Skin eruptions associated with microscopic polyangiitis

ARTICLE

Auteur(s) : Mariko SEISHIMA, Zuiei OYAMA, Makiko ODA

Department of Dermatology, Ogaki Municipal Hospital, Minaminokawa-cho 4-86, Ogaki City, 503-8502, Japan

Article accepted on 22/03/2004

Microscopic polyangiitis (MPA) that involves small vessels often show a poor prognosis in the case of patients with inappropriate initial treatments [1-3]. Serious clinical complications usually arise from renal diseases, typically focal necrotizing glomerulonephritis with crescents, and from pulmonary haemorrhage. Antineutrophil cytoplasmic antibodies (especially anti-myeloperoxidase antibodies) (MPO-ANCA) are often positive in serum [4-6]. The skin is affected in 20-70% of patients with MPA [2, 7, 8]. Oral ulcer, splinter haemorrhage, palpable purpura, and facial edema have been described as clinical features [9-12]. However, the description of skin eruptions in MPA patients has been limited. Thus, we report here 10 MPA patients with skin eruptions.

Patients

Ten Japanese patients with MPA consulted the Department of Dermatology in Ogaki Municipal Hospital during the past 5 years. The clinical background and features of 10 patients (6 men and 4 women) with MPA are summarized in Table I. These patients were aged from 38 to 80 years (62.1 ± 13.3). Written informed consent for the study was obtained from all patients.

Results

Systemic Symptoms and Laboratory Data

Systemic symptoms were fever in all 10 patients, general fatigue in 9 patients (except patient 8 in Table I), haemoptysis in 6 patients (patients 1, 2, 4, 6, 9 and 10), polyarthralgia in 4 patients (patients 4, 5, 8 and 9). Renal dysfunction with haematuria was observed in 9 patients, pulmonary haemorrhage in 6 patients, interstitial pneumonia in 2 patients (patients 7 and 8), and gastric bleeding in 2 patients (patients 3 and 7). Patient 4 had both mononeuritis and auditory disturbance. Serum MPO-ANCA was positive in all 10 patients and antibody titers determined by ELISA were 36-560 EU (196.9 ± 176.2 EU, n = 10), but serum proteinase 3-ANCA was negative in all 10 patients. Antinuclear antibody was positive in one patient (patient 10) and the titer was 1: 5120 (speckled type). Rheumatoid factor, cryoglobulin, hepatitis B and C were all negative. Complement, CPK, aldolase, myoglobin levels were within the normal range. Segmental pauci-immune necrotizing glomerulonephritis was histologically observed in 4 patients (patients 3, 4, 5 and 7) by renal biopsy.
Six patients (patients 1, 2, 4, 6, 9 and 10) showed both rapidly progressive necrotizing glomerulonephritis (RPGN) and pulmonary haemorrhage. Patient 7 had RPGN and interstitial pneumonia. Patient 3 had RPGN, gastric bleeding and purpura. Patient 5 showed RPGN and purpura. Patient 8 showed interstitial pneumonia and purpura. Polyarteritis nodosa, Wegener’s granulomatosis, Churg-Strauss syndrome and Goodpasture’s syndrome were not clinically detected. The diagnosis of MPA was made based on the Chapel Hill consensus criteria [1, 2].

Skin Eruptions

Purpura and petechiae were observed on the extremities in 6 patients (Fig. 1), livedo on the lower extremities in 2 patients. Erythema was seen on the hands in 4 patients (Fig. 2), on the face in 1 patient, on the trunk in 2 patients, and on the extremities in 1 patient (Table I). None of the patients complained of itch. Skin eruptions preceded the systemic symptoms in 2 patients (patients 4 and 8). Patient 10 showed the skin eruption and systemic symptoms simultaneously. In the other 7 patients, systemic symptoms were followed by skin eruptions.

Histological Findings

We performed a skin biopsy from the affected areas in 7 MPA patients except for patients 1, 2 and 8 (Table I). Although 4 patients (patients 5, 7, 9 and 10) showed perivascular lymphocyte infiltration in the upper dermis, 2 patients (patients 3 and 6) showed infiltration with lymphocytes and neutrophils around small arteries in the middle to deep dermis (Fig. 3- 4), and patient 4 showed diffuse infiltration of histiocytes and lymphocytes in the middle dermis (Fig. 5). Direct immunofluorescence study performed in 3 patients (patients 3, 9 10) was negative in all three patients.

Clinical Course and Treatment

All 10 patients were treated with systemic steroid therapy including steroid pulse therapy. Prednisolone was given at 60 mg/day from the beginning or after steroid pulse therapy and the dose was gradually reduced. Nine patients were given prednisolone at a dose of 2.5-12.5 mg/day and 2 patients (patients 1 and 2) were treated with haemodialysis. Skin eruptions disappeared after 2-5 months and MPO-ANCA became negative 3 to 16 months after the beginning of steroid therapy. Regression of skin eruptions preceded negative conversion of MPA-ANCA in 9 patients, except patient 8. There has not been any relapse of either skin eruptions or systemic symptoms in any patient during 2-5 year-follow-up.

Discussion

MPA is a systemic vasculitis that is histologically characterized by small-vessel involvement [13, 14]. The Chapel Hill consensus criteria for MPA include the following signs and symptoms in variable combinations: 1) presence of RPGN and/or alveolar haemorrhage, which could be associated with other systemic manifestations of vasculitis; 2) histological demonstration of small vessel vasculitis or segmental pauci-immune necrotizing glomerulonephritis; or 3) symptoms suggesting small-vessel involvement, e.g., purpura without glomerulonephritis and/or alveolar haemorrhage [1, 2]. In this study, MPA was diagnosed according to this criteria, but cutaneous leukocytoclastic vasculitis restricted to vasculitis in the skin without involvement of vessels in any other organ was excluded. Positive MPO-ANCA are diagnostic for MPA. However, they are not specific for MPA because they are positive in only 50-80% of active MPA patients and are also positive in 10-25% in Wegener’s granulomatosis, 25-30% in Churg-Strauss syndrome [4, 6].
Most patients with MPA show clinically systemic symptoms such as fever, weight loss, myalgias, and polyarthralgia for several months or years [12]. RPGN occurs in 79-90% of MPA patients, and the lung is involved in 25% to 50% of MPA [12]. In this study, RPGN occurred in 90% and lung involvement in 80% including 60% of pulmonary haemorrhage and 20% of interstitial pneumonia. Skin involvement has been reported in 20-70% of MPA [2, 7, 8]. Purpuric skin lesions are the most common cutaneous feature [8,15], and are present in 15-50% [2, 7, 8, 13]. Livedo, nodules and urticaria were observed in 13%, 13%, and 3.5%, respectively [2]. In other reports, bullae, erythema elevatum diutinum [8], and ulcer on the toes [11] were described in MPA patients. In addition, an MPA patient with a wide spectrum of cutaneous lesions such as palpable purpura, vesicles, splinter haemorrhages, subcutaneous palmar nodules and facial edema was also reported [10]. In the present study, purpura and petechiae were observed in 60% of patients, livedo in 20% of patients. Erythema was seen in 70% of patients, especially on the hands in 40%. These findings show that we should consider the possibility of MPA in patients with purpura, petechiae or livedo on the extremities. Mandl et al. showed that cutaneous vasculitis with systemic features, such as myalgias, arthralgias or arthritis, is one of the clinical indications for ANCA testing [5].
Cutaneous involvements in MPA showed a wide spectrum of clinical and histological findings. Histologically, lymphocyte infiltration around capillaries in the upper dermis in 4 patients, infiltration with lymphocytes and neutrophil infiltration around small arteries in the middle to deep dermis in 2 patients and diffuse infiltration of histiocytes and lymphocytes in the middle dermis in 1 patient. From these histological findings, not all skin eruptions in these 10 patients might be specific for MPA. Five patients (patients 1, 3, 6, 9 and 10) received antibiotics or anti-inflammatory agents before consulting our department. It is not clear whether these eruptions appeared as one of the skin manifestations of MPA or some other factors such as drugs or collagen diseases were involved in the eruptions. Drug patch tests and drug-induced lymphocyte stimulation tests were performed in patient 9 using the antibiotics and anti-inflammatory agents that were orally administered before consultation, but test results were negative. Although antinuclear antibody titer was high in patient 10, the symptoms and laboratory data did not fulfill the criteria for systemic lupus erythematosus [16]. In addition, erythema on the palms and fingers in patients 4, 8, 9 and 10 is often observed in collagen diseases such as dermatomyositis and Sjögren’s syndrome but the criteria for these diseases were not fulfilled. Therefore, further studies are necessary to determine whether these eruptions are specific for MPA. n

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