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

ARTICLE

Auteur(s) : Carlo Mattozzi¹, Antonio Giovanni Richetta¹, Carmen Cantisani¹, Simona Giancristoforo¹, Sara D'Epiro¹, Aldo Gonzalez Serva², Franca Viola¹, Salvatore Cucchiara¹, Stefano Calvieri¹

¹Policlinico Umberto I, University of Rome La Sapienza, Viale del Policlinico, 155, 00133 Rome, Italy
²Cutaneous Histopathology, Lexington, Ma 02421, USA

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 erythemato-aedematous 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 TB-Gold which led to the discontinuation of anti-TNF-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 anti-TNF-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 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 anti-TNF-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 TGF-beta-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 TNF-alpha, 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.

Acknowledgements

References

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 infliximab-induced psoriasis. Dermatol Online J 2008; 14: 9.

4 Allanore Y, Devos-François 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.