Treatment of Widespread Granuloma Annulare with Adalimumab: A Case Report

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by Heidi Kozic, MD; Guy F. Webster, MD, PhD

Dr. Kozic is from Panzer Dermatology, Newark, Delaware, and Dr. Webster is from Jefferson Medical College, Department of Dermatology, Philadelphia, Pennsylvania

Disclosure: Dr. Kozic reports no relevant conflicts of interest. Dr. Webster is a consultant for Abbott.

Abstract
The authors report a case of widespread granuloma annulare that was resistant to multiple systemic therapies, but responded rapidly to a short course of adalimumab.  (J Clin Aesthet Dermatol. 2011;4(11):42–43.)Widespread granuloma annulare (GA) can be a difficult disease to treat. Often the only drug that is effective in severe disease is an oral corticosteroid, which is unsuitable for long-term use. The authors report the case of a woman with widespread GA who had an excellent response to adalimumab.

A 50-year-old woman presented with a 15-year history of an itchy and unsightly eruption on her arms and legs. Clinical examination and biopsy were consistent with GA. Topical steroids were initially effective, but with each recurrence, the disease became more resistant to therapy. Oral prednisone (60mg) was effective, but the disease recurred quickly after the drug was discontinued. Doxycycline 100mg twice daily and pentoxyphylline 400mg twice daily were ineffective. Methotrexate 15mg/week was effective for two months, but then lost efficacy. Increasing the dose to 20mg/week was ineffective.

Adalimumab was added to methotrexate 15mg/week according to the established psoriasis regimen of two shots of 40mg initially followed by 40mg every two weeks. Improvement was noted at one week, which continued for six weeks until the patient was clear. Methotrexate was discontinued. Adalimumab was continued for one month and then stopped. Two months later, the patient remained clear and was off all medication.

Discussion
Tumor necrosis factor (TNF) inhibitors have occasionally been reported to be effective in granulomatous disease. Zhang et al[1] reported efficacy in necrobiosis lipoidica, and various reports document utility in sarcoidosis[2] and granuloma annulare.[3,4] Curiously, granulomatous disease (sarcoidosis,[5] granuloma annulare,[6,7] and interstitial granulomas[8]) has also been reported to occur during anti-TNF therapy. The reasons behind this variable response are unknown and speculation is difficult given that little is known about the development of GA. It is possible that GA is a multifactorial disease with factors in some individuals that are exacerbated by TNF inhibition or by drugs that are co-prescribed. In a study of 199 patients with rheumatoid arthritis (RA) and 127 patients with spondylopathy, Voulgari et al[7] noted that only those with RA developed GA during anti-TNF therapy. Perhaps certain states of immune activation predispose to GA development on anti-TNF therapy.

The mechanism by which anti-TNF therapy works in granulomatous disease is uncertain, but is likely linked to the ability of adalimumab and infliximab to “lyse” granulomas in tuberculosis and Crohn’s disease because of its ability to activate complement when bound to a granuloma cell surface that is expressing TNF.[9]

References
1.    Zhang KS, Quan LT, Hsu, S. Treatment of necrobiosis lipoidica with etanercept and adalimumab. Dermatology Online Journal. 2009;15(12).
2.    Werchau S, Enk A, Hartmann M. Generalized interstitial granuloma annulare—response to adalimumab. Int J Dermatol. 2010;49(4):457—460.
3.    Rosmarin D, LaRaia A, Schlauder S, Gottlieb AB. Successful treatment of disseminated granuloma annulare with adalimumab. J Drugs Dermatol. 2009;8(2):169–171.
4.    Callejas-Rubio JL, Ortego-Centenero N, Lopez-Perez L, Benticuaga MN. Treatment of therapy resistant sarcoidosis with adalimumab. Clin Rheumatol. 2009;25:596–597.
5.    Dhaille F, Viseux V, Caudron A, et al. Cutaneous sarcoidosis occuring during anti-TNF alpha treatment. Dermatology. 2010;220:234–237.
6.    Exarchou SA, Voulgari PV, Markatseli TE, Zioga A, Drosos AA. Immune-mediated skin lesions in patients treated with anti-tumour necrosis factor alpha inhibitors. Scand J Rheumatol. 2009;38(5):328–331.
7.    Voulgari PV, Markatseli TE, Exarchou SA, Zioga A, Drosos AA. Granuloma annulare induced by anti-tumour necrosis factor therapy. Ann Rheum Dis. 2008;67(4):567–570.
8.    Deng A, Harvey V, Sina B, et al. Interstitial granulomatous dermatitis associated with the use of tumour necrosis factor a inhibitors. Arch Dermatol. 2006;142:198–202.
9.    Kaymakcalan Z, Sakorafas P, Bose S, et al. Comparison of affinities, avidities and complement activation of adalimumab, etanercept, and infliximab in binding to soluble and membrane TNF. Clin Immunol. 2009;131:308–316.

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