Striking leflunomide efficacy against refractory cutaneous sarcoidosis
Authors: Gérôme Bohelay, Jean-David Bouaziz, Hilario Nunes, Michel Rybojad, Martine Bagot, Antoine Petit, Liliane Laroche
Journal: Journal of the American Academy of Dermatology (2014)

To the Editor: Sarcoidosis, a multisystemic granulomatous disease of unknown etiology, involves the skin in about 25% of cases.1Iannuzzi M.C. Rybicki B.A. Teirstein A.S. Sarcoidosis.N Engl J Med. 2007; 357: 2153-2165Crossref PubMed Scopus (1652) Google Scholar We describe leflunomide efficacy in 2 patients whose cutaneous sarcoidoses were refractory to conventional therapies. Patient 1 was a 46-year-old woman with lung (stage 1), skin, and nasosinusal sarcoidosis lasting 16 years. Her medical history included hypertension and thalidomide-induced lower limb neuropathy. Skin lesions were resistant to topical steroids, tacrolimus, hydroxychloroquine, thalidomide, and methotrexate; the patient refused oral prednisone. Leflunomide (20 mg/day) was started alone because she had progressive nasosinusal involvement and cutaneous lesions on her limbs and buttocks, and a large patch on her right cheek (Fig 1, A). Angiotensin-converting enzyme (ACE) level was 84 (normal <41 IU/mL). Dramatic cutaneous improvement was noted at 6 months, and complete remission (CR) of cutaneous (Fig 1, B) and nasosinusal lesions was obtained after 1 year of leflunomide therapy as shown by normal ACE level and normal control skin biopsy of the left arm. Because sarcoid joint manifestations occurred whenever the leflunomide dose was decreased to less than 10 mg/day, maintenance therapy with that dose was pursued without any relapse after 34 months. Vulvar and cervical intraepithelial neoplasias, diagnosed after 24 months, were treated with surgical excision and cervical conization, respectively, without recurrence 1 year later. Patient 2, a 51-year-old woman with type 1 diabetes and hypertension had stage 1 lung and nasosinusal sarcoidosis and severe facial lupus pernio (Fig 2, A) lasting 9 years that was resistant to topical and systemic corticosteroids, thalidomide, infliximab, etanercept, efalizumab, methotrexate alone, methotrexate combined with hydroxychloroquine, and intralesional corticosteroid injections. Leflunomide (20 mg/day) was added to a stable methotrexate dose (20 mg/wk). Striking regression of skin lesions and nasosinusal symptoms was obtained after 4 months of leflunomide therapy (Fig 2, B). Discontinuing methotrexate and leflunomide maintenance alone led to partial skin and nasosinusal relapses. Reintroducing methotrexate (15 mg/week) reestablished partial remission (PR). No adverse events occurred. After failure of topical steroids and antimalarials, oral corticosteroids remain the major treatment for cutaneous sarcoidosis.2Badgwell C. Rosen T. Cutaneous sarcoidosis therapy updated.J Am Acad Dermatol. 2007; 56: 69-83Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar In the case of steroid resistance or intolerance, methotrexate and tumor necrosis factor-alpha–blocking agents have the highest levels of evidence justifying their use.2Badgwell C. Rosen T. Cutaneous sarcoidosis therapy updated.J Am Acad Dermatol. 2007; 56: 69-83Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar Leflunomide, an immunomodulatory drug-inhibiting dihydroorotate dehydrogenase, a mitochondrial enzyme involved in pyrimidine synthesis, prevents the expansion of activated T lymphocytes, which are key actors in sarcoidosis pathogenesis. In 2003, Majithia and colleagues reported the first case of leflunomide efficacy in a patient with sinusal and facial sarcoidosis with sinusal CR and skin PR.3Majithia V. Sanders S. Harisdangkul V. Wilson J.G. Successful treatment of sarcoidosis with leflunomide.Rheumatology. 2003; 42: 700-702Crossref PubMed Scopus (33) Google Scholar Since then, leflunomide efficacy alone or combined with methotrexate against sarcoidosis skin lesions has been investigated in 18 patients in 2 retrospective studies focusing on refractory cases of pulmonary sarcoidosis.4Sahoo D.H. Bandyopadhyay D. Xu M. Parambil J.G. Lazar C.A. Chapman J.T. et al.Effectiveness and safety of leflunomide for pulmonary and extrapulmonary sarcoidosis.Eur Respir J. 2011; 38: 1145-1150Crossref PubMed Scopus (114) Google Scholar, 5Baughman R.P. Lower E.E. Leflunomide for chronic sarcoidosis.Sarcoidosis Vasc Diffuse Lung Dis. 2004; 21: 43-48PubMed Google Scholar Leflunomide skin response was described in 13 patients (12 with CR or PR), but detailed follow-up and digital photos were lacking. Leflunomide side effects include infections, peripheral neuropathy, liver dysfunction, and interstitial lung disease. To our knowledge, in situ squamous cell carcinomas have never been associated with leflunomide use. Our data show clear evidence of leflunomide long-term efficacy in patients with skin sarcoidosis that is difficult to treat. However, large prospective studies are needed to confirm these observations.