CHAPTER I2 AT\?ICAL PYODERMA GANGRENOSUM OF TFIE LOWER EXTREMITY A Case Presentation and Comprehensive Disease Overview

Gerard V Yu, DPM, FACFAS Robert M. Brarens, DPM Amanda Meszdt os, DPM

Pyoderma Gangrenosum (PG) is a destructive, inflamma- Von den Drieschr''' and75o/o by Bennett er al']ro the legs. tory skin disease first reported in 1916 as "phagedenisine Other variants include Pustular PG (a.k.a. Atypical PG geometrique" by Brocq. It was subsequently characterized (A?G)) that typically presents on the extensor surfaces of as PG by Brunsting, Goeckerman and O'Leary in 1930 the upper extremiry and trunk, Superficial Bullous PG and again in 7982.'''1 These authors have implicated (SBPG) generally presenting on the hands, neck and head, streptococci and staphylococci as the causative agents and Vegetative PG (a.k.a. Pyostomatitis Vegetans (\?G)) because of the seemingly purulent nature of the disease.' Of that presents in the oral cavity and genitais (all). Additional interest is after nearly 74 years the precise etiology of this forms include Malignant PG (MPG), Superficial condition still remains unclear. Multiple authors have Granulomatous PG (SGPG) and Familial PG (FPG). The suggested a noninfectious dysregulation of the immune variant's specific associated underlying disease predilection system as the primary etiology,3 while others have will be covered later in the text. hypothesized a possible genetic component.''3 Currently it is believed that PGt infectious involvement is secondary if CASE PRESENTHTION: present at all. Belonging to the dermatologic class of neutrophilic dermatoses, this pathologic condition should A 53-year-old Caucasian female presented June 2003 with be considered in a differential diagnosis of chronic non- a chief complaint of redness, sweiling, and exquisite pain healing ulcerations recalcitrant to normal therapies.' Since on the medial portion of the left ankle and adjacent the specific pathogenesis of this clinic entiry remain pretibial area. She related redness and pain beginning undefined, its management for the most part is empirically approximately one week prior at which time she sought based on clinicopathologic findings.'-3 medical assistance at the local urgent care center. She was Pyoderma Gangrenosum (PG) is a rare clinical diagnosed with cellulitis, given a short course of entity with a reported incidence of 1 in 100,000 persons Augmentin@ (Amoxicillin/Clavulanate) which she each year.t It has been reported to both be equai in completed. The erythema increased and a central bluish- distribution between the sexes,''a't with some authors purple blister developed that erupted some time during the I suggesting a preference of women to men 2'.7.2'6 week and began to express a seropurulent yellow discharge. Predominately presenting between the ages of 25 and 50, She related a fever of 100.1F the evening prior, but denies PG has been reported in both infants'r and children.'o chills, nausea, vomiting, diarrhea or generalized malaise. The associated prevalence of underlying systemic She denied any significant trauma to the area at this time. disease ranges from 50-7\o/o of affected patients with The patient was familiar to our service having Inflammatory Bowel Disease as the leading co-morbidity at previously undergone a subtalar joint fusion in 7997 for a reported incidence of 30o/o.2)t't Systemic disease onset treatment of left posterior tibial tendon dysfunction and however may precede, coincide, or follow the presentation adult acquired flat foot syndrome healing without of a PG lesion.' Death from PG is rare, generally occurring complication (Figure 1). At the time of her original surgery from complications of the associated disease or as a result her past medical history was positive for a single episode of ofits therapy. gout, rheumatoid arthritis (diagnosed in 1995), and Lupus There are four predominant variants of PG presently (diagnosed in 1995). Her Rheumatologist was managing accepted in the literature, the most common being the her medically on Plaquenilt, Voltaren'o and Prednisone. ulcerative form (UPG). UPG has a prevalence to the lower She was also treated conservatively for a Morton's extremiq, and trunk, with a reported incidence of 80% by neuroma in the right foot with complete resolution. CHAPTER 12 6t

Prior to presentation at our oflice for her current every 5-7 months since its original appearance. exacerbation, she had been managed by her primary care On her last hospitalizarion, in November 2002, she physician and had been hospitalized on multiple occasions was started on prednisone (80mg QD) for a suspected for the same problem, beginning December 99', in a vasculitis. She was referred to a dermatologist and a nationally known local tertiary care center where she second rheumatologist for further consultation. A two underwent several "complete workups" for this problem. week course of oral Levaquin@ was prescribed along with The patientt labs in December 99' were remarkable for an Iocal compressive dressings daily. At the time of her elevated platelet count of 498WuL, C-reactive protein consultation with the dermatologist her "cellulitis" had (CRP) of 4.lmgldl and erythrocyte sedimenration rate resolved completely minimizing the value of the consult. (ESR) of S3mm/hr. A CBC with differential was done and The rheumatologist questioned her previous diagnosis of within normal limits. An anti-nuclear antibody (ANA) rheumatoid arthritis (RA), and lupus, however believed panel of 0.2 and rheumatoid factor (RF) of iess than 20 there was an undefined underlying connective tissue were both considered negative. (Thble 1) She did have a disease, and continued the patient on 60 mg daily oral positive single light growth blood culture of coagulase Prednisone therapy for treatment of the connectiye tissue negative staphylococcus. An arthrocentesis ofher left ankle disorder for three and a half months. During this time her was unremarkable; cultures were negative. An MRI was leg remained symptom free, and without flare-up. She performed showing a subcutaneous effusion medial was taken off of the steroids due to a combination of and superior to the ieft medial malleolus with no bony significant weight gain and systemic side effects including involvement. She underwent rV antibiotic therapy with high blood pressure, headaches, and from Vancomycin while hospitalized and was discharged on oral prolonged steroid use. In June of 2003 (2 months after Dicloxacillin and advised to follow up with a rheumatologist. discontinuing steroids) she presented with increased She was seen for follow-up by a rheumatologist symptoms in the same area as the previous lesions. following discharge. He felt she had a cellulitis of The patientt current medical history is positive for unknown origin and suggested it was from the retained recurrent urinary tract infections, non-inflammatory hardware with possible osteomyelitis despite the negative generalized arthritis and a continuing questionable diag- MRI study. A three phase bone scan thar was interpreted nosis of RA, SLE, and inflammatory bowel disease (IBD) as subacute inflammatory arthrids involving the left rwo weeks prior to this visit. Her medications included proximal foot without significant focal abnormaliry noted Zolpidem, Propoxyphene, Hydrocodone, ketorolac, and over the left ankle. Clinical correlation was suggested. Her hormone replacement therapy. dicloxacillin and NSAID therapies were discontinued. Our physical examination on June 16th 2003 Although she was cleared of the concern of septic revealed an area of significant erythema and arthritis; he did feel the potential for osteomyelitis which was exquisitely painful to light touch making warranted treatment. A PICC line was established and examination essentially limited to our visual observation. a 6 week course of IV antibiotics was prescribed by (Figure 2) The erythema had nonspecific borders, infectious disease. In addition, the patient received an oral encompassing primarily the medial aspect of the ankle and prednisone taper. The "cellulitis" has been recurrent with Ieg. The mild calor was disproportionate to the severiry of episodes of complete resolution followed with a reoccurrence the clinical picture. There was a mild joint effusion with

Figure 1. STJ fusion completed in 1997 for the treatment ofAdult Acquired Figrrre 2. 6.16.03-Clinical presentation Nonspecific erythematous border. Flat Foor. Unevenrlul po\(operJri\e couh(. Three 0.5cm bullae without obsenable drainage and a yellow opaque crust proximally. CHAPTER 12

Thble 1

SUMMARY OF I-ABORAIORY FINDINGS IN THIS PAIIENT

Date Test Result Normal Values 12.12.99 synovial fluid analysis bloody, turbid clear, yellow o/oNeut = 80 0-25o/o no organisms on GS/C&S 12.13.99 \xtsc 10.65 4.0-1 1.0 k/ul PLI 4t9 150-400 K/uL 12.t4.99 Haptoglobin 3t4 37-246 mgldL LD 159 t00-220 ulL 72.15.99 \TBC 8.74 4.0-11.0 k/ul- PLT 457 150-400K/uL %Neut 65.t 40-70o/o o/oLymph 24.5 22-44o/o Albumin 3.5 3.5-5.0 gldL CRP 5) 0-1.0mg/dl Iron 20 30-140 ug/dl TIBC 301 210-415 ug/dl IronSat 7 11-46 o/o ANA 0.2 (negative) <1.5 OD ratio RF <20 (negative) <20IUlmL C3 complement 140 76-199 mg/dl C4 complement t5 16-64 mgldL 12.78.99 CRP 2.8 0-2.0 mgldL X-ray O for osteo MRI (-) for osteo 12.27.99 CRP 4.1 0-1.0 mg/dl ESR 83 0-30 mm/hr 12.30.99 triphase Tech-99 scan (-) for osteo 3.22.00 \TBC 6.55 4-1t.]kluL o/oNeut 54.40o/o 40-70o/o CRP ) 0-1.0mg/dl ESR 57 0-3Omm/hr C3 complement 96 75-t99mgldL C4 complement 14 r6-64mgldL 11.2001 ANA 1:640 positive, diffuse pattern ESR 173 0-30mm/hr Anti SS-A negative Anti SS-B negarive Anti double stranded DNA negarive 1.2002 ESR 71 0-30mm/hr serum protein electrophoresis polyclonal gammopathy 10.28.02 \7BC c)5 4-11.0 k/ul- CRP 10.1 0-1.Omg/dl ESR 95 0-30mm/hr ASO AB 22 <201 IU/mL

conrinued on nexr page CHAPTER 12 63

11.4.02 \xtsc l2 4-11.0 k/ul- PLT 530 150-400 K/uL ESR 84 0-30mm/hr ToNeut 58o/o 40-70o/o o/oLymph 32o/o 22-44o/o CRP 8.6 0-1.0 mg/dl 11.11.02 triphase Gch-99 scan O for osteo 4.t0.03 Lipid profile High cholesterol (205), high HDL (88) 6.23.03 wtsc 24.6 4-11.0 k/ul PLI 682 140-440 kluL o/oNeut 78.2 40-70o/o o/oLymph 16.2 20-30o/o ESR 77 0-30 mm/hr CRP t11 0-1.0 mg/dl X-ray (-) osteo GS/C&S normal skin flora teichoic acid Ab negative

grew out normal skin flora of staphylococcus coagulase negative light growth. Lipid profile was significant for elevated choiesterol of 205mgldl, and HDL of S8mg/dl. The teichoic acid antibody study was negative, The ID physician agreed with our assessment of the possible existence of an underlying vasculitis or granulomatous disease, and recommended a dermatology consult. Additionally, ID further supported our belief in a falsely elevated VrBC due to recent steroid utiiization. A normal bleeding time of 2.5 minutes was obtained that had been ordered as a precaution to her elevated platelet count. A TcggMDP scan revealed increased uptake in the medial ankle in the immediate and blood pool phases, with no increase in the delayed phase and was felt Figure 3. 7 days after initial presentation yielded increased erythema with a 4cm boggy bulla displaying irregular borders and peripheral yellow crusting. consistent with a cellulitis. The X-rays were negative for Gentle blunt ddbridement exposed a superficial ulcer with violet borders and any signs of osteomyelitis or changes around the retained fibropurulent bxe. fixation. The immunoglobulin electrophoresis returned with muitiple abnormalities; further analysis revealed a Five days later the patient related that the pain and positive IG-M polyclonal gammopathy. erythema had decreased significantly within the first 48 After further consideration of the extensive list of hours after starting the prednisone taper, but increased as differentials it was felt there was a high potential for PG as she completed the course of prednisone. Generally she the causative etiology. She was started on Minocycline was experiencing some GI upset, a metallic taste in her 100mg BID and 60mg prednisone QD. She responded mouth, decrease appetite and general malaise. The well with a decrease in erl,thema within 24 hours. She erythema had increased from the previous visit with the remained afebrile throughout her hospital stay with the bulla expanding in size to 4 cm with an irregular border severity of the pain decreasing slighdy however she began and persistent seropurulent discharge with yellow presenting with increased neuritic symptoms consistent peripheral crusting. (Figure 3) Gentile blunt ddbridement with the sural nerve distribution. She was started of the bulla exposed a superficial ulcer with violet borders on Neurontin 300mg TID in an effort to provide and fibropurulent base measuring 4cm in diameter. The symptomatic relief, 1VBC entire distal medial leg and foot continued to be Her decreased to 12.8K/uL, the ESR was exquisitely painful with a shiny taught appearance to the 5Smm/hr and CRP at 3.2 mgldl. Based on the clinical skin adjacent to the lesion. No lymphadenopathy or presentation of her leg, positive IGM polyclonal lymphangitis was present; she remained afebrile at 36.3C. gammopathy, suspected connective tissue disorders She was admitted for cellulitis with possible underlying (IBD/RA/Lupus) and response to systemic steroid osteomyelitis due to the increased clinical picture severity therapy, a diagnosis of Atypical Pyoderma Gangrenosum and patients generalized symptoms of malaise. was made. She was discharged home on 60mg prednisone Upon hospital admission a full blood workup QD, Neurontin 300mg TID, and Darvocet N100 for including an ANA, ASO, RF, Lipid profile, CBC with pain. ID decided to discontinue her minocycline, and differential, BMP, C-reactive protein, ESR, teichoic acid continue her on Vancomycin 1gm IV QD via PICC line, antibody study, and immunoglobulin electrophoresis to Levaquin 500mg PO QD for another two weeks as a check for monocional gammopathy was ordered. precaution. She was to be followed by ID along with our Additionaliy a new wound swab was obtained for C&S service and to obtain a dermatology consult. and gram stain; conventional x-rays, TcggMDP bone On July 2nd, two and a half weeks since admission scan, and infectious disease (ID) consult were obtained. to the hospital she was seen in the office with a significant She was started on IV Vancomycin, and Zosyn per ID. decrease in the erythema. (Figure 4) The ulceration was Her lab work was significant for a \WBC of stable in size with no active discharge. The borders 24.6KltL with neutrophil count of 78.2o/o and a remained irregular with some exfoliation and persistent Iymphocyte count of 76.20/o. Her platelet counr was yeliow peripheral crusting. Her pain had significantly 6B2KluL, ESR of 77mmlhr, and CRP 13.3 mg/dl. Her decreased and we were able now able to palpate her leg RF, ASO, and ANA were negative. The gram stain with minimal discomfort. indicated no organisms or \7BCs seen; the wound culture By July 9th her ulceration had completely resolved CHAPTER 12 65

patient was emotionally upset. The patient had also seen the vascular surgeon prior to her reoccurrence and had been told that she had venous stasis dermatitis, and to continue compression therapy. She was confident the above trauma had triggered the recurrence. It was felt by our team that the clinical presentation was more consistent with APG. This was based on the initial clinical appearance of the lesion, its clinical course and response to therapy, the recent display ofpathergy, and now its significant exacerbation with additional iesion appearance. The patient was placed on Dapsone 150mg QD, and the prednisone was increased to 40mg daily. \found care would consist of Siivadene dressings under compression to be change daily. Figure 4. 7.2.03-Significantly decreased erythema. Ulceration had stabilized with no active discharge. Borders remained irregular with mild exfoliation and As of September 2003, the patient has remained persisrenr yellou peripher.rl \ ru5ring. asymptomatic. Her lesions have healed and she has returned to work. She continues to take the dapsone and has tapered off of the prednisone. She is maintaining compression to the lower extremities with Jobst stocking.

DISCUSSION

Etiology Nearly 75 years of clinical awareness of PG as a specific clinical entiry exists, yet its precise etiology remains unclear. This is due in part to an inconsistent tendency of pyoderma gangrenosum to present concomitantly with underlying systemic disorders. 50o/o of patients with diagnosed PG do not have an underlying comorbid systemic condition. those who do have a confirmed Figure 5. 7.9.03-Complete resolution of ulcer with characteristic depressed, Of hypo pigmented scar. Only a r.ery mild erythema persisted. comorbid condition, the range of conditions is quite impressive. (Thble 2) The most consistent of these are the and a depressed, hypo pigmented scar developed with Inflammatory Bowel diseases with ulcerative colitis leading only a very mild erythema persisting. (Figure 5) ID the list.3 Other common pathoiogic conditions include agreed with our diagnosis and discontinued all Crohn disease, rheumatoid arthritis, leukemia and antibiotics. She was asymptomatic and pain free. The myeloproliferative disorders.2'3'12 Several theories have been patient was anxious to taper off of the steroids due to her proposed as to the actual etiology of this rare ulcerative previous experience with sustained high doses. With near disease, all of which are suggestive of either a vascular or complete resolution of the lesion, a tapering of her immunologic etiology. prednisone was begun with intention of decreasing 1Omg The concept of pathergy, or the tendency to form weekly as long as she remained asymptomatic. A vascular new lesions in sites of minor or severe trauma, is thought consult was also obtained for recurrent vasculitis and any to represents an exaggerated immune response. It is further insight that might be offered. unknown whether it is of vascular or immunologic origin. The patient remained asymptomatic until August Those that believe this disease to be of immunologic 20th when she presented with a severe reoccurrence of the origins site PG's response to cyclosporine, an immuno- ulceration to the same area after dropping a frying pan on suppressive drug, as an indicator suggesting a disturbance her foot. The lesion measured 3.5cm with an irregular in immune cell function.3'" Further supporting the border and the same yellow seropurulent discharge. dysregulated immune theory is PG's association with a Additionally, she was beginning to develop the same number of autoimmune diseases. However, there remains symptoms on the contralateral limb with a 3mm bulla insufficient evidence to support these claims.'''3 present centrally. Both were exquisitely painful and the Another proposed mechanism associated with altered 66 CFIAPTER 12

second hypothesis as to a possible vascular basis is venous Table 2 hypertension. Samitz et al propose that extravasation of an "unknown circulating agent" through venule walls leads to ASSOCIAIED SYSTEMIC CONDITIONSI',' sequestration of the "unknown agent" in the interstitial layers of the skin, causing necrosis and ulceration.'a Ulcerative colitis = 50% Khandpur et al offer more complex, mixed Crohn'.s disease a etiology defining pyoderma gangrenosum as a syndrome Hepatic disease = Active chronic hepatitis Primary biliary cirrhosis of acute vascular insufficiency to the skin secondary to Sclerosing cholangitis Iympho-toxicity. They concluded that immune complex Carcinoid deposition leads to vascular infarcts and subsequent ulcer- Diverticulitis ation. Their theory is supported by the typical Myeloproliferative disorders findings of immune reactant deposition on immunofluo- Rheumatic = Polyarthritis rescence testing and visibie features of vasculitis on light Rheumatoid arthritis microscopy.t3 Ankylosing spondylitis Some authors have elucidated to a possible autosomal \Tegener's granulomatosis recessive mode of inheritance.'3 Though literature in the Behcett syndrome area of familial predisposition is extremely limited, a case of Paraproteinemia (multiple myeloma) pyoderma gangrenosum in siblings with unaffected parents Drug reactions has been presented. The authors suggested a probable Delayed altered hypersensirivi ry Takayasu arteritis etiology of genetic surface glycoprotein deficiency of the leukocytes Suppurariva hiraden i ris resulting in impaired chemotaxis, phagocposis Cryoglobulinemia and aggregation.l3'r8'1e In spite of numerous articles and Autoimmune anemia papers offering various hypotheses, none of them have sufficient clinical evidence to substantiate their theories leaving the exact etiology of pyoderma gangrenosum a immunologic response is akin to rhar of the Schwartzmarr continued enigma. reaction. It is hypothesized that the PG lesions are comparable to skin graft rejection reacrions in which a Clinical Manifestations combination of intravascular coagulation and altered On initial presentation the lesions of UPG, the most immunoglobulins Iead to the necroric ulcerations.'a common form of the disease, appear as moderateiy painful Additionally, it has been shown that by increasing levels of papulopustular lesion(s) or which eventually IL-B expression on human fibroblasts in mice with a ulcerate, giving rise to a dark, duslq. lesion characteristic of combined immunodeficiency syndrome having under- the disease. The mature lesion typically exhibits marked gone human skin grafting, massive infiltration of edema with a raised undermined red to purple border neutrophils resulted. This infiltration led ro ulceration surrounded by a strikingly erythematous halo as the which both clinically and histologically resembled ulceration advances.3''o The base of the lesion is typically pyoderma gangrenosum.3''5''6''7 boggy and necrotic with multiple scattered sterile abscesses Immunofluorescence testing has offered no producing a purulent andlor hemorrhagic exudate.' UPG additional conclusions with only 10o/o patients of can present as a solitary expanding lesion or multiple diagnosed with pyoderma gangrenosum displaying an IgA smaller lesions that typically coalesce into a larger lesion type monoclonal gammopathy. Though also suggestive with irregular borders. In rare cases, the disease begins in of an immunologic etiology, further resting also the subcutaneous tissue as a tremendously painful substantiates a vascular etiology in which 50% of patients panniculitis which eventually produces purulent bullae and show perivascular deposition of C3 and IgM, both are ulcerate, spreading circumferentially to again produce the generai indicators of a non-specific vasculopathy" adding characteristic lesion.' yet another variable to the equation. The data regarding distribution of UPG between the Though the basis of the close relationship between sexes is inconclusive. It has been reported to both be equal GI disease such as ulcerative colitis and Crohnt disease to in distribution,''ar and to favor women to men 2'l.z'6't'8 pyoderma gangrenosum is unknown, a vascular etiology is Predominately presenting between the ages of 25 and 50, again suggested based only on the inflammarory nature of PG has been reported in both inftntsl2'6'7'8'e and children.'o these disorders without any research to supporr it.'a A UPG has a prevalence to the lower extremity and trunk,"r'' CFIAPTER 12 67 though they can present anpvhere on the body, with supposition he believed that the possibility of neutrophilic approximately 57o/o of patients presenting with more than infiltration of organ systems potentially contributed to the one lesion.'' The oral cavity, larynx, pharynx, vulva, cervix elevated mortalify rate.'3''4 and eyes occasionally exhibit massive ulcerative A second variant is Superficial Granulomatous PG involvement.3 If the lungs become involved they may (SGPG). It is generally characterized by its non-aggressive produce pulmonary infiltrates that are culture-negative.2'10 nature and its tendency to follow a chronic, Iimited The clinical progression of pyoderma gangrenosum course." Initially appearing as an abscess-like lesion, it typically follows two general patterns.3 1: An aggressive develops into a violaceous superficial ulceration with a and rapid onset of quickly spreading ulcerations with the strong predilection for the trunk, back and buttocks. The patient potentially showing signs of toxiciry including ulcers show a relatively clean base and vegetative wound significant pain, fever, highly inflammatory ulcers with margins. SGPG lacks any strong association with extensive necrosis and exudate, and multiple hemorrhagic systemic disease; however, it does exhibit pathergy and blisters. 2: An indolent slowly progressing disease usually appears at sites of previous surgery or other characterized by considerable granulation tissue at the traumatic stimuli." This form of pyoderma carries a more wound base with a hyperkeratotic rim and crusting at the favorable prognosis than other forms and generally wound margins. Both forms may demonstrate responds well to more conservative treatment options, as spontaneous regression resulting in a classic thin, was rhe case with our patient. atrophic, stellate hypo-pigmented scar like those seen in Malignant PG (MPG) differs from the traditional Atrophie Blanche.' form in that it presents as multiple small ulcerations of the AII variants of PG may exhibit the phenomenon of scalp, face and neck which slowly spread to encompass the pathergy. Simply defined, it is the development or trunk and extremities as well. The ulcers are rather typical exacerbation of new or existing lesions following minor in appearance, being necrotic in nature but are small, trauma or aggravation.s]2)l'D Pathergy is reportedly present 2-4 cm in diameter, with smooth, not irregular in 20-30o/o of PG patients .3 However, the possibility of its wound edges and are accompanied by erythematous presence has lead most authors to an aggressively papulopustular lesions.'6 This variant affects younger minimalist approach to ulcer ddbridement, some stating adults, ages 15-45, and lacks any correlation with systemic that an existing PG lesion is an absolute contraindication disease. It can however induce temporary neurological to surgery.2'3''a dysfunction, for example sensorimotor loss and cranial nerve palsies. Histologically, pseudo-acantholytic changes Clinical Variants are indicative of this malignant form.'6 With prompt systemic treatment, complete remission The most typical variant, Ulcerative PG, described above initiation of is possible. accounts for the vast majoriry of al1 cases reported in the The variant of PG (VPG) is closely Iiterature. There are, however, several atypical variants. Vesiculopustular associated inflammatory bowel disease. Hemorrhagic bullous pyoderma gangrenosum differs from with It rypically presents as painful, small pustular lesions with an the traditional ulcerative disease in that it is characterized erythematous inflammatory border arising on otherwise by rapidly arising dark bullous plaqueJike lesions.'r3''a The normal skin. It has a predilection for the extensor surfaces lesion eventually ulcerates but remains more superficial trunk.'o The lesions usually recede than typical UPG lesions. These atypical lesions very of the arms and upper treatment of the underlying GI disease. closely resemble the violaceous plaques associated with with proper Lastly, may arise as a vegetative form, or Sweet's syndrome or acute febrile neutrophilic dermatosis PG pyostomatitis vegetans. This variant affects adults only potentially making a clinical diagnosis difficult.' This rare oral mucosa and trunk only.'o variant is frequendy associated with leukemias and and usually involves the lesions superficial necrotic ulcers and myeloproliferative disorders; therefore, any suspected The begin as progress exophytic vegetative lesion. malignancy should be a primary concern when evaluating gradually to an notable feature this syndrome, unlike in typical a patient who presents with the bullous form of this A of ulcerative pyoderma, is that the wound edges do not have disease.\'3''a A confirmed diagnosis of bullous pyoderma an undermined inflammatory border.'o bears a poor prognosis and usually progresses on a parallel course with the underlying hematologic disorder. Koester, et al reported an 82.5o/o mortaliry rate in the presence of Histopathology underlying systemic disease with death occurring at an tMithin the PG lesion there are generally three distinctly average of 7 months from time of diagnosis. \With further different histological areas. Centrally, a necrotizing 68 CHAPTER 12

suppurative inflammation surrounded is present Table 3 peripherally by a region of lymphocytic and perivascular infiltrates. Transitionally, vessel involvement may be DIFFERENTIAL DIAGNOSES21,2O,19,8 absent, but in fully developed lesions may present as focal vasculitis or fibrinoid necrosis.'2,'o In the vesiculopusrular Infection: variant, associated with ulcerative colitis or hepatobiliary Bacterial infection (i.e. Syphilitic gumma, disease, the central nidus is often composed of a Necrotizing fasciitis) necrotizing pustular folliculitis. In contrasr, the superficial Mycobacterial infection (i.e. granulomatous lesion is comprised of pseudoepithelioma- Deep fungal infecrion North American Blasromycosis) tous hyperplasia with suppurative dermal inflammation Parasitic infection (i.e. cutaneous amebiasis) marked by the presence of eosinophils and plasma cells.'',,t Viral infection (i.e. chronic ulcerative herpes simplex) APG is distinguished by a diffuse neutrophilic dermatitis Ti,rberculosis Gumma without primary vasculitis.' Anthrax Histological findings in pyoderma gangrenosum are Vascular Diseases: Venous insufficiency considered essentially nonspecific, aiding only as a Arterial insufficiency function of exclusion toward a definitive diagnosis. Most Thrombophlebitis with gangrene authors describe an intense neutrophilic infiltrate with Antiphospholipid antibody-associated occlusive potential predilection for follicuiar srructures. The disease principal invading cell associated with the pathology of this Vasculitis associated syndromes: disorder is the neutrophil leading to the classification of Systemic Lupus Erythematosus Atrophie Blanche PG as a neutrophilic dermatosis.r In differentiating Behget disease pyoderma gangrenosum from other neutrophilic \7e gener granulomatosis dermatoses, such as Sweett syndrome, PG typically Rheumatoid arthritis presents with a deeper more exrensive infiltrate, the Polyarteritis nodosa presence of pustular vasculitis with involvement of the Collagen vascular disease (i.e. RA, SLE) Necrotizing Vasculitis reticular dermis and subcutaneous tissue. Biopsy is Hypersensitivity vasculitis (i.e. leukocytoclastic reported be minimal to of aid to the practitioner in vasculitis) reaching the final diagnosis of pyoderma gangrenosum. Malignancy: Cutaneous T-cell lymphoma Diagnosing pyoderma gangrenosum Squamous cell carcinoma Basal cell carcinoma Pyoderma gangrenosum is a diagnosis of exclusion after Kaposi's Sarcoma similar lesions caused by infection, rrauma, diabetes, Melanoma malignancy, vasculitis and collagen vascular diseases have Angiosarcoma been ruled out. Several differential diagnoses musr be Metastatic carcinoma Verrucous carcinoma considered when evaluating a patienr for possible Endocrinologic Diseases: pG.1,z,3,ro (Thble 3) Diabetic foot ulcer Laboratory testing for pyoderma gangrenosum also Ulcerative necrobiosis lipoidica diabeticorum plays an exclusionary role. The initial evaluation should Hologenoderma: focus on identifying the presence or absence of secondary infection via gram stain and rourine cultures. If a chronic Iododerma Other: infectious process is suspected (i.e. chronic osteomyelitis) Insect Bites (i.e. Brown Recluse spider) plain film radiographs, triphasic or '}(/BC labeled bone Aphthous stomatitis scan and MRI should be considered. Leukocl,tosis and an Sweets Syndrome (Acute febrile neutrophilic elevated erythroclte sedimentation rate are consistently dermatosis) present; however, they are neither specific nor diagnostic of Factitial ulceration Drug (i.e. overdose) pyoderma gangrenosum. In addition, C-reacrive protein Reaction barbiturate Sickle cell disease may be elevated, anemia and iron deficiency may or Psychosomatic disease may not be identified and the presence of hypo- or hyper- Churg-Strauss Syndrome (a.k.a. Allergic globulinemia may occur.3 Suggested diagnostic tesrs Granulomatosis) include an exclusionary 2-section biopsy for histological Acute febrile neutrophilic dermatosis evaluation and culture as well as studies to confirm the Post-op gangrene Ecthyma gangrenosum Pemphigus Vegetans CI-IAPTER 12 69 diagnosis of a concomitant systemic disease, for example, Table 4 GI evaluation, CBC and bone marrow, preps for RA, ANA, SLE, serum protein electrophoresis, cryoglobulins, DIAGNOSTIC TESTING FOR VDRL, serum bromide/iodide and evaluations for delayed-type hypersensitivities.la'20 Minimum recom- PYODERMA GANGRENOSUM mended laboratory testing of a suspected new onset PG CBC patient including other diagnostic modalities are presented CMP as a guideline. (Thble 4) ANA RF Treatment Hepatitis profile Rapid plasma reagent The management of pyoderma gangrenosum is challenging, Serum protein electrophoresis often involving the combination of several topical and Urinalysis systemic therapeutic modalities. The combination of disease VDRL rariry and general lack of an understanding of its true Antineutrophil cytoplasmic Ab test CXR pathogenesis causes increased difficulry when attempting to Complete GI evaluation (upper and iower GI) provide the most effective treatment options. The prognosis Biopsy for microbiologic and histologic examination for a patient diagnosed with pyoderma gangrenosum is CRP entirely dependent on prompt recognition of the entity ESR and initiation of treatment. fleatment begins with a X-rays (if indicated) comprehensive therapy regiment for the underlying MRI / bone scan Bone marrow aspiration disease when applicable.'r' associated systemic Serum bromide / iodide Local wound care may be effective in mild, early Total iron stage pyoderma gangrenosum in conjunction with topical therapy. tWet-to-dry dressings, bio occlusive semipermeable dressings, rest and elevation serve to promote daily, wifi a slow gradual taper employed to discontinuation reepithelialization and improve symptoms. Proper wound after the lesion has completely resolved. It is imperative that care also serves to enhance and prolong the function of the cessation of steroid utilization occur gradually, and topical medications, for instance, potent topical steroids. under diligent supervision, for if withdrawn to quickly can In regard to lesion ddbridement one must remember PGt lead to reoccurrence with potential severe exacerbation. The tendency for pathergy. Removal of only the loose adverse effects of long-term usage of systemic corticosteroids peripheral sloughing skin is recommended over aggressive may be avoided by also administering steroid-sparing agents sharp ddbridement wound therapies. know to have an antiinflammatory effect.3'" Topical applications of corticosteroids have been Dapsone and other sulfa drugs, like prednisone, are shown to dramatically improve early stage lesions but are very widely utilized in the treatment of pyoderma deemed ineffective in advanced or recurrent lesions.''3'" gangrenosum.zr':o They are not relied upon for their Intralesional injections of corticosteroids or cyclosporine antimicrobial action but rather utilized because of their has proven not only to hasten healing but to actually halt effects in altering neutrophiiic function and their actions the progression of even advanced ulcers when used as an as anti-inflammatory agents.'6 Dapsone has proven adjunct to systemic therapies.2r'2t''e Thcrolimus, formerly successful as a solitary agent in mild disease in dosages of F-505, has shown promising results in clinical trial as up to 400 mglday. In aggressive, severe cases, dapsone a topical therapy not reliant on concomitant systemic may augment the function of tapered or pulsed treatment.3 Other topical options include hyperbaric corticosteroids and intralesional steroids as well."'30 oxygen, nicotine patch, and sodium cromoglycate, all of Recalcitrant or severe disease has been successfully which have not been well-studied. A sumrnary of topical treated with immunosuppressive medications, most treatment modalities is provided. (Thble 5) notably cyclosporin, an immunosuppressive 2gen1.:t':u-:+ Systemic corticosteroid therapy is generally required in Still, immunosuppressive agents are most effective when cases of severe disease remaining one of the most combined with corticosteroid therapy.3'28'2e'32'34 A complete successful methods studied.l"" The administration of list of successfully employed systemic treatment options corticosteroids halts fie advancement of existing ulcerations for pyoderma gangrenosum is provided. (Table 6) while preventing the development of new lesions.3 Initially, Surgical intervention as a treatment for pyoderma high doses of prednisone are recommended, 100-200 mg gangrenosum is an area of contention. Most authors agree 70 CHAPTER 12

that any ddbridement or arrempt at skin grafting brings again falls on clinical suspicion and exclusion. a significant risk for promoting exacerbation or new ulcera- fleatment is another missing piece of the puzzle. The tions due to PGt associated pathergy, discussed earlier.l2s most definite protocol for successful treatment is defined If surgical intervention is required due to an underlying when caused by a treatable underlying condition. The systemic illness, the most widely accepted srrategy includes tteatment of PG itself both systemically and locally is based delaying any non-emergent surgery until the course of on high dose steroids and/or immunosuppressive agenrs. ulceration has remised. This preferential delay also applies to Glucocorticoid therapy remains the gold standard of the patient still being treated with anti-inflammatory and/or therapy, with Cyclosporine becoming increasingly more immunosuppressive agents.3,28,2e,35 Others believe the effects popular. However even these drugs are not considered of pathergy can be avoided with aggressive, yet careful effective 100o/o of the time, Ieaving the trearment if unsuc- ddbridement and allogenic skin grafting employing careful cesslirl ro trial and error. plastic closure techniques thereby minimizing any additional Our treatment course would seem to us typical of a puncture trauma to the skin.35 patient with this disease having undergone nearly 4 years of combined therapy without a definitive diagnosis. One can CONCLUSION appreciate the.difficulty the previously treating physicians would have had in. attaining an appropriate diagnosis based PG as a disease entiry remains one of many pathologic on the subclinical presentation they were faced with. 'X/e manifestations without a defined etiology, or diagnostic believe the reason she had not expressed the full extenr of criteria. Its diagnosis is based on its clinical appearance and the disease prior to the June 2003 presentation was her course of presentation. The presence of underlying systemic preexisting oral antiinflammatory therapies for RA/SLE. comorbidity can aid the practitioner by cluing him in the This would also explain her ability to abate and heal the right realm of differential diagnoses, however with the lack partial eruptions without focused appropriate rrearmenr. It of this co-association in as many as 50o/o of the patients it was shortly after her discontinuation of the Plaquenil@,

Thble 5

LOCAL THERAPY FOR PG3,27,2e

Modaliw Dose Time to Healins Notes Intralesional triamcinolone 3-8 weeks skin atrophy if concentration corticosteroids acetonide 6-40mglml >1Omg/ml, more successful in small ulcers, must avoid introducing infection Topical corticosteroids beramethasone Iittle literature exists, l7-va,lerate lotion 0.1% ineffective in most parienrs

Topical 5- 10olo cream dailv/ 5 weeks suppresses leukocyte motility aminosalicylic acid and cytotoxiciry Topical sodium 2%o aqueous solution 3 weeks cromoglycate Intralesional 35 mg, twice weekly 12 weeks adverse .gfs61 = pain cyclosporine Thcrolimus (FK506) inhibits transcription of pro-inflammatory cytokine genes in T-cells Granulocyte may acr by correcting the local defe.i in macrophage colony chemotaris and medlator release srimrrlerino fecror Nicorine Hyperbaric oxygen 80+ treatments promotes healing, relives pain, permits successful skin grafting Topical nitrogen mustard 20o/o aqueots solution 12 weeks CHAPTER 12 7t

Thble 6

SYSTEMIC TREAIMENT OPTIONS'J5

Glucocorticoid-DOC Prednisone l-3 mglkglday PO. Taoer as condirion resolves. Withdraw 'th.r.py Decrease to approximately 75o/o of of to quickly generally results in initial dose, or to minimum level a reoccurrence, and possible severe controlling disease process. exacerbation. May require low dose maintenance therapy to control disease processes. Methylprednisolone To be considered in severe cases quickly 1 em/day IV X 5davs gain conrrol oFrhe disease process. ( Pirlsed Suprapharmacologic doses) Parienr then either placed on oral sreroid therapy or preferably to a non-steroid medication Immunosuppressive Agents Cyclosporine A Considered by some to be the primary 5-10 mg/kg/day PO/IV DOC for treatment of PG when using rhis class of drug. Most advantageous after/ or in combination wirh glucocorticoid therapy. Tapered in same manner as steroids. Thalidomide (Thalomid) Steroid sparing function. 100-300mg/d PO Azathioprine (Imuran) Allopurinol increases effects. Steroid L-2mglkglday PO sparing function. (50-200ms) Methotrexate Steroid sparing function 70-25mg PO/IM/IV q wk Mycophenolate mofetil Steroid sparing function 1-2glday PO Tacrolimus ( raf) Do not administer simultaneously with 0.05mg/kg/da Ior cyclosporine; tonic clonic seizures may 0.15-0.30m d"y PO BID occur Antimicrobials Dapsone Steroid sparing function 100-300mg/day PO Sulfasalazine (Azulfidine) 2gldPO divided QID Steroid sparing function Clofazimine (Lamprene) 100mg/d PO Dapsone may inhibir anti-infl ammatory effects of clofazimine Minocycline 100mg/day PO BID Steroid sparing Others Plasmaphoresis Skin graft Autogenous graft not recommended due to pathergy

Voltarent and prednisone that there was a full presentation a specific clinical entiq/. For examPle, venous stasis ulcers of the disease process. Howeve! even with the complete are usually preceded by a well know and easily recognized clinical picture some of the treating physicians remained venous insufficiency with chronic pitting edema and skeptical of our diagnosis until clinical cure was achieved typical pigmentation changes. Our patient had no such utilizing her current appropriate therapy. findings or complaints. In addition, she healed unevent- One should be suspicious of this clinical entity and fully from her original foot surgery with no issues of other atypical ulcerative disorders when the clinical prolonged edema as a post operative complication. presentation does not follow a "normal" clinical course for Arterial ulcers are typically exquisitely painful, 72 CHAPTER 12

punched out lesions with a classic presentation that is not 9. Glass AT et al. Pyoderma Gangrenosum in infancy. J Amer Acad suppurative in nature. Typically located on the medial Dermatol 1991;25 109. 10. Choucair MM, Fivenson DP. Leg Ulcer Diagnosis and pretibial area this was a consideration early in the patientt Management. Dam Clin 2001;19 :659 -7 8. presentation. patient's as Our diagnosis became clearer we 11.Holt PJA et al. Pyoderma Gangrenosum: Clinical and Laboratory further investigated and researched potential etiologies. Findings in 15 patients with special reference to polyarthritis. Diligence and persistent search yielded the diagnosis of Medicine (Baltimore) l9B0 ;59 :114-23. PG. With the exception of one consuhant, all other 12. "Pyoderma Gangrenosum". Elder D, Ed. et al. Levert Histopathology of the Skin, Eighth Edition. Philadelphia: Lippincom-Raven; 1997. individuals involved in her care agreed that this was not a l3.Khandpur S, et al. Pyoderma Gangrenosum in two siblings: a problem, and that there appears to be an underlying rypical familial predisp osition. Ped Derm 2001;18:308-12. atypical connective tissue disorder componenr as 14."Pyoderma Gangrenosum". Samitz MH, Ed. Cutaneous Disorders conventional treatment of ulcers had proven unsuccessful. of the Lower Extremities. Philadelphia: J.B. Lippincon;1981. Her predictable and rapid clinical response to rhe rreatment 15.Oka M, et al. Interleukin-B overexpression is present in pyoderma of PG, once initiated, was impressive and convincing that gangrenosum ulcers and leads to ulcer formation inhuman skin xenografts. Lab Inuest 2000;80: our suspected diagnosis was correct. Her family history, 595. l6.Shapiro D, et al. Pyoderma Gangrenosum successfully treated with particularly the similar lesion appearing on her sister, added perilesional granulocyte macrophage colony stimulattngfactor. Br J additional weight against a typical venous or arterial Dermdto I 1 998; 1 3B:369. ulcerative disorder. \X/hile a biopsy may have been of some 17. Shore RN. Pyoderma Gangrenosum, defective neutrophil additional value, we chose not to perform one based on chemotaxis and leukemia. Arch Dermatol 1976;112:792. the inconclusive findings reported in the literature and 18.Al-fumawi S, et al. Familial pyoderma gangrenosum presenting in infanry. Eur J Pediatrics 1996;155:759-62. our concern of causing additional trauma to the area 19. Miller M, Dooley R. Deficient random mobiliry, normal chemotaxis potentiating a pathers, response. and impaired phagocytosis. A new abnormality of neutrophil \7e also considered more likely etiologies including function. Pediatr Res 1973;7:365. insect bites, factitial ulceration, and metal reaction from the 20."Pyoderma Gangrenosum". Habif, Thomas P, Ed. Clinical retained fixation devices. However, the history physical D ermato logt 3rd Edition. St. Louis:Mosby: 199 6. 21 . Mlika RB, et al. Pyoderma Gangrenosum: a report of 2l cases. Int examination, and clinical course were not consistent with J Derm 2002;47:65-8. any ofthese potential diagnoses. 22. "Pyoderma Gangrenosum". Dockery GL Ed., et aI. Cutaneous Finally, chronic lesions of any q/pe must always be Disorders of the lower Extremity. Philadelphia: \7.B. Saunders; 1997. suspect for ma-lignancy. A number of malignant skin 23.Koester G, et al. Bullous Pyoderma Gangrenosum. J Amer Acad lesions should be considered in the differential including Dem 1993;29875-8. squamous cell carcinoma, malignant melanoma, and 24.Ntunay IK, et a1. Atypical Bullous Pyoderma Gangrenosum. Int J Dem 2007;40:327-9. Kaposit sarcoma. A biopsy would be appropriate and 25.Miralles J, et al. Superficial Granulomatous Pyoderma,. Cutis essential to confirming a diagnosis and providing 2000;66:277-9. appropriate treatment recommendations. 26.Fldi H, et al. 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