Rheum Loyola 2019.Pdf

1 2 3 EVERYONE HAS AN IMMUNE SYS THAT IS SUPPOSED TO PROTECT THEM FROM CANCER AND INFEC

By Mikael Häggström ‐ All used images are in public domain., Public Domain, https://commons.wikimedia.org/w/index.php?curid=25706373 22 April 2013 English: Based on en:Image:Signal_transduction_pathways.jpg which was released to the public domain by en:User:Roadnottaken Date 6 September 2008 (original upload date) Source Transferred from en.wikipedia to Commons. AuthorBoghog2 at English Wikipedia By Boghog2 at English Wikipedia ‐ Transferred from en.wikipedia to Commons., Public Domain, https://commons.wikimedia.org/w/index.php?curid=4851717

4 Intracellular = mtx Block cellular activation/differentiation = rituximab Intercellular = anti tnf Back end approach = warfarin in aplas

5 6 FOCUS ON CLINICAL PATTERN One joint Four joints or less More than 4 joints Symmetric Spine

Remember Long‐term studies have shown that patients with ill‐defined rheumatic symptoms seldom progress to develop serious complications or disability so do not overtreat

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Monoarticular Arthritis Singh, Namrata MD Division of Immunology: Rheumatology and Allergy, Department of Internal Medicine, University of Iowa Carver College of Medicine, 200 Hawkins Drive 2017 Iowa City, Iowa Gout in men and post menopausal women; very intense; podagra initially; definitive dx by synovial fluid demonstrating intracellular, negatively birefringent monosodium urate

7 crystals; tx acute episode (colchine, nsaids, steroids) and prevent future attack; ACR 2012 guidelines recommend using 0.5 mg/kg/d of prednisone or methylprednisolone for 5 to 10 days and then stopping; ACR guidelines to start urate lowering tx if (1) presence of 1 or more tophi (a cutaneous collection of uric acid crystals), (2) frequent gout attacks defined as 2 or more attacks per year, (3) chronic kidney disease (CKD) stages 2 to 5, (4) or previous urolithiasis; pharmacologic mechanisms used to lower urate levels are decreasing the synthesis of urate by inhibiting enzyme xanthine oxidase (XO) and increased renal excretion of uric acid (uricosurics); allopurinol (XO inhib) started at low dose and increased until uric acid < 6 mg/dL but watch for allopurinol hypersensitivity syndrome (AHS) assoc with HLA‐ B*5801 in Koreans with stage 3 CKD or worse, Han Chinese and Thai individuals, independent of renal function; Febuxostat (XO inhib) used after intolerance or inefficacy of allopurinol; Probenecid (uricosuric agent); pegloticase (enzyme that converts uric acid to allantoin); used in combination with XO inhibitor is lesinurad (inhibiting transporter proteins URAT1 and OAT4 that reabsorb uric acid in kidney) CPPD in older patient with metabolic issues; knee and wrist; less intense CPP arthritis (from inflammation caused by CPP crystals aka pseudogout; crowned dens syndrome; defin dx by positively birefringent, rhomboid shaped crystals in synovial fluid; chondrocalcinosis on xrays (should not be exclusively used to diagnose CPP arthritis); risk factors are older age (> 60), OA, metab dz (hyperparathyroidism, hemochromatosis, and hypomagnesemia); tx with injection, colchicine, steroids, nsaids Gonococcal arthritis, caused by Neisseria gonorrhoeae in young sexually active adults; knee Septic arthritis is most important in adults with mono‐ articular arthritis usu in knee; dx by synovial fluid WBC > 50,000 cells per mm3 Bacterial causes include staphylococci, streptococci, gram‐negative bacilli, mycobacteria, and anaerobes. Gonococcal arthritis, caused by Neisseria gonorrhoeae, can be seen in young, healthy, and sexually active adults and often has a coexistent rash; disseminated gonococcal infection includes migratory arthralgias, tenosynovitis, and/or nonerosive arthritis; Mycobacterium marinum in people who clean fish tanks; Pasteurella multocida with cat bite; ingestions of unpasteurized dairy products with Brucella species; Pseudomonas aeruginosa or Staphylococcus aureus with iv drug use Lyme disease: early with arthralgias and myalgias  arthritis weeks to months after the initial infec with a monoarticular inflammatory arthritis usu of knee; testing with ELISA and then western blot; inflammatory synovial fluid with no crystals and a negative Gram stain; tx doxycycline 100 mg twice a day for 10 to 21 days. Foreign body synovitis ; MRI may help identify foreign material and surgical removal of foreign material is recommended Pigmented villonodular synovitis; rare tumor when localized form and affect knee or ankle; arthrocentesis shows dark brown or frankly bloody fluid; MRI shows hyperplastic synovium and heterogeneous signal intensity; surgery usu needed Hemarthrosis; in anti‐coagulants or hemophilia etc; arthrocentesis with frankly bloody fluid; blood is irritative and chronic hemarthroses causes severe DJD; tx with evacuation of joint fluid and reversing anticoagulation Avascular necrosis or osteonecrosis; pain with weight‐bearing; risk factors for include trauma, steroids, alcohol abuse, tobacco abuse, systemic dx like SLE or kidn failure, organ

7 transplant recipients, sickle cell disease, use of chemotherapy or radiation, infection with HIV, myeloproliferative dz, and Gaucher disease; CT or MRI for dx; tx with PT or surgery Palindromic rheumatism; rare migratory joint pain, swelling lasting hours to days only; synovial fluid is inflammatory, sterile, and does not contain crystals; about 30% go on to RA Leukemic arthritis more common in children with pain in long bones and not specifically joints

A diagnostic approach to the common arthritic conditions Tikly MD Division of Rheumatology, Chris Hani Baragwanath Hospital and University of the Witwatersrand South African Family Practice 2009 Johannesburg, South Africa Generalized pain and neurogenic pain = FM A quarter of all consultations to primary care practitioners are for musculoskeletal symptoms The clinical assessment, which includes history and examination, is the diagnostic cornerstone of musculoskeletal medicine; special investigations like serological tests and X‐ rays are important as confirmatory tests but should never be used as surrogates of clinical assessment. Medical causes of generalised musculoskeletal pain: Rheumatic (FM, PMR, Primary hypermobility syndrome), endocrine (Hypothyroidism, Osteomalacia, Hyperparathyroidism), Drugs (Statins, Zidovudine, Fluoroquinolones, Chloroquine) Mode and pattern of onset help to narrow differential diagnosis. Investigate with synovial fluid analysis, CBC, CRP, RF, ANA, uric acid, xrays, usn, mri Long‐term studies have shown that patients with ill‐defined rheumatic symptoms seldom progress to develop serious complications or disability so do not overtreat

7 Gout In men and post menopausal women Very intense; podagra initially Negatively birefringent monosodium urate crystals Allopurinol hypersensitivity syndrome (AHS) assoc with HLA‐B*58:01 mostly in Han Chinese

CPPD Older patient with metabolic issues or aging Less intense; knee and wrist positively birefringent, rhomboid shaped crystals Crowned dens syndrome

Septic arthritis Gonococcal arthritis, caused by Neisseria gonorrhoeae in young sexually active adults; knee Septic arthritis with staphylococcus in knee, gonococcal in young women around menses (Secrets) Mycobacterium marinum in people who clean fish tanks Pseudomonas aeruginosa or Staphylococcus aureus with iv drug use

Lyme disease Arthritis weeks to months after the initial infec

8 Knee Diagnosis is important to facilitate early treatment to decrease morbidity and mortality and should often be initiated before a definitive diagnosis is made. In summer in wooded areas Before Lyme disease was described in literature, an aberrant number of children in Lyme, Connecticut, were diagnosed with JIA Transmission with longer attachment periods of at least 48 to 72 h Stage I: occurs 7 to 10 d after tick bite; bull’s eye rash Stage II: occurs days to weeks after the initial infection; rash of disseminated erythema migrans that spares the palms and sole; lethargy; radiculoneuritis or mononeuritis multiplex; conduction delay at AV node; monarticular arthritis with chronic knee effusions Stage III: year or more after initial presentation with chronic persistent symptoms that involve multiple organ systems. Removing ticks as soon as possible helps prevent disease

Podagra 1st MTP Very intense Usu first presentation of gout Description English: Gout - monosodium urate crystals (20X, polarized, red compensator) Date 25 February 2014, 10:47:20 Source Own work AuthorGabriel Caponetti https://commons.wikimedia.org/wiki/File:Podagra.jpg Description Deutsch: Akuter Gichtanfall im Großzehengrundgelenk, Mann, 50 Jahre Das Gelenk ist gerötet, stark geschwollen und überwärmt Fotographiert am 5. Tag English: Gout (podagra) in the big toe of a 50 year old male Date 12.7.2010 Source Own work AuthorGonzosft

CPPD Medscape Updated: Jan 23, 2018 Author: Constantine K Saadeh, MD; Chief Editor: Herbert S Diamond, MD more...

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8 Psoriatic arthritis Includes enthesopathy, dactylitis, and abnormal bone remodeling Skin lesions precede onset of joint manifestation in nearly 80% of cases; Dactylitis involves both digits of hands and feet But dactylitis is characteristic symptom of PsA with a high specificity and assoc with radiologically evident erosive damage to joints Important to detect PsA early bc joint damage occurs and progresses in “early” stage of PsA (< 2 yrs) Higher cardiovascular risk Significant benefit with tight control in terms of peripheral arthritis, skin disease and patient reported outcomes

Spondyloarthropathy Includes PsA, IBD (Crohns, UC) assoc, ReA ReA with circinate balaninitis, keratoderma blenorrhagicum , usu with Chlamydia New studeis show gut biome important in all these dz

Dactylitis PsA has several unique characteristics such as enthesopathy, dactylitis, and abnormal bone remodeling Dactylitis involves both digits of hands and feet But dactylitis is characteristic symptom of PsA with a high specificity and assoc with radiologically evident erosive damage to joints

9 Due to tenosynovitis with soft tissue involvement

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Optimal management of dactylitis in patients with psoriatic arthritis Yamamoto, Toshiyuki MD Department of Dermatology, Fukushima Medical University 2015 Fukushima, Japan Dove Medical Press Limited PsA has several unique characteristics such as enthesopathy, dactylitis, and abnormal bone remodeling Due to Th1/Th17 subsets that release IL‐17 and IL‐22, which promote neutrophil recruitment and keratinocyte hyperproliferation, respectively Joint inflamm of DIP and all 3 joints of fingers unique Skin lesions precede onset of joint manifestation in nearly 80% of cases; severity of skin lesions does not always correlate with joint lesions Nail involvement is almost always seen in cases of distal type PsA Dactylitis involves both digits of hands and feet; also seen in sarcoidosis, tuberculosis, and gout but dactylitis is characteristic symptom of PsA with a high specificity and assoc with radiologically evident erosive damage to joints Important to detect PsA early bc joint damage occurs and progresses in “early” stage of PsA (< 2 yrs) Enthesitis or enthesopathy when inflammation at site of attachment of tendons, ligaments, or joint capsules to bones driven by CD8+ T‐cells Tenosynovitis with soft tissue involvement  dactylitis Polymorphonuclear leukocytic infiltrates are more pronounced in synovium of PsA Dysregulated (altered) bone remodeling with both extensive bone erosion and exaggerated bone formation by increase RANKL, IL‐23, sclerostin and down regulate Wnt path and together this promotes osteoclasts Tx with NSAIDs, DMARDs (ssz, mtx, cyclosporine, arava) and biologics (anti TNF)

9 Remember You can wear a boot But you cannot be a swan

Rheumatoid arthritis Humans can wear a boot (boutinneire) vs swan neck deformity Deformity means erosive dz This means systemic dz

Ulnar subluxation Description English: A hand severely effected by rheumatoid arthritis. Date Source Own work AuthorJames Heilman, MD https://commons.wikimedia.org/wiki/File:Rheumatoid_Arthritis.JPG James Heilman, MD [CC BY-SA 3.0 (https://creativecommons.org/licenses/by- sa/3.0)]

Jaccoud’s Arthropathy, Reducible Result of long term dz Despite tx

10 Due to of soft‐tissue abnormalities, like laxity of ligaments, fibrosis of capsule, and muscular imbalance

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Jaccoud’s Arthropathy Santiago, Mittermayer M.D., Ph.D., Escola Bahiana de Medicina e Saúde Pública 2015 Salvador, Brazil 58‐year‐old man presented with a 15‐year history of (SLE) (long term dz) Despite treatment with glucocorticoids, hydroxychloroquine, and azathioprine; hand deformities, including swan neck deformity, Z deformity of the thumb, and ulnar deviation of the fifth digit, developed over a 10‐year period. These deformities were reducible and are characteristic of Jaccoud’s arthropathy. Deformities due to result mainly from soft‐tissue abnormalities, such as laxity of ligaments, fibrosis of the capsule, and muscular imbalance MRI of hands showed no erosions. Tx with PT and devices

10 Ankylosis = fusion of whole spine Fun fact = radiographs do not change but clinically patient looks normal

Enthesitis = inflam where tendon inserts into bone

By Mehlauge ‐ eigenes Archiv, CC BY‐SA 3.0, https://commons.wikimedia.org/w/index.php?curid=39719714

11 Gout In men and post menopausal women Very intense; podagra initially Negatively birefringent monosodium urate crystals Allopurinol hypersensitivity syndrome (AHS) assoc with HLA‐B*58:01 mostly in Han Chinese

CPPD Older patient with metabolic issues or aging Less intense; knee and wrist positively birefringent, rhomboid shaped crystals Crowned dens syndrome

Lyme disease Arthritis weeks to months after the initial infec

12 Knee Diagnosis is important to facilitate early treatment to decrease morbidity and mortality and should often be initiated before a definitive diagnosis is made. In summer in wooded areas Before Lyme disease was described in literature, an aberrant number of children in Lyme, Connecticut, were diagnosed with JIA Transmission with longer attachment periods of at least 48 to 72 h Stage I: occurs 7 to 10 d after tick bite; bull’s eye rash Stage II: occurs days to weeks after the initial infection; rash of disseminated erythema migrans that spares the palms and sole; lethargy; radiculoneuritis or mononeuritis multiplex; conduction delay at AV node; monarticular arthritis with chronic knee effusions Stage III: year or more after initial presentation with chronic persistent symptoms that involve multiple organ systems. Removing ticks as soon as possible helps prevent disease

Psoriatic arthritis Includes enthesopathy, dactylitis, and abnormal bone remodeling Skin lesions precede onset of joint manifestation in nearly 80% of cases; Dactylitis involves both digits of hands and feet But dactylitis is characteristic symptom of PsA with a high specificity and assoc with radiologically evident erosive damage to joints Important to detect PsA early bc joint damage occurs and progresses in “early” stage of PsA (< 2 yrs) Higher cardiovascular risk Significant benefit with tight control in terms of peripheral arthritis, skin disease and patient reported outcomes

Spondyloarthropathy Includes PsA, IBD (Crohns, UC)assoc, ReA ReA with circinate balaninitis, keratoderma blenorrhagicum , usu with Chlamydia New studeis show gut biome important in all these dz

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Tick‐Borne Illnesses Choi, Edwin MD Madigan Army Medical Center, Department of Family Medicine 2016 Fort Lewis, Washington Current Sports Medicine Reports Diagnosis is important to facilitate early treatment to decrease morbidity and mortality and should often be initiated before a definitive diagnosis is made.

12 Lyme most common vector‐borne infectious disease in the United States; incidence 9/1000; in woody areas usu Caused by the spirochete Borrelia and transmitted by black‐legged tick (or deer tick) or western black‐legged tick. Majority of cases occur during summer. Transmission is associated with longer attachment periods of at least 48 to 72 h Stage I: occurs 7 to 10 d after tick bite; rash of central erythema with central clearing or central purpura (bull’s eye rash) Stage II: occurs days to weeks after the initial infection when spirochetes have disseminated from the skin to the bloodstream or lymphatic system; rash of disseminated erythema migrans usually smaller and may lack central clearing; rash spares the palms and sole; lethargy, forgetfulness, disorientation, somnolence, dizziness, photophobia, and incoordination; paralysis of facial nerve transiently; radiculoneuritis or mononeuritis multiplex; conduction delay at AV node; monarticular arthritis with chronic knee effusions Stage III: presents about a year or more after initial presentation and includes chronic persistent symptoms that involve multiple organ systems. Rheumatologic manifestations occur in 50% of patients; neurologic symptoms present months to years after the initial infection Clinical diagnosis based on a history of possible exposure to infected ticks and signs or symptoms. Laboratory tests may be helpful if used correctly but generally confirm or rule out presence of disease; results are considered diagnostic only if both EIA/IFA and the immunoblot are positive Rocky Mountain spotted fever RMSF; caused by Rickettsia rickettsia and transmitted by wood tick, Dermacentor andersoni, in western usa and by dog tick, Dermacentor variabilis, in eastern and southern usa; most common rickettsial disease in usa in and occurs in all states except Maine, Hawaii, and Alaska; occur usu April‐Sep in kids with more than 6 hours of tick attachment; mortality high as 30% but less than 5% if tx with abx; present with sudden HA, fever, chills, rashes (red can become petechial and dark red or black, necrosis of fingertips) on palms, soles, wrists, ankles, forearms and then spreads proximally; can get DIC; dx clinically and skin bx with immunofluorescent staining for Rickettsia; after 10 d of sx, elevated ELISA and latex agglutination titers confirm dx; tx with doxycycline until pass 3 d after fever resolves Ehrlichiosis and Anaplasmosis; human monocytic ehrlichiosis (HME) due to Ehrlichia chaffeensis and transmitted by lone star ticki in SE usa between May‐July, up to 60% need hospital care; human granulocytic ehrlichiosis due to bacteria Anaplasma phagocytophilum in upper MW and NE usa; incubation period is 1 to 2 wk. and then present with malaise, back pain, GI sx and fever; rashes more with HME; also with HME get meningoencephalitis, bone marrow, hepatic granuloma, and multiorgan perivascular lymphohistiocytic infiltrates; with anaplasmosis, opportunistic fungal and viral infections; severe cases with renal failure, pancytopenia, DIC, acute respiratory distress syndrome (ARDS), hepatic failure, hypotension, and death; dx mostly clinical and then confirmed by labs; tx with doxycycline Babesiosis; caused by protozoan Babesia divergens or Babesia microti and transmitted by Ixodes ticks; usu in May‐Sept in NE usa; risk factors are asplenia, advanced age, and impaired immune function; presents 1 wk after inoculation and like flu in kids and young adults but

12 more severe in older adults; dx clinical by fever, hx of tick bite, Giemsa‐stained blood smears with Maltese cross appearances; tx with atovaquone and azithromycin for 10d or clinda iv for severe cases for 6 wk Colorado Tick Fever caused by RNA Orbivirus vector is D. andersoni (wood tick); found in Rocky Mountain region and southwest Canada at elevations of 4,000 to 10,000 ft; presents as benign influenza‐like illness but has biphasic or “saddleback” fever in 50% of patients; dx blood cx and reverse transcriptase PCR during first 2 wk; tx supportive Tularemia caused by bacterium Francisella tularensis transmitted by ingestion, inoculation, inhalation, or contamination and carried by ticks, deer flies, and horse flies; esp eating undercooked infected meat and contaminated water; presents with rapid onset fever, chills, headache, malaise, fatigue, nausea, vomiting, and myalgias; dx clinical; chest radiography may show a triad of oval opacities, hilar adenopathy, and pleural effusions; tx streptomycin IM for 10 d Powassan disease (POW) caused by Powassan virus in NE usa, Canada and Russia; incubation 1‐4 wk then fever, headache, vomiting, and generalized weakness and may progress to meningoencephalitis; dx clinical; tx supportive Tick‐borne relapsing fever (TBRF) caused by spirochetes of Borrelia spp with hosts include rodents, rabbits, and hares; occur in west of Mississippi river in mountains; incubation period 7 d f/b recurring febrile episodes lasting 3 d. with arthralgias, dizziness, nausea, vomiting, and high fever; dx with smears of blood, bone marrow, or cerebrospinal fluid obtained when febrile; tx oral tetracycline for 10 d To prevent tick bites, individuals should wear proper clothing Removing ticks as soon as possible helps prevent disease; any method that attempts to disrupt or suffocate tick leads to an increased chance of regurgitation of infected material into body or formulation of a granuloma

Psoriatic arthritis: state of the art review Coates NIHR clinical lecturer, Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK and Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust 2017 Leeds, UK Clinical Medicine Almost 50% of cases of PsA in primary care and secondary care clinics are unrecognised; incidence 6/100,000 Higher cardiovascular risk significantly contributed to by high risk of metabolic syndrome Registry data has shown destructive and progressive nature of the disease even early on PsA is a heterogeneous condition with musculoskeletal involvement, including arthritis, enthesitis, dactylitis and axial involvement as well as potential skin and nail disease. Tx with nsaids, DMARDs (mtx for arthritis, ssz for enthesitis), biologics (adalimumab, certolizumab, etanercept, golimumab and infliximab benefit on arthritis, psoriasis, enthesitis and dactylitis as well as on radiographic damage) (Ustekinumab an IL‐ 12/23 inhibitor

12 effective for arthritis, skin, enthesitis and dactylitis but slightly less effective than TNF inhibitors for musculoskeletal manifestations despite being superior for skin disease) (Secukinumab, a monoclonal antibody to IL‐17A, has excellent efficacy in psoriasis with superiority to both etanercept and ustekinumab and Psa), apremilast (a phosphodiesterase‐4 inhibitor, efficacy lower than biologics), Tight Control of PsA (TICOPA) trial; the study recruited 206 patients with early PsA who were randomised 1:1 to receive either tight control or standard care; confirmed a significant benefit with tight control in terms of peripheral arthritis, skin disease and patient reported outcomes but used step up tx so biologics used last

An approach to joint pain and inflammatory arthropathies Glanville MD Specialist Registrar in Rheumatology and General Internal Medicine in the Department of Rheumatology, Northwick Park Hospital 2016 Harrow, London British Journal of Hospital Medicine Key to assessment of joint pathology is determining whether it is inflammatory, degenerative or secondary to another cause Determine if: 1. Does the problem arise from the joint, tendon or muscle? 2. Is the condition acute or chronic? 3. Is the condition inflammatory or non‐ Inflammatory? 4. What is the pattern of the affected sites? 5. What is the impact on the patient’s life? Key musculoskeletal symptoms: Pain, Stiffness, Joint swelling; inflammatory conditions have early morning stiffness that diminishes with activity. Onse: acute vs chronic Examination: use a ‘look, feel, move and special tests’ approach to assess for significant abnormalities of musculoskeletal system; pattern of joint involvement (Oligoarticular: up to and including four joints); note whether large or small joints are affected, and whether they are weight‐bearing joints; assess for any abnormal gait, colour or skin changes, deformity, swelling, asymmetry or wasting. It is important to diagnose inflammatory arthritis as early in disease course as possible. Early and aggressive treatment with disease‐modifying antirheumatic drugs improves outcomes in terms of function, joint damage, quality of life, and reduces costs to health service and society. In order to provide this, use systematic history taking and examination skills

12 Gout in men and post menopausal women; very intense; podagra initially; definitive dx by synovial fluid demonstrating intracellular, negatively birefringent monosodium urate crystals; tx acute episode (colchine, nsaids, steroids) and prevent future attack; ACR 2012 guidelines recommend using 0.5 mg/kg/d of prednisone or methylprednisolone for 5 to 10 days and then stopping; ACR guidelines to start urate lowering tx if (1) presence of 1 or more tophi (a cutaneous collection of uric acid crystals), (2) frequent gout attacks defined as 2 or more attacks per year, (3) chronic kidney disease (CKD) stages 2 to 5, (4) or previous urolithiasis; pharmacologic mechanisms used to lower urate levels are decreasing the synthesis of urate by inhibiting enzyme xanthine oxidase (XO) and increased renal excretion of uric acid (uricosurics); allopurinol (XO inhib) started at low dose and increased until uric acid < 6 mg/dL but watch for allopurinol hypersensitivity syndrome (AHS) assoc with HLA‐B*5801 in Koreans with stage 3 CKD or worse, Han Chinese and Thai individuals, independent of renal function; Febuxostat (XO inhib) used after intolerance or inefficacy of allopurinol; Probenecid (uricosuric agent); pegloticase (enzyme that converts uric acid to allantoin); used in combination with XO inhibitor is lesinurad (inhibiting transporter proteins URAT1 and OAT4 that reabsorb uric acid in kidney) CPPD in older patient with metabolic issues; knee and wrist; less intense CPP arthritis (from inflammation caused by CPP crystals aka pseudogout; crowned dens syndrome; defin dx by positively birefringent, rhomboid shaped crystals in synovial fluid; chondrocalcinosis on xrays (should not be exclusively used to diagnose CPP arthritis); risk factors are older age (> 60), OA, metab dz (hyperparathyroidism, hemochromatosis, and hypomagnesemia); tx with injection, colchicine, steroids, nsaids Gonococcal arthritis, caused by Neisseria gonorrhoeae in young sexually active adults; knee Septic arthritis with staphylococcus in knee, gonococcal in young women around menses (Secrets) Septic arthritis is most important in adults with mono‐ articular arthritis usu in knee; dx by synovial fluid WBC > 50,000 cells per mm3 Bacterial causes include staphylococci, streptococci, gram‐negative bacilli, mycobacteria, and anaerobes. Gonococcal arthritis, caused by Neisseria gonorrhoeae, can be seen in young, healthy, and sexually active adults and often has a coexistent rash; disseminated gonococcal infection includes migratory arthralgias, tenosynovitis, and/or nonerosive arthritis; Mycobacterium marinum in people who clean fish tanks; Pasteurella multocida with cat bite; ingestions of unpasteurized dairy products with Brucella species; Pseudomonas aeruginosa or Staphylococcus aureus with iv drug use Lyme disease: early with arthralgias and myalgias  arthritis weeks to months after the initial infec with a monoarticular inflammatory arthritis usu of knee; testing with ELISA and then western blot; inflammatory synovial fluid with no crystals and a negative Gram stain; tx doxycycline 100 mg twice a day for 10 to 21 days. Foreign body synovitis ; MRI may help identify foreign material and surgical removal of foreign material is recommended Pigmented villonodular synovitis; rare tumor when localized form and affect knee or ankle; arthrocentesis shows dark brown or frankly bloody fluid; MRI shows hyperplastic synovium and heterogeneous signal intensity; surgery usu needed

12 Hemarthrosis; in anti‐coagulants or hemophilia etc; arthrocentesis with frankly bloody fluid; blood is irritative and chronic hemarthroses causes severe DJD; tx with evacuation of joint fluid and reversing anticoagulation Avascular necrosis or osteonecrosis; pain with weight‐bearing; risk factors for include trauma, steroids, alcohol abuse, tobacco abuse, systemic dx like SLE or kidn failure, organ transplant recipients, sickle cell disease, use of chemotherapy or radiation, infection with HIV, myeloproliferative dz, and Gaucher disease; CT or MRI for dx; tx with PT or surgery Palindromic rheumatism; rare migratory joint pain, swelling lasting hours to days only; synovial fluid is inflammatory, sterile, and does not contain crystals; about 30% go on to RA Leukemic arthritis more common in children with pain in long bones and not specifically joints

Rheumatology Secrets West, Sterling MD Professor, Medicine‐Rheumatology, University of Colorado Hospital 2014 Aurora, Colorado Septic arthritis with staphylococcus in knee, gonococcal in young women around menses ECM= erythema chronica migrans ReA with circinate balaninitis (painless serpiginous ulceration of glans penis), keratoderma blenorrhagicum (psoriaform lesions on plantar portion of heel and MTP heads) usu with

12 Chlamydia urogenital infec OA prevalence15% Sarcoidosis incidence 20/100,000 Lupus incidence 5/100,000 RA incidence 3/10,000 AS incidence 0.5% gen pop SpA incidence 1%

ARTICLES NOT CITED ON SLIDE

Biologics in the Treatment of Gout –Bringing High‐Tech Therapies to an Ancient Disease Mandell, Brian MD, PhD Cleveland clinic 2007 Cleveland, Ohio A wide array of effective traditional therapies is available to treat hyperuricemia and acute gout attacks; Nonetheless, some patients, for various reasons, fail to achieve adequate control of their serum urate level, total body uric acid load, or acute inflammation; use of biologic agents (pegylated uricase and specific interleukin‐1 antagonists) to manage patients with treatment‐resistant gout is possible

Lyme Disease Presenting as a Spontaneous Knee Effusion Matzkin, Elizabeth MD Department of Orthopaedic Surgery, Brigham and Women’s Hospital 2015 Journal of the American Academy of Orthopaedic Surgeons Before Lyme disease was described in literature, an aberrant number of children in Lyme, Connecticut, were diagnosed with JIA Most frequently observed in children and middle‐aged adults Joint aspirate typically has a cell count of 1,000 to 50,000 WBC cells/μL and is primarily composed of neutrophils, but Gram stain may be negative Readily treatable with antibiotics; 99% of patients diagnosed during early localized infection period and 90% of patients with Lyme arthritis respond to therapy. Transient episodes of spontaneous knee effusion are common early in the progression of Lyme disease, and, if left untreated, 60% of patients diagnosed with the disease develop Lyme arthritis

The genetics of hyperuricaemia and gout Reginato MD, anthony Rheumatology Division, Rhode Island Hospital, The Warren Alpert Medical School of Brown

12 University 2012 Providence, Rhode Island Nat Rev Rheumatol Polygenic mode of inheritance for both hyperuricaemia and fractional excretion of urate by kidneys bc encode proteins that are involved in renal urate‐transport system Strong pharmacogenetic associations between HLA‐ B*5801 alleles and severe allopurinol‐ hypersensitivity reactions were shown in Asian and European populations. Genetic testing for HLA‐B*5801 alleles could be used to predict these potentially fatal adverse effects. Serum uric acid levels and gout are both strongly associated with metabolic syndrome and risk of cardiovascular disease; whether these relations are causal is unclear.

New therapies for psoriasis and psoriatic arthritis Ritchlin, Christopher T MD rheumatologist University of Rochester Medical Center 2016 Rochester, NY Current Opinion in Rheumatology Secukinumab, an interleukin‐17A antibody, has been approved for treatment of psoriasis and PsA in the United States; effective with a good safety profile. Ixekizumab, another anti‐interleukin‐17A antibody, is currently in clinical trials Brodalumab, an interleukin‐17 receptor antagonist, was removed from clinical trials because of safety concerns despite demonstrated efficacy in psoriasis and PsA. Targeting interleukin‐23 with antibodies to p19 is another approach with encouraging results in psoriasis. Apremilast, an oral agent, approved to treat psoriasis and PsA demonstrates moderate efficacy with an excellent safety record. Tofacitinib in psoriatic disease remains to be determined pending a safety review in psoriasis and completion of PsA trials.

Calcium Pyrophosphate Deposition Disease Rosenthal, Ann M.D. Division of Rheumatology, Department of Medicine, Medical College of Wisconsin 2016 Milwaukee, WI NEJM Acute CPP crystal arthritis (or pseudogout) is the most widely recognized form of CPPD disease. Chronic CPP crystal arthritis comprises several clinical phenotypes. The crowned dens syndrome is caused by the deposition of CPP crystals around the C2 vertebra and manifests as acute severe neck pain, fever, and high levels of inflammatory markers.8

12 Inorganic pyrophosphate plays a central role in CPPD that is analogous to that of urate in gout and may be a key therapeutic target. Once CPP crystals are generated, they mediate tissue damage by means of multiple mechanisms. CPPD (calcium pyrophospgate deposition) disease appears to affect 4 to 7% of the adult population in Europe and the United States CPPD disease is clearly a disease of aging and is rare in patients younger than 60 years of age. CPPD disease results from a high ratio of inorganic pyrophosphate to phosphate ions in patients with hypophosphatasia that is congenital Metabolic conditions are well established risk factors for CPPD disease: hyperparathyroidism, hemochromatosis, hypomagnesemia (Gitelman’s variant of Bartter’s syndrome) Familial CPPD does exist. CPPD disease is most accurately diagnosed by the finding of positively birefringent, rhomboid shaped crystals in synovial fluid from the affected joint but underdiagnosed about 20% of time Conventional radiography provides important support for the diagnosis of CPPD but chondrocalcinosis on xray does not make dx Treatment with steroids, colchicine, methotrexate, IL‐1 inhibitors

Current advances in therapies for calcium pyrophosphate crystal arthritis Sivera, Francisca MD Sección de Reumatología, Hospital General Universitario de Elda 2016 Alicante, Spain Current Opinion in Rheumatology New data from case series indicate that interleukin‐1[beta] inhibitors can help patients with refractory forms of CPPD. Methotrexate, formerly a promising agent, failed to demonstrate benefits in a recent trial, but still merits consideration for some patients. No significant advances on crystal dissolution have been achieved to date. Proper characterization of the CPP crystal disease picture is needed

The Intestinal Microbiome in Spondyloarthritis Gill, T PhD Pediatric Translational Research Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health 2015 Bethesda, MD Curr Opin Rheumatol. Gut commensals are important for educating our immune system Decreased numbers of Firmicutes, a major phyla of gut commensals, especially the species Faecalibacterium prausnitzii and Clostridium leptum have been found in various

12 inflammatory disorders including SpA and IBD, and could be an important link between SpA and gut inflammation. There was an increase in the abundance of Lachnospiraceae, Ruminococcaceae, and Prevotellaceae in AS patients. Coprococcus was inversely associated with psoriasis with or without arthritis (PsA), whereas a decline in relative abundance of Ruminococcus and Akkermansia were unique to PsA. Microbiome research has the potential to revolutionize research, diagnosis and treatment of spondyloarthritis.

12 Generalized pain and neurogenic pain = FM A quarter of all consultations to primary care practitioners are for musculoskeletal symptoms Confirmatory tests but do not use them as surrogates of clinical assessment. Long‐term studies have shown that patients with ill‐defined rheumatic symptoms seldom progress to develop serious complications or disability so do not overtreat

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13 rays are important as confirmatory tests but should never be used as surrogates of clinical assessment. Medical causes of generalised musculoskeletal pain: Rheumatic (FM, PMR, Primary hypermobility syndrome), endocrine (Hypothyroidism, Osteomalacia, Hyperparathyroidism), Drugs (Statins, Zidovudine, Fluoroquinolones, Chloroquine) Mode and pattern of onset help to narrow differential diagnosis. Investigate with synovial fluid analysis, CBC, CRP, RF, ANA, uric acid, xrays, usn, mri Long‐term studies have shown that patients with ill‐defined rheumatic symptoms seldom progress to develop serious complications or disability so do not overtreat

Fibromyalgia Rahman, Anisur Professor Department of Rheumatology, University College London 2014 London, England British medical Journal Symptoms of fibromyalgia are chronic widespread pain associated with unrefreshing sleep and tiredness Chronic widespread pain is defined in epidemiological studies as pain for at least three months, affecting both sides of body, both above and below the waist Incidence 2‐10% but most in white women Fibromyalgia is not a diagnosis of exclusion and often occurs in patients with other conditions, such as inflammatory arthritis and osteoarthritis No clear pathophysiological mechanism for fibromyalgia has been established, but evidence suggests that there is an abnormality in central pain processing genetic component is probably involved; a genome wide linkage study of people from 116 American families with multiple cases of FM reported that siblings of patients with fibromyalgia have a 13.6‐fold increased risk of developing FM compared with general population. Diagnosing fibromyalgia is helpful; can allow patient's polysymptomatic distress to be explained, thereby reducing fear and doubt However 25% of patients diagnosed as having fibromyalgia do not have 11 tender points But request autoantibodies only if H&P suggest that specific autoimmune rheumatic diseases bc ANA and RF often positive in healthy people (13%0 Consider dx if pain is out of proportion to physical signs on examination or is associated with sleep disturbance, fatigue, or muscular tender points Fibromyalgia has no cure, but a range of drug and non‐drug treatments can reduce symptoms and their impact on the patient's life Passive physical therapy including warm water therapy and manual manipulation therapy helps most Trial evidence for all forms of treatment in fibromyalgia generally shows only small to moderate average effects Tx drugs most effective are: tramadol combined with paracetamol, antidepressant, second

13 generation anticonvulsant pregabalin

13 14 Description Portrait of Sir William Osler at the age of 28. https://wellcomecollection.org/works/fu9fzkdh https://wellcomecollection.org/works/fu9fzkdh#licenseInformation

Credit Portrait of Sir William Osler at the age of 28. Credit: Wellcome Collection. CC BY

15 Now focus on weakness Myositis and vascular inflammation leading to bursitis Pay attention to clinical pattern

16 Gottron papules and heliotrope rash are pathognomonic 20% to 30% also have interstitial lung disease Increased risk of malignancy

Autoimmune Myopathies Very rare Few per million but immune mediated necrotizing may be one per 10,000

Dermatomyositis Gottron papules and heliotrope rash are pathognomonic 20% to 30% also have interstitial lung disease Increased risk of malignancy Should undergo age‐appropriate screening + pelvic ultrasound (in women) + contrast‐ enhanced CT scan of the chest, abdomen, and pelvis

Heliotrope rash Elizabeth M. Dugan, Adam M. Huber, Frederick W. Miller, Lisa G. Rider [CC BY‐SA 3.0 (https://creativecommons.org/licenses/by‐sa/3.0)] https://commons.wikimedia.org/wiki/File:Dermatomyositis10.jpg

V‐sign rash Photosensitive

17 Shawl‐sign rash Photosensitive

Gottron’s papules Raised redness over joints Description English: En:Dermatomyositis, Gottron's papules. Erythematous to violaceous raised papules overlying the metacarpal and interphalangeal joints in a patient with juvenile dermatomyositis. Date Source http://dermatology.cdlib.org/1502/reviews/photoessay/2.jpg AuthorElizabeth M. Dugan, Adam M. Huber, Frederick W. Miller, Lisa G. Rider By Elizabeth M. Dugan, Adam M. Huber, Frederick W. Miller, Lisa G. Rider - http://dermatology.cdlib.org/1502/reviews/photoessay/2.jpg, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=9748012

Nailfold abnormalites Changes mimic dz Poor mans test of dz progression Extensively studied in JDM at Children’s NW

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Heliotrope rash https://medplexus.blogspot.com/2017/02/dermatomyositisdm.html Mammen 2016

Gottron’s papules https://medplexus.blogspot.com/2017/02/dermatomyositisdm.html Mammen 2016

V‐sign rash Medscape Mammen 2016

Shawl‐sign rash https://medplexus.blogspot.com/2017/02/dermatomyositisdm.html

Nailfold abnormalites ACR

17 Mammen 2016

17 Polymositis Now dx of exclusion

Immune mediated necrotizing myopathies Severe proximal muscle weakness, dysphagia, and muscle atrophy Anti‐HMG‐CoA reductase autoantibodies in 40% and statin use But develop a progressive myopathic process that requires immunosuppressive therapy to control

Antisynthetase syndrome Multisystem disease Myositis, interstitial lung disease, arthritis, Raynaud phenomenon, fevers, mechanic’s hands;

Raynaud’s Vasospastic dz Raynaud’s : pallor, cyanosis then erythema (white, blue then red) Occurs in 4/1000 but only 1 has ctd Others that’s how God made them WaltFletcher [CC BY‐SA 4.0 (https://creativecommons.org/licenses/by‐sa/4.0)] Description English: Example picture of my Raynaud's Disease. Date 9 November 2012, 13:56:51 Source Own work

18 AuthorWaltFletcher

Mechanic’s hands Very severe dz Multisystem disease ILD

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Raynaud’s http://coldhands.info/raynauds‐phenomenon/ Mammen 2016

Mechanic’s hands https://understandingmyositis.org/diagnose‐myositis/mechanics‐hands/ Mammen 2016 Secrets 2015

18 PAIN, NOT WEAKNESS

Polymyalgia Rheumatica: Common Disease, Elusive Diagnosis Mostly older (>50 yo) white women Proximal muscle pain and weakness in the arms and hips suddenly CRP tends to be a more sensitive 15% of patients with PMR will also develop giant cell arteritis May be paraneoplastic Incidence 52/ 100,000 so more common

Description English: Polymyalgia rheumatica, man Date 1 November 2008 (upload date) Source Own work AuthorTwisp https://commons.wikimedia.org/wiki/File:Polymyalgia_rheumatica_man.svg

19 Autoimmune Myopathies Very rare Few per million but immune mediated necrotizing may be one per 10,000

Polymositis Now dx of exclusion

Antisynthetase syndrome Multisystem disease Myositis, interstitial lung disease, arthritis, Raynaud phenomenon, fevers, mechanic’s

20 hands;

Includion body myositis White males over age 50 Slow painless weakness Assymmetric, proximal and distal muscles affected Dysphasia end stage Associated with Sjogren’s, have neuropathy Red rimmed vacuoles on histopathology

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Polymylagia Rheumatica: Common Disease, Elusive Diagnosis Mager, Diana R. DNP, RN‐BC Assistant Professor, Fairfield University School of Nursing 2015 Fairfield, Connecticut Home Healthcare Now Mostly older (>50 yo) white women Symptoms abruptly and symmetrically Persistent, severe aching pain and stiffness in the neck, shoulders, upper arms, hips, and pelvis Proximal muscle pain and weakness in the arms and hips suddenly CRP tends to be a more sensitive disease indicator than ESR Approximately 10% to 15% of patients with PMR will also develop giant cell arteritis (GCA), a vasculitis that affects medium‐ to large‐sized blood vessels Tx with steroids, sometimes mtx Long‐term 15‐20 mg/day glucocorticoids alleviating symptoms within 12 to 48 hours and leveling acute‐phase reactants within a week; after approximately 1 month of glucocorticoid use, doses are tapered gradually by 2.5 mg every 2 to 4 weeks;. when 10 mg/day is reached, the dose is then decreased by 1 mg/month, a regimen that takes approximately 1 year to complete though the length of treatment can vary to 3 or even 5 years May be paraneoplastic

20 Autoimmune Myopathies Mammen, Andrew L. MD, PhD National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health 2016 Bethesda, Maryland Continuum: Lifelong Learning in Neurology; Muscle and Neuromuscular Junction Disorders DERMATOMYOSITIS: skin and muscle involvement; difficulty lifting their heads off the bed because of neck flexor weakness, impaired swallowing due to pharyngeal muscle weakness, or shortness of breath due to diaphragmatic weakness; Gottron papules and heliotrope rash are pathognomonic for dermatomyositis; shawl sign covering the upper arms and shoulders or a V‐shaped rash affecting sun‐exposed surfaces on the upper chest less specific; calcinosis; amyopathic dermatomyositis; 20% to 30% also have interstitial lung disease most often found in patients with autoantibodies recognizing one of the aminoacyl‐tRNA synthetases (eg, Jo‐1) or the melanoma differentiation‐associated protein 5 (MDA5); increased risk of malignancy with a standardized incidence ratio of 3.0 to 6.2; In patients with tumors, the autoimmune disease may improve with successful treatment of the cancer; Still, those with an underlying malignancy have a decreased survival rate (62% of patients) compared to patients with dermatomyositis who do not have a malignancy (92% of patients); newly diagnosed dermatomyositis should undergo age‐appropriate screening (eg, mammography and colonoscopy) as well as pelvic ultrasound (in women) and a contrast‐enhanced CT scan of the chest, abdomen, and pelvis IMMUNE‐MEDIATED NECROTIZING MYOPATHIES: used to be form of polymyositis with minimal inflammation on muscle biopsy; unique muscle biopsy and serologic features; Anti‐ SRP autoantibodies are found in approximately 5% of patients with autoimmune myopathy and in approximately 16% of patients with a necrotizing muscle biopsy. Patients who are anti‐SRP positive tend to be women by a nearly 2 to 1 ratio and have severe proximal muscle weakness, dysphagia, and muscle atrophy; Anti‐HMG‐CoA reductase autoantibodies are found in approximately 40% and statin use has been reported to precede the development of anti‐HMG‐CoA reductase myopathy in 11% to 100% of cases; patients who are exposed to statins who are anti‐HMG‐CoA reductase positive do not usually improve following discontinuation of statin medications. Rather, these patients develop a progressive myopathic process that requires immunosuppressive therapy to control ANTISYNTHETASE SYNDROME: Autoantibodies recognizing histidyl‐tRNA synthetase (ie, Jo‐1) and several other aminoacyl‐tRNA synthetases found in approximately 20% of patients with myositis and are associated with a multisystem disease; myositis, interstitial lung disease, arthritis, Raynaud phenomenon, fevers, or hyperkeratotic lesions along the radial and palmar surfaces of the fingers, known as mechanic’s hands; Patients with antisynthetase syndrome are often referred to as having dermatomyositis or polymyositis when such rashes are present or absent, respectively; incidence 0.5/ million POLYMYOSITIS: Bohan and Peter 39 defined polymyositis in 1975 however, many of the patients diagnosed with polymyositis would now be recognized as another disease; polymyositis is now a very rare diagnosis of exclusion made when muscle biopsy reveals

20 normal‐appearing muscle fibers invaded by T cells and when the patient does not have an inclusion body myositis or muscular dystrophy phenotype; no polymyositis‐specific autoantibodies are known. OVERLAP SYNDROMES: autoimmune myopathy occurs within a CTD like SLE, ScL, RA then have myositis overlap syndrome. TREATMENT OF INFLAMMATORY MYOPATHIES: high‐dose corticosteroids, appropriate prophylaxis for Pneumocystis jirovecii pneumonia and osteoporosis; add another agent, such as methotrexate, azathioprine (esp with ILD over mtx), or mycophenolate mofetil, tacrolimus and if dev very severe weakness then after 6 to 8 weeks, IV immunoglobulin (IVIg; esp for NAM), rituximab A few treated patients recover full strength even though CK levels remain markedly elevated; some underlying disease activity still exists; especially anti‐HMG‐CoA reductase myopathy. Other patients have persistent muscle weakness even after muscle enzyme levels have normalized; active disease process in which no muscle necrosis and, therefore, no release of muscle enzymes into the bloodstream is present (often in those with dermatomyositis)

Rheumatology Secrets West, Sterling MD Professor, Medicine‐Rheumatology, University of Colorado Hospital 2014 Aurora, Colorado Bohan and Peter 1975 classification: PM, DM, PM/DM with malignancy, JDM, PM/DM with CTD, IBM Anti‐155/140: cancer in adults Anti‐MDA‐5 (anti‐CADM‐140): amyopathic DM, poor prognosis, targets melanoma differentiation associated gene Anti signal recognition peptide syndrome SRP: severe PM with cardiac Anti‐Mi‐2 syndrome: skin, responds well to steroids NAM (necrotizing autoimmune myopathy): marked muscle necrosis with regeneration; incidence 1.6/10,000 DM incidence 9/ million PM incidence 5/ million IBD: white males over age 50, slow painless weakness, asymmetric, proximal and distal muscles affected, dysphasia end stage, associated with Sjogren’s, have neuropathy; red rimmed vacuoles on histopathology; prevalence 20/ million over the age 50 yo PMR incidence of 52/ 100,000

ARTICLES NOT CITED ON SLIDE

Rheumatic Manifestations of Skin Disease Clarke, JT

20 MD Department of Dermatology, Hershey Medical Center 2010 Hershey, PA Curr Opin Rheumatol Review covers new outcome measures, treatments, and unusual manifestations of cutaneous lupus, dermatomyositis, scleroderma, and rheumatoid arthritis Cutaneous Lupus Erythematosus: tx with sunscreen, avoidance of sun, vit d supplement, thalidomide Dermatomyositis: drug triggers of DM, including hydroxyurea, IFN‐beta‐1a, and TNF blockers Systemic Sclerosis: rapid worsening of cutaneous sclerosis has been associated with renal crisis and reduced survival among patients with anti‐ topoisomerase antibodies; tx of Raynaud’s with iloprost, bosentin Rheumatoid Arthritis: nodules more in men with seropositivity; vasculitis with purpura, livedo reticularis, atrophie blanche, and ulcers associated with longstanding, erosive, seropositive disease, and is more frequent in those with antibodies to citrullinated peptides; TNF‐inhibitor therapy has been associated both with onset and improvement of rheumatoid vasculitis; Interstitial granulomatous dermatitis (IGD) and palisaded neutrophilic and granulomatous dermatitis (PNGD) represent reaction patterns related to cutaneous immune complex deposition; Spontaneous resolution is common, but treatments including NSAIDS, prednisone, dapsone, colchicine, oral tacrolimus and TNF‐ inhibitorshave been reported. TNF‐inhibitors have also been linked to onset of the eruption

20 Anticardiolipin antibodies can be increased in active GCA, but normalize after onset of glucocorticoid treatment Fundoscopy shows a ‘chalky white’ optic disc, a sign of infarction of optic nerve caused by vasculitis in GCA Ultrasonography visualizes well superficial branches of aortic arch including temporal arteries, although it cannot depict thoracic, and often abdominal, aorta (need CT or MRI); halo sign in temporal arteries specific and sensitive for GCA PET is useful in diagnosing early large‐vessel involvement in GCA Angiography show stenoses or aneurysms in GCA with large‐vessel involvement but lesions occur quite late (an average of 4 years) after diagnosis of GCA. Hallmark lesion of PMR is bilateral subacromial‐subdeltoid, trochanteric and cervical bursitis (MRI, usn, PET) About 12% of patients with PMR present with RS3PE syndrome Ddx: GCA r/o Takayasu, PMR r/o late onset RA, SpA, cancer Tx GCA with high dose steroids but reduce to 10 mg qd by 3 months; tx PMR with 10‐15 mg prednisone qd; mtx as steroid sparing agent; IL‐6 receptor antagonist Tocilizumab may help in GCA; asa may prevent GCA‐related ischaemic complications. PMR and GCA usually remit within 6 months to 2 years from disease onset

20 21 SOMETIMES IN MEDICINE YOU NEED FRIENDS LIKE DERMATOLOGISTS…

Description Top: John's Hopkins Hospital. Bottom: The first group of Hopkins Internes with 'The Chief'. c. April 1890 https://wellcomecollection.org/works/cv2w7up8

Credit Osler and group of Hopkins Internes, c. 1890. Credit: Wellcome Collection. CC BY

22 Now switch to skin lesions Most noticeable part of phys exam Have patient take pictures bc most are transient Focus on clinical pattern

Description Svenska: Ryssk kamera "Zorki-4K" Date 2007 Source Own work AuthorHolger.Ellgaard 10:53, 21 October 2007 (UTC) https://commons.wikimedia.org/wiki/File:Zorki-4K.jpg Holger.Ellgaard 10:53, 21 October 2007 (UTC) [CC BY 3.0 (https://creativecommons.org/licenses/by/3.0)]

23 Malar rash Spares nasolabial fold Photosensitive Usually raised Do not confuse with rosacea https://commons.wikimedia.org/wiki/File:Lupusfoto.jpg Doktorinternet [CC BY‐SA 4.0 (https://creativecommons.org/licenses/by‐sa/4.0)]

Discoid lesions D for deforming bc leaves scars SLE https://emedicine.medscape.com/article/1065529‐overview

Frequency of cutaneous manifestations high as 70%

24 incidence of CLE is 4/100,000 Acute is malar rash and eruption with erythema and edema of the hands, with prominent sparing of the joint Subacute is annular or psoriasiform plaques in a photodistribution Chronic is discoid vs tumid (juicy papules ) vs panniculitis (painful subcutaneous nodules that heal with depression and atrophy) Disoid with erythematous scaly plaques with prominent follicular plugging that results in scarring and atrophy Remember: discoid is for deforming https://emedicine.medscape.com/article/1065657‐clinical

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Rheumatic Manifestations of Skin Disease Clarke, JT MD Department of Dermatology, Hershey Medical Center 2010 Hershey, PA Curr Opin Rheumatol Review covers new outcome measures, treatments, and unusual manifestations of cutaneous lupus, dermatomyositis, scleroderma, and rheumatoid arthritis Cutaneous Lupus Erythematosus: tx with sunscreen, avoidance of sun, vit d supplement, thalidomide Dermatomyositis: drug triggers of DM, including hydroxyurea, IFN‐beta‐1a, and TNF blockers Systemic Sclerosis: rapid worsening of cutaneous sclerosis has been associated with renal crisis and reduced survival among patients with anti‐ topoisomerase antibodies; tx of Raynaud’s with iloprost, bosentin Rheumatoid Arthritis: nodules more in men with seropositivity; vasculitis with purpura, livedo reticularis, atrophie blanche, and ulcers associated with longstanding, erosive, seropositive disease, and is more frequent in those with antibodies to citrullinated peptides; TNF‐inhibitor therapy has been associated both with onset and improvement of rheumatoid vasculitis; Interstitial granulomatous dermatitis (IGD) and palisaded neutrophilic and granulomatous dermatitis (PNGD) represent reaction patterns related to cutaneous immune complex deposition; Spontaneous resolution is common, but treatments including NSAIDS, prednisone, dapsone, colchicine, oral tacrolimus and TNF‐ inhibitorshave been reported. TNF‐inhibitors have also been linked to onset of the eruption

Cutaneous lupus erythematosus: updates on pathogenesis and associations with systemic lupus Stannard, Jasmine N

24 MD Division of Rheumatology, Department of Internal Medicine 2016 Ann Arbor, Michigan Current Opinion in Rheumatology Despite ongoing research into the cause of CLE, it remains unclear how CLE relates to SLE pathogenesis Frequency of cutaneous manifestations in SLE is as high as 70% Prevalence of CLE is reported as greater than 0.07% One current diagnostic challenge is definition of what constitutes SLE with cutaneous features versus CLE as an independent disease Pathogenesis of CLE is multifactorial and involves genetic predisposition, environmental triggers, and abnormalities in innate and adaptive immune response UV exposure common trigger for CLE, with photosensitivity rates 81% SLE has autoantibodies and in CLE autoantibodies frequently deposit at dermal‐‐epidermal junction and may facilitate antibody‐dependent cell‐mediated cytotoxicity but their specific role in pathogenesis of cutaneous lupus remains unclear. Tx: prevention, topical corticosteroids, antimalarials, mycophenolate, methotrexate, dapsone Limited evidence for the efficacy of tocilizumab in cutaneous disease

Rheumatology Secrets West, Sterling MD Professor, Medicine‐Rheumatology, University of Colorado Hospital 2014 Aurora, Colorado SLE incidence of 5/ 100,000 CLE divided into acute, subacute, and chronic; incidence of 4/100,000 ACLE: butterfly rash, diffuse morbilliform eruption with erythema and edema of the hands, with prominent sparing of the joint SCLE: annular or psoriasiform plaques in a photodistribution; 40% of cutaneous lupus incidence of 0.63/ 100,000 CCLE divided into discoid lupus erythematosus (DLE), tumid lupus, and lupus panniculitis Tumid lupus: juicy papules and plaques that heal without scarring Lupus panniculitis: involves subcutaneous tissue, painful subcutaneous nodules that heal with depression and atrophy. DLE with erythematous‐to‐violaceous, scaly plaques with prominent follicular plugging that often results in scarring and atrophy SSc: women between ages 35‐64 Raynaud’s : pallor, cyanosis then erythema (white, blue then red)

ARTICLES NOT CITED ON SLIDE

24 Systemic Lupus Erythematosus (SLE) Bartels, C MD, MS Assistant Professor of Rheumatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health 2017 Emedicine ACR mnemonic of SLE diagnostic criteria: "SOAP BRAIN MD” Serositis Oral ulcers Arthritis Photosensitivity Blood disorders Renal involvement Antinuclear antibodies Immunologic phenomena (eg, dsDNA; anti‐Smith [Sm] antibodies) Neurologic disorder Malar rash Discoid rash

24 Psoriasis Gets better with sunlight Precedes arthritis in 80% Psoriasis By Jacopo188 ‐ Own work, CC BY‐SA 3.0, https://commons.wikimedia.org/w/index.php?curid=23498619 https://commons.wikimedia.org/wiki/Category:Psoriasis#/media/File:Psoriasis_003.jpg Description English: Psoriasis in 15 years old boy. فارسی: داءالصدف در يک پسر پانزده ساله. Date 24September 20:33:29 ,2013 Source Own work AuthorJacopo188

Nail pits In PsA Predicts more erosive and peripheral dz early on (<2yr) Nail pits https://emedicine.medscape.com/article/1943419‐overview

Subacute cutaneous CLE

25 Gets worse with sunlight

Psoriatic arthritis Almost 50% of cases of PsA in primary care and secondary care clinics are unrecognised Skin lesions precede onset of joint manifestation in nearly 80% of cases; Scaly plaques on extensor areas

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25 Clinical Medicine Almost 50% of cases of PsA in primary care and secondary care clinics are unrecognised; incidence 6/100,000 Higher cardiovascular risk significantly contributed to by high risk of metabolic syndrome Registry data has shown destructive and progressive nature of the disease even early on PsA is a heterogeneous condition with musculoskeletal involvement, including arthritis, enthesitis, dactylitis and axial involvement as well as potential skin and nail disease. Tx with nsaids, DMARDs (mtx for arthritis, ssz for enthesitis), biologics (adalimumab, certolizumab, etanercept, golimumab and infliximab benefit on arthritis, psoriasis, enthesitis and dactylitis as well as on radiographic damage) (Ustekinumab an IL‐ 12/23 inhibitor effective for arthritis, skin, enthesitis and dactylitis but slightly less effective than TNF inhibitors for musculoskeletal manifestations despite being superior for skin disease) (Secukinumab, a monoclonal antibody to IL‐17A, has excellent efficacy in psoriasis with superiority to both etanercept and ustekinumab and Psa), apremilast (a phosphodiesterase‐4 inhibitor, efficacy lower than biologics), Tight Control of PsA (TICOPA) trial; the study recruited 206 patients with early PsA who were randomised 1:1 to receive either tight control or standard care; confirmed a significant benefit with tight control in terms of peripheral arthritis, skin disease and patient reported outcomes but used step up tx so biologics used last

Cutaneous lupus erythematosus: updates on pathogenesis and associations with systemic lupus Stannard, Jasmine N MD Division of Rheumatology, Department of Internal Medicine 2016 Ann Arbor, Michigan Current Opinion in Rheumatology Despite ongoing research into the cause of CLE, it remains unclear how CLE relates to SLE pathogenesis Frequency of cutaneous manifestations in SLE is as high as 70% Prevalence of CLE is reported as greater than 0.07% One current diagnostic challenge is definition of what constitutes SLE with cutaneous features versus CLE as an independent disease Pathogenesis of CLE is multifactorial and involves genetic predisposition, environmental triggers, and abnormalities in innate and adaptive immune response UV exposure common trigger for CLE, with photosensitivity rates 81% SLE has autoantibodies and in CLE autoantibodies frequently deposit at dermal‐‐epidermal junction and may facilitate antibody‐dependent cell‐mediated cytotoxicity but their specific role in pathogenesis of cutaneous lupus remains unclear. Tx: prevention, topical corticosteroids, antimalarials, mycophenolate, methotrexate, dapsone Limited evidence for the efficacy of tocilizumab in cutaneous disease

25 Rheumatology Secrets West, Sterling MD Professor, Medicine‐Rheumatology, University of Colorado Hospital 2014 Aurora, Colorado SLE incidence of 5/ 100,000 CLE divided into acute, subacute, and chronic; incidence of 4/100,000 ACLE: butterfly rash, diffuse morbilliform eruption with erythema and edema of the hands, with prominent sparing of the joint SCLE: annular or psoriasiform plaques in a photodistribution; 40% of cutaneous lupus incidence of 0.63/ 100,000 CCLE divided into discoid lupus erythematosus (DLE), tumid lupus, and lupus panniculitis Tumid lupus: juicy papules and plaques that heal without scarring Lupus panniculitis: involves subcutaneous tissue, painful subcutaneous nodules that heal with depression and atrophy. DLE with erythematous‐to‐violaceous, scaly plaques with prominent follicular plugging that often results in scarring and atrophy SSc: women between ages 35‐64 Raynaud’s : pallor, cyanosis then erythema (white, blue then red)

25 Lupus ulcers Painless oral lesions https://www.healthtap.com/topics/what‐do‐lupus‐mouth Clarke JT 2010

Behcet’s Oral and genital ulcers that are painful and usu scarring Very painful Usu leave scars but not always In usa get more ulcerative form of dz vs Turkey (Yazici father in Turkey and son in NY) Oral and GU ulcers https://www.physio‐pedia.com/Behcet%27s_Disease

RA again Pyoderma gangrenosum Punched out ulcer on lower extremities Looks more painful than it is bc nerves are damaged through inflammation Balance of treatment vs conservative tx Pyoderma gangrenosum Description Pyoderma gangrenosum, A medical condition which the body attacks itself in painful ulcers seen in Crohn's patients. This is a picture of the lower half of

26 the left leg. Date 27 March 2002 Source Own work AuthorCrohnie https://commons.wikimedia.org/wiki/File:Crohnie_Pyoderma_gangrenosum.jpg Crohnie [Public domain]

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26 Despite ongoing research into the cause of CLE, it remains unclear how CLE relates to SLE pathogenesis Frequency of cutaneous manifestations in SLE is as high as 70% Prevalence of CLE is reported as greater than 0.07% One current diagnostic challenge is definition of what constitutes SLE with cutaneous features versus CLE as an independent disease Pathogenesis of CLE is multifactorial and involves genetic predisposition, environmental triggers, and abnormalities in innate and adaptive immune response UV exposure common trigger for CLE, with photosensitivity rates 81% SLE has autoantibodies and in CLE autoantibodies frequently deposit at dermal‐‐epidermal junction and may facilitate antibody‐dependent cell‐mediated cytotoxicity but their specific role in pathogenesis of cutaneous lupus remains unclear. Tx: prevention, topical corticosteroids, antimalarials, mycophenolate, methotrexate, dapsone Limited evidence for the efficacy of tocilizumab in cutaneous disease

Vasculitis: Approach to diagnosis and therapy Palit, Aparna MD Department of Dermatology, Venereology and Leprosy, BLDEA's SBMP Medical College, Hospital and Research Centre

26 2006 Bijapur, Karnataka, India Indian J Dermatology Venereology Leprology Cutaneous presentations of vasculitis important to recognize so the treatment can minimize effective systemic disease Cutaneous features: Palpable purpura in cryoglobulinemic vasculitis; Wheals with urticarial vasculitis; Subcutaneous nodules with involvement of larger vessels with systemic involvement (like EN in TA); 'starburst' pattern of livedo reticularis (LR), which may ulcerate, is the predominant cutaneous feature in c‐ PAN; Ulceration in medium to large‐sized vessels; Raynaud's phenomenon and peripheral cyanosis in cryo; maculopapular rash which subsides with periungual and perineal desquamation with Kawasaki disease Mucosal involvement: Persistent oral and nasal mucosal ulcers and hyperplastic gingivitis with petechiae (strawberry gingival hyperplasia) pathognomonic feature of Weg; Nasal polyps in Churg strauss; Recurrent pansinusitis and septal perforation and saddle‐nose deformity in Weg; Cheilitis (dry, fissured lips) and strawberry tongue in Kawasaki; swollen, cyanotic, cold, tender tongue, which later becomes atrophic due to ischemia in TA. Systemic involvement: GI like abdominal angina, hematemesis, melena, bloody diarrhea and intestinal with small vessel vasculitis like cryo, HSP, and urticarial vasculitis; Renal like GN in cryo, marked renal like renovasc htn and renal failure in PAN, pulm renal syndrome in Weg, Churg S and MPA; Asthma and granulomatous myocarditis in Churg S; Arthralgia / arthritis with most; Peripheral neuropathy and mononeuritis multiplex of lower limbs with CSS but also cryo, PAN, RA vasculitis; Orchitis with Hep B assoc PAN; HUV have systemic manifestations like arthritis, asthma and gastrointestinal symptoms; overlap of clinical features in HUVS and SLE Cutaneous vasculitis is idiopathic in 50% cases Dx with skin bx and immunoflorecense and ANCA Tx with steroids, antivirals, mtx, rituxan, IVIG

26 gout but dactylitis is characteristic symptom of PsA with a high specificity and assoc with radiologically evident erosive damage to joints Important to detect PsA early bc joint damage occurs and progresses in “early” stage of PsA (< 2 yrs) Enthesitis or enthesopathy when inflammation at site of attachment of tendons, ligaments, or joint capsules to bones driven by CD8+ T‐cells Tenosynovitis with soft tissue involvement  dactylitis Polymorphonuclear leukocytic infiltrates are more pronounced in synovium of PsA Dysregulated (altered) bone remodeling with both extensive bone erosion and exaggerated bone formation by increase RANKL, IL‐23, sclerostin and down regulate Wnt path and together this promotes osteoclasts Tx with NSAIDs, DMARDs (ssz, mtx, cyclosporine, arava) and biologics (anti TNF)

26 ScL Sclerosis rapid worsening of cutaneous sclerosis has been associated with renal crisis and reduced survival Women between ages 35‐64 Raynaud’s : pallor, cyanosis then erythema (white then blue then red) https://medical‐ dictionary.thefreedictionary.com/_/viewer.aspx?path=MosbyMD&name=sclerodactyly.jpg& url=https%3A%2F%2Fmedical‐dictionary.thefreedictionary.com%2Fsclerodactyly Sclerodactyly (Firestein and Kelley, 2009)

27 XXXX

27 with depression and atrophy. DLE with erythematous‐to‐violaceous, scaly plaques with prominent follicular plugging that often results in scarring and atrophy SSc: women between ages 35‐64 Raynaud’s : pallor, cyanosis then erythema (white, blue then red)

27 Vasculitis Palpable purpura Dependent portions of body Cryoglobulinemia (discuss further later) can also get Raynaud's Important so treatment can minimize effect of systemic disease Cutaneous vasculitis is idiopathic in 50% cases Description English: Petechia / purpura on the low limb due to medication induced vasculitis. Date Source Own work AuthorJames Heilman, MD https://commons.wikimedia.org/wiki/File:Vasculitis.JPG James Heilman, MD [CC BY-SA 3.0 (https://creativecommons.org/licenses/by- sa/3.0)]

Panniculitis with sarcoid and IBD Erythema nodosum Very small blood vessel inflammation so will also see in small ves vasculitis (like GPA, will discuss further later) Erythema_nodosum.JPG (295 × 338 pixels, file size: 20 KB, MIME type: image/jpeg) MsUpload

28 https://wikem.org/wiki/File:Erythema_nodosum.JPG#file https://commons.wikimedia.org/wiki/File:Vasculitis.JPG

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28 Tumid lupus: juicy papules and plaques that heal without scarring Lupus panniculitis: involves subcutaneous tissue, painful subcutaneous nodules that heal with depression and atrophy. DLE with erythematous‐to‐violaceous, scaly plaques with prominent follicular plugging that often results in scarring and atrophy SSc: women between ages 35‐64 Raynaud’s : pallor, cyanosis then erythema (white, blue then red)

ARTICLES NOT CITED ON SLIDE

Systemic Lupus Erythematosus (SLE) Bartels, C MD, MS Assistant Professor of Rheumatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health 2017 Emedicine ACR mnemonic of SLE diagnostic criteria: "SOAP BRAIN MD” Serositis Oral ulcers Arthritis Photosensitivity Blood disorders Renal involvement Antinuclear antibodies Immunologic phenomena (eg, dsDNA; anti‐Smith [Sm] antibodies) Neurologic disorder Malar rash Discoid rash

Lyme Disease Presenting as a Spontaneous Knee Effusion Matzkin, Elizabeth MD Department of Orthopaedic Surgery, Brigham and Women’s Hospital 2015 Journal of the American Academy of Orthopaedic Surgeons Before Lyme disease was described in literature, an aberrant number of children in Lyme, Connecticut, were diagnosed with JIA Most frequently observed in children and middle‐aged adults Joint aspirate typically has a cell count of 1,000 to 50,000 WBC cells/μLand is primarily composed of neutrophils, but Gram stain may be negative Readily treatable with antibiotics; 99% of patients diagnosed during early localized infection period and 90% of patients with Lyme arthritis respond to therapy.

28 Transient episodes of spontaneous knee effusion are common early in the progression of Lyme disease, and, if left untreated, 60% of patients diagnosed with the disease develop Lyme arthritis

Vasculitis: Approach to diagnosis and therapy Palit, Aparna MD Department of Dermatology, Venereology and Leprosy, BLDEA's SBMP Medical College, Hospital and Research Centre 2006 Bijapur, Karnataka, India Indian J Dermatology Venereology Leprology Cutaneous presentations of vasculitis important to recognize so the treatment can minimize effective systemic disease Cutaneous features: Palpable purpura in cryoglobulinemic vasculitis; Wheals with urticarial vasculitis; Subcutaneous nodules with involvement of larger vessels with systemic involvement (like EN in TA); 'starburst' pattern of livedo reticularis (LR), which may ulcerate, is the predominant cutaneous feature in c‐ PAN; Ulceration in medium to large‐sized vessels; Raynaud's phenomenon and peripheral cyanosis in cryo; maculopapular rash which subsides with periungual and perineal desquamation with Kawasaki disease Mucosal involvement: Persistent oral and nasal mucosal ulcers and hyperplastic gingivitis with petechiae (strawberry gingival hyperplasia) pathognomonic feature of Weg; Nasal polyps in Churg strauss; Recurrent pansinusitis and septal perforation and saddle‐nose deformity in Weg; Cheilitis (dry, fissured lips) and strawberry tongue in Kawasaki; swollen, cyanotic, cold, tender tongue, which later becomes atrophic due to ischemia in TA. Systemic involvement: GI like abdominal angina, hematemesis, melena, bloody diarrhea and intestinal with small vessel vasculitis like cryo, HSP, and urticarial vasculitis; Renal like GN in cryo, marked renal like renovasc htn and renal failure in PAN, pulm renal syndrome in Weg, Churg S and MPA; Asthma and granulomatous myocarditis in Churg S; Arthralgia / arthritis with most; Peripheral neuropathy and mononeuritis multiplex of lower limbs with CSS but also cryo, PAN, RA vasculitis; Orchitis with Hep B assoc PAN; HUV have systemic manifestations like arthritis, asthma and gastrointestinal symptoms; overlap of clinical features in HUVS and SLE Cutaneous vasculitis is idiopathic in 50% cases Dx with skin bx and immunoflorecense and ANCA Tx with steroids, antivirals, mtx, rituxan, IVIG

Optimal management of dactylitis in patients with psoriatic arthritis Yamamoto, Toshiyuki MD Department of Dermatology, Fukushima Medical University 2015 Fukushima, Japan Dove Medical Press Limited

28 PsA has several unique characteristics such as enthesopathy, dactylitis, and abnormal bone remodeling Due to Th1/Th17 subsets that release IL‐17 and IL‐22, which promote neutrophil recruitment and keratinocyte hyperproliferation, respectively Joint inflamm of DIP and all 3 joints of fingers unique Skin lesions precede onset of joint manifestation in nearly 80% of cases; severity of skin lesions does not always correlate with joint lesions Nail involvement is almost always seen in cases of distal type PsA Dactylitis involves both digits of hands and feet; also seen in sarcoidosis, tuberculosis, and gout but dactylitis is characteristic symptom of PsA with a high specificity and assoc with radiologically evident erosive damage to joints Important to detect PsA early bc joint damage occurs and progresses in “early” stage of PsA (< 2 yrs) Enthesitis or enthesopathy when inflammation at site of attachment of tendons, ligaments, or joint capsules to bones driven by CD8+ T‐cells Tenosynovitis with soft tissue involvement  dactylitis Polymorphonuclear leukocytic infiltrates are more pronounced in synovium of PsA Dysregulated (altered) bone remodeling with both extensive bone erosion and exaggerated bone formation by increase RANKL, IL‐23, sclerostin and down regulate Wnt path and together this promotes osteoclasts Tx with NSAIDs, DMARDs (ssz, mtx, cyclosporine, arava) and biologics (anti TNF)

28 Lyme Bulls eye Central clearing Appears in Stage I: occurs 7 to 10 d after tick bite Children and middle‐aged adults Remember: 99% of patients diagnosed during early localized infection period and 90% of patients with Lyme arthritis respond to therapy. Before Lyme disease was described in literature, an aberrant number of children in Lyme, Connecticut, were diagnosed with JIA http://commons.wikimedia.org/wiki/File:Erythema_migrans_- _erythematous_rash_in_Lyme_disease_-_PHIL_9875.jpg https://wikem.org/wiki/File:Erythema_migrans_‐_erythematous_rash_in_Lyme_disease_‐ _PHIL_9875.jpg

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Rheumatic Manifestations of Skin Disease

29 Clarke, JT MD Department of Dermatology, Hershey Medical Center 2010 Hershey, PA Curr Opin Rheumatol Review covers new outcome measures, treatments, and unusual manifestations of cutaneous lupus, dermatomyositis, scleroderma, and rheumatoid arthritis Cutaneous Lupus Erythematosus: tx with sunscreen, avoidance of sun, vit d supplement, thalidomide Dermatomyositis: drug triggers of DM, including hydroxyurea, IFN‐beta‐1a, and TNF blockers Systemic Sclerosis: rapid worsening of cutaneous sclerosis has been associated with renal crisis and reduced survival among patients with anti‐ topoisomerase antibodies; tx of Raynaud’s with iloprost, bosentin Rheumatoid Arthritis: nodules more in men with seropositivity; vasculitis with purpura, livedo reticularis, atrophie blanche, and ulcers associated with longstanding, erosive, seropositive disease, and is more frequent in those with antibodies to citrullinated peptides; TNF‐inhibitor therapy has been associated both with onset and improvement of rheumatoid vasculitis; Interstitial granulomatous dermatitis (IGD) and palisaded neutrophilic and granulomatous dermatitis (PNGD) represent reaction patterns related to cutaneous immune complex deposition; Spontaneous resolution is common, but treatments including NSAIDS, prednisone, dapsone, colchicine, oral tacrolimus and TNF‐ inhibitorshave been reported. TNF‐inhibitors have also been linked to onset of the eruption

29 Lyme Disease Presenting as a Spontaneous Knee Effusion Matzkin, Elizabeth MD Department of Orthopaedic Surgery, Brigham and Women’s Hospital 2015 Journal of the American Academy of Orthopaedic Surgeons Before Lyme disease was described in literature, an aberrant number of children in Lyme, Connecticut, were diagnosed with JIA Most frequently observed in children and middle‐aged adults Joint aspirate typically has a cell count of 1,000 to 50,000 WBC cells/μLand is primarily composed of neutrophils, but Gram stain may be negative Readily treatable with antibiotics; 99% of patients diagnosed during early localized infection period and 90% of patients with Lyme arthritis respond to therapy. Transient episodes of spontaneous knee effusion are common early in the progression of Lyme disease, and, if left untreated, 60% of patients diagnosed with the disease develop Lyme arthritis

29 SLE Frequency of cutaneous manifestations high as 70%

CLE Unclear how CLE relates to SLE pathogenesis Challenge is definition of what constitutes SLE with cutaneous features versus CLE as an independent disease UV exposure common trigger for CLE, with photosensitivity rates 81% Divided into acute, subacute, and chronic; incidence of CLE is 4/100,000 Acute is malar rash and eruption with erythema and edema of the hands, with prominent sparing of the joint Subacute is annular or psoriasiform plaques in a photodistribution Chronic is discoid vs tumid (juicy papules ) vs panniculitis (painful subcutaneous nodules that heal with depression and atrophy) Disoid with erythematous scaly plaques with prominent follicular plugging that results in scarring and atrophy Remember: discoid is for deforming

30 Gets better with sunlight Can be hidden behind ears, in scalp, in umbilicus, gluteal fold Nail involvement is almost always seen in cases of distal type PsA Important to detect PsA early bc joint damage occurs and progresses in “early” stage (<2yrs)

ScL Sclerosis rapid worsening of cutaneous sclerosis has been associated with renal crisis and reduced survival Women between ages 35‐64 Raynaud’s : pallor, cyanosis then erythema (white then blue then red)

RA Nodules on elbows Sometimes with tx like mtx

Vasculitis Palpable purpura Dependent portions of body Cryoglobulinemia (discuss further later) can also get Raynaud's Important so treatment can minimize effect of systemic disease Cutaneous vasculitis is idiopathic in 50% cases

Panniculitis with sarcoid and IBD Erythema nodosum Very small blood vessel inflammation so will also see in small ves vasculitis (like GPA, will discuss further later)

Behcet’s Oral and genital ulcers that are painful and usu scarring More cutaneous in usa

Lupus again Painless oral lesions

RA again Pyoderma gangrenosum Punched out ulcer on lower extremities Looks more painful than it is bc nerves are damaged through inflammation Balance of treatment vs conservative tx

Lyme Bulls eye Central clearing

30 Appears in Stage I: occurs 7 to 10 d after tick bite Children and middle‐aged adults Remember: 99% of patients diagnosed during early localized infection period and 90% of patients with Lyme arthritis respond to therapy.

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30 Higher cardiovascular risk significantly contributed to by high risk of metabolic syndrome Registry data has shown destructive and progressive nature of the disease even early on PsA is a heterogeneous condition with musculoskeletal involvement, including arthritis, enthesitis, dactylitis and axial involvement as well as potential skin and nail disease. Tx with nsaids, DMARDs (mtx for arthritis, ssz for enthesitis), biologics (adalimumab, certolizumab, etanercept, golimumab and infliximab benefit on arthritis, psoriasis, enthesitis and dactylitis as well as on radiographic damage) (Ustekinumab an IL‐ 12/23 inhibitor effective for arthritis, skin, enthesitis and dactylitis but slightly less effective than TNF inhibitors for musculoskeletal manifestations despite being superior for skin disease) (Secukinumab, a monoclonal antibody to IL‐17A, has excellent efficacy in psoriasis with superiority to both etanercept and ustekinumab and Psa), apremilast (a phosphodiesterase‐4 inhibitor, efficacy lower than biologics), Tight Control of PsA (TICOPA) trial; the study recruited 206 patients with early PsA who were randomised 1:1 to receive either tight control or standard care; confirmed a significant benefit with tight control in terms of peripheral arthritis, skin disease and patient reported outcomes but used step up tx so biologics used last

Rheumatology Secrets West, Sterling MD Professor, Medicine‐Rheumatology, University of Colorado Hospital

30 2014 Aurora, Colorado SLE incidence of 5/ 100,000 CLE divided into acute, subacute, and chronic; incidence of 4/100,000 ACLE: butterfly rash, diffuse morbilliform eruption with erythema and edema of the hands, with prominent sparing of the joint SCLE: annular or psoriasiform plaques in a photodistribution; 40% of cutaneous lupus incidence of 0.63/ 100,000 CCLE divided into discoid lupus erythematosus (DLE), tumid lupus, and lupus panniculitis Tumid lupus: juicy papules and plaques that heal without scarring Lupus panniculitis: involves subcutaneous tissue, painful subcutaneous nodules that heal with depression and atrophy. DLE with erythematous‐to‐violaceous, scaly plaques with prominent follicular plugging that often results in scarring and atrophy SSc: women between ages 35‐64 Raynaud’s : pallor, cyanosis then erythema (white, blue then red)

ARTICLES NOT CITED ON SLIDE

Lyme Disease Presenting as a Spontaneous Knee Effusion Matzkin, Elizabeth MD Department of Orthopaedic Surgery, Brigham and Women’s Hospital

30 2015 Journal of the American Academy of Orthopaedic Surgeons Before Lyme disease was described in literature, an aberrant number of children in Lyme, Connecticut, were diagnosed with JIA Most frequently observed in children and middle‐aged adults Joint aspirate typically has a cell count of 1,000 to 50,000 WBC cells/μLand is primarily composed of neutrophils, but Gram stain may be negative Readily treatable with antibiotics; 99% of patients diagnosed during early localized infection period and 90% of patients with Lyme arthritis respond to therapy. Transient episodes of spontaneous knee effusion are common early in the progression of Lyme disease, and, if left untreated, 60% of patients diagnosed with the disease develop Lyme arthritis

30 Tx with steroids, antivirals, mtx, rituxan, IVIG

30 31 NOW WE GET MORE INTENSE; COMPLICATED https://www.collectionscanada.gc.ca/obj/030002/f1/nlc012031‐v6.jpg

32 Best to do by size bc then don’t have to memorize where occurs and symptoms

Large Medium Small Variable Other

33 General points In vasculitis Inflammation can shift balance promoting a prothrombotic state; arterial or venous  can get more clots in general Usu with active dz High prevalence of cardiovascular events soon after diagnosis suggests that active disease may play a role in triggering arterial thrombosis 4 granulomatous vasculitis: GCA, TA, GPA, EGPA 3 anca assoc vasculitis: GPA, EGPA, MPA

GCA PMR and GCA occur together more frequently New headache, jaw claudication. visual loss, fevers, weight loss Transmural large vessel inflammation with skip lesions and multinucleated giant cells About 2/3 have headache Total or partial visual loss affects up to 20% of GCA, mostly at disease onset Can get arm claudication and arterial bruits after 3‐4 years Can get lung involvement Anticardiolipin antibodies can be increased in active GCA Asa may prevent GCA‐related ischaemic complications. Usu lasts 2 years from disease onset Description Nederlands: Arteria temporalis superficialis Deutsch: Arteria temporalis superficialis English: Superficial temporal artery

34 Italiano: Arteria temporale superficiale Latina: Arteria temporalis superficialis Français : Artère temporale superficielle Date 2 September 2017, 15:20:24 Source Own work AuthorOpzwartbeek

TA Large vessel vasculitis of unknown etiology Can be seen in all ethnicities around world (not just Asians) Young women Affects aorta and its major branches Thoracic aorta and its branches was more common among females vs males have a tendency toward limited involvement of abdominal aorta and its branches Pregnancy seems to cause serious risks for both maternal and fetal health IBD frequently Cardiac echo bc aortic aneurysms and phtn later on Assessment of disease activity in Takayasu arteritis is difficult. Restenosis or occlusion risks are still high with vascular interventions. Just like GCA can use Asa to prevent ischemic events Mortality seems to be decreasing in recent years but still 3‐20%

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Diagnosis and management of ANCA associated vasculitis Berden, A MD Department of Pathology, Leiden University Medical Centre 2012 Leiden, Netherlands The British medical Journal Avoid diagnostic delay to prevent end organ damage, particularly renal disease Overall annual incidence of ANCA associated vasculitis in Europe and Northern America is 20 per million Disease onset at 65‐74 years; prevalence is higher in men, but women more often develop disease at younger age Prevalence of ANCA associated vasculitis is highest in white people GPA higher in northern Europe, whereas MPA higher in southern Europe and Japan Presents with prodromal “flu‐like” symptoms of several weeks' or months' duration; rash, cutaneous vasculitis, bloody‐purulent rhinitis, scleritis, or arthritis Ear, nose, and throat problems—such as hearing loss, otalgia, (bloody) rhinorrhoea, otorrhoea, sinusitis, nasal crusting, and recurrent otitis media—occur in about 90% of

34 patients with GPA and in 35% of those with MPA Negative ANCA does not exclude the diagnosis of ANCA associated vasculitis because 5‐10% of patients do not develop ANCA. Referral to specialists without experience with vasculitis may delay diagnosis Natural history survival was about five months; 82% of patients did not survive the first year after diagnosis and more than 90% of patients died within two years due to rapidly progressive renal failure, and second most common cause was respiratory failure without tx With modern treatment (steroids, mtx, aza, rituxan, plasmapharesis) disease has changed from being universally fatal to being a chronic relapsing and remitting disease The first few weeks of treatment can be difficult because patients usually still have symptoms associated with vasculitis; frequent hospital visits and blood tests are needed to monitor disease activity and response to treatment. Patients are susceptible to infections particularly during induction treatment Prevent and tx for tx for ckd, osteoporosis, diabetes, cancer, cad, strokes, dvt, PCP, gerd Relapse can occur after many years in remission, patients often remain on indefinite follow‐up TA: inflamm  vessel pain  bruits and ischemia; young asian women; skip lesions like GCA; cardiac echo bc aortic aneurysms and phtn Risk of death for patients treated with current treatments is still 2.6 times higher due to infections and active vasculitis early on and infections, cardiovascular disease, and cancer later on

Cryoglobulinemia vasculitis: how to handle Desbois, A Sorbonne Universités, UPMC Univ Paris 2017 Paris, France Current Opinion in Rheumatology Dx: Fatigue, palpable purpura begins lower limbs, arthralgia (40–60%) large joints bilateral symmetric, neurologic from pure sensory polyneuropathy to mononeuritis multiplex, most frequently described form is a distal sensory or sensory‐motor polyneuropathy, painful, asymmetric paresthesia, which later becomes symmetric, proteinuria with microscopic haematuria, mesenteric vasculitis Type I cryoglobulins: monoclonal immunoglobulins; underlying B‐cell lymphoproliferative disorder, usu Waldenström macroglobulinemia, multiple myeloma or monoclonal gammopathy of unknown significance Type II cryoglobulins: monoclonal immunoglobulin with rheumatoid factor associated with polyclonal IgG; chronic hepatitis C virus Type III cryoglobulins: polyclonal IgG and IgM with rheumatoid factor activity; hepatitis C, Sjögren syndrome and systemic lupus Mixed cryoglobulinemia lesions in HCV‐infected patients are often related to small vessel vasculitis induced by immune complex deposits  Fatigue, palpable purpura, arthralgia,

34 pure sensory polyneuropathy to mononeuritis multiplex, proteinuria with microscopic haematuria and sometimes a variable degree of renal insufficiency; other < 5% like abdominal pains and gastrointestinal bleeding secondary to mesenteric vasculitis, mitral valvular damage, coronary vasculitis, interstitial lung fibrosis, pleural effusions or pulmonary intra‐alveolar haemorrhages. Defin dx: cryoglobulinemia in serum Cryoglobulinemia is confirmed by the detection of protein that precipitates in the patient's serum maintained at 4°C during at least 7 days, and dissolved when heated at 37°C Decreased early components (C1q, C2, C4) and CH50, with normal C3 level. Elevated RF, Hep C, SPEP Prognosis 63% at 10 years usu die from liver dz or infec Most common causes of death in HCV‐CryoVas are infection, end‐stage liver disease, cardiovascular disease and more rarely vasculitis and lymphoma/neoplasia Tx with direct‐acting IFN‐free antivirals, ribavirin + rituxan +/‐pharesis HCV‐CryoVas manifestations improve or disappear when a sustained clearance of HCV is achieved by use of triple HCV therapy combining PegIFN, ribavirin and a direct‐acting antiviral (DAA) (NS3/4A protease inhibitor, i.e. boceprevir or telaprevir) led to improved SVR rates but need to tx for 48 weeks

Hepatitis B virus and hepatitis C virus treatment and management in patients receiving immune‐modifying agents Juan, J Toronto Centre for Liver Disease, Toronto Western Hospital, Francis Family Liver Centre, University of Toronto, 2014 Toronto, Ontario, Canada Current Opinion in Rheumatology HBV: 95% clear infec in adults; in chronic phase interacts with host immune response (immunotolerant phase  inactive carrier state  few are cleared, most are inactive); when lose host immunity then reactivates Starting antiviral therapy for Hep B prior to or concomitant with immunosuppression is more effective than treating reactivation once it occurs HBV reactivation occurs with immune reconstitution so antiviral therapy continue 6‐12 mo after stopping immunosuppression HCV: only 20% clear infec in adults; immune suppression meds do not usu cause progression of HCV but immune compromised host can accelerate progression like in hiv Current guidelines do not reflect that country of origin is most important risk factor for chronic HBV infection Screening all patients who are to receive immunosuppressive therapy more effective and is likely cost‐effective

Clinical features of polymyalgia rheumatica and giant cell arteritis

34 Salvarani, Carlo MD Rheumatology Unit, Department of Internal Medicine 2012 Reggio Emilia, Italy Nature Reviews Rheumatology PMR and GCA occur together more frequently than expected by chance. PMR are pain and stiffness in the shoulders, and often in the neck and pelvic girdle. GCA is a large‐vessel and medium‐vessel arteritis with new headache, jaw claudication and visual loss due to transmural large vessel inflammation with skip lesions and multinucleated giant cells About 2/3 of GCA have headache, typically temporal, but can also be felt over other cranial areas, and is resistant to standard analgesia Total or partial visual loss affects up to 20% of GCA, mostly at disease onset GCA usu has fever, fatigue and weight loss About 1/5 of GCA develop large‐vessel involvement including arm claudication and arterial bruits; usually become apparent only 3‐4 years after onset of symptoms PMR pain is bilateral, worse at night and on movement, and usually radiates distally About 4% of patients with pure PMR have TAB lesions consistent with GCA; nearly 1/3 with pure PMR have subclinical large‐vessel arteritis on PET; suggest that PMR and GCA might represent two ends of same disease spectrum. Anticardiolipin antibodies can be increased in active GCA, but normalize after onset of glucocorticoid treatment Fundoscopy shows a ‘chalky white’ optic disc, a sign of infarction of optic nerve caused by vasculitis in GCA Ultrasonography visualizes well superficial branches of aortic arch including temporal arteries, although it cannot depict thoracic, and often abdominal, aorta (need CT or MRI); halo sign in temporal arteries specific and sensitive for GCA PET is useful in diagnosing early large‐vessel involvement in GCA Angiography show stenoses or aneurysms in GCA with large‐vessel involvement but lesions occur quite late (an average of 4 years) after diagnosis of GCA. Hallmark lesion of PMR is bilateral subacromial‐subdeltoid, trochanteric and cervical bursitis (MRI, usn, PET) About 12% of patients with PMR present with RS3PE syndrome Ddx: GCA r/o Takayasu, PMR r/o late onset RA, SpA, cancer Tx GCA with high dose steroids but reduce to 10 mg qd by 3 months; tx PMR with 10‐15 mg prednisone qd; mtx as steroid sparing agent; IL‐6 receptor antagonist Tocilizumab may help in GCA; asa may prevent GCA‐related ischaemic complications. PMR and GCA usually remit within 6 months to 2 years from disease onset

Takayasu arteritis: an update Seyahi, E MD Division of Rheumatology, Department of Internal Medicine, Cerrahpasa Medical Faculty, University of Istanbul

34 2017 Istanbul, Turkey Current Opinion in Rheumatology TA is large vessel vasculitis of unknown etiology Recent evidence shows that disease can be seen in all ethnicities around world with increasing prevalence rates; so not so rare More common among young women and predominantly affects aorta and its major branches Involvement of thoracic aorta and its branches was more common among females, (aortic arch and its branches were mainly involved in Japanese patients whereas abdominal aorta and its branches were chiefly involved in Indian patients and lower abdominal aorta involvement was more common in African populations) vs males have a tendency toward limited involvement of abdominal aorta and its branches. Pregnancy seems to cause serious risks for both maternal and fetal health TA affects women of child‐bearing age, pregnancy itself without vasculitis carry considerable risk for cardiovascular and cerebral accidents, may flare‐up anytime during or after pregnancy, uncontrolled hypertension, myocardial infarction, congestive heart failure, and renal failure may lead to maternal comorbidity and mortality, preeclampsia and intrauterine death are frequent, medical management during pregnancy with antihypertensive agents or immunosuppressives/corticosteroids is challenging Frequently coexist with inflammatory bowel diseases Prevalence of IBD is around 6% in TA; both diseases have granulomatous histopathology; more likely to carry HLA B52:01 Assessment of disease activity in Takayasu arteritis is difficult. Conventional angiography used to be gold standard for dx but now CTA or MRA done; PET/CT Biological agents such as anti‐tumor necrosis factor agents, tocilizumab and rituximab could be used effectively in refractory cases but first line is steroids; methotrexate, azathioprine, leflunomide, mycophenolate mofetil, and cyclophosphamide also used Restenosis or occlusion risks are still high with vascular interventions. Mortality seems to be decreasing in recent years Reported mortality ranges between 3 and 21.0%

34 asymptomatic patient But low rate of embolic phenomenon to lungs because of tight adhesions of peripheral thrombosis to venous walls Due to multifactorial causes Clots in AAV especially when dz active Risk of VTE in GPA was seven times the risk of VTE in SLE Statins, known for their anti‐inflammatory effects, have recently been recognized to have antithrombotic effects as well Risk of arterial thrombotic disease is also increased in GPA, MPA, and Churg–Strauss High prevalence of cardiovascular events soon after diagnosis suggests that active disease may play a role in triggering arterial thrombosis In EGPA eosinophils contain preformed protein‐containing granules that are released when activated; some of these proteins have known prothrombotic effects PAN have more DVT and PE GCA and TA use aspirin to prevent ischemic events Strokes with premature atherosclerosis related to endothelial dysfunction in TA and atherosclerosis in GCA

34 medium‐sized arteries, and pulmonary artery thrombotic occlusions, in smaller branches PAAs are a rare manifestation of Behçet's syndrome, but they are leading cause of death; mainly in young men, after 5 years of dz onset; hemoptysis bc of rupture of aneurysm into an eroded bronchi. PAAs assoc with DVT and intracardiac thrombosis in Behcets Takayasu arteritis often involves pulmonary artery, but rarely at onset Lung involvement may be present in large proportion of patients with giant cell arteritis (GCA) Goodpasture syndrome is a rare dz with pathogenetic autoantibodies directed against glomerular and alveolar basal membranes presenting as acute renal failure, due to rapidly progressive glomerulonephritis, and pulmonary haemorrhage

Rheumatology Secrets West, Sterling MD Professor, Medicine‐Rheumatology, University of Colorado Hospital 2014 Aurora, Colorado GPA: upper and the lower respiratory tract; + PR3; generalized versus limited; sinusitis, saddle nose deformity, hoarseness; granulomas on CT scan only, pauci immune focal and segmental necrotizing glomerulonephritis, active urinary sediment, episcleritis, mononeuritis multiplex, pericarditis; very rare disease, ANCA titers do not reflect disease activity; fatal without treatment; treatment with steroids, rituximab, mtx MPA: effects small vessels without immune deposits and without granulomas; ILD and acute renal failure EGPA: asthma with GPA; can affect small veins and arteries; has eosinophilia; death usu from MI and CHF bc granulomatous myocarditis PAN: hepatitis B, affects men more, mononeuritis multiplex, abdominal pain due to mesenteric vasculitis, hypertension with hematuria and proteinuria; incidence of 2/ 1,000,000, middle age 40s, focal and segmental transmural necrotizing vasculitis of medium and small arteries with fibrinoid necrosis; angiogram shows small aneurysms Behcets: recurr oral and genital ulcers, pathergy, turkish and japanese, age 30s, genital ulcerations in men more painful, uveitis, hypopyon, erythema nodosum, thrombosis of large veins and arteries and inf vena cava, aneurysms of pulmonary tree; cns dz high mortality; polychondritis + oral and genital ulcers = MAGIC syndrome Mouth And Genital ulceration with Inflamed Cartilage GCA, TA, GPA, EGPA are the 4 granulomatous vasculitis

34 Norwich, UK Royal College of Physicians AAV = granulomatosis with polyangiitis (GPA, previously known as Wegener’s granulomatosis), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA, previously known as Churg‐Strauss syndrome). GPA, MPA and EGPA have respective annual incidence rates of 2.1–14.4, 2.4–10.1 and 0.5– 3.7 per million in Europe More common in those aged over 60 years and slightly more common in men. GPA has nasal crusting, stuffiness and epistaxis, uveitis, upper respiratory tract involvement and often renal involvement MPA are typically older and present with more severe renal disease with rash and neuropathy EGPA typically presents with a multisystem disease on a background of asthma, nasal polyposis and peripheral blood eosinophilia. Rituximab in AAV has been tested in two randomised controlled trials: RAVE and RITUXVAS; In both trials, rituximab was non‐inferior to cyclophosphamide and appeared more effective for relapsing disease in RAVE; In the RAVE trial, a better response was seen in PR3 positive patients Definition of remission = no detectable disease activity; after successful remission induction, guidelines recommend withdrawing initial immunosuppressive agent and commencing a maintenance regimen with either azathioprine or methotrexate continued for at least 18–24 months before being gradually withdrawn MAINRITSAN (efficacy study of two treatments in remission of vasculitis) trial reported that rituximab 500 mg given at days 0, 14 and at months 6, 12 and 18 was more effective in remission maintenance than azathioprine regimen Mortality in first year is due to active vasculitis or infection, late mortality due to infection, cardiovascular disease and malignancy; 5‐year survival is 75%. Morbidity accumulates with time because of consequences of active disease and therapies.

34 General points In vasculitis Inflammation can shift balance promoting a prothrombotic state; arterial or venous  can get more clots in general Usu with active dz High prevalence of cardiovascular events soon after diagnosis suggests that active disease may play a role in triggering arterial thrombosis 4 granulomatous vasculitis: GCA, TA, GPA, EGPA 3 anca assoc vasculitis: GPA, EGPA, MPA

PAN More DVT and PE

Foot drop English: Peripheral neuritis, with foot-drop of right side, after enteric fever (typhoid fever) Identifier: internalmedicine02wils (find matches) Title: Internal medicine; a work for the practicing physician on diagnosis and treatment, with a complete Desk index Year: 1920 (1920s) Authors: Wilson, J. C. (James Cornelius), 1847-1934 Potter, Nathaniel Bowditch, 1869-1919 Subjects: Medicine Diagnosis

35 Publisher: Philadelphia, London, J. B. Lippincott Company Contributing Library: Columbia University Libraries Digitizing Sponsor: Open Knowledge Commons angiogram https://emedicine.medscape.com/article/418126‐overview

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35 MPA: effects small vessels without immune deposits and without granulomas; ILD and acute renal failure EGPA: asthma with GPA; can affect small veins and arteries; has eosinophilia; death usu from MI and CHF bc granulomatous myocarditis PAN: hepatitis B, affects men more, mononeuritis multiplex, abdominal pain due to mesenteric vasculitis, hypertension with hematuria and proteinuria; incidence of 2/ 1,000,000, middle age 40s, focal and segmental transmural necrotizing vasculitis of medium and small arteries with fibrinoid necrosis; angiogram shows small aneurysms Behcets: recurr oral and genital ulcers, pathergy, turkish and japanese, age 30s, genital ulcerations in men more painful, uveitis, hypopyon, erythema nodosum, thrombosis of large veins and arteries and inf vena cava, aneurysms of pulmonary tree; cns dz high mortality; polychondritis + oral and genital ulcers = MAGIC syndrome Mouth And Genital ulceration with Inflamed Cartilage GCA, TA, GPA, EGPA are the 4 granulomatous vasculitis

35 General points In vasculitis Inflammation can shift balance promoting a prothrombotic state; arterial or venous  can get more clots in general Usu with active dz High prevalence of cardiovascular events soon after diagnosis suggests that active disease may play a role in triggering arterial thrombosis 4 granulomatous vasculitis: GCA, TA, GPA, EGPA 3 anca assoc vasculitis: GPA, EGPA, MPA

GPA Avoid diagnostic delay to prevent end organ damage, particularly renal disease GPA higher in northern Europe in older men Presents with prodromal “flu‐like” symptoms Have lung dz in 50% 5‐10% of patients do not develop ANCA Clots in AAV especially when dz active; VTE in GPA was seven times the risk of VTE in SLE More than 90% of patients died within two years due to rapidly progressive renal failure, and second most common cause was respiratory failure without tx Relapse can occur after many years in remission; remain on indefinite follow‐up Risk of death for patients treated with current treatments is still 2.6 times higher due to infections and active vasculitis early on and infections, cardiovascular disease, and cancer later on (includes lung)

36 Description English: Typical saddle nose damage from GPA. Date 15 March 2016 Source Own work AuthorVw38 https://commons.wikimedia.org/wiki/File:Saddle_nose_38.jpg Vw38 [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)]

EGPA GPA + asthma/allergies in older men Clots in AAV especially when dz active Eosinophils contain preformed protein‐containing granules that are released when activated; some of these proteins have known prothrombotic effects MI and CHF bc granulomatous myocarditis

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36 Natural history survival was about five months; 82% of patients did not survive the first year after diagnosis and more than 90% of patients died within two years due to rapidly progressive renal failure, and second most common cause was respiratory failure without tx With modern treatment (steroids, mtx, aza, rituxan, plasmapharesis) disease has changed from being universally fatal to being a chronic relapsing and remitting disease The first few weeks of treatment can be difficult because patients usually still have symptoms associated with vasculitis; frequent hospital visits and blood tests are needed to monitor disease activity and response to treatment. Patients are susceptible to infections particularly during induction treatment Prevent and tx for tx for ckd, osteoporosis, diabetes, cancer, cad, strokes, dvt, PCP, gerd Relapse can occur after many years in remission, patients often remain on indefinite follow‐up TA: inflamm  vessel pain  bruits and ischemia; young asian women; skip lesions like GCA; cardiac echo bc aortic aneurysms and phtn Risk of death for patients treated with current treatments is still 2.6 times higher due to infections and active vasculitis early on and infections, cardiovascular disease, and cancer later on

Thrombosis in vasculitis Springer, J MD, Department of Rheumatic and Immunologic Diseases, Center for Vasculitis Care and Research, Cleveland Clinic 2013 Cleveland, Ohio Current Opinion in Rheumatology Venous and arterial thrombosis in vasculitis seen Inflammation can shift balance promoting a prothrombotic state Behcet’s dz increasing immune med decreases thrombosis but watch for hemmorrhage Most commonly have DVT in the extremities and superficial thrombophlebitis in asymptomatic patient But low rate of embolic phenomenon to lungs because of tight adhesions of peripheral thrombosis to venous walls Due to multifactorial causes Clots in AAV especially when dz active Risk of VTE in GPA was seven times the risk of VTE in SLE Statins, known for their anti‐inflammatory effects, have recently been recognized to have antithrombotic effects as well Risk of arterial thrombotic disease is also increased in GPA, MPA, and Churg–Strauss High prevalence of cardiovascular events soon after diagnosis suggests that active disease may play a role in triggering arterial thrombosis

36 In EGPA eosinophils contain preformed protein‐containing granules that are released when activated; some of these proteins have known prothrombotic effects PAN have more DVT and PE GCA and TA use aspirin to prevent ischemic events Strokes with premature atherosclerosis related to endothelial dysfunction in TA and atherosclerosis in GCA

Systemic vasculitis and the lung Talarico, R MD Rheumatology Unit, University of Pisa 2017 Pisa, Italy Current Opinion in Rheumatology Lungs often involved in systemic vasculitis In GPA and MPA have overt lung dz 25–55%; however, MPA may have abnormal CT in 97% suggesting subclinical lung especially in patients with higher dz activity and myeloperoxidase (MPO)‐ANCA positivity Underlying pathogenesis that has not yet been fully defined; adropin (protein involved in protection of endothelium, which may be involved in the pathogenesis of lung injury) low levels of mutation of assoc with lung injury; Oxidative stress Lung dz more MPO‐ANCA‐positive AAV, mostly in MPA DAH (diffuse alveolar hemorrhage) most severe lung manifestation, but ILD most common; but prognosis of ILD is better than those with DAH in short term, but may be worse long‐ term High prevalence (32%) of pulmonary fibrosis in MPA that could occur as first clinical symptom of the disease Isolated cases of ANCA‐positive ILD have been recently described Currently there is no specific treatment for patients with ILD and AAV/ANCA‐positivity AAV may have more malignant neoplasms; nonmelanoma skin cancers; increasing incidence of lung cancer Behçet's syndrome can affect venous and arterial vessels of any size; can involve the entire pulmonary artery tree, leading to pulmonary artery aneurisms (PAAs), usually of large and medium‐sized arteries, and pulmonary artery thrombotic occlusions, in smaller branches PAAs are a rare manifestation of Behçet's syndrome, but they are leading cause of death; mainly in young men, after 5 years of dz onset; hemoptysis bc of rupture of aneurysm into an eroded bronchi. PAAs assoc with DVT and intracardiac thrombosis in Behcets Takayasu arteritis often involves pulmonary artery, but rarely at onset Lung involvement may be present in large proportion of patients with giant cell arteritis (GCA) Goodpasture syndrome is a rare dz with pathogenetic autoantibodies directed against glomerular and alveolar basal membranes presenting as acute renal failure, due to rapidly progressive glomerulonephritis, and pulmonary haemorrhage

36 Rheumatology Secrets West, Sterling MD Professor, Medicine‐Rheumatology, University of Colorado Hospital 2014 Aurora, Colorado GPA: upper and the lower respiratory tract; + PR3; generalized versus limited; sinusitis, saddle nose deformity, hoarseness; granulomas on CT scan only, pauci immune focal and segmental necrotizing glomerulonephritis, active urinary sediment, episcleritis, mononeuritis multiplex, pericarditis; very rare disease, ANCA titers do not reflect disease activity; fatal without treatment; treatment with steroids, rituximab, mtx MPA: effects small vessels without immune deposits and without granulomas; ILD and acute renal failure EGPA: asthma with GPA; can affect small veins and arteries; has eosinophilia; death usu from MI and CHF bc granulomatous myocarditis PAN: hepatitis B, affects men more, mononeuritis multiplex, abdominal pain due to mesenteric vasculitis, hypertension with hematuria and proteinuria; incidence of 2/ 1,000,000, middle age 40s, focal and segmental transmural necrotizing vasculitis of medium and small arteries with fibrinoid necrosis; angiogram shows small aneurysms Behcets: recurr oral and genital ulcers, pathergy, turkish and japanese, age 30s, genital ulcerations in men more painful, uveitis, hypopyon, erythema nodosum, thrombosis of large veins and arteries and inf vena cava, aneurysms of pulmonary tree; cns dz high mortality; polychondritis + oral and genital ulcers = MAGIC syndrome Mouth And Genital ulceration with Inflamed Cartilage GCA, TA, GPA, EGPA are the 4 granulomatous vasculitis

36 neuropathy EGPA typically presents with a multisystem disease on a background of asthma, nasal polyposis and peripheral blood eosinophilia. Rituximab in AAV has been tested in two randomised controlled trials: RAVE and RITUXVAS; In both trials, rituximab was non‐inferior to cyclophosphamide and appeared more effective for relapsing disease in RAVE; In the RAVE trial, a better response was seen in PR3 positive patients Definition of remission = no detectable disease activity; after successful remission induction, guidelines recommend withdrawing initial immunosuppressive agent and commencing a maintenance regimen with either azathioprine or methotrexate continued for at least 18–24 months before being gradually withdrawn MAINRITSAN (efficacy study of two treatments in remission of vasculitis) trial reported that rituximab 500 mg given at days 0, 14 and at months 6, 12 and 18 was more effective in remission maintenance than azathioprine regimen Mortality in first year is due to active vasculitis or infection, late mortality due to infection, cardiovascular disease and malignancy; 5‐year survival is 75%. Morbidity accumulates with time because of consequences of active disease and therapies.

36 Vasculitis

MPA MPA higher in southern Europe and Japan in older men Profoundly lung and renal Abnormal CT in 97% suggesting subclinical lung (more at risk for lung ca) Prognosis of ILD is better than those with DAH in short term, but may be worse long‐ term Clots in AAV especially when dz active Patient who comes in with neuro stuff; then sob; then hematuria/renal failure

Cryo Small vessel vasculitis induced by immune complex deposits Palpable purpura begins lower limbs Pure sensory polyneuropathy to mononeuritis multiplex; very painful, asymmetric paresthesia, which later becomes symmetric, Proteinuria with microscopic haematuria Mesenteric vasculitis Pulmonary hemorrhage Type I cryoglobulins: Waldenström macroglobulinemia Type II cryoglobulins: chronic hepatitis C virus Type III cryoglobulins: Sjögren syndrome and systemic lupus Defin dx: cryoglobulinemia in serum

37 Protein that precipitates in the patient's serum maintained at 4°C during at least 7 days, and dissolved when heated at 37°C Prognosis 63% at 10 years usu die from liver dz or infec

Palpable purpura Dependent portions of body Cryoglobulinemia can also get Raynaud's Important so treatment can minimize effect of systemic disease Cutaneous vasculitis is idiopathic in 50% cases Description English: Petechia / purpura on the low limb due to medication induced vasculitis. Date Source Own work AuthorJames Heilman, MD https://commons.wikimedia.org/wiki/File:Vasculitis.JPG James Heilman, MD [CC BY-SA 3.0 (https://creativecommons.org/licenses/by- sa/3.0)]

37 General points In vasculitis Inflammation can shift balance promoting a prothrombotic state; arterial or venous  can get more clots in general Usu with active dz High prevalence of cardiovascular events soon after diagnosis suggests that active disease may play a role in triggering arterial thrombosis 4 granulomatous vasculitis: GCA, TA, GPA, EGPA 3 anca assoc vasculitis: GPA, EGPA, MPA

TA Large vessel vasculitis of unknown etiology

38 Can be seen in all ethnicities around world (not just Asians) Young women Affects aorta and its major branches Thoracic aorta and its branches was more common among females vs males have a tendency toward limited involvement of abdominal aorta and its branches Pregnancy seems to cause serious risks for both maternal and fetal health IBD frequently Cardiac echo bc aortic aneurysms and phtn later on Assessment of disease activity in Takayasu arteritis is difficult. Restenosis or occlusion risks are still high with vascular interventions. Just like GCA can use Asa to prevent ischemic events Mortality seems to be decreasing in recent years but still 3‐20%

PAN More DVT and PE

MPA MPA higher in southern Europe and Japan in older men Profoundly lung and renal

38 Abnormal CT in 97% suggesting subclinical lung (more at risk for lung ca) Prognosis of ILD is better than those with DAH in short term, but may be worse long‐term Clots in AAV especially when dz active

Behcet’s Can involve any size vessel Uveitis, hypopyon, erythema nodosum, oral and genital ulcers Can involve entire pulmonary artery tree  pulmonary artery aneurysms and pulmonary artery thrombotic occlusions Increasing immune med decreases thrombosis but watch for hemmorrhage DVT in the extremities and superficial thrombophlebitis in asymptomatic patient Low rate of embolic phenomenon to lungs because of tight adhesions of peripheral thrombosis to venous walls Young men after 5 years of dz leading cause of death is pulm artery anuerysms and bleeds Can get strokes bc higher incidence of anti cardiolipin ab

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38 Overall annual incidence of ANCA associated vasculitis in Europe and Northern America is 20 per million Disease onset at 65‐74 years; prevalence is higher in men, but women more often develop disease at younger age Prevalence of ANCA associated vasculitis is highest in white people GPA higher in northern Europe, whereas MPA higher in southern Europe and Japan Presents with prodromal “flu‐like” symptoms of several weeks' or months' duration; rash, cutaneous vasculitis, bloody‐purulent rhinitis, scleritis, or arthritis Ear, nose, and throat problems—such as hearing loss, otalgia, (bloody) rhinorrhoea, otorrhoea, sinusitis, nasal crusting, and recurrent otitis media—occur in about 90% of patients with GPA and in 35% of those with MPA Negative ANCA does not exclude the diagnosis of ANCA associated vasculitis because 5‐10% of patients do not develop ANCA. Referral to specialists without experience with vasculitis may delay diagnosis Natural history survival was about five months; 82% of patients did not survive the first year after diagnosis and more than 90% of patients died within two years due to rapidly progressive renal failure, and second most common cause was respiratory failure without tx With modern treatment (steroids, mtx, aza, rituxan, plasmapharesis) disease has changed from being universally fatal to being a chronic relapsing and remitting disease The first few weeks of treatment can be difficult because patients usually still have symptoms associated with vasculitis; frequent hospital visits and blood tests are needed to monitor disease activity and response to treatment. Patients are susceptible to infections particularly during induction treatment Prevent and tx for tx for ckd, osteoporosis, diabetes, cancer, cad, strokes, dvt, PCP, gerd Relapse can occur after many years in remission, patients often remain on indefinite follow‐up TA: inflamm  vessel pain  bruits and ischemia; young asian women; skip lesions like GCA; cardiac echo bc aortic aneurysms and phtn Risk of death for patients treated with current treatments is still 2.6 times higher due to infections and active vasculitis early on and infections, cardiovascular disease, and cancer later on

38 haematuria, mesenteric vasculitis Type I cryoglobulins: monoclonal immunoglobulins; underlying B‐cell lymphoproliferative disorder, usu Waldenström macroglobulinemia, multiple myeloma or monoclonal gammopathy of unknown significance Type II cryoglobulins: monoclonal immunoglobulin with rheumatoid factor associated with polyclonal IgG; chronic hepatitis C virus Type III cryoglobulins: polyclonal IgG and IgM with rheumatoid factor activity; hepatitis C, Sjögren syndrome and systemic lupus Mixed cryoglobulinemia lesions in HCV‐infected patients are often related to small vessel vasculitis induced by immune complex deposits  Fatigue, palpable purpura, arthralgia, pure sensory polyneuropathy to mononeuritis multiplex, proteinuria with microscopic haematuria and sometimes a variable degree of renal insufficiency; other < 5% like abdominal pains and gastrointestinal bleeding secondary to mesenteric vasculitis, mitral valvular damage, coronary vasculitis, interstitial lung fibrosis, pleural effusions or pulmonary intra‐alveolar haemorrhages. Defin dx: cryoglobulinemia in serum Cryoglobulinemia is confirmed by the detection of protein that precipitates in the patient's serum maintained at 4°C during at least 7 days, and dissolved when heated at 37°C Decreased early components (C1q, C2, C4) and CH50, with normal C3 level. Elevated RF, Hep C, SPEP Prognosis 63% at 10 years usu die from liver dz or infec Most common causes of death in HCV‐CryoVas are infection, end‐stage liver disease, cardiovascular disease and more rarely vasculitis and lymphoma/neoplasia Tx with direct‐acting IFN‐free antivirals, ribavirin + rituxan +/‐pharesis HCV‐CryoVas manifestations improve or disappear when a sustained clearance of HCV is achieved by use of triple HCV therapy combining PegIFN, ribavirin and a direct‐acting antiviral (DAA) (NS3/4A protease inhibitor, i.e. boceprevir or telaprevir) led to improved SVR rates but need to tx for 48 weeks

38 after stopping immunosuppression HCV: only 20% clear infec in adults; immune suppression meds do not usu cause progression of HCV but immune compromised host can accelerate progression like in hiv Current guidelines do not reflect that country of origin is most important risk factor for chronic HBV infection Screening all patients who are to receive immunosuppressive therapy more effective and is likely cost‐effective

Clinical features of polymyalgia rheumatica and giant cell arteritis Salvarani, Carlo MD Rheumatology Unit, Department of Internal Medicine 2012 Reggio Emilia, Italy Nature Reviews Rheumatology PMR and GCA occur together more frequently than expected by chance. PMR are pain and stiffness in the shoulders, and often in the neck and pelvic girdle. GCA is a large‐vessel and medium‐vessel arteritis with new headache, jaw claudication and visual loss due to transmural large vessel inflammation with skip lesions and multinucleated giant cells About 2/3 of GCA have headache, typically temporal, but can also be felt over other cranial areas, and is resistant to standard analgesia Total or partial visual loss affects up to 20% of GCA, mostly at disease onset GCA usu has fever, fatigue and weight loss About 1/5 of GCA develop large‐vessel involvement including arm claudication and arterial bruits; usually become apparent only 3‐4 years after onset of symptoms PMR pain is bilateral, worse at night and on movement, and usually radiates distally About 4% of patients with pure PMR have TAB lesions consistent with GCA; nearly 1/3 with pure PMR have subclinical large‐vessel arteritis on PET; suggest that PMR and GCA might represent two ends of same disease spectrum. Anticardiolipin antibodies can be increased in active GCA, but normalize after onset of glucocorticoid treatment Fundoscopy shows a ‘chalky white’ optic disc, a sign of infarction of optic nerve caused by vasculitis in GCA Ultrasonography visualizes well superficial branches of aortic arch including temporal arteries, although it cannot depict thoracic, and often abdominal, aorta (need CT or MRI); halo sign in temporal arteries specific and sensitive for GCA PET is useful in diagnosing early large‐vessel involvement in GCA Angiography show stenoses or aneurysms in GCA with large‐vessel involvement but lesions occur quite late (an average of 4 years) after diagnosis of GCA. Hallmark lesion of PMR is bilateral subacromial‐subdeltoid, trochanteric and cervical bursitis (MRI, usn, PET) About 12% of patients with PMR present with RS3PE syndrome Ddx: GCA r/o Takayasu, PMR r/o late onset RA, SpA, cancer

38 Tx GCA with high dose steroids but reduce to 10 mg qd by 3 months; tx PMR with 10‐15 mg prednisone qd; mtx as steroid sparing agent; IL‐6 receptor antagonist Tocilizumab may help in GCA; asa may prevent GCA‐related ischaemic complications. PMR and GCA usually remit within 6 months to 2 years from disease onset

Takayasu arteritis: an update Seyahi, E MD Division of Rheumatology, Department of Internal Medicine, Cerrahpasa Medical Faculty, University of Istanbul 2017 Istanbul, Turkey Current Opinion in Rheumatology TA is large vessel vasculitis of unknown etiology Recent evidence shows that disease can be seen in all ethnicities around world with increasing prevalence rates; so not so rare More common among young women and predominantly affects aorta and its major branches Involvement of thoracic aorta and its branches was more common among females, (aortic arch and its branches were mainly involved in Japanese patients whereas abdominal aorta and its branches were chiefly involved in Indian patients and lower abdominal aorta involvement was more common in African populations) vs males have a tendency toward limited involvement of abdominal aorta and its branches. Pregnancy seems to cause serious risks for both maternal and fetal health TA affects women of child‐bearing age, pregnancy itself without vasculitis carry considerable risk for cardiovascular and cerebral accidents, may flare‐up anytime during or after pregnancy, uncontrolled hypertension, myocardial infarction, congestive heart failure, and renal failure may lead to maternal comorbidity and mortality, preeclampsia and intrauterine death are frequent, medical management during pregnancy with antihypertensive agents or immunosuppressives/corticosteroids is challenging Frequently coexist with inflammatory bowel diseases Prevalence of IBD is around 6% in TA; both diseases have granulomatous histopathology; more likely to carry HLA B52:01 Assessment of disease activity in Takayasu arteritis is difficult. Conventional angiography used to be gold standard for dx but now CTA or MRA done; PET/CT Biological agents such as anti‐tumor necrosis factor agents, tocilizumab and rituximab could be used effectively in refractory cases but first line is steroids; methotrexate, azathioprine, leflunomide, mycophenolate mofetil, and cyclophosphamide also used Restenosis or occlusion risks are still high with vascular interventions. Mortality seems to be decreasing in recent years Reported mortality ranges between 3 and 21.0%

Thrombosis in vasculitis

38 Springer, J MD, Department of Rheumatic and Immunologic Diseases, Center for Vasculitis Care and Research, Cleveland Clinic 2013 Cleveland, Ohio Current Opinion in Rheumatology Venous and arterial thrombosis in vasculitis seen Inflammation can shift balance promoting a prothrombotic state Behcet’s dz increasing immune med decreases thrombosis but watch for hemmorrhage Most commonly have DVT in the extremities and superficial thrombophlebitis in asymptomatic patient But low rate of embolic phenomenon to lungs because of tight adhesions of peripheral thrombosis to venous walls Due to multifactorial causes Clots in AAV especially when dz active Risk of VTE in GPA was seven times the risk of VTE in SLE Statins, known for their anti‐inflammatory effects, have recently been recognized to have antithrombotic effects as well Risk of arterial thrombotic disease is also increased in GPA, MPA, and Churg–Strauss High prevalence of cardiovascular events soon after diagnosis suggests that active disease may play a role in triggering arterial thrombosis In EGPA eosinophils contain preformed protein‐containing granules that are released when activated; some of these proteins have known prothrombotic effects PAN have more DVT and PE GCA and TA use aspirin to prevent ischemic events Strokes with premature atherosclerosis related to endothelial dysfunction in TA and atherosclerosis in GCA

38 but prognosis of ILD is better than those with DAH in short term, but may be worse long‐ term High prevalence (32%) of pulmonary fibrosis in MPA that could occur as first clinical symptom of the disease Isolated cases of ANCA‐positive ILD have been recently described Currently there is no specific treatment for patients with ILD and AAV/ANCA‐positivity AAV may have more malignant neoplasms; nonmelanoma skin cancers; increasing incidence of lung cancer Behçet's syndrome can affect venous and arterial vessels of any size; can involve the entire pulmonary artery tree, leading to pulmonary artery aneurisms (PAAs), usually of large and medium‐sized arteries, and pulmonary artery thrombotic occlusions, in smaller branches PAAs are a rare manifestation of Behçet's syndrome, but they are leading cause of death; mainly in young men, after 5 years of dz onset; hemoptysis bc of rupture of aneurysm into an eroded bronchi. PAAs assoc with DVT and intracardiac thrombosis in Behcets Takayasu arteritis often involves pulmonary artery, but rarely at onset Lung involvement may be present in large proportion of patients with giant cell arteritis (GCA) Goodpasture syndrome is a rare dz with pathogenetic autoantibodies directed against glomerular and alveolar basal membranes presenting as acute renal failure, due to rapidly progressive glomerulonephritis, and pulmonary haemorrhage

38 mortality; polychondritis + oral and genital ulcers = MAGIC syndrome Mouth And Genital ulceration with Inflamed Cartilage GCA, TA, GPA, EGPA are the 4 granulomatous vasculitis

ANCA‐associated vasculitis Yates, Max Arthritis Research UK clinical research fellow, Norfolk and Norwich University Hospital NHS Foundation Trust, and Norwich Medical School, University of East Anglia 2017 Norwich, UK Royal College of Physicians AAV = granulomatosis with polyangiitis (GPA, previously known as Wegener’s granulomatosis), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA, previously known as Churg‐Strauss syndrome). GPA, MPA and EGPA have respective annual incidence rates of 2.1–14.4, 2.4–10.1 and 0.5– 3.7 per million in Europe More common in those aged over 60 years and slightly more common in men. GPA has nasal crusting, stuffiness and epistaxis, uveitis, upper respiratory tract involvement and often renal involvement MPA are typically older and present with more severe renal disease with rash and neuropathy EGPA typically presents with a multisystem disease on a background of asthma, nasal polyposis and peripheral blood eosinophilia. Rituximab in AAV has been tested in two randomised controlled trials: RAVE and RITUXVAS; In both trials, rituximab was non‐inferior to cyclophosphamide and appeared more effective for relapsing disease in RAVE; In the RAVE trial, a better response was seen in PR3 positive patients Definition of remission = no detectable disease activity; after successful remission induction, guidelines recommend withdrawing initial immunosuppressive agent and commencing a maintenance regimen with either azathioprine or methotrexate continued for at least 18–24 months before being gradually withdrawn MAINRITSAN (efficacy study of two treatments in remission of vasculitis) trial reported that rituximab 500 mg given at days 0, 14 and at months 6, 12 and 18 was more effective in remission maintenance than azathioprine regimen Mortality in first year is due to active vasculitis or infection, late mortality due to infection, cardiovascular disease and malignancy; 5‐year survival is 75%. Morbidity accumulates with time because of consequences of active disease and therapies.

38 39 40 NOW UNEXPECTED STUFF https://www.collectionscanada.gc.ca/obj/030002/f1/xx012028‐v6.jpg

41 XXXX

42 Oligoclonal expansions of plasmablasts are a good biomarker for disease activity. An oligoclonally expanded population of CD4+ cytotoxic T lymphocytes is found not only in peripheral blood but also at tissue sites of active disease. Dx by bx Tx with steroids, rituxan, abatacept Cancer 2.5 times more likely in; Prostate cancer bc affects middle aged and elderly men most IgG4‐RD patients with malignancy history develop IgG4‐RD at a later age and had higher serum IgG4 concentrations compared with subgroup without malignancy.

Rheumatology Secrets West, Sterling MD Professor, Medicine‐Rheumatology, University of Colorado Hospital 2014 Aurora, Colorado Class IV diffuse lupus nephritis hematuria + alveolitis = pulmonary renal syndrome in SLE TO: Young male smokers, biopsy may lead to ulceration, panvasculitis with highly cellular thrombus including microabscesses in thrombus and vessel wall Retroperitoneal fibrosis: 50 yo with flank pain and lower extremity swelling; tx with steroids 1‐3 years; need bx IgG4 RD: older men, bx of storiform pattern with fibrosis; pancreatitis, sclerosing cholangitis, sclerosing sialadenitis, salivary gland enlargement; can occur in any organ giving tumor but usu involved in one organ primarily, chronic lymphoplasmacytic aortitis; tx wigh high dose steroids, steroid sparing agent, rituximab Pulmonary renal syndromes = GPA, SLE, goodpastures

42 Lupus Class IV diffuse lupus nephritis hematuria + alveolitis = pulmonary renal syndrome in SLE Only 3 pulm renal syndr autoimmune dz = GCA (older male), SLE (younger female) and Goodpastures (younger male)

IgG4 RD Chronic fibroinflammatory condition with tumefactive lesions, dense lymphoplasmacytic infiltrates, and abundant IgG4‐bearing plasma cells in affected tissues Older men with prostate ca but has 2.5 rimes higher rate of ca Retroperitoneal fibrosis; usu found incidentally Dx by bx https://www.pancreapedia.org/reviews/extra‐pancreatic‐features‐of‐autoimmune‐ pancreatitis‐igg4‐related‐disease‐0 Stone, John. (2013). Extra-Pancreatic Features of Autoimmune Pancreatitis (IgG4- Related Disease) Pancreapedia: Exocrine Pancreas Knowledge Base, DOI: 10.3998/panc.2013.19

TO Smoking only way to resolve https://commons.wikimedia.org/wiki/File:55_year_old_female_with_advanced_Buerger% 27s_disease.jpg Onthelist [CC BY‐SA 4.0 (https://creativecommons.org/licenses/by‐sa/4.0)] Description English: 55 year old female with advanced Buerger's disease.

43 Date 9 February 2016 Source Own work AuthorOnthelist

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IgG4‐related disease Bozzalla Cassione, E MD Rheumatology Clinic/Yawkey 2, Massachusetts General Hospital 2017 Boston, Massachusetts Current Opinion in Rheumatology Chronic fibroinflammatory condition characterized by tumefactive lesions, dense lymphoplasmacytic infiltrates, and abundant IgG4‐bearing plasma cells in affected tissues Oligoclonal expansions of cells of both B and T lymphocyte lineages are present in blood of patients with IgG4‐RD. Once in bloodstream, plasmablasts differentiate into antibody‐secreting short‐lived or long‐ lived plasma cells, accounting for excess IgG4 production in this disease CD4þ CTLs are expanded in both peripheral blood and in affected organs and contribute to chronic inflammation T follicular helper (Tfh) cells contribute significantly to class switching of B cells Plasmacytoid dendritic cells important in dev of pancreatic inflammation through production of IFN‐alpha Oligoclonal expansions of plasmablasts are a good biomarker for disease activity. An oligoclonally expanded population of CD4+ cytotoxic T lymphocytes is found not only in peripheral blood but also at tissue sites of active disease. Dx by bx Tx with steroids, rituxan, abatacept Cancer 2.5 times more likely in; Prostate cancer bc affects middle aged and elderly men most IgG4‐RD patients with malignancy history develop IgG4‐RD at a later age and had higher serum IgG4 concentrations compared with subgroup without malignancy.

43 TO: Young male smokers, biopsy may lead to ulceration, panvasculitis with highly cellular thrombus including microabscesses in thrombus and vessel wall Retroperitoneal fibrosis: 50 yo with flank pain and lower extremity swelling; tx with steroids 1‐3 years; need bx IgG4 RD: older men, bx of storiform pattern with fibrosis; pancreatitis, sclerosing cholangitis, sclerosing sialadenitis, salivary gland enlargement; can occur in any organ giving tumor but usu involved in one organ primarily, chronic lymphoplasmacytic aortitis; tx wigh high dose steroids, steroid sparing agent, rituximab Pulmonary renal syndromes = GPA, SLE, goodpastures

43 APLAS Sister of lupus Lots of arterial and venous thrombosis

Relapsing polychondritis Rare; only 3 per million Usu present with auricular chondritis (red and very painful), nasal chondritis (painful swollen nasal brige), inflammatory eye dz in white female 40‐60  cauliflower ear, saddle nose Inflammation of cartilage anywhere Can cause aortic insufficiency (due to dilatation of aortic root) and trachel stenosis (due to inflammation of trachea) so monitor Seronegative, nonerosive, asymmetric oligo/polyarthritis Any size vasculitis can occur and poor prognosis Assocated with myelodysplastic syndrome

Saddle nose Description English: Typical saddle nose damage from GPA. Date 15 March 2016 Source Own work AuthorVw38 https://commons.wikimedia.org/wiki/File:Saddle_nose_38.jpg Vw38 [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)]

44 Cauliflower ear https://commons.wikimedia.org/wiki/File:623158.fig.001.jpg Description English: Ear inflammation with sparing of ear lobe in a person with relapsing polychondritis Date 31 May 2010 Source http://www.hindawi.com/journals/crim/2010/623158/ AuthorJohn C. Starr et al.

Sjogren’s Can be dz on its own or part of another dz Like lupus light

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44 AND NOW WE ARE DONE

ANY QUESTIONS? https://hiddencityphila.org/2018/02/on‐the‐hunt‐for‐brains‐discovering‐the‐wistar‐ institute/

The original Hewitt Brothers-designed Wistar Institute building in the late 1800s. | Image courtesy of The Wistar Institute

45 46 47 48 49 50 51 emedicine

52 emedicine