Morphea, an unusual side effect of anti-TNF-alpha treatment

ageal carcinoma. The evidence linking solid malignancies to reactive cutaneous amyloidosis is limited. Investigations for an underlying malignancy should be taken not only with diffuse biphasic cutaneous amyloidosis but also with any cutaneous type of amyloidosis. ■ Acknowledgements. Conflict of interest: none. Financial support: none. Department of Dermatology, Fudan University Huashan Hospital, No.12 Wulumuqi Zhong Road, 200040 Shanghai, China

Jinran LIN Minghua CHEN

1. Bedi TR, Datta BN. Diffuse biphasic cutaneous amyloidosis. Dermatologica 1979; 158: 433-7. 2. Bourke JF, Berth-Jones J, Burns DA. Diffuse primary cutaneous amyloidosis. Br J Dermatol 1992; 127: 641-4. 3. Chung VQ, Moschella SL, Zembowicz A, et al. Clinical and pathologic findings of paraneoplastic dermatoses. J Am Acad Dermatol 2006; 54: 745-62. 4. Nunziata V, di Giovanni G, Lettera AM, et al. Cutaneous lichen amyloidosis associated with multiple endocrine neoplasia type 2A. Henry Ford Hosp Med J 1989; 37: 144-6. 5. de Argila D, Ortiz-Romero PL, Ortiz-Frutos J, et al. Cutaneous macular amyloidosis associated with multiple endocrine neoplasia 2A. Clin Exp Dermatol 1996; 21: 313-4. doi:10.1684/ejd.2010.0914

TB-Gold which led to the discontinuation of antiTNF-alpha. Treatment with isoniazid 300 mg a day for 6 months was started while Crohn’s disease was managed with azatioprine, 100 mg a day. Morphea was treated with local applications of clobetasone diproprionate for 20 days and the fibrosis was managed with the LPG (Louis Paul Guitay) technique (Endermology treatment). Complete clinical resolution of the lesion occurred in about 60 days, with a reduction of induration, pain and an improvement of cutaneous elasticity. At the present time, after 12 months, there is no evidence of disease recurrence. For anti-TNF-alpha inhibitors, various cutaneous side effects have been reported [2, 3].To the best of our knowledge, this is the first case reported in which antiTNF-alpha acted as a trigger for cutaneous sclerosis. The association between morphea and Crohn’s disease is not very common and the development of sclerodermic lesions may have been coincidental. A hypothetical explanation of this clinical manifestation might be an overall enhanced susceptibility to bacterial infections caused by

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Morphea, an unusual side effect of anti-TNF-alpha treatment Localized scleroderma, also called morphea, is a chronic cutaneous disorder characterized by fibrosis of skin and subcutaneous tissue. The pathogenesis is very complex and several hypotheses have been advanced. It can be triggered or exacerbated by drugs such as appetite suppressants, bleomycin, pentazocine, isoniazid, taxols, D-pencillamin, antimalarian chloroquine and hydroxychloroquine, cathepsin K inhibitor balicatib, capecitabin, gemcitabin, chemicals (silica, organic solvents, polyvinyl chloride) and injections (vitamin K) [1]. Anti-tumor necrosis factor (Anti-TNF)-alpha is a group of drugs able to inhibit this cytokine action, treating diseases in which TNF-alpha is mainly involved. Although systemic side effects have been well described, cutaneous adverse reactions have not yet been clearly elucidated. A 17-year-old woman developed a round erythematoaedematous plaque on the abdomen. The central part of the lesion was warm and markedly indurated, with an associated violaceous border (figure 1A). She showed no signs or symptoms of internal organ involvement. She was on treatment with adalimumab 40 mg for Crohn’s disease with the following schema: 1 vial every 14 days. The skin reaction appeared distant from the afflicted area, after the sixth injection. The blood examination was normal, immunological investigations were all negative. Chest computed tomography (CT) did not show pulmonary fibrosis or other disease. Kidney function was not compromised. The skin biopsy was consistent with localized scleroderma (figure 1B). She continued the treatment but one month later developed a positivity of Quantiferon

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Figure 1. A) Rounded erythematous and aedematous plaques on the abdomen, with a indurated central part and violaceous border. B) Presence of fibrosis with proliferation of collagen bundles of the superficial papillary dermis and perivascular infiltration of lymphocytes, macrophages and plasma cells. EJD, vol. 20, n° 3, May-June 2010

TNF-alpha inhibition, which may act as a trigger for localized scleroderma. In fact, superantigens released from streptococci might activate T cells, inducing sclerodermic lesions. A few reports demonstrated the role of anti-TNF-alpha in the development of fibrosis. A case of fibrosing alveolitis and Buschke’s Scleroedema in a patient treated with antiTNF-alpha has been described [4]. The reason for this phenomenon is not clear, but it is possible that TNF-alpha may have antifibrotic properties and its suppression may lead to the development of sclerodermic lesions; in vitro studies have demonstrated the role of TNF-alpha in the inhibition of fibrosis, preventing TGFbeta-induced gene trans activation and the expression of type II TGF-beta receptor (TbetaRII) proteins [5]. Another study points out the role of Th2 cells in the regulation of fibrosis reducing type I collagen synthesis by dermal fibroblasts; because of the dominant effect of TNFalpha, inhibition of this cytokine may disregulate the balance between pro-fibrotic and anti-fibrotic triggers, promoting collagen deposition [6]. Although no conclusion can be reached with this case, TNF-alpha may play a pivotal role in the turnover of collagen synthesis and for this reason fibrosis might occur in predisposed individuals. Obviously further studies are needed to evaluate the role of adalimumab in the development of fibrosis. ■

Heparin is an anticoagulant drug commonly administered for the prevention and treatment of thromboembolic diseases. The side effects of heparin, such as hemorrhage, alopecia and osteoporosis, are mostly known. Although hypersensitivity to heparin has been frequently reported, eosinophilic panniculitis caused by heparin has rarely been mentioned [1]. A 32-year-old, Japanese female with an 18-week intrauterine pregnancy (IUP) presented with a 2-month history of hypereosinophilia and multiple subcutaneous nodules at the sites of a subcutaneous injection of calcium heparin (Caprocin®, 20,000 IU/0.8 mL). She had experienced 5 gravidities and 4 spontaneous abortions. As she was diagnosed with sero-negative anti-phospholipid syndrome (APS), she started oral administration of low-dose aspirin (LDA) and subcutaneous injection of calcium heparin at a 5-week IUP. The skin lesions developed 5 weeks after the initiation of subcutaneous injections. A physical examination revealed multiple subcutaneous nodules on her abdominal wall (figure 1A) and upper arms. Abnormal laboratory findings included leukocytosis of 18,300/μL,

Acknowledgements. Financial support: none. Conflict of interest: none.

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Policlinico Umberto I, University of Rome La Sapienza, Viale del Policlinico, 155, 00133 Rome, Italy 2 Cutaneous Histopathology, Lexington, Ma 02421, USA

Eosinophilic panniculitis and hypereosinophilia caused by hypersensitivity to calcium heparin

Carlo MATTOZZI1 Antonio Giovanni RICHETTA1 Carmen CANTISANI1 Simona GIANCRISTOFORO1 Sara D’EPIRO1 Aldo GONZALEZ SERVA2 Franca VIOLA1 Salvatore CUCCHIARA 1

Stefano CALVIERI1 1. Krieg T, Hunzelmann N, Gabrielli A, Jablonska S. EDF. Scleroderma. Eur J Dermatol 2008; 18: 213-4. 2. European, Agency, for et al. http://www.emea.eu.int/pdfs/ human/press/pus/444500en.pdf. 3. Richetta A, Mattozzi C, Carlomagno V, et al. A case of infliximabinduced psoriasis. Dermatol Online J 2008; 14: 9. 4. Allanore Y, Devos-Franc¸ois G, Caramella C, Boumier P, Jounieaux V, Kahan A. Fatal exacerbation of fibrosing alveolitis associated with systemic sclerosis in a patient treated with adalimumab. Ann Rheum Dis 2006; 65: 834-5. 5. Yamane K, Ihn H, Asano Y, Jinnin M, Tamaki K. Antagonistic effects of TNF-alpha on TGF-beta signaling through down-regulation of TGF-beta receptor type II in human dermal fibroblasts. J Immunol 2003; 171: 3855-62. 6. Chizzolini C, Parel Y, De Luca C, Tyndall A, Akesson A, Scheja A, et al. Systemic sclerosis Th2 cells inhibit collagen production by dermal fibroblasts via membrane-associated tumor necrosis factor alpha. Arthritis Rheum 2003; 48: 2593-604. doi:10.1684/ejd.2010.0946

EJD, vol. 20, n° 3, May-June 2010

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Figure 1. A) Multiple subcutaneous nodules and erythematous plaques at the calcium heparin injection sites on the abdomen. B) A photomicrograph showing fibrous thickening of the septa and perivascular inflammatory infiltrations in the dermis and subcutis (H and E staining; × 40). C) The infiltration of eosinophils and lymphocytes in the septum of fat tissue (H and E staining; × 200).

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