) are a group of rare and integumentary system. PV and PF are caused primarily by fatal blistering diseases involving autoantibodies that antibodies to desmoglein 1 (Dsg 1) in PF, desmoglein 3 (Dsg target desmosomal proteins. The pathogenesis of pem- 3) in mucosal dominant PV, or both in mucocutaneous PV.6 phigus involves the production of activated B-cells and Dsg 1 and 3 are found in varying amounts in the epidermis IgG with stimulation by IL-4 by T-helper 2 cells. Clinical- of the skin and mucosa. Dsg 1 is found in higher amounts ly these diseases present most often with epidermal ero- in the upper layers of the epidermis, especially on the skin, sions of the mucosae and skin caused by rapid rupturing while Dsg 3 is found in the lower layers of the epidermis of flaccid bullae. These lesions correlate histologically with higher concentrations in the mucosa and skin.2,6 It is with splits forming in the epidermis, leaving a blister this variability in distribution which explains the 3 distinct roof composed of a few cell layers. Standard treatment of clinical diseases. pemphigus involves oral corticosteroids, often with the The disease usually occurs in patients with certain HLA addition of adjuvant therapies, to improve disease con- genotypes who generate B-cells responsible for the specific trol, minimize corticosteroids side-effects, and increase autoantibodies. The activation of these B-cells requires a the odds of remission. complex interaction with CD4+ T helper 2 (Th2) cells and Keywords: pemphigus vulgaris, pemphigus foliaceus, it is this Th2 cell over-activation that leads to the autoan- 1,2,6 paraneoplastic pemphigus, desmoglein 1, desmoglein 3, tibody production that is necessary for PV and PF. Th2 corticosteroids cells are known for secreting multiple interleukins (IL), of which IL-4 plays a major role in pemphigus and the humoral immune response.2 IL-4 promotes antibody production by primed B cells and an isotype switching from IgG1 to IgG4 Introduction antibodies which have been shown to be important in the Pemphigus includes a group of blistering diseases involving active form of PF and PV.2,6 IL-4 also perpetuates the dis- autoantibodies that target proteins found in the desmosome, ease by causing naïve CD4+ T cells to differentiate into intercellular adhesion protein complexes. Most forms of Th2 cells.6 The production of autoantibodies and epitope pemphigus are classified as being a subtype of pemphigus binding is sufficient to cause loss of adhesions between vulgaris (PV), pemphigus foliaceus (PF), or paraneoplastic desmosomes leading to separation of keratinocytes which pemphigus (PNP). They are a rare group of disorders that is directly related to disease activity.1 Therefore the disease have an incidence of 2-10 cases per one million inhabitants does not require other components of the immune system in some areas of the world and a prevalence of 0.1-0.7 per for activity, such as complement or cytotoxic T cells. Based one hundred thousand inhabitants.1,2 Pemphigus was a on this pathogenesis, treatment for pemphigus focuses pri- highly fatal disease until the introduction of corticosteroids marily on the prevention of antibody production and pre- (CS) which have reduced its mortality rate from 75% to less vention of isotype switching from an IgG1 to IgG4. When than 10% ,with most morbidity and mortality today due to pemphigus enters remission there is a known upregulation iatrogenic causes rather than the disease itself.3,4 The one of IL-10 and a T helper 1 response that induces antibody iso- exception is paraneoplastic pemphigus, which has a mortal- type switching from IgG4 back to IgG1.1,2,6 Tumor necrosis ity rate around 50% ,most often due to pneumonia, the asso- factor α, IL-1, and other cytokines also play a smaller role in ciated malignancy, or pulmonary involvement, resulting in the pathogenesis of pemphigus.2 bronchiolitis obliterans, despite treatment.5 PNP is unique from PV and PF in that it may contain autoimmune antibodies to Desmoglein 1 and 3, but has more specific antibodies to envoplakin and periplakin.7 Pathogenesis While envoplakin and periplakin are the most specific for The pathogenesis underlying all forms of pemphigus involves PNP, patients with this disease can develop multiple auto- the development of autoantibodies to the desmosomal antibodies primarily to desmosomal proteins, including the

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plakin family of proteins (plectin, BP230, and desmoplakin), pemphigus is best confirmed with a combination of histo- desmocollins, and alpha-2-macroglobubin-like antigen-1.5,8 pathology and laboratory testing. Most commonly a biopsy of a fresh vesicle or the edge of a blister, with adjacent non-blistered skin, should be performed for histopathology. Clinical A biopsy of normal skin at least 1cm away from any blis- While pemphigus is classified as an auto-immune blistering tered or inflamed skin should also be obtained and sent for disease, usually the most prominent findings are epidermal direct immunofluorescence (DIF).9 The key histological fea- erosions from rapid rupturing of blisters with thin roofs. PV ture of pemphigus is an intra-epidermal split with the loss of often begins with oral erosions primarily involving the buc- adhesion and separation of normal appearing keratinocytes cal and gingiva mucosae. If patients have developed antibod- referred to as acantholysis. In PV, the histology shows supra- ies to both Dsg 1 and 3, they will likely manifest erosions basilar split with acantholysis of keratinocytes and DIF will and flaccid bullae on the skin over weeks to months. Gen- be positive for intercellular IgG involving the entire epider- erally the chest, face, scalp, upper back, and areas of trauma mis. PF will have a subcorneal split with acantholysis of are common sites for cutaneous involvement.1,6,9,10 PF often keratinocytes and a DIF showing positive intercellular stain- can present very similarly to the cutaneous involvement of ing in the upper epidermal layers.9 PNP can have a histology PV. Clinical differences include the lack of mucosal involve- and DIF with variable amounts of suprabasal acantholysis, ment and an exfoliative presentation due to the shallow lymphocytic infiltrate, and necrotic keratinocytes.7 (Table depth that the erosions occur in the epidermis.9 (Table 1) 1) Histopathology and DIF can have overlapping features PNP, due to the presence of multiple different autoanti- between the various forms of pemphigus. But the histologic bodies, may have a more variable clinical presentation. All picture may be non-diagnostic and serologic studies are rec- patients present with severe involvement of at least a single ommended. Enzyme-linked immunosorbent assay (ELISA) mucosal surface, with the majority reporting oral involve- to quantitate Dsg antibody titers can be done or, if unavail- ment. However, there is a high percentage of patients who able, serum should be sent for indirect immunofluorescence have involvement of the ocular, genital, and nasal mucosa.5 (IIF) on monkey esophagus for a qualitative measurement of Up to two thirds of patients will have cutaneous involvement serum Dsg antibodies.8-10 Specific to PV, ELISA can be used to presenting with classic erosions of pemphigus. But as many monitor Dsg 3 antibodies which can correlate with disease as 50% of patients will present with cutaneous lesions simi- severity.10 Specific to PNP, if suspected, IIF can be performed lar to erythema multiforme, bullous pemphigoid, and lichen on monkey or rat bladder urothelium which lacks Dsg 1 and planus. The most commonly reported malignancies with 3 but still contains plakins making it a specific test for PNP.5,8 PNP are lymphoid malignancies, most often non- Hodgkin lymphoma and chronic lymphocytic leukemia, followed by Castleman disease, thymoma, and a mix of other solid organ Treatment tumors.5,7 Of note, only two thirds of patients will have been Due in part to its rarity and the lack of standard definitions diagnosed with a malignancy when presenting with PNP.9 for tracking disease activity, studies on the treatment of pem- The diagnosis of any patient with a clinical suspicion for phigus are few and limited by small sample sizes.3 First-line

Table 1. Summary of disease classification, clinical features, autoantibody targets, histological, and immunofluorescence findings.

Disease Clinical Features Autoantibodies Histology Direct Indirect Immunofluorescence Immunofluorescence Pemphigus Vulgaris Mucosal erosions Desmoglein 3 Suprabasilar split with Intercellular IgG on Intercellular IgG on – Mucosal Dominant and flaccid bullae acantholysis the entire epidermis Monkey Esophagus Pemphigus Vulgaris Cutaneous and Desmoglein 1 and 3 Suprabasilar split with Intercellular IgG on Intercellular IgG on – Mucocutaneous mucosal erosions acantholysis the entire epidermis Monkey Esophagus and flaccid bullae Pemphigus Foliaceus Cutaneous erosions Desmoglein 1 Subcorneal split with Intercellular IgG on Intercellular IgG on and exfoliative acantholysis the upper epidermis Monkey Esophagus dermatitis Paraneoplastic Severe mucosal Envoplakin Suprabasilar split Intercellular IgG on Intercellular IgG on Pemphigus involvement, Periplakin with acantholysis, the entire epidermis Monkey Esophagus, pemphigus- Plectin lymphocytic infiltrate, Rat Bladder, and like, erythema BP230 Desmoplakin and necrotic Monkey Bladder multiform-like, or Desmocollin keratinocytes lichen planus-like Desmoglein 1 and 3 cutaneous lesions Alpha-2-macroglobubin-like antigen-1

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therapy for all forms of pemphigus should be CS. Initial daily have failed treatment. Failed adjuvant doses are defined as doses equivalent to 0.5 to 1.0 mg/kg of prednisone are rec- 12 weeks of daily oral regimens of 2mg/kg of cyclophospha- ommended. However, smaller studies have shown that there mide, 2.5 mg/kg of azathioprine, 3 grams of mycophenolate may be no difference in outcomes for either initial dose.3 IV mofetil, or a weekly dose of methotrexate at 20 mgs.12 methylprednisolone has been shown in pemphigus patients European guidelines have since recommended that all to decrease tumor necrosis factor α and interleukin 6.2 patients with pemphigus be treated with prednisone ini- With the initiation of a CS it is common practice to also tially. Second-line therapy involves the addition of azathi- start an adjuvant therapy for disease control. The exact mech- oprine, mycophenolate mofetil, or mycophenolic acid as anism of immunosuppressive medications in pemphigus is an adjuvant. Third-line therapy is the replacement of the unknown but it is believed that these therapies act by inhib- failed adjuvant with an anti-CD20 antibody, IVIG, immu- iting B cell and autoantibody production which contribute to noadsorption, cyclophosphamide, dapsone, or methotrex- disease activity.2 Adding an adjuvant agent is proven to lower ate.9 An alternative proposed algorithm included starting all the risk of relapse. However this effect is lost when compar- pemphigus patients with CS and an adjuvant initially. If the ing specific adjuvant medications. Also, adjuvant therapy treatment fails after 3 months of therapy the adjuvant ther- does not improve remission rates, time to disease control, apy should be replaced with rituximab at 4 weekly doses of time to relapse, or the incidence of death in pemphigus.3,4 375 mg/m2. For patients with PNP, CS with rituximab as an In addition to traditional immunosuppressive medica- adjuvant are recommended as first line therapy, often due to tions, another recently utilized adjuvant is intravenous the concurrent Non-Hodgkin lymphoma.13 immunoglobulin (IVIG). IVIG has been shown to decrease IL-1 levels in patients with PV and also provide immune modulation and reconstitution.2 IVIG also causes a decrease Conclusion in IgG4 and IgG1 antibodies to Dsg 1 and 3 within 2 weeks Despite the rarity of pemphigus in the general population, of therapy.11 A recent meta-analysis demonstrated that IVIG research continues to better elucidate the mechanisms under- was the only adjuvant that improved disease control com- lying this group of diseases. Treatment regimens with long- pared to more traditional immunosuppressive medications.4 term remissions and new medications are being evaluated In combination with CS, IVIG has been shown to induce as potential treatment options. clinical improvement in over half of treated patients.11 B-cell depleting therapies have also been studied as standard adjuvant therapy for the treatment of pemphigus and References have increased remission rates up to 65%.10 Rituximab is a 1. Di Zenzo G, Amber KT, Sayar BS, Müller EJ, Borradori L. Im- monoclonal antibody against the CD20 surface glycoprotein mune response in pemphigus and beyond: progresses and on mature B cells while sparing plasma cells. In pemphigus emerging concepts. Semin Immunopathol. 2016 Jan;38(1):57-74. there is a decrease in autoantibodies to Dsg and peripheral PubMed PMID: 26597100. 2. Giordano CN, Sinha AA. Cytokine networks in Pemphi- blood B cells that lasts several months. Those levels may rise gus vulgaris: An integrated viewpoint. Autoimmunity. 2012 with the return of peripheral B cells and this may signal a Sep;45(6):427-39. PubMed PMID: 22686612. relapse. However, not every patient with this reconstitution 3. Martin LK, Werth VP, Villaneuva EV, Murrell DF. A system- relapses, suggesting a restoration of immune tolerance.10 atic review of randomized controlled trials for pemphigus vulgaris and pemphigus foliaceus. J Am Acad Dermatol. 2011 Tumor necrosis factor α inhibitors have also been studied May;64(5):903-8. PubMed PMID: 21353333. as adjuvant therapy as well in pemphigus. However, these 4. Atzmony L, Hodak E, Leshem YA, Rosenbaum O, Gdalevich agents may not be as successful in inducing remissions and M, et al. The role of adjuvant therapy in pemphigus: A sys- the role of TNF- in pemphigus is still not well understood.2 tematic review and meta-analysis. J Am Acad Dermatol. 2015 α Aug;73(2):264-71. PubMed PMID: 26088689. While IL-4 has been shown to play a major role in the patho- 5. Ohzono A, Sogame R, Li X, Teye K, Tsuchisaka A, et al. Clinical genesis of pemphigus and currently there are medications and immunological findings in 104 cases of paraneoplastic pem- that block IL-4, such as dupilumab, no studies evaluating phigus. Br J Dermatol. 2015 Dec;173(6):1447-52. PubMed PMID: 26358412. its role in the treatment of pemphigus have been published.6 6. Tavakolpour S, Tavakolpour V. Interleukin 4 inhibition as a po- Expert consensus panels have convened to define goals tential therapeutic in pemphigus. Cytokine. 2016 Jan;77:189-95. for treating patients with pemphigus as well as the doses PubMed PMID: 26440137. required before considering a treatment to be a failure. 9,12 7. Zimmermann J, Bahmer F, Rose C, Zillikens D, Schmidt E. Per such consensus, “disease control” was defined as no Clinical and immunopathological spectrum of paraneoplastic pemphigus. J Dtsch Dermatol Ges. 2010 Aug;8(8):598-606. new lesions forming and established lesions improving over PubMed PMID: 20180886. several weeks. CS doses should be maintained until no new 8. Poot AM, Siland J, Jonkman MF, Pas HH, Diercks GF. Direct lesions have developed for at least 2 weeks and most erosions and indirect immunofluorescence staining patterns in the di- 9,12 agnosis of paraneoplastic pemphigus. Br J Dermatol. 2015 Nov have healed. Doses of 1.5 mg/kg of prednisone or an alter- 11;PubMed PMID: 26556228. native CS equivalent should be used daily for 3 weeks with 9. Hertl M, Jedlickova H, Karpati S, Marinovic B, Uzun S, et al. or without an adjuvant before a patient has been deemed to Pemphigus S2 Guideline for diagnosis and treatment--guided by

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the European Dermatology Forum (EDF) in cooperation with the Author European Academy of Dermatology and Venereology (EADV). J Christopher DiMarco, MD, Assistant Professor, Department of Eur Acad Dermatol Venereol. 2015 Mar;29(3):405-14. PubMed Dermatology, The Warren Alpert Medical School of Brown PMID: 25338479. University. 10. Feldman RJ, Christen WG, Ahmed AR. Comparison of immunological parameters in patients with pemphigus vulgar- Correspondence is following rituximab and IVIG therapy. Br J Dermatol. 2012 Mar;166(3):511-7. PubMed PMID: 21967407. [email protected] 11. Green MG, Bystryn JC. Effect of intravenous immunoglobulin therapy on serum levels of IgG1 and IgG4 antidesmoglein 1 and antidesmoglein 3 antibodies in pemphigus vulgaris. Arch Der- matol. 2008 Dec;144(12):1621-4. PubMed PMID: 19075146. 12. Murrell DF, Dick S, Ahmed AR, Amagai M, Barnadas MA, et al. Consensus statement on definitions of disease, end points, and therapeutic response for pemphigus. J Am Acad Dermatol. 2008 Jun;58(6):1043-6. PubMed PMID: 18339444; NIHMSID: NIHMS82304; PubMed Central PMCID: PMC2829665. 13. Hertl M, Zillikens D, Borradori L, Bruckner-Tuderman L, Burck- hard H, et al. Recommendations for the use of rituximab (anti-CD20 antibody) in the treatment of autoimmune bullous skin diseases. J Dtsch Dermatol Ges. 2008 May;6(5):366-73. PubMed PMID: 18201220.

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Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP): Clinical Features, Diagnosis, and Current Treatment Strategies

Jacques Reynolds, DO; George Sachs, MD, PhD; Kara Stavros, MD

32 35 EN ABSTRACT is rare, occurring in only 10-20% of patients.3 Autonomic Chronic inflammatory demyelinating polyradiculoneu- involvement is also rare and typically mild.4 Symptoms fol- ropathy (CIDP) is an acquired immune-mediated disor- low either a progressive or relapsing course, with a relapsing der characterized by weakness and sensory deficits that course being more likely in younger individuals.5 can lead to significant neurological disability. The diagnosis is based on a combination of clinical examination findings, electrodiagnostic studies, and other supportive CIDP VERSUS GUILLAIN-BARRE SYNDROME evidence. Recognizing CIDP and distinguishing it from CIDP and acute inflammatory demyelinating polyradiculo- other chronic polyneuropathies is important because neuropathy (AIDP or Guillain-Barre Syndrome) may share many patients with CIDP are highly responsive to treat- many clinical features but can be distinguished primar- ment with immunosuppressive or immunomodulatory ily based on the time from onset to peak of clinical symp- therapies. This review summarizes the clinical features, toms. AIDP is a monophasic illness that typically occurs diagnosis, and current treatment strategies for CIDP. with acute onset and progresses to a clinical nadir over a 6 KEYWORDS: chronic inflammatory demyelinating period of less than four weeks. It is often associated with polyradiculoneuropathy, CIDP, polyneuropathy, an antecedent event such as vaccination or diarrheal ill- immune-mediated neuropathy ness. By comparison, CIDP symptoms typically progress for a period greater than 8 weeks. Unlike in AIDP, patients with CIDP may experience a relapsing course of symptoms and onset is only rarely preceded by vaccination or illness.7 Additionally, in CIDP involvement of the cranial nerves, INTRODUCTION respiratory muscles, and autonomic nervous system is more Chronic inflammatory demyelinating polyradiculoneuropa- rare than in AIDP. In some cases the temporal delineation thy (CIDP) is an acquired, immune-mediated disorder char- outlined above may be difficult and only observation over acterized by progressive symptoms of proximal and distal time can clarify whether the clinical course is that of AIDP muscle weakness, often accompanied by sensory deficits. or CIDP. Another consideration is that of treatment-related CIDP is a common, albeit frequently underdiagnosed con- fluctuation of symptoms. Approximately 8-16% of AIDP dition with an estimated prevalence of 1 to 2 per 100,000 patients can show a clinical deterioration within 8-9 weeks adults.1 Distinguishing CIDP from other chronic sensorimo- after their initial improvement or stabilization following tor polyneuropathies is imperative as numerous therapeutic immunotherapy.8 options are now available.

PATHOGENESIS CLINICAL FEATURES CIDP is an immune-mediated disorder generated from both In adults, peak incidence occurs at 40-60 years of age with a cellular and humoral immune responses that are directed slight male predominance.2 Classic presentation of CIDP is against peripheral nerve antigens, leading to demyelination slow progression of both proximal and distal muscle weak- and often secondary axonal loss.9 Studies of the pathogen- ness. Predominantly distal weakness may occur but this esis of CIDP suggest that activated T lymphocytes invade finding should prompt further investigation to exclude other the peripheral nervous system through derangement of the types of neuropathy (as discussed below). Although weak- blood-nerve barrier. Once within the peripheral nervous ness predominates in CIDP, the majority of patients also system these activated T cells generate pro-inflammatory have sensory symptoms such as numbness or paresthesias, cytokines and produce cytotoxic activity against myelin.9 classically in a stocking-glove pattern. On examination, The myelin sheath is composed of numerous proteins, many there may be diminished sensation to multiple modalities. of which are being investigated as possible targets for anti- Deep tendon reflexes are absent or reduced. Gait may be wide body responses in CIDP. Potential auto-antigens include based and unsteady. Cranial nerve and bulbar involvement myelin protein zero, myelin basic protein, connexin 32, and

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gangliosides.9 Overall, the mechanisms for these immune and secondary axonal changes may obscure the underlying responses and the precise peripheral nerve antigens that are demyelinating process.9 However, nerve biopsies can be use- targeted have not been fully elucidated. Further research may ful to identify or exclude other etiologies including amyloid assist in defining subtypes of disease and how they respond or vasculitic, toxic, or hereditary neuropathies. to particular treatments. For example, recent research has demonstrated that patients with antibodies against Imaging findings paranodal proteins contactin-1 (CNTN1) and neurofascin- MRI studies of CIDP patients may show gadolinium enhance- 155 (NF155) comprise a specific phenotype of CIDP that is ment or enlargement of the nerve roots or the lumbosacral/ refractory to first line therapies.10 brachial plexi, thought to reflect chronic inflammation and demyelination/re-myelination. In addition, advanced neuromuscular ultrasound techniques are now being investigated DIAGNOSTIC WORK-UP for utility in the diagnosis of CIDP,12 though ultrasound is Diagnostic criteria still experimental in its applications for polyneuropathy. As CIDP has become better recognized, researchers and professional societies have proposed various diagnostic criteria Other laboratory workup based on clinical features, specific electrodiagnostic criteria, The differential diagnosis of CIDP is broad. Depending on and ancillary studies including nerve biopsy or lumbar punc- the clinical scenario, a variety of laboratory studies may be ture. Unfortunately, consensus is lacking. Review of the considered to rule out neuropathy from other causes, includ- details of the various diagnostic criteria and their differences ing (but not limited to) toxicology screen, hemoglobin A1c, is outside the scope of this review. In general, the diagnosis thyroid function studies, hepatitis profile, HIV antibody, of CIDP is primarily based on clinical presentation and elec- serum immunofixation, Lyme titers, vasculitic markers, and trodiagnostic studies, whereas CSF analysis and histologic angiotensin converting enzyme. Hereditary neuropathies, studies provide additional supportive data in selected cases. in particular the demyelinating forms of Charcot-Marie- Tooth disease, must also be considered in the differential Nerve conduction studies and Electromyography (EMG) diagnosis, especially in cases where there is a family history Electrodiagnostic studies are key for determining if the of neuropathy. underlying pathology is demyelinating or axonal. Hallmark findings of a demyelinating disorder in a nerve conduction study may include evidence of conduction block, pro- TREATMENT longed distal latencies, slowing of conduction velocity, or Treatment is aimed at stopping the inflammatory response absent/delayed F responses. 2 The pattern of demyelination to prevent further demyelination and secondary axonal seen on these studies may be patchy or multifocal, in con- injury. The mainstays of treatment for CIDP include cor- trast to hereditary demyelinating polyneuropathies such as ticosteroids (CS), intravenous immunoglobulin (IVIg), and Charcot-Marie-Tooth disease, where demyelination is more plasma exchange. uniform and conduction block is not seen. The needle EMG CS have been used in the treatment of CIDP for many may reveal signs of secondary axonal loss. years. While there is no strong evidence from controlled trials for oral CS, they are used commonly in practice and Lumbar Puncture with good effect. Initial treatment with oral prednisone is Similar to AIDP, in CIDP there may be elevation of CSF pro- typically high dose at 60-100 mg per day.13 Once the patient tein with a normal cell count (albuminocytologic dissocia- is stabilized clinically the dose is slowly tapered. Unfortu- tion). Sampling of the CSF is not necessary in every patient nately, CS cause many undesirable systemic side effects so suspected to have CIDP but may help further support the alternative dosing regimens have been considered. Trials diagnosis in certain cases. Finding a pleocytosis in the CSF comparing pulsed dexamethasone to standard daily prednis- should prompt consideration of alternative diagnoses. olone therapy show no significant difference in efficacy.14 Another small study comparing IV methylprednisolone Nerve biopsy to oral prednisone and IVIG demonstrated no difference A nerve biopsy may be considered in the workup of CIDP; in efficacy and fewer side effects as compared to predni- however the diagnostic value is controversial. In patients sone.15 Alternate day dosing of oral prednisone may also with classic CIDP, the hallmark pathology includes demy- be considered. There is no clearly preferred regimen for CS elination and re-myelination changes, however this is only administration in CIDP. seen in about one-half to two-thirds of biopsies.11 Other IVIg has proven to be an effective alternative to CS16 with findings that may be seen include nerve edema, nerve fibro- generally fewer side effects.17 There are no strong guidelines sis, and inflammatory infiltrates.11 Unfortunately, the most regarding dosing and frequency of IVIG. Typically a loading prominent abnormalities in CIDP may lie in the proximal dose of 2 g/kg is given over 2-5 days but subsequent main- nerve segments or roots, which are not amenable to biopsy, tenance therapy is variable and dependent upon how rapidly

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the patient relapses. Maintenance doses may range from Experimental treatments such as peripheral blood stem 0.4-2 g/kg given as frequently as every 3-4 weeks.13 Patients cell transplantation, have not demonstrated safety or efficacy can be maintained on IVIg long-term but weaning or dis- to date.28 There is little data regarding non-pharmacological continuing IVIg may be considered after a period of clinical interventions such as regular exercise but physical therapy stability of about six months or more. As with the dosing, referral should be considered for patients with CIDP for gait there are no universal guidelines for tapering or discontin- training and fall prevention when clinically indicated. uing the medication and it is done on an individual basis. Side effects of IVIg include increased risk of thromboembolic events, renal dysfunction, and aseptic meningitis. Subcuta- CONCLUSIONS neous immunoglobulin, administered weekly, is more cost- Recognition of CIDP in a patient presenting with chronic effective and may be a consideration for patients who do neuropathy is crucial because treatments such as CS, IVIg, not tolerate IVIg well but more data is needed to establish plasmapheresis, and other alternative agents may yield sig- whether it provides the same efficacy as the IV formulation.18 nificant benefit with increased quality of life and reduction Plasmapheresis is another treatment modality that has in disability. Future directions include advancing our under- demonstrated efficacy in small trials.19, 20 However, it is standing of the underlying pathogenesis of CIDP and honing more time consuming and invasive than IVIg, requiring the the diagnostic criteria. Further research is needed to estab- placement of a central venous catheter rather than a periph- lish the optimum treatment doses and durations for estab- eral intravenous line. It can be used as initial therapy in a lished therapies and to further investigate the utility of the patient with prominent weakness followed by other, less alternative, less well-studied agents. invasive immunotherapy, or in some cases may be used for long-term treatment. References 1. Mcleod J, Pollard J, Macaskill P, et al. Prevalence of chronic REFRACTORY CASES inflammatory demyelinating polyneuropathy in New South First line therapy for CIDP typically consists of IVIG, CS, Wales, Australia. Ann Neurol. 1999; 46: 910-913. plasmapheresis, or some combination of these agents. Other 2. Dimachkie M, Saperstein D, Lewis S. Acquired Immune Demy- elinating Neuropathies. Continuum. 2014; 20: 1241-1260. treatments may be considered in patients with refractory 3. Saperstein D, Katz J, Amato A, Barohn R. Clinical spectrum disease but strong supportive data for their efficacy is gener- of chronic acquired demyelinating polyneuropathies. Muscle ally lacking. Additionally, many of these second- and third- Nerve. 2001; 24(3):311. line agents pose the risk of rare but serious side effects and 4. Figueroa J, Dyck P, Laughlin R, et al. Autonomic dysfunction in chronic inflammatory demyelinating polyradiculoneuropathy. should be considered with caution. Neurology. 2012;78(10):702. Cyclophosphamide and cyclosporine A have both shown 5. McCombe P, Pollard J, McLeod, J. Chronic inflammatory demy- positive results in small case series.21, 22 Unfortunately they elinating polyradiculopathy. A clinical and electrophysiological also pose the risk of significant side effects and use should study of 92 cases. Brain. 1987; 110(6): 1617-1630. 6. Hughes R, Sanders E, Hall S, et al. Subacute idiopathic demye- be considered with caution. A small study of azathioprine linating polyradiculoneuropathy. Arch Neurol. 1992; 49 (6):612. 23 showed no benefit in patients on oral prednisone therapy 7. Hahn A. Guillain-Barré Syndrome. Lancet. 1998; 352 (9128): 635. though there may be anecdotal support for its use. Methotrex- 8. Ruts L, van Konigsveld R, van Doorn P. Distinguishing acute-on- ate has been reported to yield some benefit in case reports, set CIDP from Guillain-Barre syndrome with treatment related but a randomized, placebo-controlled trial of oral meth- fluctuations. Neurology. 2005; 65: 138-140. 9. Koller H, Kieseier B, Jander S, Hartung H. Chronic inflamma- otrexate (adjuvant to IVIg or corticosteroid maintenance) tory demyelinating polyneuropathy. N Engl J Med. 2005; 352: demonstrated no significant clinical benefit.24 1343-1356. Rituximab is another consideration in patients not respon- 10. Querol L, Rojas-Garcia R, Diaz-Manera J, et al. Rituximab in sive to traditional therapies but more research is needed to treatment-resistant CIDP with antibodies against paranodal proteins. Neurol Neuroimmunol Neuroinflamm 2015; 2: e149. establish its potential benefit; so far a significant treatment 11. Dyck P, Lais A, Ohta M, et al. Chronic inflammatory polyradic- effect has not been proven in CIDP. However, as described uloneuropathy. Mayo Clin Proc. 1975; 50 (11); 621-637. above, recent data may suggest that rituximab is beneficial 12. Kerasnoudis A. The Role of Neuromuscular Ultrasound in the in a subset of treatment-resistant patients with antibodies Diagnostic of the Chronic Inflammatory Demyelinating Poly- neuropathy. European Neurological Review. 2013;8(1):62–4. against node of Ranvier proteins CNTN1 and NF155.10 Lim- 13. Dalaskas M. Clinical trials in CIDP and chronic autoimmune ited data suggests that alemtuzumab may also offer an alter- demyelinating polyneuropathies. J Periph Nerv Syst. 2012 May; native to traditional therapies for patients with refractory 17 Suppl 2: 34-9. illness25 but further studies are needed and its use is experi- 14. Van Schaik I, Eftimov F, van Doorn P, et al. Pulse high-dose mental at this time. There have been several trials of inter- dexamethasone versus standard prednisolone treatment for chronic inflammatory demyelinating polyradiculoneuropathy ferons (interferon-alfa 2a and interferon beta 1a) that did not (PREDICT study): a double-blind randomized, controlled trial. demonstrate efficacy.26,27 Lancet Neurol. 2010; 9(3): 245-253.

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15. Lopate G, Pestronk A, Al-Lozi M. Treatment of chronic inflam- Authors matory demyelinating polyneuropathy with high-dose intermit- Jacques Reynolds, DO, Warren Alpert Medical School of Brown tent intravenous methylprednisolone. Arch Neurol. 2005; 62(2): University, Rhode Island Hospital, Providence, RI. 249-254. 16. Hughes RA, Donofrio P, Bril V, et al. Intravenous immune glob- George Sachs, MD, PhD, Warren Alpert Medical School of Brown ulin (10% caprylate-chromatography purified) for the treatment University, Rhode Island Hospital, Providence, RI. of chronic inflammatory demyelinating polradiculoneuropathy Kara Stavros, MD, Warren Alpert Medical School of Brown (ICE study): a randomized placebo-controlled trial. Lancet Neurol. University, Rhode Island Hospital, Providence, RI. 2008; 7: 136-144. 17. Nobile-Orazio E, Cocito D, Jann S, et al. Intravenous immuno- Correspondence globulin versus intravenous methylprednisolone for chronic in- Kara Stavros, MD flammatory demyelinating polyradiculoneuropathy: a random- Assistant Professor, Department of Neurology ized controlled trial. Lancet Neurol. 2012; 11(6): 493-502. Rhode Island Hospital 18. Lee D, Linker R, Paulus W, et al. Subcutaneous immunoglobulin infusion: a new therapeutic option in chronic inflammatory de- 593 Eddy Street APC 5 myelinating polyneuropathy. Muscle Nerve. 2008; 37(3): 406-409. Providence, RI 02903 19. Dyck P, Litchy W, Kratz K et al. A plasma exchange versus im- 401-444-2596 mune globulin infusion trial in chronic inflammatory demye- Fax 401-444-3205 linating polyradiculoneuraopthy. Ann Neurol. 1994; 36: 838-45. [email protected] 20. Hahn A, Bolton C, Pillay N, et al. Plasma-exchange therapy in chronic inflammatory demyelinating polyneuropathy: a double-blind, sham-controlled, cross-over study. Brain. 1996; 119: 1055-1066. 21. Good J, Chehrenama M, Mayer R, Koski C. Pulse cyclophosphamide therapy in chronic inflammatory demyelinating polyneuropathy. Neurology. 1998; 51(6): 1735-1739. 22. Matsuda M, Hoshi K, Gono T, et al. Cyclosporin A in treatment of refractory patients with chronic inflammatory demyelinating polyradiculoneuropathy. J Neurol Sci. 2004; 224(1-2): 29-35. 23. Dyck P, O’Brien P, Swanson C, et al. Combined azathioprine and prednisone in chronic inflammatory demyelinating polyneuropathy. Neurology. 1985; 35(8): 1173-1176. 24. RMC Trial Group. Randomised controlled trial of methotrexate for chronic, inflammatory demyelinating polyradiculoneuropathy (RMC trial): a pilot, multicenter study. Lancet Neurol. 2009; 8(2): 158-164. 25. Marsh E, Hirst C, Llewelyn J, Cossburn M, et al. Alemtuzumab in the treatment of IVIG-dependent chronic inflammatory demyelinating polyneuropathy. J Neurol. 2010; 257(6): 913-919. 26. Gorson K, Ropper A, Clark B, et al. Treatment of chronic inflammatory demyelinating polyneuropathy with interferon-alpha 2a. Neurology 1998; 50(1): 84-87. 27. Hadden R, Sharrack B, Bensa S, et al. Randomized trial of interferon beta-1a in chronic inflammatory demyelinating polyradiculoneuropathy. Neurology. 1999; 53(1): 57-61. 28. Mahdi-Rogers M, Kazmi M, Ferner R, et al. Autologous peripheral blood stem cell transplantation for chronic acquired demyelinating neuropathy. J Peripher Nerv Syst. 2009; 14(2): 118-124.

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Autoimmune Cytopenias: Diagnosis & Management

Christian P. Nixon, MD, PhD; Joseph D. Sweeney, MD

36 40 EN ABSTRACT T cells (Tregs) and CD8+ suppressor T lymphocytes which The autoimmune cytopenias are a related group of disor- maintain anergy or suppression against self-antigens. (1) ders in which differentiated hematopoietic cells are de- Numerous mechanisms to account for central and periph- stroyed by the immune system. Single lineage disease is eral tolerance breakdown in the context of autoimmune characterized by the production of autoantibodies against cytopenias have been proposed. The emergence of “forbid- red cells (autoimmune hemolytic anemia [AIHA]), plate- den clones” as proposed by Burnett more than sixty years lets (autoimmune thrombocytopenia [ITP]) and neutro- ago, (2) hinges on the persistence of self-reactive clones that phils (autoimmune neutropenia [AIN]) whereas multilin- should have been deleted via central tolerance, and may eage disease may include various combinations of these play a role in autoimmunity seen in lymphoproliferative conditions. Central to the genesis of this disease is the diseases or polyclonal lymphocyte activation in viral infec- breakdown of central and/or peripheral tolerance, and the tion. Molecular mimicry in the context of viral, bacterial subsequent production of autoantibodies by both tissue and mycoplasma infections may also result in the initiation and circulating self-reactive B lymphocytes with support and acceleration of autoimmunity due to the presence of from T helper lymphocytes. These disorders are classified common antigenic epitopes in proteins and carbohydrates, as primary (idiopathic) or secondary, the latter associated particularly on the surface of red blood cells. (3) Additional with an underlying malignancy, systemic autoimmune mechanisms to account for the failure to maintain self disease, infectious disease or a specific drug. Non-specif- tolerance include neo-antigen generation by environmen- ic immunosuppression with corticosteroids remains the tal agents or drugs, as observed in drug-induced AIHA, (4) first-line therapy for many of these disorders, and although and immunoregulatory disturbances stemming from the associated with high response rates, is compromised by alteration of cytokine networks. Interestingly, although significant toxicity and high relapse rates. Management autoimmunity is commonly thought to arise from the inter- of patients with chronic refractory autoimmune cytope- play between environmental factors and genetic predis- nias who have failed first-line and second-line (cytotoxic position, the HLA linkages documented for various organ immunosuppressant therapy and or splenectomy) is par- and systemic autoimmune diseases such as type-1 insulin- ticularly complex, with definitive treatment in select pa- dependent diabetes, pemphigus vulgaris, systemic lupus tients requiring hematopoietic stem cell transplantation. erythematosus, rheumatoid arthritis, etc., have not yet been Given the toxicity concerns of non-selective immuno- clearly demonstrated for the autoimmune cytopenias. suppressants, development of therapeutic regimens that avoid steroids has progressed rapidly in recent decades. AUTOIMMUNE HEMOLYTIC ANEMIAS KEYWORDS: autoimmune cytopenias, WAIHA, CAD, ITP, AIN Pathogenesis Autoimmune hemolytic anemia (AIHA) is defined by the destruction of mature red blood cells (RBCs) by anti-RBC autoantibodies produced by autoreactive B lymphocytes facilitated as otherwise by complement. Autoantibodies can INTRODUCTION result in erythrocyte destruction via numerous mechanisms Failure to maintain self-tolerance is the dominant pathophys- including; a) phagocytosis of erythrocytes opsonized by iologic mechanism binding the autoimmune cytopenias, autoantibodies and complement by activated macrophages, a group of disorders characterized by the immune mediated b) direct erythrocyte osmotic lysis through complement destruction of differentiated hematopoietic cells. Central fixation and sequential activation of the membrane attack tolerance is governed by apoptosis of autoreactive cells upon complex (MAC), and c) antibody-dependent cell-mediated binding to self-antigen (negative selection), which occurs cytotoxicity (ADCC) mediated by cytotoxic CD8+ T cells early in B and T cell differentiation in the bone marrow and natural killer (NK) cells that carry membrane recep- and thymus, respectively. In contrast, the active process of tors for the Fc portion of bound immunoglobulin G (IgG). peripheral tolerance, is driven by CD4+/CD25+ regulatory ADCC and erythrophagocytosis preferentially occur in the

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spleen and lymphoid organs, Table 1. The Autoimmune Cytopenias whereas complement medi- Disorder Clinical Features Laboratory Tests Treatment ated destruction is primarily Warm Autoimmune Fatigue, jaundice CBC, MCV, reticulocyte count, Steroids intravascular or occurs in the Hemolytic Anemia bilirubin, haptoglobin, LDH, Splenectomy liver. AIHAs are divided into haptoglobin, direct Coomb’s Erythropoiesis-stimulating warm and cold types accord- test (IgG ± C3), blood smear agents (ESA) ing to the thermal charac- examination for spherocytes Rituximab teristics (reactivity at 37°C Cold Autoimmune Fatigue, jaundice, CBC, direct Coomb’s test (C3+/ RBC transfusion or 4°C) of the predominant Hemolytic Anemia passage of brown IgG-), blood smear examination Chlorambucil urine induced by for agglutination, spherocytes or Cyclosporine autoantibody formed, which cold erythrophagocytosis (Figure 1) Rituximab in large part is predicated on Autoimmune Bruising, bleeding Platelet count, antigen-specific Steroids the antibody class (IgG ver- Thrombocytopenia from mucosal autoantibody assays, blood Splenectomy sus IgM), and the chemical surfaces smear examination to exclude Rituximab characteristics of the epitope pseudothrombocytopenia and IVIG (protein or carbohydrate). confirm large platelets Thrombopoeitin (TPO) mimetics Autoimmune Recurrent infections Total white cell, differential and G-CSF WARM AUTOIMMUNE Neutropenia neutrophil count HEMOLYTIC ANEMIA Clinical Features & Laboratory Findings Optimal reactivity of the autoantibody at 37°C (mainly or refractory cases. Binding of rituximab to CD20-positive IgG1 and IgG3 subclass), defines warm autoimmune hemo- cells results in B-lymphocyte depletion via a combination lytic anemia (WAIHA) which can affect all age groups and of apoptosis, complement activation and antibody-depen- accounts for 80-90% of adult cases of AIHA. Clinical and dent cell cytotoxicity. (13) Small case series have supported laboratory features are shown in Table 1. In vivo binding of the efficacy and safety of this drug in children and adults antibody and/or complement to the red blood cell (RBC) sur- with WAIHA with durable responses of up to 3 years. (14,15) face can be detected in a direct Coomb’s or antiglobulin test Response rates of 33–s77% with complete remission in (DAT). In nearly half of all WAIHA cases, these pan-reactive 29–55% have been reported in an evidence-based focused autoantibodies exhibit specificity for Rh protein epitopes. (5) review, (16) with the beneficial effect greatest in neonates and children compared to adult patients with WAIHA. Management (14,15,17) Long-term side effects remain to be explored, yet Transfusion of allogeneic red cells for rapid symptomatic mild infusion reactions including hypotension and fever are improvement of hypoxic anemia along with controlled the most common complications of rituximab with a very non-specific immunosuppression with pharmacologic doses low incidence of serious infection. (18) A battery of addi- of corticosteroids represents front-line therapy. Initial hemo- tional treatment modalities in various stages of the inves- globin stabilization and prompt symptomatic improvement tigational and licensure pipeline include such drugs as is observed in up to 70–80% of patients. However, disease alemtuzumab (anti-CD52), bortezumib, kinase inhibitors relapse after steroid-induced remission is common. (6) and IgG-specific endoglycosidase EndoS. (19-22) Corticosteroid non-responders can be managed with other non-specific immunosuppressants such as cyclosporin A, azathioprine and cyclophosphamide. (7) Although splenec- COLD ANTIBODY AUTOIMMUNE tomy has played a dominant historical role in the manage- HEMOLYTIC ANEMIAS ment of WAIHA, with the first series of patients (n = 28) Pathogenesis described by Chertkow and Dacie in 1955, (8) data regard- Cold antibody autoimmune hemolytic anemias are sero- ing durable remission remains unclear with an approximate logically characterized by autoantibodies with optimal response rate of 38-70% in patients with WAIHA. (9) Recom- reactivity at 4°C, with the majority of cases being either binant erythropoiesis-stimulating agents (ESA) represent an cold agglutinin syndrome (CAS) or paroxysmal cold hemo- alternative promising treatment modality that may be more globinuria (PCH). The autoantibodies in primary CAS are widely employed in the future, (10,11) and high dose IVIG, monoclonal IgM, and polyclonal IgM in secondary CAS due although less successful than in ITP, may be efficacious in to infectious diseases such as Mycoplasma pneumonaie and some non-responder cases. (12) infectious mononucleosis. The polyclonal antibodies pro- Targeted therapy with Rituximab, a potent, humanized duced in response to these infections typically demonstrate monoclonal antibody directed against CD20 on pre-B cells, specificity to the RBC blood group antigens I and i, respec- mature B lymphocytes, and immature plasma cells, has tively. The antibody specificity in PCH is a polyclonal IgG been increasingly used as second-line therapy in relapsed immunoglobulin directed toward the P blood group antigen.

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This bi-phasic hemolysin (Donath-Landsteiner antibody) CAS, complete responses in 5% and disease improvement reacts with RBCs in the peripheral circulation when the in those who had previously received rituximab. However, temperature drops below 20°C, and initiates complement median duration response of 11 months and failure rates of fixation. Upon returning to the warmer central circulation, 40-50% remain impediments to universal implementation complement mediated erythrocyte osmotic lysis ensues. (23) of this drug in the treatment of CAS. In PCH, the severe acute intravascular hemolysis (Figure 2), may necessitate Clinical Features & Laboratory Findings transfusion of red blood cells along with supportive care Clinical features are shown in Table 1. CAS typically mani- provided in a heated room. fests as moderate chronic hemolytic anemia in middle-aged or elderly patients, often with cold exacerbation of signs Figure 2. Three plasma samples collected from the same patient with (acrocyanosis of the extremities), splenomegaly, anemia and PCH at 0 (A), 3 days (B), and 4 days (C) after admission. Hemoglobin- mild jaundice. Prognosis is generally fair although signifi- emia resulting from intravascular hemolysis is most readily apparent cant mortality has been described. (24) PCH is characterized in the plasma sample collected on presentation (day 0), which quick- clinically by acute hemolytic anemia often with hemoglo- ly resolved in the ensuing week. Hemoglobin concentrations (mg/dL): binuria, predominantly in children with a history of a recent A = 83; B = 43; C = 28 (normal < 2 mg/dL). viral illness. Although PCH typically follows a mercurial, acute, often severe course, prognosis is excellent with the majority of cases spontaneously resolving within a few days to several weeks following onset. The direct Coomb’s test will be positive for complement (C3) and negative for IgG. Erythrophagocytosis of complement sensitized cells can be observed in the peripheral blood films of up to 80% of young children with acute transient PCH (Figure 1).

Figure 1. Peripheral blood smear of a biphasic hemolysin positive case of paroxysmal cold hemoglobinuria (PCH) in a four-year-old child, exhibiting prominent monocytic erythrophagocytosis with occasional spherocytes.

AUTOIMMUNE THROMBOCYTOPENIA Pathogenesis Immune mediated destruction of platelets along with atten- uated platelet production characterize ITP (27) which is mediated in part by anti-platelet IgG and T-cell subset abnormalities. (28,29) Using antigen-specific assays that measure autoantibodies capable of binding to platelet surface gly- coproteins, anti-platelet autoantibodies can be detected in only 50-60% of ITP patients. (30) A limited number of B-cell clones produce these antiplatelet antibodies as a result of antigen-driven somatic mutation. (31) Platelets coated with autoantibody are cleared in the reticuloendothelial system by phagocytosis and possibly complement-mediated lysis. (32) Hepatic clearance of platelets by an anti-GPIb-IX mediated Fc-independent mechanism involving the Ashwell- Morell receptor may also occur. (33) Furthermore, the lack of autoantibodies in many ITP patients has led to the discovery that cytotoxic CD8+ T lymphocytes can lyse platelets in Management vitro and impair megakaryocyte function. (34) Cold exposure avoidance, red cell transfusion for hypoxic anemia, and immunosuppression with the alkylating agents Clinical Features & Laboratory Findings chlorambucil and/or cyclophosphamide represent front-line Autoimmune thrombocytopenia (ITP) is the most common therapy for CAS. B lymphocyte depletion with rituximab to of the autoimmune cytopenias with an incidence of five out remove the pathologic clonal B cells, has been investigated of 100,000 children per year and two out of 100,000 per year in case reports, small retrospective series and phase 2 trials. in adults. ITP may be primary, secondary to autoimmune (25,26) In these studies, rituximab monotherapy achieved disease, infection (CMV, HIV, Hepatitis C, Helicobacter partial responses in greater than 50% of patients with pylori) and malignancy, drugs (35) or occur in association

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with AIHA (Evan’s syndrome). Common clinical features such as large granular lymphocyte leukemia, autoimmune are listed in Table 1. Adults tend to run a chronic course, diseases and primary immune deficiency syndromes. Anti- whereas shorter disease duration (approximately 6 months) gens in the polymorphic human neutrophil antigen system and much higher spontaneous remission rates occur in chil- (HNA), particularly HNA-1 and HNA-4, located on the dren. Bone marrow biopsy indicated in patients > 60 years of FcγRIIIb (CD16) and CD11b molecules respectively, are the age to exclude an underlying B cell malignancy may reveal primary targets of anti-neutrophils antibodies which can normal or increased megakaryopoiesis. (36) be demonstrate in up to 70% of cases. (48) Cell-mediated destruction of granulocytes may also occur due to inhibitory Management CD8+ cytotoxic T-cells present within the marrow space. Corticosteroid taper and intravenous immunoglobulin represent front line therapy for ITP, with approximately Clinical Features & Laboratory Findings 70-80% response rate in newly-diagnosed, previously As with other autoimmune cytopenias, the natural history untreated ITP patients. (37) However, recurrence of throm- of AIN varies between children and adults, with a rela- bocytopenia in the majority of patients, necessitates addi- tively benign course and spontaneous remission within 6-24 tional intervention. Optimal second line therapy remains months commonly occurring in children, in contrast to a uncertain, although traditionally splenectomy for steroid more pronounced, chronic course in adults. Upper respira- refractory patients has been employed at the risk of post-op- tory tract infections, skin sepsis, recurrent fevers, otitis erative complications and 1% mortality due to septicemia. media in children and chronic tiredness in adults may all be (38) High-dose dexamethasone instead of prednisone has presenting signs. been advocated in adults as a different strategy to avoid second-line therapy altogether. Numerous alternative strate- Management gies such as B-cell depletion with the monoclonal antibody Front line therapy with recombinant human granulocyte col- rituximab, anti-D immunoglobulin, thrombopoiesis-stim- ony stimulating factor (rhG-CSF) can be used in the imme- ulating agents and Fc receptor blockade have been investi- diate treatment of severe infections as well as for infection gated. Retrospective and prospective single-arm trials have prophylaxis at a decreased dosing schedule. (49) Immuno- shown a beneficial effect of rituximab therapy in adult and suppression, intravenous immunoglobulin and splenectomy childhood ITP, (39) which may be boosted with combinato- have produced variable to disappointing results in the treat- rial regimes involving rituximab and dexamethasone, (40) or ment of AIN. Rituximab likewise, has met with limited effi- even triple therapy with the inclusion of cyclosporine (TT4). cacy in this disorder, presumably due to the central role of (41) Rapid platelet responses have been observed with the the inhibitory CD8+ cytotoxic T cells. (50) thrombopoeitin (TPO) receptor agonists (romiplostim and eltrombopag), although medication discontinuation is often followed by a platelet count drop to pretreatment levels. SUMMARY (42,43) In non-splenectomized Rhesus positive individuals Immune mediated destruction of hematopoietic cells charac- with ITP, anti-D immunoglobulin therapy may be similarly terize the autoimmune cytopenias. The complexity of these efficacious as conventional treatments through the satura- cases indicate that referral to a hematologist is indicated tion of macrophage Fc receptors by opsonized red blood cells. in nearly all cases. Viral infections, autoimmune diseases, (44) Targeted Fc receptor blockade with monovalent anti-Fcγ drugs, solid tumors and hematopoietic malignancies under- receptor/albumin fusion proteins and/or neutralization of lie many of the cases of secondary autoimmune cytopenias. autoimmune IgG Fc by soluble FcγRs is also being pursued. Natural history variation between children and adults gen- (45,46) Inhibition of platelet glycoprotein desialylation with erally predicts higher rates of spontaneous remission and the antiviral sialidase inhibitor, oseltamivir phosphate, has shorter disease duration in children. Non-specific immuno- resulted in significant platelet count increases in anti-GP1b suppression with corticosteroids represents front-line ther- autoantibody positive chronic ITP patients refractory to all apy for many of these disorders yet active investigation into other conventional therapies, representing a promising anti- steroid sparing regimes has uncovered multiple new treat- gen specific area of future research. (47) Platelet transfusion is ment modalities. Notably, autoreactive B lymphocyte deple- usually reserved only for patients with acute life-threatening tion via targeted therapy with the humanized, chimeric bleeding (retinal or intracranial hemorrhage) due to the rapid monoclonal anti-CD20 antibody, rituximab, has provided clearance of infused platelets. durable responses in AIHA and ITP, whereas the mamma- lian target of rapamycin inhibitor, sirolimus, may provided safe and efficacious mono-therapy treatment for patients AUTOIMMUNE NEUTROPENIA with refractory autoimmune multilineage cytopenias. (51) Pathogenesis Recombinant erythropoiesis-stimulating agents may in the Autoantibodies directed against neutrophils are primar- future become standard therapy in WAIHA, and newly vetted ily responsible for the rare entity autoimmune neutrope- targets to treat ITP include monovalent Fc receptor blockade nia (AIN). AIN be primary or secondary to viral infections, and combinatorial therapy including rituximab, dexameth- drug-induced mechanisms, hematological malignancies asone, thrombopoietin receptor analogues and cyclosporine.

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References Authors 1. Abbas AK, Lichtman AH, Pillai S. Cellular and Molecular Im- Christian P. Nixon, MD, PhD, Center for International Health munology, Philadelphia, Saunders, 2012. Research, Rhode Island Hospital and Alpert Medical School 2. Burnett FM. A reassessment of the forbidden clone hypothesis of Brown University, Providence, RI. Aust J Exp Biol Med Sci of autoimmune disease. 1972;50:1-9. Joseph D. Sweeney, MD, Department of Transfusion Medicine, 3. Fagiolo E. Immunological tolerance loss vs. erythrocyte self an- Rhode Island Hospital and The Miriam Hospital, Alpert tigens and cytokine network dysregulation in autoimmune he- Medical School of Brown University, Providence, RI. molytic anaemia. Autoimmun Rev 2004;3:53-9. 4. Salama A. Drug-induced hemolytic anemia. Expert Opin Drug Conflicts of Interest Saf 2009;8:73-79. None. 5. Vos GH, Petz L, Funenberg HH. Specificity of acquired haemolytic anaemia autoantibodies and their serological characteris- Funding tics. Br. J Haematol 1970;19:57-66. Christian P. Nixon, MD, PhD, is funded by NIGMS Exploratory Curr 6. Petz LD. Treatment of autoimmune hemolytic anemias. Grant # 1P20GM104317-01 Opin Hematol 2001;8:411-6. 7. Elebute M, Marsh J. Autoimmune cytopenias. Medicine Correspondence 2009;37:159-163. Christian P. Nixon, MD, PhD 8. Chertkow G, Dacie JV. Results of splenectomy in autoimmune Center for International Health Research, haemolytic anemia. Br J Haematol 1956;2:237-49. Rhode Island Hospital 9. Salama A. Treatment options for primary autoimmune hemolytic anemia; A short comprehensive review. Transfus Med 593 Eddy St. Hemother 2015;42:294-301. Providence, RI, 02903 10. Sinclair AM. Erythropoiesis stimulating agents: approaches to 401-444-3164 modulate activity. Biologics 2013;7:161-74. Fax 401-444-7854 11. Salama A, Hartnack D, Lindemann HW, Lange HJ, Rummel M, [email protected] Loew A. The effect of erythropoiesis-stimulating agents in patients with therapy-refractory autoimmune hemolytic anemia. Transfus Med Hemother 2014;41:462-8. 12. Bussel JB, Cunningham-Rundles C, Abraham C. Intravenous treatment of autoimmune hemolytic anemia with very high dose gammaglobulin. Vox Sang 1986;51:264-69. 13. Reff ME, Carner K, Chambers KS, Chinn PC, Leonard JE, Raab R, Newman RA, Hanna N, Anderson DR. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 1994;83:435-45. 14. Zecca M, Nobili B, Ramenghi U, Perrotta S, Amendola G, Rosi- to P, et al. Rituximab of the treatment of refractory autoimmune hemolytic anemia in children. Blood 2003;101:3857-61. 15. D’Arena G, Califano C, Annunziata M, Tartarone A, Capalbo S, Villani O, et al. Rituximab for warm-type idiopathic autoimmune hemolytic anemia: a retrospective study of 11 adult patients. Eur J Haematol 2007;79:53-8. 16. Crowther M, Chan YL, Garbett IK, Lim W, Vickers MA, Crowther MA. Evidence-based focused review of the treatment of idiopathic warm immune hemolytic anemia in adults. Blood 2011;118:4036-40. 17. Svahn J, Fioredda F, Calvillo M, Molinari AC, et al. Ritux- imab-based immunosuppression for autoimmune haemolytic anaemia in infants. Br J Haematol 2009;145:96-100. 18. Newman K, Owlia MB, El-Hemaidi I, Akhtari M. Management of immune cytopenias in patients with systemic lupus erythematosus-old and new. Autoimmunity Reviews 2013;12:784-91. 19. Cheung WW, Hwang GY, Tse E, Kwong YL. Alemtuzumab induced complete remission of autoimmune hemolytic anemia refractory to corticosteroids, splenectomy and rituximab. Hae- matologica 2006;91:ECR13. 20. Dasanu CA. Bortezomib: friend or foe of hemolytic anemia? J Oncol Pharm Pract 2011;17:233-5.

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Fibromyalgia Syndrome, A Geriatric Challenge

Julio C. DeFillo-Draiby, MD; John S. Page

41 44 EN Introduction 0 and 19. (Shoulders, upper and lower arms, hips, upper and Fibromyalgia syndrome (FMS) is a syndrome characterized lower legs, jaw, chest, abdomen, upper and lower back, and by waxing and waning widespread musculoskeletal pain, neck. Left and right limbs are counted individually). muscle stiffness, fatigue and sleep disturbance, all of which SS takes into consideration the degree of unrefreshed result in functional impairment without an identifiable sleeping, fatigue and impaired cognition of the patient. Each cause. The US prevalence is 2%, with a female predomi- of these three symptoms is scored from 0–3, depending on nance (18). FMS incidence increases with age; it has been the severity over the past week. (0: no problem, 1: mild, found to be as high as 7% between 60–79 years (16). Its peak 2: moderate 3: severe). The SS also factors in the extent onset is between 30–50 years of age (14, 19). Given the high (severity) of general somatic symptoms, e.g., muscle pain, prevalence of multiple morbidities in older adults, many of irritable bowel syndrome, weakness, headache, cramps, which share symptoms with FMS, diagnosis can be chal- blurred vision, dry eyes, hives. (0: no symptoms, 1: few lenging. Co-morbidities (COPD, CHF, renal insufficiency, symptoms, 2: moderate symptoms, 3: many symptoms). anemia, mood disorders, dementia, rheumatologic diseases, SS is the sum of the severity of the three symptoms osteoporosis, malnutrition) often interact with, precipitate (fatigue, unrefreshed sleep and cognitive symptoms) plus the or exacerbate FMS. Therapeutic options are limited, not extent (severity) of somatic symptoms in general. The final only due to medication side effects but also due to impaired score ranges from 0–12. patient function, which may prevent participation in non-pharmacologic interventions, such as aerobic exercise or cognitive behavioral therapy. Approaches to Treatment In elderly patients, FMS is usually diagnosed after multi- in the Elderly Patient ple medical visits and costly diagnostic testing. The etiology To properly manage FMS, focus should be on predisposing is not known, but there are several theories concerning the and precipitating factors, prevalent symptoms and patient cause of FMS, including abnormalities in pain processing preferences. Research on the effectiveness of treatment of and neurotransmitter release (low serotonin, elevated sub- FMS is limited, and optimal treatment for elders remains stance P) that provoke increased perception of pain, often unknown. Multiple review articles recommend a stepwise with non-painful stimuli. Additional theories on its origin approach, combining pharmacological and non-pharmaco- include muscle disease, stage 4 non-rapid eye movement logical interventions. Since the etiology remains unclear, sleep disorders and psychological factors (14). The revision therapy is focused on the treatment of symptoms. Knowing to the 1990 classification criteria by The American College precipitating factors and how to avoid them becomes all-im- of Rheumatology in 2010 incorporated a new case defini- portant in the prevention of flares. Some known triggers tion that includes widespread pain and symptoms of fatigue, include emotional stress, cold weather, illness and exertion. waking up unrefreshed, cognitive complaints and somatic Elderly patients may find it challenging to adhere to symptoms. These revisions were implemented to improve exercise or physical medicine and rehabilitation (PM&R). the clinical diagnosis of FMS, emphasizing that the old cri- Additionally, for many it proves difficult to tolerate pharma- terion of 11 out of 18 tender points is no longer necessary. cological intervention due to various side effects or a lack Instead, with these revised guidelines the clinical diagnosis of efficacy. Because of these obstacles, a shared understand- of FMS is made when the following 3 conditions are met (19): ing of the goals of treatment by both patient and physician (1) The Widespread Pain Index (WPI) ≥ 7 and the Symptom is crucial. Treatment targets include underlying causes, Severity Score (SS) ≥ 5, or the WPI is 3-6 and the SS ≥ 9; symptom management and activities of daily living (ADLs), (2) Symptoms have been present at a similar level knowing that not all symptoms can be eliminated. Patients for at least 3 months; also need to monitor symptoms and report them. Intact cog- (3) The patient does not have a disorder that would nitive function is essential; when impaired, management otherwise explain the pain. becomes more challenging. Ascertainment: WPI notes the number of areas in which Currently 3 medications are FDA-approved for the treat- the patient has had pain over the last week, scoring between ment of FMS; duloxetine, pregabalin and milnacipran (9). In

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addition, multiple other medications and non-pharmacolog- choices. In this analysis, milnacipran did not have any effect ical interventions have been studied; the extent and rigor of on sleep, duloxetine did not affect fatigue, and pregabalin evidence varies widely, and some should be avoided or used did not affect depressive symptoms (9). When choosing these with caution in the treatment of elders. medications for elderly patients, slow titration should be used to reach the minimum effective dose.

FDA-approved Medications A comparative analysis was done in 2010 of the three med- Pharmacological Intervention ications approved by the FDA for FMS; subjects were 30–50 It is of great importance to take the minimum effective dose years of age (9). The author presented comparative data on because of the wide profile of side effects that accompany the short-term (6-month) efficacy and harms of duloxetine, many of the medications given to ameliorate the symptoms milnacipran, and pregabalin in FMS (9). Among the 3 medi- of FMS. The Beers Criteria for Potentially Inappropriate cations, there were no differences in pain control or dropout Medication in Older Adults is particularly useful, as the rate due to side effects. If depression was the predominant long-term results and applications of these medications for symptom, duloxetine showed the best response. If fatigue the elderly FMS patient remain unknown. In some cases, the was predominant, milnacipran or pregabalin were better side effects outweigh the therapeutic benefit; e.g.: NSAIDs. The administration of tramadol with acet- Table 1. Medications used in Fibromyalgia Syndrome aminophen, taken at average doses of 151 Drug Recommended dose Comments mg/d and 1238 mg/d respectively, has been shown to be effective in treatment for some Anti-epileptics of the pain associated with FMS (3). Anal- Gabapentin 100-600 mg daily Target symptoms: Fatigue and pain. gesics can be very beneficial initially, as we Max dose 1800 mg daily Titrate slowly. May cause sedation and dizziness. Dose should be adjusted for introduce other interventions to the man- Pregabalin 150-300 mg daily agement of symptoms; however, long-term Max dose 450 mg daily renal failure. use of pain medications is rarely a good Tricyclic antidepressants (TCA)* solution, especially in an older population. Nortriptyline 10-50 mg nightly Target symptoms: Pain, fatigue and sleep. Tramadol may increase the risk of seizure Sedation and confusion. Avoid in narrow when combined with other drugs for FMS, angle glaucoma. Recommend baseline EKG and avoid if QT prolongation. and may increase the risk of serotonin syndrome when administered with SSRIs or Serotonin reuptake inhibitors (SSRIs) SSNRIs (14). SSRIs and SSNRIs alone have Fluoxetine 5-60 mg daily Target symptoms: Depression. been shown to be effective not only in treat- Citalopram 10-20 mg daily Better tolerability than TCA Insomnia. Hyponatremia. Fluoxetine has ing the depressive symptoms of FMS, but long half life. also other symptoms as well. Serotonin norepinephrine reuptake inhibitors (SNRI) Although no SSRI is FDA-approved for the treatment of FMS, citalopram, parox- Venlafaxine 25-100 mg daily Target symptoms: Depression and pain. etine, and fluoxetine have been shown to Duloxetine 30-60 mg daily Avoid in those with uncontrolled hypertension, liver disease and open angle have therapeutic effects in non-depressed glaucoma. patients but the mean age of subjects in the Milnacipran 25-200 mg daily Target symptoms: Fatigue and pain. following studies was only 50. Citalopram Contraindicated with monoamine oxydase in doses of 20–40 mg/d improved well-be- inhibitors and open angle glaucoma. ing, without affecting other symptoms over Analgesics a 4-month follow-up (1). In elders, no more Tramadol 25-50 mg every 6 hrs as Target symptoms: Pain. than 20 mg/d is recommended because of needed May cause sedation and confusion. risk of QT prolongation per FDA Drug Safety Avoid in patients with seizures. May Communication. Paroxetine, administered cause serotonin syndrome in combination at a mean dose of 40 mg/d, was found useful with SSRI or other antidepressants. in treating FMS symptoms in a randomized Dose adjustment for renal failure. trial (12). Fluoxetine has also been shown to Muscle relaxants* be beneficial in the treatment of all aspects Cyclobenzaprine 5-10 mg nightly Target symptoms: Pain, sleep and mood. of FMS in multiple studies, with dosages Sedation. Similar side effects to TCA. ranging from 20–50 mg/d. Duloxetine and milnacipran are SSNRIs that are FDA- * Part of the Beers Criteria for Potentially Inappropriate Medication in Older Adults. Bolded medications are FDA-approved. Adapted from Hazzard’s Geriatric Medicine and Gerontology, approved for use in FMS. Duloxetine was Sixth Edition. Chapter 123. Bernstein, C; Weiner, D. 2009. approved on the basis of its ability to reduce

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pain, fatigue, and depression. Recent studies have found Non-pharmacological Approaches that it is no more effective when administered at 120 mg/d to Treatment compared to 60 mg/d (6). It has a higher incidence of nau- Patient Education sea and headache than the other two approved medications Patient education is paramount in the control of FMS symp- (9, 10). Milnacipran, approved for its efficacy in improving toms, beginning by acknowledging the disease and learning pain, fatigue, and sleep quality, does not appear to have such about its complexity. Clinicians need to work closely with limiting side effects. Twice-daily dosage is superior for pain patients to establish goals of treatment, and to encourage control, and can be titrated up to a total of 200 mg/d. Two of patients to report changes in symptoms (4, 14). three randomized, controlled trials showed improvement in cognition. Pain and fatigue improvements were seen within Exercise one week in responders to milnacipran. Milnacipran has no Multiple studies and systematic reviews demonstrate that effect on depressive symptoms (2, 7, 14). Nortriptyline, a supervised, paced aerobic exercises have positive effects on tricyclic antidepressant (TCA), has been minimally studied global well-being and physical function, and possibly on pain but 10–30 mg/d before bedtime is a safer option for the elder and tender points. Gradual increase in exercise intensity patient when compared to other TCAs; of note, nortripty- prevents exacerbation of the pain that ultimately could lead line is a prominent potentially inappropriate medication to patient non-adherence to the program or acute worsening according to the Beers Criteria (5, 10). of symptoms (16, 17). Water-based exercise programs have NOTE: A 2012 systematic review and meta-analysis of the also been shown to be helpful in improving tender points role of antidepressants in the treatment of FMS noted that and sleep quality (4, 11). although a small number of patients experienced substantial symptom relief, the majority of patients experienced intol- Cognitive Behavioral Therapy (CBT) erable adverse effects and only modest relief of symptoms. In most studies, CBT improved pain-related behavior, The conclusion was that physicians and patients should be self-efficacy, coping strategies and overall physical function, realistic about the potential benefits of antidepressants in and are most effective when combined with comprehensive FMS (10). programs. There was no evidence in subjects above 50 years Anticonvulsants are another class of drugs that have some of age (7, 13, 15). utility in the improvement of symptoms of FMS in the elderly, although little research has been done in an older Multi-component intervention population (8). Gabapentin was shown in a 2007 random- and Multidisciplinary Approach ized, double-blind, placebo-controlled trial to be useful in A 2009 meta-analysis of 9 randomized controlled clinical tri- the treatment of pain and also improved sleep and quality als that met the inclusion criterion of utilizing at least two of life. Higher doses produced excess adverse effects, espe- non-pharmacological therapies (educational or psychologi- cially in older adults (8, 16). Pregabalin, unlike gabapentin, cal interventions and at least one exercise program), showed is FDA-approved for FMS and has more data supporting its that multi-component therapy could effectively reduce pain, use. A recent meta-analysis that included 5 RCTs showed fatigue and depressed mood. It also showed that efficacy that doses ranging from 150–600 mg/d were effective in declines over time; long-term effects are inconclusive (7). improving pain, sleep, and quality of life. Like gabapentin, This major analysis, like every study noted above, may not higher doses result in more adverse effects in older adults be relevant to older adults as subject age was 30–50 years. – accordingly, the dose should be titrated slowly to the min- Unfortunately, a non-pharmacological approach, including imum effective dose (8, 16). multi-component interventions, seems to lack conclusive For patients struggling with side effects and contraindi- results. Further research will be of utmost importance in cations, a low dose (1–4 mg/d) of cyclobenzaprine, although targeting appropriate treatment (16). not FDA-approved, has been shown in clinical trials to cause significant improvements in pain, and depressive symptoms, without limiting side effects (5, 17). In older adults, a low Conclusion starting dose of 1–5 mg/d is recommended. In general how- Fibromyalgia-related physical disability and discomfort ever, muscle relaxants should be used as a last resort for the affects older adults profoundly. It is important to acknowl- management of FMS symptoms in elderly patients, in accor- edge that the complexity of symptoms and the lack of dance with the Beers Criteria. A 2004 meta-analysis showed specific treatment make FMS challenging to manage. The that there were no improvements in fatigue or tenderness in evidence base in the FMS literature is limited to patients studies that used doses of 10–30 mg/d; however, tenderness <50 years. The limited response to drug treatment in elderly has been shown to improve with administration of 1–4 mg/d patients, and their increased susceptibility to adverse effects, (5, 17). Lower dosages have been shown to be beneficial, and as well as baseline restriction in mobility make treatment have fewer side effects. Along with these improvements even more challenging. Both the short-term and long-term comes increased nights of restorative sleep (17). effects of any treatment remain unknown. Accordingly,

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individualized treatment programs are recommended. Rec- 16. Siler A, Gardner H, Yanit K, Cushman T, McDonagh M. Sys- ognizing treatment limitations, educating patients and tematic review of the comparative effectiveness of antiepileptic drugs for fibromyalgia.The journal of pain. 2011;12(4):407-415. implementing multimodal therapy is currently recom- doi: 10.1016/j.jpain.2010.09.007. mended to limit disease burden and disability. 17. Tofferi J, Jackson J, O’Malley P. Treatment of fibromyalgia with cyclobenzaprine: A meta-analysis. Arthritis rheumatism. 2004;51(1):9-13. doi: 10.1002/art.20076. 18. Wolfe F, Ross K, Anderson J, Russell IJ, Hebert L. The preva- References lence and characteristics of fibromyalgia in the general popu- 1. Anderberg UM, Marteinsdottir I, von Knorring L. Citalopram in lation. Arthritis rheumatism. 1995;38(1):19-28. doi: 10.1002/ patients with fibromyalgia--a randomized, double-blind, place- art.1780380104. bo-controlled study. European journal of pain. 2000;4(1):27-35. 19. Wolfe F, Clauw D, Fitzcharles M, et al. The american college doi: 10.1053/eujp.1999.0148. of rheumatology preliminary diagnostic criteria for fibromyal- 2. Arnold L, Palmer R, Gendreau RM, Chen W. Relationships gia and measurement of symptom severity. Arthritis Care Re- among pain, depressed mood, and global status in fibromyalgia search. 2010;62(5):600-610. doi: 10.1002/acr.20140. patients: Post hoc analyses of a randomized, placebo-controlled trial of milnacipran. Psychosomatics. 2012. doi: 10.1016/j. Authors psym.2012.02.005. Julio C. Defillo-Draiby, MD, Assistant Professor of Medicine, 3. Bennett R, Kamin M, Karim R, Rosenthal N. Tramadol and Division of Geriatrics and Palliative Medicine, Alpert Medical acetaminophen combination tablets in the treatment of fibro- School of Brown University; Lead Geriatrician for the Total myalgia pain: A double-blind, randomized, placebo-controlled Joint Center at The Miriam Hospital, Providence, RI. study. Am J Med. 2003;114(7):537-545. doi: 10.1016/S0002- John S. Page is a Pre-Medical Student. 9343(03)00116-5. 4. Burckhardt CS, Mannerkorpi K, Hedenberg L, Bjelle A. A ran- Correspondence domized, controlled clinical trial of education and physical Julio C. Defillo-Draiby, MD training for women with fibromyalgia.J Rheumatol. 1994;21(4): 714-720. Division of Geriatrics & Palliative Medicine 5. Carette S, Bell MJ, Reynolds WJ, et al. Comparison of amitripty- University Medicine Patient Center line, cyclobenzaprine, and placebo in the treatment of fibromy- 375 Wampanoag Trail, Suite 102 algia. A randomized, double-blind clinical trial. Arthritis rheu- East Providence, RI 02915 matism. 1994;37(1):32-40. doi: 10.1002/art.1780370106. 401-649-4010 6. Curran M. Duloxetine: In patients with fibromyalgia.Drugs . Fax 401-649-4011 2009;69(9):1217-1227. doi: 23. [email protected] 7. Huser W, Bernardy K, Arnold B, Offenbcher M, Schiltenwolf M. Efficacy of multicomponent treatment in fibromyalgia syndrome: A meta-analysis of randomized controlled clinical trials. Arthritis rheumatism. 2009;61(2):216-224. doi: 10.1002/ art.24276. 8. Huser W, Bernardy K, Ueyler N, Sommer C. Treatment of fibromyalgia syndrome with gabapentin and pregabalin--a meta-analysis of randomized controlled trials. Pain. 2009;145(1-2):69-81. doi: 10.1016/j.pain.2009.05.014. 9. Häuser W, Petzke F, Sommer C. Comparative efficacy and harms of duloxetine, milnacipran, and pregabalin in fibromyalgia syndrome. The journal of pain. 2010;11(6):505-521. doi: 10.1016/j. jpain.2010.01.002. 10. Häuser W, Wolfe F, Tlle T, Ueyler N, Sommer C. The role of antidepressants in the management of fibromyalgia syndrome: A systematic review and meta-analysis. CNS drugs. 2012;26(4):297-307. doi: 10.2165/11598970-000000000-00000. 11. Mungua-Izquierdo D, Legaz Arrese A. Assessment of the effects of aquatic therapy on global symptomatology in patients with fibromyalgia syndrome: A randomized controlled trial. Arch Phys Med Rehabil. 2008;89(12):2250-2257. doi: 10.1016/j. apmr.2008.03.026. 12. Patkar A, Masand P, Krulewicz S, et al. A randomized, controlled, trial of controlled release paroxetine in fibromyalgia. Am J Med. 2007;120(5):448-454. doi: 10.1016/j.amjmed.2006.06.006. 13. Roskell N, Beard S, Zhao Y, Le T. A meta-analysis of pain response in the treatment of fibromyalgia. Pain practice. 2011;11(6):516-527. doi: 10.1111/j.1533-2500.2010.00441.x. 14. Ryan S. Fibromyalgia: An overview and comparison of treatment options. British journal of nursing. 2011;20(16):991-2, 994. 15. Sarzi Puttini P, Buskila D, Carrabba M, Doria A, Atzeni F. Treat- ment strategy in fibromyalgia syndrome: Where are we now? Semin Arthritis Rheum. 2008;37(6):353-365. doi: 10.1016/j. semarthrit.2007.08.008.

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Fournier’s gangrene of the penis in a 12-year-old patient secondary to phimosis

Luther Ward, MD, MPH, FACS; Daniel Eisenson, BA; Jean-Louis Fils, MD

45 46 EN

Abstract The patient returned to the operating room two weeks We report a case of Fournier’s gangrene in a 12-year-old later for a meshed 1:1 split-thickness skin graft to cover the boy from St. Boniface Hospital in Fond-des-Blancs, Haiti. remaining defect on the shaft of the penis. Fournier’s gangrene, a fulminant necrotizing fasciitis of the penis and scrotum, is a rare and life-threatening infection that requires hospitalization, broad-spectrum antibi- Discussion otics, and surgical debridement.1–3 It is usually associated Fournier’s gangrene (FG) is a life threatening disease of with impaired cellular immunity due to systemic disor- the perineum and genitalia in which a bacterial infection ders such as diabetes and liver disease.4,5 This patient had results in small vessel occlusion, gangrene of the overlying none of those risk factors, but had severe, longstanding skin, and expansion of the necrotizing infection along fascial phimosis, for which circumcision had been recommend- planes through bacterial enzymatic degradation.3,5 The por- ed many years before. This case illustrates how lack of ac- tal of entry may be genitourinary, anorectal, or cutaneous, cess to basic surgical care for an easily treatable condition and causal organisms are usually normal flora that interact leads to advanced presentation of a severe disease process. synergistically in a polymicrobial infection.5–7 Accordingly, Keywords: Fournier’s gangrene in pediatric patient, FG is typically associated with conditions that impair host necrotizing fasciitis of the penis, phimosis, global surgery, cellular immunity, such as diabetes mellitus, alcoholism, 4,5,8,7 lack of access to surgery liver disease, HIV, chronic illnesses, and malignancy. It is rarely seen in children, and most reported pediatric cases have involved children younger than 3 months.6 The patient presented in this case did not have any of the commonly Case Report associated risk factors, but developed Fournier’s gangrene A 12-year-old boy presented to St. Boniface Hospital with secondary to phimosis. pain and swelling of the penis and scrotum and an inabil- Phimosis is a condition in which inflammation and scar- ity to urinate for two days. On examination, the patient ring of the foreskin leads to a permanently un-retractable was noted to have severe phimosis with patchy necrosis prepuce that cannot be drawn back to reveal the glans and a grossly edematous penis and penis.9,10 Narrowing of the foreskin scrotum. The patient’s bladder was Figure 1. Patient at time of presentation, before orifice may compress the meatus, drained of 1100cc of urine with a surgical debridement causing high-pressure flow that suprapubic catheter. Laboratory leads to inflammation of the peri- analysis revealed a creatinine of 3.6. urethral tissues; in some cases, phi- The patient was taken to the operat- mosis may lead to complete urethral ing room for an emergency debride- obstruction. ment. The foreskin and more Obstruction, inflammation, and proximal shaft skin were necrotic penile edema may create an isch- through Buck’s and into Dartos emic process prone to infection.12 Fascia, and were debrided. The cor- The etiology of infection in this case pora cavernosa and spongiosum cannot be confirmed due to the diag- were intact. The area of debridement nostic limitations of the facility, but was irrigated with normal saline the authors suspect that phimosis and Dakin’s solution, and packed and balanoposthitis led to obstruc- with dressings soaked in Dakin’s. No tion and a subsequent urinary tract damage to the urethra was observed, infection; leaking of infected urine and a Foley catheter was placed into un-retractable foreskin led to to facilitate wet-to-dry dressing cellulitis which soon progressed to changes for two weeks. Fournier’s gangrene.

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Figure 2. Patient after surgical debridement Figure 3. Patient two weeks after surgical References debridement 1. Manganiello, M, Hughes, CD, Hagander, L, Bayne, D, Pierre, JH, Buckley, JC, Meara, JG: Uro- logic disease in a resource-poor country. World J Surg 2013;37:344–348. 2. Tauro, L, Roshan, M, Satish Rao, B, Ravikrish- nan, J, Menezes, L: Fournier′s gangrene of the penis. Indian J Plast Surg 2005;38:154. 3. Talwar, A, Puri, N, Singh, M: Fournier′s gangrene of the penis: A rare entity. J Cutan Aesthetic Surg 2010;3:41. 4. Ghnnam, W: Fournier’s gangrene in Mansou- ra Egypt: A review of 74 cases. J Postgrad Med 2008;54:106. 5. Thwaini, A, Khan, A, Malik, A, Cherian, J, Ba- rua, J, Shergill, I, Mammen, K: Fournier’s gangrene and its emergency management. Postgrad Med J 2006;82:516–519. 6. Cundy, TP, Boucaut, HAP, Kirby, CP: Fournier’s gangrene in a child with congenital genitourinary anomalies. J Pediatr Surg 2012;47:808–811. Figure 4. Patient after split-thickness skin graft 7. Efem, SE: The features and aetiology of Fourni- er’s gangrene. Postgrad Med J 1994;70:568–571. 8. Shyam, DC, Rapsang, AG: Fournier’s gangrene. The Surgeon 2013;11:222–232. 9. Division of Paediatric Surgery, Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Chan, IH, Wong, KK: Common urological problems in children: prepuce, phimosis, and buried penis. Hong Kong Med J 2016;doi:10.12809/hkmj154645. 10. Morris, BJ: Why circumcision is a biomedi- cal imperative for the 21st century. BioEssays 2007;29:1147–1158. 11. Vaughan E, Jr., Alfert HJ, Gillenwater JY: Ob- structive uropathy secondary to phimosis and balanoposthitis. Am J Dis Child 1970;120:72–73. 12. Obi, A: Isolated Fournier’s gangrene of the penis. Niger J Clin Pract 2016;19:426. 13. Meara, JG, Leather, AJM, Hagander, L, Alkire, BC, Alonso, N, Ameh, EA, Bickler, SW, Conteh, L, Few cases of Fournier’s gangrene secondary to phimosis Dare, AJ, Davies, J, et al.: Global Surgery 2030: evidence and solu- have been described in the literature. While rare, these tions for achieving health, welfare, and economic development. The Lancet 2015;386:569–624. are usually seen associated with other more common risk factors for Fournier’s gangrene. In this case, the patient’s Authors mother explained that he had been diagnosed with phimo- Luther Ward, MD, MPH, FACS, St. Boniface Haiti Foundation, sis when he was two years old, and the parents were told Fond-des-Blancs. that he needed circumcision and would be placed on a list Daniel Eisenson, BA, Alpert Medical School of Brown University, for a visiting surgical team. However, the patient’s family Providence, Rhode Island. was never contacted and never returned to the hospital; the Jean-Louis Fils, MD, Hopital Universitaire de Mirebalais, Mirebalais, Haiti. patient’s increasingly stenotic foreskin led to complete urethral obstruction and gangrenous infection, ten years after Correspondence his initial diagnosis of phimosis. Daniel Eisenson The Lancet Commission on Global Surgery estimates 508-479-4251 that 5 billion people worldwide lack access to surgical care Fax 508-358-1602 when needed, including nine out of ten people in low mid- [email protected] dle income countries (LMICs) like Haiti.13 This case is a striking example of how lack of access to basic surgical care transformed a relatively benign process (phimosis), into a devastating and life-threatening emergency (necrotizing fasciitis of the penis with complete urethral outflow obstruction) requiring multiple surgical procedures and producing permanent genital disfigurement.

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Right in Front of Our Eyes: Evolution of Streptococcal Toxic Shock Syndrome with Ischemic Optic Neuropathy

Salaheldin M. Elhamamsy, MD; Mazen O. Al-Qadi, MD; Taro Minami, MD; Marguerite Neill, MD

47 49 EN Abstract Case Report Introduction: Toxic shock syndrome occurs from A 28-year-old man drove himself to our emergency depart- dysregulation of host inflammatory responses. Toxin- ment with a 1-week history of fever and sore throat. On producing strains of Group A streptococcus cause TSS. arrival to the emergency department, he was afebrile, normo- Ischemic optic neuropathy rarely complicates septic tensive, but had exudative pharyngitis. A rapid streptococcal shock. We present a rare case of streptococcal pharyngitis antigen test was positive. Oral penicillin and intravenous flu- complicated by septic arthritis and TSS with reversible ids were administered. While awaiting for discharge (within blindness due to non-arteritic ischemic optic neuropathy. 2 hours of initial triage), left knee pain developed and he became hypotensive. Over 3 hours, effusion developed in the Case: A 28-year-old man drove to our ED with exuda- other knee as did refractory hypotension. This was followed tive pharyngitis. A rapid streptococcal test was positive. by progressive dimming of his vision to complete blindness. While awaiting oral penicillin he became hypotensive Vancomycin, piperacillin-tazobactam and clindamycin were refractory to IV fluids and developed knee effusion. The given for toxic shock syndrome. A central venous catheter patient noted progressive dimming of his vision. Arthro- was inserted; vasopressors were started and the patient was centesis yielded GAS. ICU course was complicated by admitted to the intensive care unit (ICU). An MRI of the ARDS but after 2 weeks the patient was weaned off va- brain was performed to evaluate his blindness, which showed sopressors and the ventilator. He regained his vision and widespread cerebral cortical diffusion abnormality with no had no neurological sequelae. The patient’s GAS isolate infarction, bleeding or vascular abnormalities. Immediately was M protein gene (emm) type 1 and T type 1. He was after MRI, which was hours after the arrival to the emer- followed in the IM clinic for 9 months post discharge gency department, the patient suffered a generalized ton- with complete resolution of symptoms. ic-clonic seizure and was intubated because of respiratory Conclusion: The rapidity of the development of shock distress. Arthrocentesis yielded purulent fluid that grew is attributed to streptococcal exotoxins acting as superan- GAS. Blood cultures were negative as were imaging studies tigens. GAS type M1 is commonly associated with severe for thigh abscess or necrotizing fasciitis. The patient had a shock in TSS. The severe shock was the likely cause of his stormy ICU course complicated by acute respiratory distress ischemic optic neuropathy. Early recognition and aggres- syndrome (ARDS) and ventilator associated pneumonia sive management of TSS are crucial to clinical outcome. (VAP). After 1 week of intensive treatment, he was slowly Keywords: Toxic shock syndrome, TSS, Staphylococcus weaned off vasopressors and the ventilator. The patient’s aureus, Group A streptococcus GAS isolate was M protein gene (emm) type 1 and T type 1. He was discharged from the hospital to the acute rehabilitation facility on day 21, where he stayed 8 more days for rehabilitation. Twenty-nine days after admission to the Introduction ICU, he was discharged home. He maintained follow-up in Toxic shock syndrome (TSS) is a severe illness caused by the internal medicine clinic for several months where he dysregulation of host inflammatory responses resulting in initially complained of weakness, knee pain, diplopia and multi-organ failure. Toxin-producing strains of Staphylococ- dry cough. His diplopia resolved within 4 months after dis- cus aureus (S. aureus) or Group A streptococcus (GAS) cause charge, followed by resolution of knee pain and cough. His TSS. Streptococcal pharyngitis is almost never associated symptoms resolved completely and he was able to return to with TSS. Ischemic optic neuropathy rarely complicates sep- work 8 months post discharge. tic shock, particularly in young individuals. We present a rare case of streptococcal pharyngitis complicated by septic arthritis and TSS with reversible blindness due to non-arteritic Discussion ischemic optic neuropathy. Toxic shock syndrome (TSS) is a toxin-related severe illness that occurs due to dysregulation of host inflammatory responses, causing hypotension and multi-organ failure.

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Toxin-producing strains of S. aureus (including methicillin- Patients with invasive streptococcal disease and TSS are resistant, MRSA) or Group A streptococcus (GAS) are the typically very ill and, therefore, treatment should include most common pathogens for TSS. Although uncommon, empiric broad-spectrum antibiotics to cover potential patho- other bacteria, such as groups C and G β-hemolytic strep- gens (including coverage for both GAS and S. aureus) until tococci, Clostridium spp. and coagulase negative staph- GAS is confirmed. Other infections may produce signs and ylococci may cause TSS as well. Furthermore, probable symptoms that can be confused with TSS and should be association with influenza infection has been described considered depending on the clinical context. These include [1]. The annual incidence of invasive GAS infection has leptospirosis, Rocky Mountain spotted fever and gram-neg- been estimated to be 1.4/100,000 population, of which TSS ative sepsis. Prompt recognition and control of the infection develop in 13% of patients [2]. Streptococcal TSS is primar- source is of paramount importance (e.g. surgical debridement ily caused by skin and soft tissue infection (nearly 50%), fol- of necrotizing fasciitis). De-escalation to penicillin G (3 to 4 lowed by pneumonia. Approximately 15% of patients with million units i.v. every 4 h) plus clindamycin (600 to 900 mg TSS will have streptococcal bacteremia with no clear source. i.v. every 6 to 8 h) for 10 to 14 days is recommended [4]. Clin- Streptococcal TSS is more common in patients who are damycin, a protein synthesis inhibitor, may provide addi- younger than 50-years-old. Furthermore, chronic alcohol- tional benefit by suppressing the production of M proteins ism, uncontrolled diabetes mellitus, varicella infection, and and superantigens. Further, clindamycin has been shown recent plastic surgery are recognized risk factors. Compared (in animal models of streptococcal myositis) to be more to staphylococcal TSS, most patients with streptococcal effective than penicillin due to the “Eagle effect” of reduced TSS have invasive syndromes such as necrotizing fasciitis, expression of penicillin binding proteins by GAS during the myonecrosis, or bacteremia. GAS causes TSS by producing stationary growth phase [5]. The use of intravenous immu- superantigens, which are extracellular toxins that bypass noglobulin (IVIG) has been described in small series, and a antigen presentating cells, resulting in antigen-independent survival benefit with IVIG therapy was reported in a Cana- release of proinflammatory mediators and massive activa- dian observational study [6]. A multicenter, randomized, tion of T cells without major histocompatibility complex double-blind, placebo-controlled trial demonstrated signifi- (MHC) class II restriction. Extensive inflammatory response cant decrease in sepsis-related organ dysfunction and a trend and shock quickly ensue with widespread tissue damage and toward improved survival with IVIG (mortality at 28 days multi-organ dysfunction. Virulent factors responsible for was 3.6-fold higher in the placebo group), which was not invasive streptococcal disease and TSS include antiphago- statistically significant [7]. cytic proteins (called M proteins), cytotoxic toxins (A, B, C), Ischemic optic neuropathy (ION), also known as stroke of and certain enzymes such as streptokinase and hyaluroni- the optic nerve, is a devastating condition that results from dase. Among these factors, the M proteins (M1 and M3) and transient ischemia of the optic nerve. ION can affect one pyrogenic exotoxin A (80% of streptococcal TSS) are more eye or both eyes simultaneously. Two different forms of ION likely to cause invasive GAS infection and TSS. The diagno- exist: arteritic form (seen mostly in elderly patients with sis of streptococcal TSS is made by fulfilling the diagnostic hypoperfusion of the optic nerve due to large vessel vascu- criteria (Table) [3] litis, eg. temporal arteritis); and non-arteritic ION (NAION) that can affect patients of any age and has been associated with transient hypotension presumably due to hypoperfu- Table. Diagnostic criteria of streptococcal TSS sion of the paraoptic branches of the posterior ciliary artery. The incidence of NAION is 2.3–10.2 per 100 000 popula- A. Isolation of group A Streptococcus tion in the United States [8]. Approximately 10% of non- 1. From a sterile site arteritic ION occurs in individuals under the age of 45. The 2. From a non-sterile site presence of atherosclerosis (e.g. due to diabetes mellitus), B. Clinical signs of severity hypercoagulable state (e.g. anti-phospholipid antibody syn- 1. Hypotension drome), or migraine increases the risk of NAION. Other risk 2. ≥ 2 of the followings: factors include the traditional atherosclerosis risk factors a. Renal impairment such as smoking and hyperlipidemia. NAION presents with b. Coagulopathy c. Liver abnormalities a rapidly progressive painless loss of vision (hours to days), d. Acute respiratory distress syndrome usually described as dimness or blurring of the visual field. e. Extensive tissue necrosis, ie. necrotizing fasciitis Hypotension from any cause can result in NAION; this f. Erytheromatous rash includes septic shock (as seen in our patient), hemorrhagic shock, or drug-induced hypotension (esp. beta blockers). Definite Case = A1 + B (1+2) Probable Case = A2 + B (1+2) In fact, several non-antihypertensive medications have been described to cause NAION, such as interferon-alpha, Source: Stevens DL. Invasive group A streptococcal infections: the past, present amiodarone, and phosphodiesterase-5 inhibitors [9]. NAION and future. Pediatr Infect Dis J. 1994; 13:561-6. remains stable in the majority of patients, although some

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recovery of vision can be expected in up to 42% of patients References [10]. The development of NAION may signify the presence of 1. MacDonald KL, Osterholm MT, Hedberg CW, et al. Toxic shock diffuse vasculopathy, and may be associated with increased syndrome. A newly recognized complication of influenza and influenzalike illness. JAMA. 1987;257:1053–8. risk of strokes and cardiovascular events [11]. Treatment of 2. Eriksson BK, Andersson J, Holm SE. Epidemiological and clin- NAION is largely supportive and consists of prompt recog- ical aspects of invasive group A streptococcal infections and nition and correction of shock. The role of other therapies the streptococcal toxic shock syndrome. Clin Infect Dis. Dec 1998;27(6):1428-36. (e.g. aspirin or corticosteroids) remains to be elucidated. 3. Stevens DL. Invasive group A streptococcal infections: the past, present and future. Pediatr Infect Dis J. 1994; 13:561-6. 4. Stevens DL, Bisno AL, Chambers HF, Everett ED, Dellinger P, Conclusion Gold- stein EJ, Gorbach SL, Hirschmann JV, Kaplan EL, Mon- Streptococcal pharyngitis is an exceedingly rare cause toya JG, Wade JC, Infectious Diseases Society of America. 2005. Practice guidelines for the diagnosis and management of skin of TSS. In our patient, it was most likely the source of a and soft-tissue infections. Clin. Infect. Dis. 41:1373–1406. transient bacteremia seeding the knee joint, a process that 5. Stevens DL, Gibbons AE, Bergstrom R, Winn V. 1988. The Ea- probably was occurring as he was evaluated for pharyngi- gle effect revisited: efficacy of clindamycin, erythromycin, and penicillin in the treatment of streptococcal myositis. J. Infect. tis. The rapidity of the development of shock is attributed Dis. 158:23–28. to streptococcal exotoxins acting as superantigens, directly 6. Kaul R, McGeer A, Norrby-Teglund A, Kotb M, Schwartz B, unleashing host inflammatory responses. GAS type M1 (our O’Rourke K, Talbot J, Low DE. 1999. Intravenous immunoglob- patient’s type) is commonly associated with severe shock in ulin therapy for streptococcal toxic shock syndrome—a comparative observational study. The Canadian Streptococcal Study TSS. The profound hypotension was the likely cause of his Group. Clin. Infect. Dis. 28: 800 – 807. ischemic optic neuropathy, which fortunately was revers- 7. Darenberg J, Ihendyane N, Sjolin J, Aufwerber E, Haidl S, Follin ible as he regained full vision. Early recognition and aggres- P, Andersson J, Norrby-Teglund A. 2003. Intravenous immuno- sive management that keep pace with the evolution of TSS globulin G therapy in streptococcal toxic shock syndrome: a Eu- ropean randomized, double-blind, placebo-controlled trial. Clin. are crucial to improve clinical outcome. Infect. Dis. 37:333–340. 8. Hattenhauer MG, Leavitt JA, Hodge DO, Grill R, Gray DT. Inci- dence of nonarteritic anterior ischemic optic neuropathy. Am J Ophthalmol.1997;123: 103–107. 9. Pomeranz HD, Smith KH, Hart Jr WM, Egan RA. Sildenafil-associated nonarteritic anterior ischemic optic neuropathy. Oph- thalmology. 2002; 109: 584–587. 10. Ischemic Optic Neuropathy Decompression Trial Research Group. Optic nerve decompression surgery for nonarteritic anterior ischemic optic neuropathy (NAION) is not effective and may be harmful. JAMA.1995; 273: 625–632. 11. Guyer DR, Miller NR, Auer CL, Fine SL. The risk of cerebrovascular and cardiovascular disease in patients with anterior ischemic optic neuropathy. Arch Ophthalmol. 1985;103: 1136–1142.

Authors Salaheldin M. Elhamamsy MD, Department of Medicine, Memorial Hospital of Rhode Island, Alpert Medical School of Brown University. Mazen O. Al-Qadi, MD, Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Memorial Hospital of Rhode Island, Alpert Medical School of Brown University. Taro Minami, MD, Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Memorial Hospital of Rhode Island, Alpert Medical School of Brown University. Marguerite Neill, MD, Department of Medicine, Division of Infectious Diseases, Memorial Hospital of Rhode Island, Alpert Medical School of Brown University.

Correspondence Mazen O. Al-Qadi, MD 401-834-0709 [email protected]

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Ten Years and Growing: Medical Marijuana in Rhode Island – Where Are We Now?

James V. McDonald, MD, MPH; Mike Simoli 50 52 EN Background stating that, in the practitioner’s professional opinion, the The Edward O. Hawkins and Thomas C. Slater Medical Mar- potential benefits of the Medical Marijuana would likely ijuana Act1 (“Hawkins-Slater”– Rhode Island General Laws outweigh the health risks for a patient.” 2 21-28.6-1) became law in 2005. Regulations were promul- At present, Rhode Island has ten years of experience in 3 gated initially in July of 2006. The legislative findings incorpo- regulating MM. rated in Hawkins-Slater assert that modern medical research recognizes beneficial uses for marijuana, including the treatment of pain, nausea and other debilitating conditions, Use of Medical Marijuana in Rhode Island noting that ten states (other than Rhode Island) had passed Currently, the Medical Marijuana Program lists 12,755 cit- statutes approving the use of medical marijuana (“MM”). izens10 with QDMCs. The number of certifications grew Hawkins-Slater allows citizens with qualifying debilitat- steadily between 2005 and 2013, then increased substan- ing medical conditions (“QDMCs”) to grow, possess and use tially. The number of primary caregivers also grew steadily marijuana without fear of prosecution from state or federal between 2009 and 2012, then leveled off. (Figure 1) Three law. “It is in the state’s interests of public safety, public welfare, and the integrity of the medical marijuana program to Figure 1. MM Registration Counts as of December 31, 2015 ensure that the possession and cultivation of marijuana for the sole purpose of medical use for alleviating symptoms caused by debilitating medical conditions is adequately regulated.”4 The law also allows individuals to become “primary caregivers” for citizens with QDMCs. The subsequent development of compassion centers (centers in which MM is grown commercially) was made possible by amending Hawkins-Slater in 2009.5 Three centers were subsequently opened in Rhode Island between spring, 20136 and fall, 2014.7

“‘Primary caregiver’ means either a natural person, who is at least twenty-one (21) years old, or a compassion center. A natural person primary caregiver may assist no more than five compassion centers are available to citizens with QDMCs.11 (5) qualifying patients with their medical use of marijuana.”8 A At present, a patient may access any one – but only one – primary caregiver provides MM to citizens with QDMCs. A natural of the three centers (Table 1). Each patient is obligated to person primary caregiver may obtain MM either by growing it or register with a center. Compassion centers offer marijuana- by legally purchasing it (e.g., from a compassion center). infused products in addition to the raw product. A citizen with at least one QDMC12 must be certified by Hawkins-Slater affords several legal protections for citizens a physician before applying to the Rhode Island Department with one or more QDMCs, as well as their caregivers.9 of Health (RIDOH) to be approved to use MM. A physician’s Additionally, licensed professionals who certify patients as certification indicates that “in the practitioner’s professional having QDMCs are afforded legal protection from the state: “(i) A practitioner shall not be subject to arrest, prose- Table 1. Number of current citizens with a qualifying diagnosis or cution, or penalty in any manner, or denied any right or debilitating condition who have registered with a compassion center16 privilege, including, but not limited to, civil penalty or Compassion Center Number of Registrations disciplinary action by the Rhode Island board of medi- Thomas Slater 7,025 cal licensure and discipline, or by any other business or Summit 3,058 occupational or professional licensing board or bureau solely for providing written certifications, or for otherwise Greenleaf 2,244

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Table 2. Count and percentage of MM program patients by diagnosis Table 3. Count of MM program patients by diagnosis and by gender Number Percent Males Females Ratio M:F Total 17433 100.0% Total 11825 5608 2.1 Severe, Debilitating, Chronic Pain 10937 62.7% Severe, Debilitating, Chronic Pain 7675 3262 2.4 Severe Nausea 1632 9.4% Severe Nausea 1040 592 1.8 Severe and Persistent Muscle Spasms 1484 8.5% Severe and Persistent Muscle Spasms 905 579 1.6 Cancer or Treatment 984 5.6% Cancer or Treatment 539 445 1.2 Other 785 4.5% Other 546 239 2.3 Hepatitis C or Treatment 480 2.8% Hepatitis C or Treatment 357 123 2.9 Seizures, Including Epilepsy 394 2.3% Seizures, Including Epilepsy 245 149 1.6 Cachexia or Wasting Syndrome 364 2.1% Cachexia or Wasting Syndrome 228 136 1.7 Glaucoma or Treatment 180 1.0% Glaucoma or Treatment 134 46 2.9 Positive Status for HIV or Treatment 134 0.8% Positive Status for HIV or Treatment 112 22 5.1 AIDS or Treatment 43 0.2% AIDS or Treatment 34 9 3.8 Agitation Related to Alzheimer’s Disease 16 0.1% Agitation Related to Alzheimer’s Disease 10 6 1.7

Note: Many patients have more than one diagnosis code. Therefore the count of Note: Many patients have more than one diagnosis code. Therefore the count of diagnosis codes exceeds the number of patients. diagnosis codes exceeds the number of patients.

Table 4. Count of MM program patients by diagnosis

Age Group Total < 21 22-29 30-39 40-49 50-59 60-69 70-79 80-89 89+ Unk Total 17433 275 2240 3573 3230 4140 3199 635 115 19 7 Severe, Debilitating, Chronic Pain 10937 158 1499 2439 2105 2481 1835 340 63 14 3 Severe Nausea 1632 60 393 424 282 269 163 30 9 0 2 Severe and Persistent Muscle Spasms 1484 15 170 302 308 374 263 45 5 1 1 Cancer or Treatment 984 4 32 71 114 300 332 109 19 3 0 Other 785 0 17 104 175 240 213 32 4 0 0 Hepatitis C or Treatment 480 1 12 41 65 173 175 13 0 0 0 Seizures, Including Epilepsy 394 30 59 97 75 77 44 11 0 0 1 Cachexia or Wasting Syndrome 364 5 51 55 49 94 77 23 10 0 0 Glaucoma or Treatment 180 0 6 12 23 55 59 21 4 0 0 Positive Status for HIV or Treatment 134 1 1 21 29 53 27 2 0 0 0 AIDS or Treatment 43 0 0 7 5 23 5 3 0 0 0 Agitation Related to Alzheimer’s Disease 16 1 0 0 0 1 6 6 1 1 0

Note: Many patients have more than one diagnosis code. Therefore the count of diagnosis codes exceeds the number of patients. opinion, the potential benefits of the medical marijuana (3.8:1), hepatitis-C (2.9:1), glaucoma (2.9:1), and pain (2.4:1). would likely outweigh the health risks for a patient.”13 The Finally, more than half of all approved patients (53%) are process does not require medical review of the application below age 50. (Table 4) or verification of a diagnosis. Among all QDMCs, “chronic pain and persistent muscle spasms” is the most common (63%) reason for MM approval. Certifying Physicians (Table 2) Of note, the QDMC, “cancer or related treatment,” Currently, only physicians licensed in Rhode Island, Massa- accounts for only 5.6% of all MM approvals.14 chusetts or Connecticut15 may certify that a citizen residing Among all patients approved to use MM, males outnum- in Rhode Island has a QDMC. Currently, 69% are Rhode Island- ber females 2:1. (Table 3) Males are more likely than females licensed physicians and 31% are licensed in Massachusetts to be certified on the basis of HIV positivity (5:1), AIDS or Connecticut.

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Physician Assistants and Advanced Prac- Figure 2. Number of Current MM Registrants for Top 5 Physicians (specialty & state of tice Registered Nurses are not allowed to practice) November 2015 certify a patient for MM. Under Hawkins- Slater no medical or surgical specialty is designated for authorizing MM use; physicians who do so come from various specialties. Of all physicians who attest for MM use, (Figure 2) 52% of current patients are attested by only five physicians, two of whom are licensed in Massachusetts (and practice there).(Figure 3)

Concluding Thoughts Most physicians have not been trained in the pharmacology and clinical applications of MM, given its Schedule-1 designation. Of note, only five physicians account for 52% of Rhode Islanders approved for MM use. The diversity of the top five prescribers (internal medicine, surgery, anatomic path- Figure 3. Percentage of Rhode Island physicians with current registrants on MM ology and obstetrics) is unexplained but raises questions. The vast majority of physicians in Rhode Island have not authorized MM for any of their patients, while another 13% have done so infrequently. What are the reasons for this? We have no data to provide answers.

References 1. Edward Hawkins and Thomas Slater MM Act: http://webserver.rilin.state.ri.us/Stat- utes/TITLE21/21-28.6/INDEX.HTM accessed 1.13.2016 2. Rules and Regulations MM Program: http:// sos.ri.gov/documents/archives/regdocs/released/pdf/DOH/7659.pdf 3. The Edward O. Hawkins and Thomas C. Slater MM Act SEC- 13. The Edward O. Hawkins and Thomas C. Slater MM Act SEC- TION 21-28.6-2 http://webserver.rilin.state.ri.us/Statutes/TI- TION 21-28.6-4: http://webserver.rilin.state.ri.us/Statutes/TI- TLE21/21-28.6/21-28.6-2.HTM TLE21/21-28.6/21-28.6-4.HTM (2) (i) accessed 1.13.2016 4. Ibid (7) 14. Rhode Island Department of Health MM Program: Data ac- 5. The Edward O. Hawkins and Thomas C. Slater MM Act SEC- cessed 1.12.2016 TION 21-28.6-12 http://webserver.rilin.state.ri.us/Statutes/TI- 15. The Edward O. Hawkins and Thomas C. Slater MM Act SEC- TLE21/21-28.6/21-28.6-12.HTM TION 21-28.6-3 (8), http://webserver.rilin.state.ri.us/Statutes/ 6. The Thomas Slater Center: http://slatercenter.com/ TITLE21/21-28.6/21-28.6-3.HTM accessed 1.14.2016 7. Providence Journal: http://www.providencejournal.com/article/ 16. Rhode Island Department of Health MM Program as of 20141105/news/311059982 accessed 1.13.2016 12.31.2015 8. Rhode Island General Laws § 21-28.6-3(9). Authors 9. The Edward O. Hawkins and Thomas C. Slater MM Act SECTION 21-28.6-4 James V. McDonald, MD, MPH, is Chief Administrative Officer, 10. Rhode Island Department of Health MM program as of Board of Medical Licensure and Discipline, Rhode Island 12.31.2015 Department of Health. 11. The Edward O. Hawkins and Thomas C. Slater MM Act SEC- Mike Simoli is Health Program Administrator, Center for TION 21-28.6-12 (5) http://webserver.rilin.state.ri.us/Statutes/ Professional Licensing, Rhode Island Department of Health. TITLE21/21-28.6/21-28.6-12.HTM accessed 1.14.2016 12. The Edward O. Hawkins and Thomas C. Slater MM Act SEC- TION 21-28.6-3: http://webserver.rilin.state.ri.us/Statutes/TI- TLE21/21-28.6/21-28.6-3.HTM accessed 1.13.2016

www.rimed.org | rimj archives | DECEMBER webpage DECEMBER 2016 Rhode Island medical journal 52 health by numbers Public health Nicole E. Alexander-Scott, md, MPH director, rhode island department of health edited by samara viner-brown, ms

Surveillance of Suicide and Suicide Attempts Among Rhode Island Youth Using Multiple Data Sources

Yongwen Jiang, PhD; Deborah N. Pearlman, PhD; Jeffrey Hill, MS; Samara Viner-Brown, MS 53 56 EN In the United States, the need for surveillance of suicide and Figure 1. Percentage of RI middle and high school students who, in the 12 suicide attempts is well recognized. In 2014, suicide was the months before the survey, actually attempted suicide one or more times. second leading cause of death in the United States among young adults 15 to 24 years of age.1 During 1999-2014, the age-adjusted suicide rate in the United States increased by 50% for females aged 15 to 24, from 3.0 per 100,000 to 4.6 per 100,000. In contrast, the suicide rate for males aged 15 to 24 increased more slowly (16.8 per 100,000 in 1999 to 18.2 per 100,000 in 2014), but adolescent and young adult males are 4.0 to nearly 6.0 times more likely to die by suicide than their female counterparts.2 We characterize the burden of youth suicide injuries and deaths in Rhode Island (RI) using multiple data sources.

METHODS

The national and state Youth Risk Behavior Survey (YRBS) Data source: 2003–2015 Rhode Island high school and 2009–2015 Rhode Island monitors self-reported health risk behaviors including vio- middle school Youth Risk Behavior Survey. lence-related behavior.3 Data for this study came from the 2003–2015 RI high school and 2009–2015 RI middle school Across all years, middle and high school students who YRBS. Attempted suicide was defined as the number of mid- had attempted suicide were more likely to report recent dle and high school students who, in the 12 months before depression than their peers who had not attempted suicide the survey, actually attempted suicide one or more times. (data not shown). In 2014, there were 388 ED visits and 474 Data from the 2014 RI Emergency Department (ED) Visit hospitalizations for suicide attempts among RI youth aged Data and RI Hospital Discharge Data (HDD) for 11 acute 24 and younger. Most of the children and youth seen in the care hospitals were used to estimate attempted suicides and ED or hospitalized for a suicide attempt were female, non- self-injuries among children and youth under age 25 using Hispanic white, and resided in suburban regions. Over half E950-E959 external cause of injury codes.4 Most payers of the suicide attempts seen in the ED were in the public require a single bill for patients seen in multiple units of or self-pay insurance category. One-third of patients hospi- the same hospital for a single stay. ED visits in this analysis talized for a suicide attempt were transferred to psychiatric did not include subsequent admissions to the same hospital. units or psychiatric hospitals (Table 1). The Rhode Island Violent Death Reporting System From 2004 to 2014, 127 RI youth under age 25 died of sui- (RIVDRS) collects information from death certificates, med- cide. Youth who died by suicide were more likely to be 18–24 ical examiner reports, and law enforcement sources. Suicide years old, male, and non-Hispanic white. Suburban regions deaths came from the 2004 to 2014 RIVDRS using ICD-10- had higher proportions of suicide deaths compared to other CM codes X60–X84, Y87.0.5 areas of the state. Hanging, strangulation, or suffocation Characteristics of suicide attempts and suicide deaths, were the most common methods of suicide (61%). (Table 2) respectively, in young people under age 25 are shown in Nearly all suicide deaths had toxicology testing for alcohol, Tables 1 and 2. We performed all analyses using SAS version marijuana, antidepressants, and opiates (Table 3). Eleven- 9.4 (SAS Institute, Inc. Cary, NY). year combined toxicology data showed 23% of cases tested positive for alcohol, 21% for marijuana, and 21% for anti- RESULTS depressants. In 57 (45%) cases, the decedent had a current Trend analysis over 12 years revealed that self-reported mental health problem. About 74% of youth with a cur- suicide attempts among RI middle school and high school rent mental health problem had a diagnosis of depression/ students did not change significantly from 2003 to 2015, dysthymia, with attention deficit or hyperactivity disorder except for a striking change in 2013 (Figure 1). (19%), anxiety disorder (16%), bipolar disorder (11%), and

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Table 1. Characteristics of suicide attempts in young people under age 251 Table 2. Characteristics of suicide deaths in young people under age 251

Emergency Hospital Characteristics of Suicide Death n % Department Visits Discharges Age group (mean: 19.7 years) Characteristic (N=388) (N=474) Less than 18 years 30 23.6 n % n % 18-24 years 97 76.4 Age group Sex Less than 18 years 195 50.3 301 63.5 Male 102 80.3 18-24 years 193 49.7 173 36.5 Female 25 19.7 Sex Race/Ethnicity Male 139 35.8 140 29.5 Non-Hispanic white 90 70.9 Female 249 64.2 334 70.5 Non-Hispanic black 11 8.6 Race/Ethnicity Hispanic 18 14.2 Non-Hispanic white 291 75.6 337 71.9 Other 8 6.3 Non-Hispanic black 25 6.5 27 5.7 Occupation Hispanic 52 13.5 83 17.7 Middle school student 10 8.0 Other 17 4.4 22 4.7 High school student 27 21.6 City/Town of Residence College student 28 22.4 Urban core cities2 110 28.5 179 38.7 Employed 41 32.8 Suburban regions 202 52.3 189 40.8 Unemployed 9 7.2 Rural areas 59 15.3 63 13.6 Other 10 8.0 Out of state 15 3.9 32 6.9 City/Town of Residence Primary insurance Urban core cities2 38 30.2 Private 191 49.2 295 62.2 Suburban regions 57 45.2 Medicaid 164 42.3 157 33.1 Rural areas 18 14.3 Self-pay 28 7.2 17 3.6 Out of state 13 10.3 Medicare 5 1.3 5 1.1 Injury Location Patient Status House, apartment 85 67.5 Discharged to home/self-care 258 66.5 303 63.9 Natural area (e.g., field, river, beaches, woods) 16 12.7 Transferred to psychiatric unit 76 19.6 155 32.7 or hospital Street/road, sidewalk, alley <5 2.4 Other 54 13.9 16 3.4 Other* 22 17.4 1 Data source: 2014 Rhode Island Emergency Department (ED) Visit and Hospital Injured at Victim Home Discharge Data (HDD). ED visits do not include those subsequent admissions to Yes 77 62.6 the same hospital. 2 Urban core cities: Central Falls, Pawtucket, Providence, and Woonsocket. No 46 37.4 Weapon Type schizophrenia (7%) occurring in smaller proportions (data Firearm 20 15.8 not shown). Over one-third of youth (36%) were in current Hanging, strangulation, suffocation 78 61.4 mental health treatment. The most common precipitating Poisoning 9 7.1 events were mental health and substance abuse problems, Other 20 15.7 relationship problems, recent crises, and school problems. 1 Data source: 2004–2014 Rhode Island Violent Death Reporting System; N=127 2 Urban core cities: Central Falls, Pawtucket, Providence, and Woonsocket. DISCUSSION Our study found that the 388 ED visits for suicide attempts attempt; and length of stay was 4,209 days (data not shown). in youth under the age of 25 resulted in medical charges of The reasons for suicide were complex. No single factor almost $1.2 million dollars with average medical charges of causes it. We found that children and youth who com- approximately $3,000 per suicide attempt visit. The total mitted suicide were more likely to be male, white, living charges for the 474 hospitalizations for suicide attempts in in suburban areas of the state, and having mental health this age group were nearly $14.7 million dollars; the aver- problems. They also were more likely to have had current age medical charges were more than $30,000 per suicide depression, intimate and non-intimate-partner relationship

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Table 3. Suicide death toxicology tests and circumstances in young are consistent with the Dahlberg et al. study,6 which found people under age 251 that suicide in youth fundamentally reflects social and emotional problems. Of note is that 47% of suicide deaths Toxicology Test and Circumstance n % among RI youth under age 25 were associated with current Tested 126 99.2 depression. Depression, which is a serious problem for ado- Toxicology test positive2 lescents, is the most significant risk factor for teen suicide.7 Alcohol 29 23.0 Data from Rhode Island’s suicide event surveillance Marijuana 27 21.4 system drew attention to the prevalence of youth suicide attempts and deaths and the magnitude of the problem. Antidepressants 27 21.4 National suicide prevention efforts have focused on school 8 6.4 Opiates education programs, crisis center hotlines, and screen- Mental health/substance abuse circumstance3 ing programs to identify at-risk adolescents. RI developed Current depressed mood 60 47.2 the Suicide Prevention Initiative (SPI) to address the link Current diagnosed mental health problem3 57 44.9 between suicide and depression; two treatable mental health conditions that, once recognized, can be treated.8 SPI Depression/Dysthymia 42 -- is a new partnership between the RI Department of Health, Attention deficit or hyperactivity disorder 11 -- Rhode Island Student Assistance Services (RISAS), and Anxiety disorder 9 -- Bradley Hospital’s Access Center and Kids’Link RI hotline Bipolar disorder 6 -- for children in emotional crisis (East Providence, RI). It is Other 17 -- funded by a five-year grant from the Substance Abuse and Mental Health Administration (2014–2019). SPI is a direct Current mental health treatment 46 36.2 referral system that links school crisis team members with 20 15.8 Other substance abuse problem Kids’Link RI emergency service clinicians. Once parental Alcohol problem 9 7.1 consent is obtained, Kids’Link clinicians provide emergency Interpersonal circumstance mental health assessments for elementary, middle and high Intimate partner problem 40 31.5 school youth who are experiencing a mental health crisis or suicidal ideation. Clinicians are available 24 hours a day, Other relationship problem (non-intimate) 28 22.1 seven days a week to help families find the appropriate next 20 15.8 Family relationship step for managing the child’s crisis. SPI is being implemented An argument or conflict led to the victim’s death 14 11.0 and evaluated in school districts throughout RI to ensure Life stressor circumstance that all public school students who express suicidal ideation or engage in non-suicidal, self-injurious behavior receive Crisis in past or impending two weeks 37 29.1 timely (within 24 to 48 hours) access to mental health School problem 13 10.2 services; thus avoiding unnecessary and costly emergency Job problem 9 7.1 department visits. Civil legal (non-criminal) problem 6 4.7 There are several limitations to the data reported in this study. Data obtained from medical examiner reports could Recent criminal legal problem 6 4.7 only determine the mental health status of the victims Financial problem 5 3.9 through medical records or the presence of certain prescrip- Suicide event circumstance tion drugs, but not all persons with a mental illness seek Left a suicide note 41 32.3 treatment.9 Data on a person’s mental health status from Disclosed intent to commit suicide 30 23.6 interviews with victims’ family members, relatives, friends, History of suicide attempt(s) 28 22.1 or other informants, may be incomplete and inaccurate because of recall bias. Information on mental health history Suicide thought history 8 6.3 was unknown in some RIVDRS cases. 1 Data source: 2004–2014 Rhode Island Violent Death Reporting System. N=127 Despite these limitations, RI’s surveillance system for sui- 2 Percentages may exceed 100% because test results can be positive for alcohol or multi-drugs. cide attempts and deaths are extremely useful for describing 3 One victim can have two or three current mental health diagnoses. the characteristics and patterns of suicidal behavior among RI youth under age 25. Ongoing surveillance of suicide- problems, experienced a crisis in the preceding two weeks, related events across the suicide-related spectrum (e.g., left a suicide note, disclosed intent to commit suicide, and thoughts, attempts, deaths) in population subgroups (e.g., made prior suicide attempts. Approximately 47% of youth sex, age, and racial/ethnic groups, geographic regions of the who died by suicide in RI were reported to have a depressed state) provide a much needed foundation for establishing mood, while 36% were receiving mental health treatment. state priorities to reduce and prevent youth suicides and for Mental health status could be underestimated. Our findings developing successful prevention efforts.10

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Acknowledgments Authors This brief was funded by a Centers for Disease Control and Pre- Yongwen Jiang, PhD, is the RIVDRS Epidemiologist, Rhode vention (CDC) grant (1U17CE002615-01 Revised) awarded to the Island Department of Health, and an Assistant Professor of Rhode Island Department of Health. We would like to express our the Practice of Epidemiology, School of Public Health, Brown special thanks to data abstractors Karen Foss and Shannon Young, University. who spent hours compiling the data and constructing sound narra- Deborah N. Pearlman, PhD, is Associate Professor of Epidemiology tives to make RIVDRS one of the best. We thank Kathy Taylor who Practice in the Department of Epidemiology, School of Public provided the 2014 emergency department and hospital discharge Health, Brown University, and Consulting Epidemiologist & data. We also thank Tara Cooper for her contribution as the YRBS Evaluator, Rhode Island Department of Health. coordinator. Jeffrey Hill, MS, is Program Manager for the Violence and Injury References Prevention Program, Rhode Island Department of Health. 1. Centers for Disease Control and Prevention.10 Leading Caus- Samara Viner-Brown, MS, is Chief, Center for Health Data and es of Death by Age Group, United States – 2014 http://www. Analysis, Rhode Island Department of Health. cdc.gov/injury/wisqars/pdf/leading_causes_of_death_by_age_ group_2014-a.pdf Disclosure 2. Curtin SC, Warner M, Hedegaard H. Increase in suicide in the The authors have no financial interests to disclose. United States, 1999–2014. NCHS Data Brief No. 241. 2016:1-8. http://www.cdc.gov/nchs/products/databriefs/db241.htm Correspondence 3. Centers for Disease Control and Prevention. Youth Risk Be- Yongwen Jiang, PhD havior Surveillance System (YRBSS) http://www.cdc.gov/ [email protected] healthyyouth/data/yrbs/index.htm 4. Thomas KE, Johnson RL. State injury indicators report: Instruc- tions for Preparing 2014 Data. In. Atlanta, GA: Centers for Dis- ease Control and Prevention, National Center for Injury Preven- tion and Control; 2016. 5. Centers for Disease Control and Prevention. National violent death reporting system (NVDRS) coding manual revised [online] version 5.1. 2015. 6. Dahlberg LL, Mercy JA. History of violence as a public health issue. AMA Virtual Mentor. 2009;11(2):167-172. 7. Galaif ER, Sussman S, Newcomb MD, Locke TF. Suicidality, depression, and alcohol use among adolescents: A review of em- pirical findings. Int J Adolesc Med Health. 2007; 19(1): 27–35. 8. American Academy for Child and Adolescent Psychiatry. Facts for Families. Teen Suicide. No. 10; Updated October 2013. http://www.aacap.org/AACAP/Families_and_Youth/Facts_for_ Families/FFF-Guide/Teen-Suicide-010.aspx 9. Lyons BH, Fowler KA, Jack SP, Betz CJ, Blair JM. Surveillance for Violent Deaths - National Violent Death Reporting System, 17 States, 2013. MMWR Surveill Summ 2016;65(10):1-42. 10. Data and Surveillance Task Force of the National Action Alli- ance for Suicide Prevention. Improving national data systems for surveillance of suicide-related events. Am J Prev Med. 2014; 47(3 Suppl 2): S122-9.

www.rimed.org | rimj archives | DECEMBER webpage DECEMBER 2016 Rhode Island medical journal 56 VITAL STATISTICS Public health Nicole E. Alexander-Scott, MD, MPH director, Rhode island department of health compiled by Roseann Giorgianni, Deputy State Registrar

Rhode Island Monthly Vital Statistics Report Provisional Occurrence Data from the Division of Vital Records

REPORTING PERIOD JUNE 2016 12 MONTHS ENDING WITH JUNE 2016 VITAL EVENTS Number Number Rates Live Births 1,006 11,662 11.0* Deaths 737 10,065 9.5* Infant Deaths 2 57 4.9# Neonatal Deaths 1 42 3.6# Marriages 840 6,828 6.5* Divorces 284 3,143 3.0* Induced Terminations 167 2,308 197.9# Spontaneous Fetal Deaths 40 566 48.5# Under 20 weeks gestation 34 501 49.8# 20+ weeks gestation 6 65 5.6#

* Rates per 1,000 estimated population # Rates per 1,000 live births

REPORTING PERIOD DECEMBER 2015 12 MONTHS ENDING WITH DECEMBER 2015 Underlying Cause of Death Category Number (a) Number (a) Rates (b) YPLL (c) Diseases of the Heart 216 2,407 227.9 3,648.5 Malignant Neoplasms 162 2,267 214.6 5,107.5 Cerebrovascular Disease 36 434 41.1 510.0 Injuries (Accident/Suicide/Homicide) 61 842 79.7 12,785.0 COPD 38 517 48.9 480.0.

(a) Cause of death statistics were derived from the underlying cause of death reported by physicians on death certificates. (b) Rates per 100,000 estimated population of 1,056,298 (www.census.gov) (c) Years of Potential Life Lost (YPLL).

NOTE: Totals represent vital events, which occurred in Rhode Island for the reporting periods listed above. Monthly provisional totals should be analyzed with caution because the numbers may be small and subject to seasonal variation.

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November 1, Tuesday November 9, Wednesday RIMS Physician Health Committee: Board of Medical Licensure and Discipline Herbert Rakatansky, MD, Chair Governor’s Opioid Taskforce Governor’s Health Care Work Force Meeting with OHIC regarding Transformation/Primary Care, Peter legislation and Modifier 25 Hollmann, MD, and Staff Blue Cross Provider Symposium: November 3, Thursday “New Frontiers in Reimbursement” Meeting with Rhode Island Bike Coalition November 10, Thursday AMPAC check presentation to Meeting with Purdue Pharma regarding Congressman Cicilline; Michael Silver, CME event Michael Silver, MD, RIMPAC Chair, presents MD, Chair RIMPAC Meeting with Chair of Senate Health AMPAC check to Congressman David Cicilline, Governor’s Health Care Work Force and Human Services Committee US Representative District 1, November 3, 2016 Transformation/Mental Health regarding legislation November 7, Monday November 11–15, Friday–Tuesday November 17, Thursday Meeting with Secretary of the Executive AMA Interim Meeting; Orlando, Florida; Senate Health and Human Services Office of Health and Human Services Sarah Fessler, MD, President; Peter Committee hearing on mental health Meeting with Blue Cross Blue Shield of RI Hollmann, MD, AMA Delegate; Alyn regarding recruitment video Adrain, MD, AMA Delegate; and staff November 18, Friday Meeting with Ailis Clyne, MD, MPH, Meeting of Weight and Wellness attending Medical Director, Division of Community Planning Committee November 16, Wednesday Health and Equity, RI Dept. of Health; RIMS Board of Directors Meeting Primary Care Physician Advisory regarding Weight and Wellness Summit Committee November 8, Tuesday November 21, Monday Meeting of opioid treatment providers Election Day Primary Care Physician Advisory Workers Compensation Advisory Committee Committee November 22, Tuesday AMA Advocacy Resource Center conference call regarding E-Prior Authorization SIMS Steering Committee, Peter Hollmann, MD Physician Advisory Committee November 23, Wednesday Interdisciplinary Pain Management at Department of Health November 28, Monday Alpert Medical School Citizen Physician Group Meeting at RIMS; Sen. Chris Ottiano, MD, and Staff

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The Rhode Island Medical Society continues to drive forward into the future with the implementation of various new programs. As such, RIMS is expanded its Affinity Program to allow for more of our colleagues in healthcare and related business to work with our membership. RIMS thanks these participants for their support of our membership.

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Body Worlds Exhibit: Anatomy Up Close & Personal

Mary Korr RIMJ Managing Editor

PROVIDENCE – The recent Body Worlds plays for the education The Soccer Player Vital exhibition at the museum gallery of future generations. Shown here and on the front cover, this in the Rhode Island Convention Center The identity, age plastinate shows all the muscles just below the offered an anatomic, athletic and artis- at death, and cause of skin. The skeletal muscles all overlap intricately. tic view of the human body. death of the donors are not revealed. Photo © Gunther von Hagens’ BODY WORLDS, The approximately 200 specimens on A few of the plastinates in the exhibi- Institute for Plastination, Heidelberg, Germany, display were preserved through a pro- tions originate in old anatomical col- www.bodyworlds.com. All rights reserved. cess Dr. Gunther von Hagens developed lections, which is particularly true of in Germany in 1977 at the Anatomical the embryos shown. The Orthopedic Body Institute of Heidelberg University he The Institute for Plastination has more (Below left) This plastinate is posed as a termed Plastination. Since that time, he than 16,000 donors on its roster, and dancer. It is fitted with artificial joints at the has refined the process; his first whole- more than 1,400 of them are Americans. knee, hip, and elbow. The jawbone has also body plastinate was created in 1992. Dr. von Hagens, who announced he been partly replaced. Some of the instruments The Plastination method extracts suffers from Parkinson’s disease, has are surgical. Others are for orthopedics. bodily fluids and fat from specimens, signed up for his own program and replaces them with acetones, which in will have his body plastinated so that (Below right) Plastinate of a man holding a second step is replaced by polymers. people can learn about PD. v his skin. The body is then positioned, with the entire anatomical structure properly Up-to-date information on the traveling exhibitions is available at www.bodyworlds.com. aligned and secured with wires, nee- dles, clamps, and foam blocks. In the final step, the specimen is hardened. Depending on the polymer used, this is done with gas, light, or heat. The Providence exhibit included whole body figures, as well as individual organs, blood vessel configura- tions, and transparent longitudinal and cross-sectional body slices, allowing viewers to observe the anatomy and working of the human body, and the effects of disease on it, often by comparing healthy and diseased organs. Two in the exhibit showed black lungs illustrating the effects of smoking. Long-term outcomes of disorders, and substance abuse are illustrated in the same way, as are the mechanics of artificial hip and knee joints. All of the specimens in Body World exhibits, which have been seen by mil- lions around the world, are from individuals who have willed their bodies to the donation program managed by the Institute for Plastination in Heidelberg, Germany.

Donors agree that their bodies will be Korr Photo s : M a ry permanently preserved and used in dis-

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Alpert Foundation awards Brown medical school $27M Funds will endow MD/PhD program; create Translational Science professorship

PROVIDENCE — A new $27 million gift to Brown from The “These scholars are integral in the research continuum and Warren Alpert Foundation will establish an endowment for a critical ingredient for any school to truly excel in transla- Brown’s program for training MD/PhD students pursuing tional research.” careers as “physician-scientists,” more than tripling funding Dr. Allan Tunkel, associate dean for medical educa- for the program, and will create the first endowed professor- tion, said that tuition assistance is particularly beneficial for ship in the Brown Institute for Translational Science. MD/PhD students and will allow Brown to attract excep- Of the total gift, $22 million will establish the endowed tional students who have the passion for combining research Warren Alpert Physician-Scientist MD/PhD and Advanced with clinical medicine. For years, Brown students have Training Program, offering more students the opportunity wanted more opportunities to engage in this extraordinary to pursue these joint degrees with tuition assistance and level of scholarship, he said. research stipends. The gift will also bolster efforts to bring researchers from Bolstering translational science different fields together to decipher disease and improve The gift’s additional $5 million will establish the Warren population health, one of the seven integrative scholarship Alpert Professorship as the first endowed professorship in themes outlined in the University’s Building on Distinction the Brown Institute for Translational Science (BITS). Estab- strategic plan. lished in fall 2015, BITS organizes researchers into inte- Dr. Jack A. Elias, Brown’s dean of medicine and bio- grated teams with a full continuum of expertise – from basic logic sciences and the Frank L. Day Professor of Biology, said science to medicine to population health and policy – to that a thriving MD/PhD program is an essential component make breakthroughs on specific diseases and other pressing for medical schools focused on translational science and that medical challenges in society. the foundation’s gift will advance the University’s vision The new professorship will enable the institute to recruit to become a world-class center of innovation in biology and support a new faculty member with in-demand exper- and medicine. tise integral in translating scientific discoveries into applica- “MD/PhD physician researchers see patients in the clinic, ble solutions for health issues, a key factor in the institute’s understand the challenges of the diseases they study and plans to assemble fully integrated teams that can attack transfer those insights to work in their labs,” Elias said. medical problems from multiple directions. v

AMA Adopts New Policies to Support Medical Student and Resident Physician Wellness and Mental Health ORLANDO – The American Medical student Omar Z. Maniya. “With a high medical schools to create mental Association (AMA) adopted new pol- number of medical students and resi- health awareness and suicide preven- icy recently aimed at ensuring med- dents experiencing depression, burnout tion screening programs that would ical students and resident and fellow and suicide, and too many physicians be available for all medical students at physicians have timely and confiden- overlooking their own health needs, we their discretion. The policy asks that tial access to the medical and mental must do everything we can to reduce these programs offer students anonym- health services they need during their the barriers and stigmas that keep them ity, confidentiality, and protection from medical training. The new policies will from receiving care.” administrative action, and provide pro- help physicians-in-training maintain To help address concerns about con- active intervention for any student their personal health and well-being fidentiality, the new policy specifi- identified as at-risk by mental health and reduce burnout so they can provide cally calls on state medical boards to professionals. These policies build the highest quality patient care. refrain from asking applicants about on the AMA’s strategic work over the “Many physicians-in-training do not past history of mental health diagnosis past several years to reduce physician seek out treatment for physical, men- or treatment, and only focus on cur- burnout and create the medical school tal health or addiction issues because rent impairment by mental illness or of the future. The AMA is committed they are concerned about confiden- addiction, and to accept “safe haven” to ensuring a healthier practice envi- tiality, the possible negative impact non-reporting, which would allow phy- ronment for physicians and closing the that receiving treatment could have on sicians-in-training who are receiving gaps that exist in medical education to their future career in medicine, or bur- mental health treatment to apply for improve the health of the nation. v dening colleagues with extra work,” licensure without having to disclose it. said AMA Board Member and medical The new policy also encourages

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Bradley Hasbro Children’s Research AMA Launches Center awarded $3.3M NIH grant to Textbook to Train study effects of trauma on teens and Physicians on value of social media in recovery ‘Third Science’

PROVIDENCE – Nicole Nugent, PhD, a pediatric psy- CHICAGO – As part of its chologist from the Bradley Hasbro Children’s Research ongoing effort to develop Center, is leading a new study to better understand the bold, innovative ways to social and biological factors that may promote resil- improve physician train- ience in teens after a traumatic event. The $3.3-mil- ing, the American Med- lion, 5-year National Institutes of Mental Health ical Association (AMA) (NIMH) study will be used to develop interventions to recently launched a new help adolescents better recover from trauma. health systems textbook. “Trauma-exposed adolescents are at risk for a host The AMA collaborated of negative outcomes, including symptoms of posttrau- with its 32-school Consor- matic stress disorder, anxiety, depression and substance tium to identify the innovations needed to create the medical abuse disorders,” said Nugent. “Although researchers school of the future. “Health Systems Science” emerged as have very generally shown that friends and family, as the third pillar of medical education that should be integrated well as an adolescent’s own biological responses, are with the two existing pillars: basic and clinical sciences. important for adjustment after trauma, there is much Jeffrey Borkan, MD, PhD, assistant dean for the Primary we still don’t know about the exact timing and types of Care-Population Medicine Program Planning at the Alpert help that friends and family can provide. In particular, Medical School, contributed to the textbook, which focuses we know very little about how the use of social media on value in health care, patient safety, quality improvement, may affect a teen’s adjustment after trauma.” teamwork and team science, leadership, clinical informatics, The study will evaluate 200 trauma-exposed adoles- population health, socio-ecological determinants of health, cents between the ages of 13 and 17 who have been health care policy and health care economics. medically evaluated in the Hasbro Children’s Hospital Many schools within the Consortium have already begun emergency department after a traumatic injury, such implementing Health Systems Science into their curricula as a physical assault or a serious vehicular accident. and will soon use the textbook with their students, including Participants will be asked to wear a watch and carry a Brown, which also received a $1 million AMA grant to support phone to track their heart rate, skin conductance and its curriculum transformation, created its Primary Care-Popu- acoustic environment, as well as participate in clinical lation Medicine program—awarding graduates both a Doctor interviews and stress testing for a follow-up period. of Medicine and a Master of Science in Population Medicine. Nugent’s hope is that the study findings will help The first-in-the-nation program is designed to develop physi- make clearer recommendations to families about how cians who, with training focused on population health, can be they can best support their adolescent after trauma, future leaders in community-based primary care at the local, including clearer recommendations about the effects state or national level. of social media use for adolescents during the first few Topics in the textbook include: weeks following trauma. • Patient safety “This research is the first of its kind that allows us • Quality improvement to really understand how social supports play out in the real world over the course of the critical first few • Teamwork and team science weeks after trauma,” said Nugent. “These findings will • Leadership help us to also develop new interventions that could be • Clinical informatics provided for families, possibly including interventions • Population health that incorporate ways to best harness social media use.” This research is supported by the National Institutes of • Socio-ecological determinants of health Mental Health under Award Number R01MH108641. v • Health care policy and economics

Nugent’s principal affiliation is the Bradley Hasbro “Health Systems Science,” published by Elsevier, can be Children’s Research Center, a division of the Lifespan preordered from the AMA Store and Elsevier, as well as from health system in Rhode Island. She is also an associate Amazon and other online booksellers. The textbook retails for professor (research) at The Warren Alpert Medical School $59.99. AMA members may order it from the AMA Store for of Brown University, departments of psychiatry and $54.99. Individual chapters will also be available from Elsevier human behavior and pediatrics. for $5.99 each. v

www.rimed.org | rimj archives | DECEMBER webpage DECEMBER 2016 Rhode Island medical journal 70 N G T I A R B

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Women & Infants Files Letter of Intent for Renovation of Labor and Delivery Suite

PROVIDENCE – Women & Infants Hos- focus, Women & Infants is a well-cher- The project design will be based pital of Rhode Island has filed a letter ished jewel, providing incomparable around a universal room that exceeds of intent (LOI) with the Rhode Island care to the women and newborns of our the needs for all levels of patient and Department of Health for its proposal, region. But our physical environment family centered care. The renovation “Women & Infants Hospital Labor & in labor and delivery no longer pro- will integrate the newest technologies Delivery Renovation.” This LOI is the vides the optimal support for today’s and include upgrades to the electrical, first step in the hospital’s plan to file modern birth approach,” said Mark HVAC, plumbing and medical gasses a certificate of need (CON) application R. Marcantano, president and chief systems. in January 2017. operating officer of Women & Infants The renovation, with a projected As one of the largest stand-alone Hospital. “It’s time for our physical cost of approximately $18.6 million, is obstetrical services in the country, environment in labor and delivery to scheduled to be completed in October Women & Infants delivered more than match the incredible level of clinical 2018 will be done in phases over 14 to 8,800 babies last year. Since the current care provided here.” 16 months in order to minimize any space was designed in 1986, there have Women & Infants’ Labor and Delivery disruption to existing service. been dramatic changes in the hospital’s Suite is comprised of 19 private labor/ “Having a baby is a wonderful expe- patient population, care models and delivery/recovery rooms, three dedicated rience for a family,” said James A. the introduction of new technologies. Cesarean birth rooms and a recovery O’Brien, MD, director of inpatient Women & Infants has seen a sizable area, and an Alternative Birthing Cen- obstetrics and an assistant professor of increase in patients with significant ter that offers a high-touch, home-like, obstetrics and gynecology at The War- chronic illness who require specialized midwife-led birthing experience for ren Alpert Medical School of Brown monitoring and care; has moved to an low-risk births. This project will con- University. “We want to provide the electronic medical records system; and sist of renovating all 20 labor rooms highest level of complex care when has instituted a team-based model of and increasing the room size from necessary, but also provide a warm, care that includes patients and families 220 square feet to the current guide- personal and engaging experience, with in all aspects of care. lines of 400 square feet with a private hidden technology that is only used “As a specialty hospital with a unique bathroom and shower in each room. as needed.” v

Stoico/FIRSTFED Charitable Foundation donates $1.1M for maternity care at St. Luke’s Hospital in New Bedford Donation is part of Southcoast Health’s $25 million capital fundraising campaign

NEW BEDFORD – Southcoast Health announced recently that services at all three sites offer a family-centered approach the Robert F. Stoico/FIRSTFED Charitable Foundation has that provides the right combination of compassionate care donated $1.1 million to the Campaign for Southcoast Health and the latest technology. – a $25 million capital fundraising campaign which is the “We are incredibly grateful to the Stoico/FIRSTFED Char- largest in the not-for-profit healthcare system’s history. The itable Foundation for this extremely generous donation, Maternity Center at St. Luke’s Hospital in New Bedford will which benefits moms, newborns and families,” saidK eith receive $1 million, while the additional $100,000 will go A. Hovan, President & CEO of Southcoast Health. “As a towards the care of drug-addicted newborns. not-for-profit healthcare system, we rely on the generosity “Healthcare is extremely important to me and my founda- of so many within our community to support vital programs tion,” said Bob Stoico, who began the foundation after retir- and services. This substantial contribution has helped us to ing as chairman, president and CEO of FIRSTFED America completely renovate our maternity department at St. Luke’s, Bancorp Inc. “By supporting excellent maternity care at St. where families in greater New Bedford can now celebrate Luke’s, we are helping to ensure the health and well-being of the birth of a child in a brand new, state-of-the-art unit that families. That is a vital service for the community.” offers privacy and comfort.” Southcoast Health is the only provider of maternity ser- The Campaign for Southcoast Health is currently raising vices in the South Coast region. Each year nearly 3,500 babies funds to support major capital initiatives across Southcoast are delivered between its three acute-care hospitals with Health’s three acute-care hospitals – St. Luke’s, Charlton 1,400 of those births taking place at St. Luke’s. Maternity Memorial in Fall River and Tobey in Wareham. v

www.rimed.org | rimj archives | DECEMBER webpage DECEMBER 2016 Rhode Island medical journal 72 IN THE NEWS

Drs. Gruppuso, Adashi question ‘residency placement fever’

PROVIDENCE — The highly successful process of matching Data, solutions needed medical graduates to residencies has nevertheless become More than anything, Gruppuso and Adashi call for more so frenzied that the authors of a new article in Academic data so that medical educators can either prove or disprove Medicine explicitly question the rationality of the system. the “more is better” hypothesis that students appear to have It’s driving up costs for students and severely disrupting the accepted as a new normal. fourth year of medical school, they say. Gruppuso and Adashi also propose a few steps that medi- “There’s been this inexorable intensification of the resi- cal education organizations such as the National Residency dency selection process such that it’s basically taken over the Matching Program, the Association of American of Medical fourth year of medical school,” said Dr. Phil Gruppuso, Colleges and the American Medical Association could take a professor of pediatrics in the Alpert Medical School and to treat what they call the “Residency Placement Fever.” a former associate dean for medical education. “It so dom- • Coordinate interview timing: If student interviews could be inates student time and energy during the fourth year that consolidated into a predictable, cohesive season, educators it’s become very difficult to do any curriculum planning.” could plan a meaningfully educational curriculum for the The statistics he uncovered with co-author Dr. Eli rest of the fourth year. Adashi, former dean of medicine and biologic sciences at • Reduce or cap the number of interviews: If students could only Brown, show that by 2005, students across the country were take on a maximum of 10 interviews, they might be more applying on average to 30.3 programs. In 2015 the number thoughtful and selective about where they sent applications. reached 45.7. For specialties deemed highly competitive, the numbers go even higher: The average student hoping to be • A “screen and schedule” system: If residency programs an orthopedic surgeon, for example, applied to 73 of the 163 employed online screening interviews before inviting appli- potential programs. cations in person, that could reduce unnecessary time and The surge of residency program applications appears to travel for students who don’t become finalists. derive from a perception among students that it’s necessary Adashi and Gruppuso readily acknowledge these partic- to ensure placement in a top program. Indeed, among all ular ideas might not take hold, but they argue it’s certainly applicants to residency programs, the number of offers per time for an examination of whether the current state of applicant fell to 0.78 in 2015 from 0.96 in 1976. residency applications makes sense. v Among MD graduates in the U.S., the number of offers per applicant has actually increased to 1.51 in 2015 from 1.37 in 1976. Disruptive, costly and maybe unfair After students file their (many, many) applications electronically, programs invite their preferred students for interviews. Here Gruppuso and Adashi could find no national data, but a survey of fourth-year students at the Alpert Medical School suggests that the number of interviews has scaled up with the number of applications. That means that students are on the road for substantial chunks of time throughout their fourth year of school. Interviews among programs and disciplines are not coordinated, making it hard for faculty members to plan a curriculum in which students can fully participate. Meanwhile, Gruppuso and Adashi wrote, the financial burden of traveling to many interviews around the country may significantly disadvantage students of low socioeconomic status, though that’s never been formally studied.

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Appointments Phyllis A. Dennery, MD, named president-elect of Society for Redox Biology and Medicine

PROVIDENCE – Phyllis A. Dennery, MD, pediatrician-in-chief Demetra C. Ouellette named at Hasbro Children’s Hospital, has been voted president-elect of President of Roger Williams the Society for Redox Biology and Medicine (SfRBM). Dennery was installed as president-elect at SfRBM’s an- Medical Center nual meeting scheduled from Nov. 16–19. Her PROVIDENCE – Demetra C. Ouel- two-year term as president will begin in 2018. lette has been named President of Established in 1987, the SfRBM is a pro- Roger Williams Medical Center fol- fessional organization of scientists and cli- lowing an extensive search. She brings nicians investigating redox biology, which is a proven track record as a leader fo- the study of free radicals and reactive oxygen cused on improving quality, patient as they relate to human diseases and potential satisfaction and safety. Ouellette joins therapeutic interventions. Roger Williams from Prime Healthcare Services, where Dennery has been a member of the society she served as Chief Operating Officer/Administrator for since 1990 and has served on various commit- Landmark Medical Center, Rehabilitation Hospital of RI, tees and on the society’s council. She served as associate editor and Landmark Physician Outpatient Services. of the society publication Free Radicals in Biology and Medicine Previously, she served as Corporate Vice President, from 2003 until March of this year. Business Development with Select Medical Corporation Not only will Dennery be the first African-American to serve in Pennsylvania and was President and CEO of Ouellette as SfRBM president, she will also be the first physician president and Associates Healthcare Interim Management. Her of the society. previous employers include The Studer Group and Tenet “I hope that in my role as president, I can use my background Healthcare Corporation. as a physician to bring clinical context to some of the diseases we A graduate of Tufts University, Ouellette holds an MBA research as a society,” said Dennery. “I would like to expand our from Northeastern University. v society’s scope to consider everything from basic science to clinical medicine. We need to examine every aspect of free radicals and Lawrence T. Saulnier, RN, BSN, delve into how biology relates to patients and their diagnoses.” Dennery hopes that an expanded view of the field of redox Joins Visiting Nurse of Hope- biology will lead to partnerships with other groups and societies, Health as Director of Nursing as well as physician groups. LINCOLN –Lawrence T. Saulnier, Dennery, a Howard University College of Medicine graduate, RN, BSN, has joined the Visiting Nurse joined Hasbro Children’s Hospital in April 2015, bringing more of HopeHealth agency as director of than 25 years of experience in pediatric care, teaching and re- nursing. In his new role, Saulnier will search. In addition to her role as pediatrician-in-chief and medical be responsible for strategic leadership director, she is also the Sylvia Kay Hassenfeld Chair of Pediatrics and program development and imple- at the Warren Alpert School of Medicine of Brown University and mentation. He will also oversee over- a professor of molecular biology, cell biology and biochemistry at all administration of nursing services in accordance with Brown University. patients’ needs, government regulations and projected At Hasbro Children’s Hospital, Dennery oversees all pediatric industry changes. clinical programs, such as centers and clinics for pediatric imag- Saulnier brings more than ten years’ of clinical exper- ing, hematology/oncology, asthma and allergies, neurodevelop- tise and leadership experience to his new position. Most ment and cardiology. Dennery’s research on lung problems and recently, he was a clinical nurse manager at the Visiting other medical conditions among newborns has been funded by Nurse Association of Care New England. There, he was re- the National Institutes of Health for 24 consecutive years. sponsible for supervising the clinical staff and admission Dennery is a member of the National Academy of Medicine team, helping to assist with their intake process. He also (formerly Institute of Medicine), the Society for Pediatric Re- championed numerous clinical initiatives designed to im- search, and the American Pediatric Society, among many others prove performance. Prior to this role, he worked at South and also serves as an associate editor of the journal Pediatrics. She County Hospital as an RN, where he provided nursing has received numerous awards during her career, including the care to patients in a variety of in-patient settings. 2014 Marion Spencer Fay Award, Best Doctors in America, and He holds his bachelor of science in nursing degree from the Alfred Stengel Health System Champion Award. Dennery was Dominican College and a bachelor of science-health and hu- recently elected to the Association of American Physicians, one man services-police science from Empire State College. v of the highest honors in academic medicine. v

www.rimed.org | rimj archives | DECEMBER webpage DECEMBER 2016 Rhode Island medical journal 75 people

Appointment Recognition

Dr. Eden Cardozo joins W&I, will oversee Fertility Preservation Program

PROVIDENCE – Eden Cardozo, MD, of Boston, has recently joined the Divi- sion of Reproductive Endocrinology and Infertility in the De- partment of Obstet- rics and Gynecology at Women & Infants Hospital. Dr. Cardo- zo is also an assistant professor at The Dr. N. Joseph Espat, Chairman of Surgery and Director of the Cancer Center at Roger Williams, Warren Alpert Medical School. speaks while Bernard Jackvony, former Lt. Governor and chairman of the ACS CAN Research Her areas of research and clinical in- Breakfast, (pictured left) listens on at the 2016 Rhode Island Research Breakfast. terest include fertility preservation and the impact of obesity on reproductive Roger Williams Cancer Center recognized at American Cancer outcomes. “I am very proud to join the team at Society’s 2016 Rhode Island Research Breakfast Women & Infants’ Fertility Center and, PROVIDENCE – The Cancer Center at Roger Williams Medical Center was recognized in particular, the Fertility Preservation at the American Cancer Society’s 3rd annual Rhode Island Research Breakfast for Program. This wonderful program al- receiving the Commission on Cancer’s “Outstanding Achievement Award.” lows patients to use cutting edge tech- The event, which took place on October 14, is hosted by the American Cancer niques to preserve their fertility for the Society’s Cancer Action Network and brings together leaders, medical professionals future,” said Dr. Cardozo. “The road and cancer survivors from across the state to address the need for increased funding to building a family – now or in the of cancer research. Dr. N. Joseph Espat, Chairman of Surgery and Director of the future – can be complicated and over- Cancer Center at Roger Williams, accepted the Certificate of Excellence from the whelming. My goal is for patients to American Cancer Society on behalf of his colleagues. feel comfortable engaging in open and “Our recognition today – and from the Commission on Cancer last year – is reflec- honest conversation with me, which I tive of the team effort that goes into the care of every single patient who comes to our feel is crucial in helping my patients to Cancer Center,” said Dr. Espat. “Exemplary cancer care is delivered when you have achieve their goals.” a highly experienced and motivated team of surgical, medical and radiation oncol- A graduate of Yale University, Dr. ogists, along with oncology nurses, laboratory professionals, and support staff. The Cardozo earned her medical degree at best care is delivered in a collaborative manner and we strive to do that every day. ” the University of Michigan Medical The goal of the Rhode Island Research Breakfast is to create an event for innova- School. She completed a residency in ob- tors, leaders in business, academia, public policy, and patient advocacy to capture stetrics and gynecology at the Feinberg the latest and best thinking about the impact of local cancer research. School of Medicine at Northwestern “It is important for all of us as individuals, companies, and health care insti- University, and a fellowship in repro- tutions to urge policymakers and leaders from across the life sciences and health ductive endocrinology and infertility at system ecosystem to do everything we can to save more lives from cancer,” said Massachusetts General Hospital, Har- Bernard Jackvony, former Lt. Governor and chair of the ACS CAN Research Break- vard Medical School. She is a member of fast. “It is my honor to recognize Roger Williams for receiving the Commission on the American Congress of Obstetricians Cancer Outstanding Achievement Award, which recognizes programs that strive for and Gynecologists, the American Soci- excellence in delivering high quality cancer care.” ety for Reproductive Medicine, the New Rhode Island Lt. Gov. Daniel McKee served as this year’s honorary event chair. England Fertility Society, and the Soci- Along with Roger Williams, others recognized at the breakfast included research- ety for Reproductive Investigation. v er Dr. Adam Olszewski, Dr. James Padbury from Brown University, and volunteer and caregiver Ramone Johnson. v

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Recognition

Left to right, Mark Foster, CRNA, MA, CRNA program director; Lisa Strait, Catherine Keyo, Mikayla Jarratt, Christopher Manion, Mical McRae, Tra- vis Henderson, Richard Guillaume, Artur Rozentsvit, Jessica Gregson, and Susan Walker, MD, medical director and interim anesthesiologist-in-chief.

Memorial Hospital School of Nurse Anesthesia Graduates 9

PAWTUCKET— Ceremonies for the 50th graduation of the Me- Gaurav Gupta, MD, of the Rhode Island Society of Eye Physicians and morial Hospital of Rhode Island School of Nurse Anesthesia Surgeons, shown in back row center, with LDP classmates and Aaron Program took place on October 28 in the hospital’s Sayles Weingeist, MD, AAO Director, Leadership Development Program. Conference Center. Hospital administration, staff, family and friends were on hand to honor the nine graduates. This year’s graduates are: Mikayla Jarratt of Bellingham, Gaurav Gupta, MD, Graduates from AAO Washington; Lisa Strait of Arizona; Catherine Keyo of Dorches- Leadership Development Program ter, MA; Jessica Gregson, Hopkinton, MA; Travis Henderson CHICAGO – On October 17 during the Society Presidents’ Rec- of Nampa, Idaho; Christopher Manion, Seekonk, MA; Richard ognition and Awards Session held in conjunction with the Guillaume, Revere, MA; Artur Rozentsvit of New York City, American Academy of Ophthalmology AAO 2016 in Chicago, NY; and Micah McRae of Henderson, NV. Gaurav Gupta, MD, was recognized for completing his par- Mark A. Foster, CRNA, MA, director of Memorial’s School of ticipation in the Academy’s Leadership Development Program Nurse Anesthesia Program, recognized the accomplishments of XVIII, Class of 2016. Dr. Gupta was among a select group of the nine nurse anesthetists. He noted how the graduates devot- seventeen participants chosen for the LDP XVIII, Class of 2016, ed the past 29 months to a comprehensive didactic and clinical from among a large group that was nominated by state, sub- curriculum, earning a Master of Science Degree in biological specialty and specialized interest societies. sciences/anesthesia. In January 2016, Dr. Gupta took part in a 2 ½ day interactive He also thanked the following individuals who supported the session in San Francisco covering a wide variety of leadership program: Susan Walker, MD, interim anesthesiologist-in-chief and association management topics. The meeting also included and medical director of the School of Nurse Anesthesia; anes- a visit to AAO headquarters to hear from the 2016 Academy thesiologists with Anesthesia Care; Ruth Rollin, PhD, and Mark President William Rich III, MD, CEO David Parke II, MD and Jackson, PhD, academic coordinators of Central Connecticut Academy Vice Presidents on key priorities for the Academy. State University; Keith Macksoud and Elena Litmanovich, both Next was a trip in April 2016 to attend the Mid-Year Forum faculty; the surgeons and staff in the operating room, Post Anes- 2017 in Washington D.C. where Dr. Gupta visited Rhode Is- thesia Care Unit, Surgical Place Recovery Unit; and Pulmonary land’s members of Congress and their staff to discuss issues Function Lab at Memorial; Cyndi Hannaway, secretary for the important to the medical profession as part of Congressional Department of Anesthesia; and the clinical coordinators and ad- Advocacy Day. During a dedicated LDP session on Capitol junct faculty at the following clinical sites - Susan Roessle, CRNA, Hill, Dr. Gupta and his LDP colleagues also heard from 2016 US from St. Luke’s Hospital in New Bedford, MA; Katie Bourski, Congressman Paul Tonko (D-NY) about building effective rela- CRNA, coordinator at Kent Hospital; and Dr. Sana Ata, chair- tionships with legislators and how best to advocate on behalf person and coordinator at Lahey Hospital and Medical Center. of patients. v Arthur Rozentsvit, on behalf of the graduates, thanked the administration, Anesthesia Department’s faculty and staff and fellow classmates for their support. v

www.rimed.org | rimj archives | DECEMBER webpage DECEMBER 2016 Rhode Island medical journal 78 一漀琀洀愀渀礀猀洀愀氀氀戀甀猀椀渀攀猀猀攀猀愀爀攀爀攀愀搀礀琀漀搀攀愀氀眀椀琀栀琀栀攀挀栀愀渀最攀猀琀漀栀攀愀氀琀栀椀渀猀甀爀愀渀挀攀Ⰰ 挀漀洀瀀氀椀愀渀挀攀Ⰰ 愀渀搀栀甀洀愀渀爀攀猀漀甀爀挀攀猀⸀ 圀栀攀琀栀攀爀椀琀ᤠ猀昀椀渀搀椀渀最琀栀攀戀攀猀琀䴀愀欀攀猀甀爀攀礀漀甀ᤠ爀攀挀漀瘀攀爀攀搀⸀ 搀攀愀氀漀渀栀攀愀氀琀栀椀渀猀甀爀愀渀挀攀Ⰰ 愀猀猀椀猀琀椀渀最礀漀甀爀挀漀洀瀀愀渀礀眀椀琀栀戀甀猀椀渀攀猀猀愀渀搀䠀䤀倀䄀䄀挀漀洀瀀氀椀愀渀挀攀Ⰰ 漀爀欀攀攀瀀椀渀最甀瀀眀椀琀栀琀栀攀洀漀猀琀爀攀挀攀渀琀栀甀洀愀渀爀攀猀漀甀爀挀攀䌀愀氀氀甀猀琀漀搀愀礀㐀㄀ⴀ㈀㈀㠀ⴀ㠀㤀㄀㔀漀爀瘀椀猀椀琀甀猀爀攀焀甀椀爀攀洀攀渀琀猀Ⰰ 䠀一䤀椀猀爀攀愀搀礀琀漀栀攀氀瀀礀漀甀眀椀琀栀琀栀攀猀甀瀀瀀漀爀琀礀漀甀渀攀攀搀琀漀昀漀挀甀猀漀渀氀椀渀攀䠀一䤀椀渀猀⸀挀漀洀漀渀眀栀愀琀爀攀愀氀氀礀洀愀琀琀攀爀猀 ጠ 礀漀甀爀瀀愀琀椀攀渀琀猀⸀

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Recognition

Robert J. Westlake, MD, honored by Butler Hospital

PROVIDENCE – At Butler Hospital’s fundraising event held Nov. 9, Robert J. Westlake, MD, received the 2016 Corporation Member of the Year award, presented each year to one of the 350 corporation members that make up the Butler Hospital Corporation. Butler’s President and Chief Operating Officer Lawrence Price, MD, presented the award in recognition of Dr. Westlake’s support and advocacy for the hospital’s work and service to the community. Dr. Westlake has been connected to Butler since 1973, and, during his tenure as a psychiatrist and administrator, is credited with creating Butler’s partial hospital program, and helping to establish the education program for psychiatry residents. He also served as the vice-chair of adult services. In his remarks, Dr. Price acknowledged Dr. Westlake for the Robert J. Westlake, MD, at left, receives the Butler Hospital Foundation’s support he provided during the earlier years of Dr. Price’s career as Corporation Member of the Year Award from Lawrence Price, MD, pres- a psychiatrist and researcher. v ident and chief operating officer at Butler Hospital.

Kent Hospital’s Women’s Care Center recently received international recognition as a Baby-Friendly® Designated birth facility, a global program spon- sored by the World Health Organization (WHO) and the United Nations Children’s Fund (UNICEF). The initiative encourages and recognizes hospitals and birthing centers that offer an optimal level of care for breastfeeding mothers and promote the best, evidences-based feeding practices for all babies.

www.rimed.org | rimj archives | DECEMBER webpage DECEMBER 2016 Rhode Island medical journal 80 First, do no harm.

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Dec. 7, 1941: 75 years ago, Japan attacks Pearl Harbor RIMJ launches special features: Doctors at War & Calling All Battle Stations

Mary Korr RIMJ Managing Editor

Seventy-five years ago this month, the a hit…He and crew were trapped on the fantail of the craft as United States Congress declared war on explosions cut off all escape forward. Swiftly administering Japan after the attack on Pearl Harbor on morphine and caring for casualties, Commander Davis and December 7, 1941. Shortly after this ‘day of another surgeon worked at their task until the heat of the infamy,’ Dr. Peter Pineo Chase, a retired deck plates became unbearable and the men had to go over surgeon, became editor-in-chief of the Rhode the side. They were picked up by a destroyer escort.” Island Medical Journal. Wherever Rhode Island physicians served in World War II, Dr. Chase made sure the journal was for-

R hode I sland M edical J ournal warded to them. He also Dr. Peter Pineo Chase, began two columns, “Doc- a surgeon, served as tors at War” and “Call- editor of the Rhode ing All Battle Stations,” Island Medical Journal which reported news from of Co ng r ess y/Libr a ry U S N av during the war years. the front. The following are excerpts: “From somewhere in Germany Capt. Donald L. DeNyse of Cranston informs us that he was in the Normandy invasion, making the landing from an LST (Landing Ship, Tank) on D-day plus 2, and since that time he has been in con- tinuous combat duty with the field ser- The USS Arizona was totally destroyed by the Japanese attack on Pearl Harbor on December 7, 1941. vice, treating casualties. He now goes on our records as our first member to report to us from inside the Nazi frontiers.” “We are pleased to report that Major Kenneth G. Burton writes that he is Korr M a ry always happy to receive the Rhode Island Medical Journal. ‘It has followed me quite regularly considering my many moves.’ Just before and for a cou- ple of months after D-day, he was in a field hospital in England treating casualties from the Channel, the beachheads and later the Continent.” “On assignment to a hospital following Gen Patton’s Army, Capt. Thomas A. Egan of Providence reports: ‘It is not the surgery that saves the lives of the severely wounded, but the pre-opera- tive care that is given them in the use of penicillin, sulfa drugs and plasma.’ ” RIMJ also reported on Commander William P. Davis after the invasion at Mindoro: “Japanese planes attacked the LST on which Commander Davis was Today, at the USS Arizona Memorial, one can look through the windows and see the remnants of the medical officer in charge and scored the ship and the final resting place of its crew of 1,102.

www.rimed.org | rimj archives | DECEMBER webpage DECEMBER 2016 Rhode Island medical journal 82 Heritage

Ledo Road The 48th was designated a semi-mobile evacuation hospital of 750 beds, to service Chinese, American, British and Indian troops fighting in Burma under Gen. Joseph “Vinegar Joe” Stilwell and along with Merrill’s (Gen. Frank Merrill) Marauders. But the Japanese had them on the run, and Stilwell and the Marauders had retreated into India to regroup. As a result, the RIH unit was declared “sur- plus,” Dr. Irving A. Beck recounted at the R hode I sland M edical J ournal Rhode Island Medical Society’s annual meeting John Dziob, MD, left, published a memoir of his experiences with the Rhode Island Hos- in 1946. The unit was dispersed. pital Army’s 48th Evacuation unit in the China-Burma-India Theater during World War ll. Some physicians in the 48th accompanied the Army engineers laying the Ledo Road – the lifeline to China – deemed necessary after the Japanese had sealed off the Burma Road. The alternative was flying over the “dreaded Himalayan Hump,” Dr. Beck reported.

At Ramgarh Meanwhile, Dr. Thomas Perry, Jr., along with 18 other RIH physicians, backtracked a thousand miles to Ramgarh, the location of the U.S. Army Chinese Training and Combat Command, northwest of Calcutta. Surgeon Frank Cutts (who left his appendix there) described the Chinese recruits as “poorly nourished, suffering from beri-beri, dysen- tery, relapsing fever and malaria; they had no conception of sanitation and were constantly spitting on the floor.” The latter was of great concern to staff; pulmonary tuberculosis was prevalent among the Chinese. Members of the RIH unit included, front, from left, Drs. Edward Greuninger, Irving Beck, The tropical heat brought unexpected chal- William Leet, John Dziob; back, from left, Isadore Garber and unidentified men. lenges. “We had no anesthesia machines and open-drop ether at 110 degrees was almost RIH Unit in Burma impossible; the ether vaporized so quickly. When the war broke out, Rhode Island Hospital (RIH) sprang Fortunately we could get chloroform from the British,” Dr. into action and formed the Army’s 48th Evacuation Hospi- Perry later wrote in the Rhode Island Medical Journal. tal with volunteers from its staff and attending physicians. The RIH unit reassembled a year later, in March 1944, in On Jan. 20, 1943, the RIH unit boarded the USS Monticello Ledo, near the Burma-India border. The long-awaited push in California, bound for Bombay. The curtain of the China- into Burma by Gen. Stilwell was about to begin and the 48th Burma-India (CBI) Theater of World War II was about to rise was deployed. on the RIH unit of 69 doctors, nurses and technicians. “The entire hospital and its equipment, including 2 ½- ton The ship, a seized and refitted Italian luxury liner, traveled trucks, were flown over the mountains into Myitkyina just unescorted and blacked-out. Lighting a cigarette at night recently cleared of Japanese. Here another hospital was set meant instant court martial. In his memoir, A Young Surgeon up on the Irrawaddy River for American, British, Chinese Goes to War, Dr. John S. Dziob describes “the dreaded and Indian troops,” Dr. Beck said. moonlit nights crossing the Pacific that exposed the ship to According to Dr. Cutts, “disease consistently produced possible enemy submarines…the sudden shrieking of the more disability than did injury or battles casualties.” He alarm horn sending the crew frantically to battle stations.” reported that in the two-year period, which ended on June Six weeks later, the transport with more than six thousand 30, 1945, the 48th Evacuation Hospital admitted slightly military and medical personnel arrived safely in Bombay. more than 37,500 patients: 7,500 Americans, 2,000 Indians From there, the RIH unit crossed the Indian subcontinent by and 28,000 Chinese. v rail and riverboat, and arrived in Margherita, 40 miles from Burma and 18,000 miles from home.

www.rimed.org | rimj archives | DECEMBER webpage DECEMBER 2016 Rhode Island medical journal 83