CASE REPORT Complete Resolution of Dermatomyositis with Refractory Cutaneous Vasculitis by Intravenous Cyclophosphamide Pulse Therapy Shizuyo Tsujimura, Kazuyoshi Saito and Yoshiya Tanaka Abstract Cutaneous ulcers associated with vasculitis are rarely reported in adult-onset dermatomyositis (DM), and are often resistant to treatment, resulting in a poor prognosis. There is no general treatment strategy and the effects of various treatments have never been confirmed histopathologically. A 43-year old man with DM developed refractory multiple cutaneous ulcers which were revealed as vasculitis by skin biopsy. Repeated intravenous cyclophosphamide pulse therapy (IV-CY) without high-dose corticosteroid therapy resulted in complete resolution of the ulcers without adverse effects or severe complications. A repeat biopsy confirmed complete remission of vasculitis. Repeated IV-CY is a useful treatment for induction of clinical remission of DM with cutaneous vasculitis. Key words: cutaneous ulcer, vasculitis, intravenous cyclophosphamide pulse therapy, dermatomyositis, steroid resistance (Inter Med 47: 1935-1940, 2008) () Introduction Dermatomyositis (DM) is defined as myositis with various cutaneous manifestations, including ulceration. In juvenile dermatomyositis (JDM), the subgroup Banker type, is characterized by vasculitis-related cutaneous and intestinal ulceration, which is often resistant to corticosteroid (CS) therapy and is associated with a poor prognosis (1). However, vasculitis-related cutaneous ulcers are rarely reported in adult-onset DM, and there is no general agreement with regard to treatment. Some studies have reported that DM with cutaneous ulceration is refractory to treatment and is associated with a poor prognosis (2, 3). Here, we report a case of an adult-onset DM with refractory vasculitis-related cutaneous ulcers, document the complete histological recovery confirmed achieved by intravenous cyclophosphamide pulse therapy (IV-CY), and discuss the relevance of vasculitis to cutaneous ulceration and the appropriate treatment in the adult-onset DM. Case Report A 40-year-old man was diagnosed with DM in 2000 based on the criteria of Bohan and Peter (4), including high fever, polyarthritis, a positive Gottoron s sign over the knuckles and elbows, myopathy with elevated serum creatine kinase (CK) levels, and interstitial pneumonia (IP). Multiple cutaneous ulcers were noted together with erythema on the back. The initial treatment of 1.0 mg/kg body weight (BW)/day of oral prednisolone (PSL) combined with 200 mg/day of cyclosporine A (CsA) and methyl-psl pulse therapy (0.5 g/day for 3 days) failed to suppress DM, the elevation of CK was progressed and cutaneous ulcers worsened. Subsequently, treatment was switched to oral betamethasone equivalent to 1.0 mg/kg BW/day of PSL and one course of IV-CY (15 mg/kg/day). After that, multiple cutaneous ulcer, IP and polyarthritis were diminished, and the level of CK was normalized. Although this treatment induced an immediate remission, IV-CY was discontinued because the patient developed severe pneumonia caused by The First Department of Internal Medicine, University of Occupational & Environmental Health, School of Medicine, Kitakyushu Received for publication May 6, 2008; Accepted for publication August 4, 2008 Correspondence to Dr. Yoshiya Tanaka, tanaka@med.uoeh-u.ac.jp 1935
Figure1. A cutaneousulcerwithmarginalinflammation andnecroticcrustontherightbutock. Pneumocystis jiroveci. Nevertheless, DM remained in remission without additional course of IV-CY, allowing tapering of betamethasone. In September 2002, while on oral betamethasone equivalent to 0.05 mg/kg BW/day of PSL, the patient noticed a large round elevated erythema measuring 10 cm in diameter on the right buttock, without any sign of infection (e.g., fever, tenderness). In November, he developed skin ulcers on the elevated erythema on his back and Gottoron s sign over the knuckles. The dose of betamethasone was increased immediately to the equivalent of 0.2 mg/kg BW/day of PSL. However, the cutaneous ulcers and Gottoron s sign worsened with the development of scalp dermatitis, nailfold bleeding, digital paresthesia, and Raynaud s phenomenon. In March 2003, he was admitted to our hospital due to progressive skin manifestations. On admission, his body temperature was 36.7, pulse rate 78 beats/min, and blood pressure of 104/62 mmhg. The patient had no complaints of muscle weakness, cough or dyspnea. Chest and abdominal examinations were normal. Neurological examination revealed bilateral digital paresthesia and thermohypesthesia. Skin examination showed various cutaneous manifestations, including bilateral heliotropic rash, scalp erythema, Gottron s signs over the knuckles, elbows, pediphalanx, and multiple keloids on the back, and cutaneous ulcers on the left scapular region (size 10 7 cm) and on the right buttock (size 6 4 cm). Cutaneous ulcer on the left scapular region was a punched-out ulcer, and a cutaneous ulcer on the large round elevated erythema on the right buttock was accompanied with necrotic crust, and livedo reticularis surrounded ulcers (Fig. 1). Laboratory tests showed elevated erythrocyte sedimentation rate (ESR) (31 mm/hr, normal <12 mm/hr), but there were no significant abnormalities in either serum level of CK, aldolase, lactic dehydrogenase, anti-jo-1 antibody, myeloperoxidase-antineutrophil cytoplasmic antibody, or tumor markers (Table 1). Computed tomography revealed no abnormalities on the lungs and abdomen. No infections or malignancies were detected. Histopathological examination of a skin biopsy from the edge of the cutaneous ulcer on the right buttock was conducted. The skin biopsy showed marked inflammatory infiltrates mainly around small blood vessels and around appendages, e.g., peripheral nerves, sweat glands and hair fol- Table1. LaboratoryFindingsonAdmision Urine Serology Protein (-) Total protein 7.1 g/dl Sugar (-) Alanine aminotransferase 22 IU/L Occult blood (-) Aspartate aminotransferase 38 IU/L Casts (-) Lactic dehydrogenase 199 IU/L CBC Creatinine 0.7 mg/dl Leukocytes 4500/µL Creatine kinase 119 IU/L Hemoglobin 14.8 g/dl Aldolase 5.1 IU/L Platelets 17.5 10 4 /µl C-reactive protein 0.0 mg/dl Erythrocyte sedimentation rate Coagulation Prothrombin time APTT 31 mm/hr 10.8 sec 24.4 sec CH50 C3 C4 ANA Fibrinogen 402 mg/dl RF (-) D-dimer 0.6 μg/ml anti-jo-1 antibody (-) MPO-ANCA KL-6 (normal 105-401 U/mL) 57 U/mL 119mg/dL 26 mg/dl (-) <10 EU 290 U/mL APTT, activated partial prothrombin time; CH50, 50% hemolytic complement activity; ANA, antinuclear antibodies; RF, rheumatoid factor; MPO-ANCA, myeloperoxidase-anti-neutrophil cytoplasmic antibody. 1936
Figure2. Histopathologicalexaminationofabiopsytakenfrom theskinulcerontherightbut tockbeforeintravenouscyclophosphamidepulsetherapy.a:markedinfiltrationoflymphocytesis seenmainlyaroundsmalbloodveselsandaroundskinappendagessuchasperipheralnervesas welasmildtisueedemawithscateredmelanophagesintheupperdermis(hematoxylinandeo sinstaining, 40).B:Highermagnificationviewshowsvasculitisofsmalveinswithintimaldegen eration,togetherwithinfiltrationoflymphocytesandplasmacels(hematoxylinandeosinstain ing, 100). Figure3. Clinicalcourse.IV-CY,intravenouscyclophosphamidepulsetherapy;PSLeq:prednisoloneequivalent,ESR:erythrocytesedimentationrate licles, with accumulation of small vessels from the dermis to the subcutaneous fat, basal keratinocyte liquefaction degeneration and mild edema with scattered melanophages in the upper dermis (Fig. 2). These findings indicated active cutaneous vasculitis associated with DM. Thus, in the present case, DM was characterized by high 1937
Figure4. Histopathologicalexaminationofabiopsytakenfrom theskinulcerscarontheright butockafter10coursesofintravenouscyclophosphamidepulsetherapy.a:notethedisappear anceofalmostallymphocytesfrom thedermistothesubcutaneousfatandofedemawithscat teredmelanophagesintheupperdermis(hematoxylinandeosinstaining, 40).B:Highermagni ficationview showingintactsmalveselsandorgans,e.g.,peripheralnervesandsweatglands, withoutinfiltrationoflymphocytesorplasmacels(hematoxylinandeosinstaining, 100). disease activity without recurrence of interstitial pneumonia (IP) and myositis but with cutaneous vasculitis. DM associated with vasculitis-related cutaneous ulceration is reported to be CS-resistant and associated with a poor prognosis (2, 3, 5-7). Accordingly, the IV-CY therapy (10 mg/kg i.v.) was repeated every 4 weeks. After three courses of IV-CY, the cutaneous ulcers and peripheral nerve signs showed some improvement, together with a reduction of ESR. Shortening of infusion interval of IV-CY to three weeks resulted in gradual improvement of the skin manifestations including cutaneous ulcers and peripheral nerve signs without any remarkable adverse effects related to IV-CY such as opportunistic infections. After repeated IV-CY, the ESR returned to normal allowing tapering of betamethasone. After 10 courses of IV-CY, the cutaneous ulcers were completely healed along with normalization of ESR despite tapering of betamethasone (Fig. 3). Re-biopsy of the skin, taken from almost the same area as the first biopsy on the right buttock showed disappearance of vasculitis and almost complete elimination of lymphocytic infiltration (Fig. 4). Discussion Cutaneous vasculitis characterized by ulceration is reported to be rare in adult-onset DM compared with JDM (1). DM with cutaneous ulcers is resistant to CS, resulting in poor prognosis, similar to the Banker subtype of JDM. Feldman et al (2) recognized cutaneous vasculitis in 7 (9%) of their 76 patients and reported that only 2 of the 7 patients had cutaneous ulcers and one of the two patients died because of resistance to treatment with CS. Kono et al (3). reported that only 3 of their 48 cases had cutaneous ulcers and that cutaneous vasculitis was significantly associated with pneumomediastinum. Furthermore, all 7 adult-onset DM patients with skin ulcers reported in the literature (Table 2) (3, 5-10) showed no response to initial CS therapy; 5 cases developed serious complications such as interstitial pneumonia and gastrointestinal perforation, and 6 had severe vasculitis on histopathological examination. Interestingly, the addition of high dose CS to the initial treatments failed to suppress disease activity in 3 of the 6 reported cases and resulted in a poor prognosis, e.g., death or further deterioration. These 3 cases had necrotizing vasculitis on histopathological examination. The characteristic histopathological features of necrotizing vasculitis are nuclear dusts, fibrinoid degeneration, erythrocyte extravasation and intimal degeneration. In the present case, histopathological examination of a skin biopsy before IV-CY showed intimal degeneration with lymphocyte infiltration, and then the clinical feature of cutaneous ulcer showed necrotic crust. Thus, the cutaneous ulcers are likely to be related to necrotizing vasculitis and the features of histopathological examination have some modifications as a result of preceding therapies. DM-related necrotic cutaneous ulceration caused by vasculitis is, therefore, an important prognostic sign and an intensive immunosuppressive therapy is recommended. However, severe complications have occurred in patients with vasculitis-related cutaneous ulceration when they were treated with high dose CS alone (3, 5). The patient reported by Niizawa and Okitaka developed ileocecal perforation and 1938
Table2. ReviewofEightPreviouslyPublishedCasesofDermatomyositisComplicatedwithCutaneousUlcers Ref Age/ Sex Jo-1 Initial treatment Clinical course supplement treatments outcome Histopathological examination of the skin ulcer 3 30/ M - PSL 50 mg/day Pneumomediastinum, hemoptysis and cutaneous ulcer following PSL tapering CsA 225 mg/day Cutaneous ulcer: gradually improved, hemoptysis: stopped but IP: no change. Perivascular infiltration of lymphocytes 5 47/ M - PSL 80 mg/day, mpsl pulse Cutaneous ulcer no change, Ileocecal perforation and Respiratory failure CsA 300 mg/day. Surgery Gradual improvement Intimal arteritis. Thrombotic occlusion 6 63/ M - PSL 15 mg/day Cutaneous ulcer and IP flared PSL up to 80 mg/day, AZA 100 mg/day died due to IP Necrotizing vasculitis 7 74/F ND PSL 20 mg/day Cutaneous ulcer flared PSL up to 40 mg/day, mpsl pulse Gradual improvement Thrombotic occlusion. Perivascular infiltration of lymphocytes 8 54/F - PSL 1 mg/kg/day MTX, HCQ Diffuse cutaneous ulceration following PSL tapering PSL up to 1 mg/kg/day, monthly IVIG 3 times Complete healing of cutaneous ulcers ND 9 68/F - PSL 80 mg/day Cutaneous ulcer and myositis flared after PSL tapering PSL up to 60 mg/day bedridden Necrotizing vasculitis 10 21/F - PSL 25 mg/day Cutaneous ulcer flared PSL up to 75 mg/day, mpsl pulse died due to intestinal perforation Necrotizing vasculitis ND, not done; IP, interstitial pneumonia; i.m., intramuscular infusion; PSL, prednisolone (or equivalent); mpsl pulse, methyl prednisolone pulse therapy; MTX, methotrexate; HCQ, hydroxychloroquine; CsA, Cyclosporin A; AZA, azathioprine; IVIG, intravenous immunoglobulin. respiratory failure due to muscle weakness of the respiratory muscles despite initial high-dose CS therapy combined with mpsl pulse therapy (5). The patient reported by Kono et al developed hemoptysis and pneumomediastinum despite initial high-dose CS therapy, and the respiratory function did not improve (3). In the present patient, repeated IV-CY therapy successfully resulted in elimination of cutaneous lymphocytic infiltration and cutaneous vasculitis and resolution of cutaneous ulcers associated with DM. This is the first report that demonstrated treatment of IV-CY resulting in clinical and histological remission of cutaneous vasculitis of DM. IV-CY is known to a potent inducer of remission in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (11) and it can be supposed that IV-CY could successfully induce remission of cutaneous vasculitis of DM. Other investigators have reported that tolerability of IV-CY is not inferior to other immunosuppressive therapy including CS (12-14). The present case developed Pneumocystis jiroveci pneumonia, when he was treated with high dose CS including methyl-psl pulse therapy, cyclosporin A and IV-CY (15 mg/kg/day). However, treatment with low-dose CS and IV- CY (10 mg/kg/day) could result in evading opportunistic infections. If timely and adequate immunosuppressive therapy is provided for cutaneous vasculitis of DM, a high-dose CS therapy might not always be required and the dose of CS could be kept as low as possible, thus reducing the likelihood of severe opportunistic infection. In the present case, IP and myositis never relapsed and no other severe complication occurred even during tapering of CS. Therefore, repeated IV-CY therapy could prevent severe complications associated with DM. In conclusion, cutaneous vasculitis in adult-onset DM, even without organ involvement, suggests a high-risk state of exacerbation and requires intensive immunosuppressive therapy. We propose repeated IV-CY as a useful treatment for the induction of clinical remission of refractory DM with cutaneous vasculitis. References 1. Winkelmann RK. Dermatomyositis in childhood. J C E Dermatol 18: 13-21, 1979. 2. Feldman D, Hochberg CM, Zizic MT, Stervens BM. Cutaneous vasculitis in adult polymyositis/dermatomyositis. J Rheumatol 10: 85-89, 1983. 3. Kono H, Inokuma S, Nakayama H, Suzuki M. Pneumomediastinum in dermatomyositis: association with cutaneous vasculopathy. Ann Rheum Dis 59: 372-376, 2000. 4. Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med 292: 344-347, 1975. 5. Niizawa M, Okitaka M. Adult dermatomyositis with angiopathy and cecum perforation. Jpn J Dermatol 101: 447-451, 1991 (in Japanese, Abstract in English). 6. Yamamoto T, Ohkubo H, Katayama I, Nishioka K. Dermatomyositis with multiple skin ulcers showing vasculitis and membrano-cystic lesion. J Dermatol 21: 687-689, 1994. 7. Kadoya A, Akahoshi T, Sekiyama N, Hosaka S, Kondo H. Cutaneous vasculitis in a patient with dermatomyositis without muscle involvement. Intern Med 33: 809-812, 1994. 8. Mark FP, Perkins P, Elston DM, Older SA, Vinson RP. Cutaneous ulcers of refractory adult dermatomyositis responsive to intravenous immunoglobulin. Cutis 62: 89-93, 1998. 1939
9. Yosipovitch G, Feinmesser M, David M. Adult dermatomyositis with livedo reticularis and multiple skin ulcers. J Eur Acad Dermatol Venereol 11: 48-50, 1998. 10. Chen GY, Liu MF, Lee JY, Chen W. Combination of massive mucinosis, dermatomyositis, pyoderma gangrenosum-like ulcer, bullae and fatal intestinal vasculopathy in a young female. Eur J Dermatol 15: 396-400, 2005. 11. de Groot K, Adu D, Savage CO; EUVAS (European Vasculitis Study Group). The value of pulse cyclophosphamide in ANCAassociated vasculitis: meta-analysis and critical review. Nephrol Dial Transplant 16: 2018-2027, 2001. 12. Tehlirian CV, Hummers LK, White B, Brodsky RA, Wigley FM. High-dose cyclophosphamide without stem cell rescue in scleroderma. Ann Rheum Dis 67: 775-781, 2008. 13. Ribi C, Cohen P, Pagnoux C, et al. Treatment of Churg-Strauss syndrome without poor-prognosis factors: a multicenter, prospective, randomized, open-label study of seventy-two patients. Arthritis Rheum 58: 586-594, 2008. 14. Okada M, Suzuki K, Matsumoto M, et al. Intermittent intravenous cyclophosphamide pulse therapy for the treatment of active interstitial lung disease associated with collagen vascular diseases. Mod Rheumatol 17: 131-136, 2007. 2008 The Japanese Society of Internal Medicine http://www.naika.or.jp/imindex.html 1940