Wegener\'s granulomatosis presenting as pyoderma gangrenosum

Cameo Oxford, UK International IJD Blackwell 0011-9059 45 Science, Publishing Journal LtdLtd, of Dermatology 2003

Cutaneous Wegener’s granulomatosis (malignant pyoderma) in a patient with Crohn’s disease Cutaneous Jacob CAMEO et al. Wegener’s and Crohn’s

Sharon E. Jacob, MD, Lucy K. Martin, MD, and Francisco A. Kerdel, BSc, MBBS

From the Department of Dermatology and Cutaneous Surgery, University of Miami School of Medicine, Miami, FL, USA Correspondence Francisco A. Kerdel, BSc, MBBS Professor of Dermatology Department of Dermatology University of Miami 1400 NW 12th Ave 6 South Dermatology Miami FL 33136 USA

We report a case of an unusual presentation of Wegener’s granulomatosis (WG) in a patient with Crohn’s disease (CD). She presented to our Wound Care Center with 7th cranial nerve palsy and facial pyoderma-like ulcerations. Although WG has a predilection for the lung, kidney, and eyes, cutaneous involvement can be seen in 50% of the cases, and it can be the presenting sign in 9–14%. Because of the lethality of WG if not properly treated, the diagnosis is imperative.

Abbreviations: ANCA: antineutrophil cytoplasmic antibodies c-ANCA: cytoplasmic antineutrophil cytoplasmic antibodies; CD: Crohn’s disease; PG: pyoderma gangrenosum; PR-3: proteinase 3; WG: Wegener’s granulomatosis.

Introduction

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Wegener’s granulomatosis (WG) is an uncommon, potentially lethal disease, with the majority of patients dying within 1–2 years if not treated.1,2 Wegener’s granulomatosis is a multisystem disease with a predilection for the lung, kidney, and eye.1,3 Cutaneous involvement has been reported in up to 50% of patients, and can be the presenting sign in 9–14%.1 Reported cutaneous manifestations include palpable purpura, pyoderma-like ulcerations, gingival hyperplasia, inflammatory papules, small ulcers, panniculitis, and subcutaneous nodules. There is no histopathology pathognomonic for WG, but characteristic findings include palisading granulomatous inflammation with or without granulomatous vasculitis, pathergic necrosis (an irregular, sharply demarcated eosinophilic necrosis), and formation of neutrophilic microabscesses. The presence of the aforementioned pathological findings and a diffuse cytoplasmic pattern of antineutrophil cytoplasmic antibodies (c-ANCA) directed against lysosomal serine proteinase-3 (PR-3) is considered diagnostic of WG.4 While c-ANCA may occasionally be seen in micropolyangiitis (MPA) and perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) on occasion in WG, anti-PR-3 is 99% specific and International Journal of Dermatology 2003, 42, 896 – 898

60% sensitive for WG.5–7 Standard treatment for this disease includes extended systemic glucocorticoid and concomitant cytotoxic drug therapy.8 Treatment options include cyclophosphamide, methotrexate with folic acid and leucovorin rescue, trimethoprim-sulfamethoxazole, and cyclosporine. We report a unique case of WG in a patient with Crohn’s disease (CD). This correlation is not well recognized and can lead to misdiagnosis given that CD is associated with PG, and has cutaneous lesions. While there has been reported associations of WG and CD, to our knowledge this is the first association of CD and cutaneous WG.9 Case Report A 78-year-old Caucasian woman with a history of CD, hypothyroidism, osteoarthritis, and hypercholesterolemia presented with a 10-month history of recurrent sinusitis and fever. At initial presentation she noted development of a pustule on her right cheek. Subsequently, the pustule developed into an abscess, which was incised and drained. The surgical incision developed pathergy and became an ulcer. As the initial ulcer expanded, she noted the simultaneous development of bilateral retroauricular ulcers. © 2003 The International Society of Dermatology

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responded well to treatment. She was seen at 6 months’ follow up and had 90% epithelialization of the wounds. Discussion

Figure 1 Facial lesions pre- and retroauricular before treatment.

Note the border and exuberant exudates

On physical exam the patient was noted to have right 7th cranial nerve palsy, a 5.5 × 3.0-cm granulating ulcer with exposed underlying facial muscle on the ipsilateral side, and peri-wound erythema (Fig. 1). She also had bilateral retroauricular ulcers measuring 2.2 × 0.8 cm on the left and 5.5 × 3.0 cm on the right. Facial ulcer biopsy showed suppurative inflammation and granulation tissue, consistent with a diagnosis of pyoderma gangrenosum (PG). The following laboratory data was obtained: ESR: 67, proteinase-3: 17 (< 6) (c-ANCA target antigen); ANA (–); dsDNA (–); CXR: no acute or chronic pulmonary processes; blood urea nitrogen/ creatinine normal; and stool occult blood positive (consistent with active CD). Paranasal sinus films reported chronic granulomatous changes and mucosal thickening in the maxillary, sphenoid and ethmoid sinuses. The patient was admitted for treatment with IV antibiotics and IV Solu-Medrol. The clinical diagnosis was suspected and cANCA/PR-3 was obtained. Based on this result cyclosporine was started. Wound cultures performed on admission demonstrated the presence of candida for which the patient received a 10-day course of oral fluconazole. The patient © 2003 The International Society of Dermatology

Wegener’s granulomatosis is a rare condition characterized by a widespread granulomatous infiltration of multiple organ systems, classically the kidney and respiratory tracts.1 There exists a limited cutaneous form of this disease in which there is no evidence of renal or pulmonary involvement. Increased awareness that the cutaneous form can present as a pattern simulating pyoderma gangrenosum may lead to the more rapid diagnosis. The diagnosis of WG depends on the clinical assessment, biopsy, and positive autoantibody against neutrophil cytoplasmic antigen PR-3.2 Of note, c-ANCA antibodies may be undetectable at the onset of WG, with limited disease, and after successful treatment.7 In our patient, the diagnosis of WG was established by the presence of chronic pansinusitis, multiple ulcerations, facial palsy, which could have been the result of granulomatous involvement of the middle ear and/or involvement of the 7th cranial nerve at the subcutaneous preauricular site, and c-ANCA /PR-3 positivity.3,10 Ours is a unique case of a patient with CD and cutaneous WG. The poor prognosis of WG underscores the need for early recognition, diagnosis and treatment. Crohn’s disease may have its own cutaneous manifestations. These are usually restricted to patients with colonic disease and generally present as ulcers, fissures and sinuses with contiguous extension from intra-abdominal sites. Sterile granulomatous skin lesions can arise at sites discontinuous with the gastrointestinal tract. This presentation is referred to as “metastatic CD”. Pyoderma gangrenosum has been reported in 1.5% of CD patients. Pyoderma gangrenosum presents with nonspecific histologic findings that can be further confused with WG. Furthermore, WG should be in the differential diagnosis of metastatic CD in that sarcoidal granulomatous inflammation in the skin are presentations of both entities. A subset of CD patients has been found to have ANCA with specificity for α-myeloperoxidase antibody.11 Our case is unique in that the patient presented with facial PG-like lesions in a patient with CD. It would have been easy to misdiagnose WG in this setting and it is possible that similar cases go unrecognized. This case emphasizes the need for specific diagnostic test markers, such as PR-3 for any given disease.

References 1 Handfield-Jones SE, Parker SC, Fenton DA, et al. WG presenting as pyoderma gangrenosum. Clin Exp Dermatol 1992; 17: 197–200. 2 Gibson LE, Daoud MS, Muller SA, et al. Malignant pyodermas revisited. Mayo Clin Proc 1997; 72: 734–736. International Journal of Dermatology 2003, 42, 896 – 898

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3 Bibas A, Fahy C, Sneddon L, et al. Facial paralysis in Wegener’s granululomatosis of the middle ear. J Laryngol Otol 2001; 115: 304–306. 4 Harris NL, McNeely WF, Sheppard JO, et al. Case records: Massachusetts General Hospital Case 18. N Engl J Med 2002; 346: 1892–1898. 5 Savige J, Davies D, Falk RJ, et al. Antineutrophil cytoplasmic antibodies and associated diseases. a review of the clinical and laboratory features. Kidney Int 2000; 57: 846 –862. 6 Schonermarck U, Lamprecht P, Csernok E, et al. Prevalence and spectrum of rheumatic diseases associated with proteinase 3-antineutrophil cytoplasmic antibodies (ANCA) and myeloperoxidase-ANCA. Rheum 2001; 40: 178–184. 7 Russell KA, Specks U. Are antineutrophil cytoplasmic antibodies pathogenic? Experimental approaches to

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understanding the antineutrophil cytoplasmic antibody phenomenon. Rheum Dis Clin NA 2001; 27: 815–832. Resnik BI, Rendon M, Kerdel FA. Successful treatment of aggressive pyoderma gangrenosum with pulse steroids and chlorambucil. JAAD 1992; 27: 635–636. Codish S, Abu-Shakra M, Depsames MP, et al. Wegner’s Granulomatosis in a patient with Crohn’s Disease. IMAJ 2000; 2: 630 –631. Cone LA, Annunziata GM, Gebhart RN. Malignant Pyoderma and Wegener’s Granulomatosis. Letter to the editor. Mayo Clin Proc 1998; 73: 390 –391. Ooi CJ, Lim BL, Cheong WK, Ling AE, et al. Antineutrophil cytoplasmic antibodies (ANCAs) in patients with inflammatory bowel disease show no correlation with proteinase 3, lactoferrin, myeloperoxidase, elastase, cathepsin G and lysozyme: a Singapore study. Ann Acad Med Sing 2000; 29: 704–707.

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Wegener’s granulomatosis presenting as pyoderma gangrenosum Werner’s granulomatosis

Hajnal Irén Szõcs, MD, Katalin Torma, MD, Edina Petrovicz, MD, Judit Hársing, MD, György Fekete, MD, Sarolta Kárpáti, MD, PhD, and Attila Horváth, MD, PhD

From the Department of DermatoVenereology, Semmelweis University, Budapest, the Department of Dermatology, Petz Aladár Country Hospital, Gyõr, and the Department of Internal Medicine, St. László Hospital, Budapest, Hungary Correspondence Dr Sci. Sarolta Kárpáti, MD PhD Semmelweis University Department of Dermato-Venereology Mária str. 41 H-1085 Budapest Hungary E-mail: [email protected]

A 59-year-old male patient developed a necrotizing ulceration on the right shin. Both clinical and histopathologic examinations suggested pyoderma gangrenosum. After temporary improvement of skin symptoms under peroral glucocorticoid treatment, a hemorrhagic-purulent discharge started from the nose, he began to have fever, malaise, cough, and a chest X-ray revealed inflammation in the lung. Cerebral CT and MRI disclosed midline bone loss within the nasal septum and granulomatosus tissue masses protruding into the right orbit. The c-ANCA test was positive, serum IgA was elevated, and he had microhaematuria and proteinuria. In this severe case of Wegener’s granulomatosis prolonged methylprednisone and cyclophosphamide treatment was initiated. Both the skin symptoms and the granulomatosus infiltrations resolved.

Introduction

Case Report

Wegener’s granulomatosis (WG) is a systemic disease of unknown origin characterized by necrotizing granulomatosus inflammation and vasculitis. The upper and the lower respiratory tracts, the kidney and the skin are the most frequently affected areas. Dermatological symptoms occur in up to 50% of cases, mostly in the form of cutaneous vasculitis or pyoderma gangrenosum.

A 59-year-old male had antroatticotomy because of recurrent otitis media in childhood, and non-insulin-dependent diabetes mellitus since 1993. A painful nodule appeared in February 1999 on his right shin, which was removed. At the site of operation a treatmentresistant necrotizing ulceration arose. In November a clinical examination suggested pyoderma gangrenosum, which was

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Figure 1 Bilateral conjunctival inflammation

Figure 3 Pyoderma gangrenosum: large ulcer on the left lower

leg with a livid-hemorrhagic border

Conjunctivitis (Fig. 1) and spontaneous hemorrhagic-purulent secretion from the nostrils (Fig. 2) were observed. On the back and on both legs (Fig. 3) there were several skin ulcers of 0.5–10 cm in size, with hemorrhagic borders. Laboratory findings

Figure 2 Purulent-hemorrhagic discharge from the nostrils

also confirmed by histology. The patient was treated with glucocorticoids, resulting in temporary improvement. During that treatment a hemorrhagic-purulent discharge started from the nose, and the chest X-ray revealed a round shade on the right lung. Histologic examination of the biopsy sample taken from the nasal septum verified WG. The patient was admitted to our department at the end of February 2000 in poor general condition with high fever. © 2003 The International Society of Dermatology

Positive High erythrocyte sedimentation rate (ESR), 110 mm /h, mild leukocytosis with 15.7% eosinophils in the differential, and anemia with a low serum iron level. Positive c-ANCA, high level of C-reactive protein, high serum IgA: 7.5 g /l, elevated serum alkaline phosphatase, and gamma-glutamyltransferase levels. Urine: protein: 0.75 g /l, and microscopic hematuria. Negative Anti-nuclear antibody, total serum complement. Bacterial and mycological cultures Identified several pathogens: Skin: Pseudomonas aeruginosa, Staphylococcus aureus. Nose secretum: methicillin resistant staphylococcus aureus (MRSA), Proteus mirabilis. Throat swab: MRSA, Pseudomonas aeruginosa, bronchial lavage, Pseudomonas aeruginosa, International Journal of Dermatology 2003, 42, 898 896 –902 –898

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Figure 4 Histology (from the margin of ulcer): Necrosis, acute

and chronic inflammation. The polymorphous infiltrate consists of lymphocytes, plasma cells, macrophages and many eosinophils. Note the multinucleated giant cells and fibrinoid deposition in the small blood vessels (H&E ×250)

Figure 5 Sinus maxillaris CT: In the midline and on the right side

of the nasal septum are bone destructions. The defect is filled with granulomatosus tissue protruding into the right orbita, involving the optic nerve

polyresistant Candida albicans . Urine culture: Proteus mirabilis 105, Enterobacter spp. 105. Histology (Fig. 4) from the margin of the skin ulcer revealed necrosis, acute and chronic infiltration with lymphocytes, plasma cells, macrophages and eosinophil granulocytes. Most of the small blood-vessel walls were homogenized and displayed fibrinoid deposition. Direct immunfluorescence taken from the skin ulcer showed C3- and IgM-positive vascular fluorescence in the upper dermis. International Journal of Dermatology 2003, 42, 896– 898– 898 902

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Figure 6 Chest X-ray (before treatment) shows a 3-cm large,

round, homogeneous shade in the apex of the right lung

Cerebral CT, MRI and the maxillar cavity CT (Fig. 5) revealed midline bone loss within the nasal septum and granulomatosus tissue masses protruding into the right orbit partially compressing the optical nerve. The chest X-ray (Fig. 6) showed a round (3 cm in diameter), homogeneous shade in the apex of the right lung showing some progression even after beginning the therapy. The naso-orbital midline and lung granuloma, the pyoderma gangrenosum, the c-ANCA positivity, the high IgA serum level, hematuria, proteinuria as well as the histological examination confirmed the diagnosis of WG. The patient was treated with methylprednisone (1 mg/ kg/ day) and CYC (2 mg /kg /day) (planned for 1 year after complete remission), and, depending on the bacterial and mycological cultures, antibiotics and antimycotics. With this treatment both the skin symptoms and the respiratory tract granulomas showed regression. In 2 months we reduced the dosage of glucocorticoids, but not the CYC. Soon a rapid progression in the respiratory tract was detected: a new 5-cm diameter cavity with fluid appeared below and lateral to the first shade, and was connected to the pleura and the main bronchi. Therefore the initial dosage of methylprednisone was restored. Although the skin ulcers began to recover, the shade in the right lung progressed into a lung abcess. Within 6 months under combined antimicrobial and the same steroid and CYC treatment, the respiratory tract recovered as well. Discussion Wegener’s granulomatosis, a clinicopathological syndrome characterized by necrotizing granulomas and vasculitis, was first recognized by Klinger in 1931 and by Wegener © 2003 The International Society of Dermatology

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in 1936.10,11 Most threatened by this disease are 45–50-yearold men, however, its occurrence in children cannot be neglected.2,13,14 The etiology is not yet clear. The initiating events in WG may include environmental factors like infectious agents and environmental toxins and also several genetic factors. The pathogenesis of this disease is complex, involving immune mechanisms, resulting in granuloma formation, followed by the necrotizing inflammation of blood vessel walls.4 Polymorphonuclear neutrophils might have an important role in the pathogenesis of WG, because they predominate the site of necrotizing vasculitis and granulomas, and also they are the main target of the ANCA antibodies. One can speculate, that in ANCA-mediated vasculitis, neutrophils and monocytes adhere to and penetrate the vessel walls, via cell-adhesion interactions, by releasing lytic enzymes and toxic oxygen radicals. A possible initiating pathway could be c-ANCAinduced leukocyte activation. Different cell-derived cytokines, lipid metabolites might be involved in initiation of the necrotizing inflammation of blood vessel walls.4 Although the respiratory tract and kidney are involved, any organ system may be affected. Diseases of the upper airway are: hemorrhagic-purulent rhinitis, sinusitis, and rarely “midline” granuloma with nasal septal perforation. In the lower respiratory tracts neutrophilic alveolitis, pulmonary hemorrhage, and cavitary nodules might develop. Renal involvement includes necrotizing glomerulonephritis, indicating generalized disease9,12. Ocular complications include obstruction of the tear duct, conjunctivitis, varying degrees of corneoscleral inflammation with ulcerations, uveitis, retinal vasculitis and granulomas within the orbit.17 Skin involvement is not unusual in WG and in 14% of cases may be the initial sign of the disease.2,12 Up to 35–50% of the cases are variable and no specific dermatological symptoms may occur.2,15,16 The most frequent skin lesions are palpable purpura, papules, ulcerations, vesicules, subcutaneous nodules, necrotizing ulcerations and papulonecrotic lesions.2,14 Often in the WG the initial sign is pyoderma gangrenosum. Skin histology might reveal panniculitis, leukocytoclastic vasculitis, extravascular palisading granuloma and granulomatous vasculitis or rarely microscopic poliangiitis/poliarteritis. Immunfluorescence studies usually show C3 and IgM-positive vasculitis.1,2,4–6,10 Serum IgG antibodies against cytoplasmatic components of neutrophils (c-ANCA) were described in 1982, and were later confirmed to be highly specific for WG.2,7,10,13,14 The sensitivity of the method depends on the extent and activity of the disease. In a patient with skin symptoms, c-ANCA is 81% positive2 but no clear correlations have been demonstrated between cutaneous expression of WG and ANCA titer.14 The patients may present with poor general condition with fever, malaise and weight loss. The most characteristic laboratory findings are: elevated ESR, leukopenia, throm© 2003 The International Society of Dermatology

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bocytopenia, elevated serum IgA and acute-phase proteins, hematuria, proteinuria. Without treatment the disease may lead to death within a few months; WG is a life-threatening systemic disease. The combination of glucocorticoids and CYC is a highly effective therapy for WG. Complete remission or marked improvement might occur in > 90% of patients, however, approximately 50% of patients have disease relapses. In 42% of cases one may experience serious CYC drug-related toxicity, including long-term adverse outcomes, such as infertility, myeloproliferative disorders, and transitional cell carcinoma of the bladder.3,8,16 Other therapeutic possibilities are methotrexate, intravenous immunglobulin, antithymocyte globulin or plasmapheresis.3,9,17 Extended antimicrobial therapy is also important. Patients with therapy-resistant pyoderma gangrenosum should be carefully evaluated to exclude the possibility of WG. The doses of glucocorticoids and CYC should not be reduced too rapidly, as this may induce disease relapses. References 1 Handfield-Jones SE, Parker SC, Fenton DA. Wegener’s granulomatosis presenting as pyoderma gangrenosum. Clin Exp Dermatol 1992; 17: 197–200. 2 Daoud MS, Gibson LE, DeRemee RA, et al. Cutaneous Wegener’s granulomatosis: clinical, histopathologic, and immunpathologic features of thirty patients. J Am Acad Dermatol 1994; 31: 605–612. 3 Hoffman GS. Treatment of Wegener’s granulomatosis: time to change the standard of care? Arthritis Rheum 1997; 40: 2099–2104. 4 Gross WL, Trabandt A, Csernok E. Pathogenesis of Wegener’s granulomatosis. Ann Med Intern 1998; 149: 280 –286. 5 Bosch X. Microscopic poliangiitis (microscopic polyarteritis) with late emergence of generalised Wegener’s granulomatosis. Ann Rheum Dis 1999; 58: 644–647. 6 Micali G, Cook B, Ronan S, et al. Cephalic pyoderma gangrenosum-like lesions as a presenting sign of Wegener’s granulomatosis. Int J Dermatol 1994; 33: 477–480. 7 Gibson LE, Daoud MS, Muller SA, et al. Malignant pyodermas revisited. Mayo Clin Proc 1997; 72: 734–736. 8 Langford CA, Talar-Williams C, Barron KS, et al. A staged approach to the treatment of Wegener’s granulomatosis: induction of remission with glucocorticoids and daily cyclophosphamide switching to methotrexate for remission maintenance. Arthritis Rheum 1999; 42: 2666–2673. 9 Taylor CT, Buring SM, Taylor KH. Treatment of Wegener’ granulomatosis with immune globulin: CNS involvement in an adolescent female. Ann Pharmacother 1999; 33: 1055– 1059. 10 Weninger W, Kain R, Tschachler E, et al. Mikoskopische Polyangiitis mit Eosinophilie-Überlappungssyndrom oder eigenstandiges Krankheitsbild? Hautarzt 1997; 48: 332– 338. International – 898 International Journal Journal of of Dermatology Dermatology 2003, 2003, 42 42,, 896 898– 902

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11 Sorense SF, Slot O, Tvede N, et al. A prospective study of vasculitis patients collected in a five year period: evaluation of the Chapel Hill nomenclature. Ann Rheum Dis 2000; 59: 478–482. 12 Csernok E, Gross WL. Primary vasculitides and vasculitis confined to skin. clinical features and new pathogenic aspects. Arch Dermatol Res 2000; 292: 427–436. 13 Perkins GD, Moudgil H, Jones R. Pyoderma gangrenosum. Thorax 2000; 55: 347. 14 Mock M, Cerottini JP, Derighetti M, et al. Wegener’s granulomatosis: description of a case where cutaneous

involvement was correlated with elevation of the c-ANCA titer. Dermatology 2001; 202: 347–349. 15 Gilliam JM, Smiley JD. Cutaneous necrotizing vasculitis and related disorders. Ann Allergy 1976; 37: 328–339. 16 Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener granulomatosis: analysis of 158 patients. Ann Intern Med 1992; 116: 488–498. 17 Blum M, Andrassy K, Adler D, et al. Early experience with intravenous immunoglobulin treatment in Wegener’s granulomatosis with ocular involvement. Arch Clin Exp Ophthalmol 1997; 235: 599–602.

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Limited Wegener’s granulomatosis manifesting as malignant pyoderma with corneal melt Wegener’s granulomatosis manifesting as malignant pyoderma

David J. Kouba, MD, PhD, Daniel Mimouni, MD, Cuong T. Ha, MD, and Carlos H. Nousari, MD

From the Department of Dermatology, The John Hopkins University, Baltimore, MD, USA

Correspondence Carlos H. Nousari, MD Johns Hopkins University School of Medicine Department of Dermatology 720 Rutland Ave Ross Research Building Suite 771 Baltimore, MD 21205 USA E-mail: [email protected]

Case Report A 56-year-old male with a history of diabetes mellitus and childhood poliomyelitis presented with a 7 month history of multiple cutaneous ulcers affecting the face, hands, chest, and perineum. He also complained of fatigue, myalgias and a 15-kg weight loss. Multiple courses of intravenous, broad-spectrum antibiotics and debridements had yielded no significant response. Two months before admission, he complained of right eye pain and conjunctival injection. Review of systems was otherwise unremarkable. Examination revealed a deep cutaneous ulceration without livid rim or pus discharge, present at the preauricular cheek, overlying the angle of the mandible (Fig. 1) with smaller, similar lesions present at the umbilicus, left wrist and peri-anal area. There was no evidence of purpura, livedo reticularis, subcutaneous nodules or digital infarcts. Pulses were equal bilaterally. International Journal of Dermatology 2003, 42, 902– 896– 904 898

Figure 1 Facial ulceration present at the right preauricular cheek

overlying the angle of the mandible © 2003 The International Society of Dermatology

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Figure 2 Right eye demonstrating focal loss of corneal integrity

Figure 3 H&E-stained section showing palisaded and

with compensatory plugging by the iris at the superior pole. Anterior chamber was intact

granulomatous vasculitis of deep dermal vessels (×40 magnification)

Opthalmologic examination revealed scleritis affecting the right eye with focal loss of corneal integrity and compensatory plugging by the iris (Fig. 2). Laboratory findings included anemia with hemoglobin 11.0 g/dl (range 13.9–16.3) but a normal white cell count and differential. Blood cultures were negative. Blood urea nitrogen, serum creatinine and urinalysis were repeatedly normal. Chest radiography was clear. Cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA) were positive at 1 : 512 (normal < 1 : 20) with antiproteinase-3 antibody titer greater than 100 (normal < 3.5). Westergren sedimentation rate was 88 mm/h (range 1–15). Rheumatoid factor was 42 U/ml (normal < 10), C3 and C4 were 84 and 36 mg /dl, respectively (normal 79–152 and 12–42, respectively). P-ANCA, cryoglobulin screen, antinuclear antibodies, HIV and hepatitis B and C serologies were all negative. Biopsy specimen from the facial ulcer was stained with hematoxylin and eosin (H&E). Small- and medium-sized vessels demonstrated fibrinoid degeneration of the walls associated with neutrophil-predominant, mixed perivascular infiltrates disrupting blood vessel architecture. Several areas showed a palisaded granulomatous infiltrate surrounding areas of fibrinoid collagen degeneration. Scattered multinucleated giant cells, neutrophils, and nuclear debris (leukocytoclasia) were also present (Fig. 3). The patient was diagnosed with limited oculocutaneous Wegener’s granulomatosis (WG) presenting with malignant pyoderma and scleritis with corneal melt. After the diagnosis of WG was made, the patient was treated with intravenous methylprednisolone followed by 1 mg / kg /d (60 mg) oral daily prednisone. Intravenous cyclophosphamide was administered at 750 mg/m2 body surface area. He showed a dramatic response, with significant healing of his lesions within 2 weeks, and was discharged on prednisone 60 mg. © 2003 The International Society of Dermatology

Discussion Wegener’s granulomatosis is a necrotizing, granulomatous vasculitis affecting medium and small arteries and veins. It can present anywhere within a spectrum encompassing a generalized, systemic form to limited involvement. In the generalized form, vasculitis of the respiratory tract and kidneys is common. Generalized WG may smolder for years before clinical signs appear, and if untreated has a greater than 90% fatality rate. C-ANCA yields a sensitivity of 96% in patients with active, generalized WG. Confirmatory antiproteinase-3 antibodies lend increased specificity to the diagnosis.1,2 The American College of Rheumatology reports that two of abnormal urinary sediment, abnormal chest radiograph, oral ulcers or nasal discharge, or granulomatous inflammation on biopsy yield a sensitivity and specificity approaching 90% in confirming a clinical diagnosis of WG.3 The clinical manifestations of WG are manifold, with the majority of patients presenting with nonspecific myalgias and arthralgias and upper airway disease. Sinusitis and serous otitis media are common initial manifestations. Pulmonary involvement frequently presents as cough, chest pain, sputum production or pulmonary hemorrhage. Renal disease is present in the majority of generalized cases as focal segmental glomerulonephritis with crescent formation. Cutaneous involvement occurs in 14–50% of cases and specific cutaneous findings may be the presenting sign of WG in 9–14% of those affected.4 The cutaneous findings, while not pathognomonic, exist in three categories: (1) small vessel vasculitis presenting as either palpable or nonpalpable purpura; (2) medium vessel vasculitis presenting as livedo reticularis, subcutaneous nodules, digital infarcts or ulcers; (3) polymorphic lesions including papulo-nodular, often necrotic lesions on extensor surfaces, pyoderma gangrenosum-like ulcers International International Journal Journal of of Dermatology Dermatology 2003, 2003, 42, 42, 896 902––898 904

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(malignant pyoderma), and a strawberry-like gingivitis. These lesions share a common histologic pattern: the palisaded and neutrophilic granulomatous dermatitis, also referred to as cutaneous extravascular necrotizing granulomas, Churg-Strauss, or Winkelman granulomas.5–7 Predominant ocular findings in WG include conjunctivitis, dacryocystitis, episcleritis and scleritis.8 Any of the three cutaneous manifestations may present in the setting of systemic vasculitis affecting multiple organ systems, or as limited extracutaneous disease involving the eye, ear or upper respiratory tract. The concept of malignant pyoderma as an atypical form of pyoderma gangrenosum (PG) vs. an unusual cutaneous manifestation of WG has been debated. Original reports cited unusually destructive, sterile ulcers partially responsive to corticosteroids. These ulcers lacked the characteristic violaceous rim of PG and occurred in patients without the usual PG-associated systemic diseases. They often occurred in the peri-auricular area of the face and the perineum. Of first reported cases, two involved facial ulceration, one with associated saddle-nose deformity, and one with hemoptysis and cavitary lung lesions.9 Early debate centered on the clinical and histopathologic features of PG and WG without the luxury of contemporary immunologic tests for WG. While not all pyoderma-like ulcers occurring on the face represent WG, pyoderma-like ulcerations seen in association with other symptoms suggestive of systemic vasculitis warrant further testing with c-ANCA and antiproteinase-3 antibodies to exclude the potentially fatal Wegener’s granulomatosis.4,10

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References 1 Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener’s granulomatosis: analysis of 158 patients. Ann Intern Med 1992; 116: 488–498. 2 Langford CA. Wegener Granulomatosis. Am J Med Sci 2001; 321: 76–82. 3 Leavitt RY, Fauci AS, Bloch DA. The American College of Rheumatology 1990 criteria for the classification of Wegener’s Granulomatosis. Arth Rheum 1990; 33: 1101–1107. 4 Gibson LE, Daoud MS, Muller SA, et al. Malignant pyodermas revisited. Mayo Clin Proc 1997; 72: 734–736. 5 Stone JH, Nousari HC. “Essential” cutaneous vasculitis: what every rheumatologist should know about vasculitis of the skin. Curr Opin Rheumatol 2001; 13: 23–34. 6 Chu P, Connolly MK, LeBoit PE. The histopathologic spectrum of palisaded neutrophilic and granulomatous dermatitis in patients with collagen vascular disease. Arch Dermatol 1994; 130: 1278–1283. 7 Wolff K, Stingl G. Pyoderma gangrenosum. In: Freedberg IM, Eisen AZ, Wolff K, et al., eds. Fitzpatrick’s Dermatology in Internal Medicine, 5th edn. New York: McGraw-Hill, 1999: 1140 –1148. 8 Harper SL, Letko E, Samson CM, et al. Wegener’s granulomatosis: the relationship between ocular and systemic disease. J Rheumatol 2001; 28: 1025–1032. 9 Perry HO, Winkelmann RK, Muller SA, et al. Malignant pyodermas. Arch Dermatol 1968; 98: 561–576. 10 Cone LA, Annunziata GM, Gebhart RN. Malignant pyoderma and Wegener’s granulomatosis. Mayo Clin Proc 1998; 73: 390 –391.

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