Hydroxychloroquine for generalized granuloma annulare: 35% response rate in a retrospective case series of 26 patients

Abstract

To the Editor: Granuloma annulare is a benign dermatosis that may present in a localized or generalized distribution (generalized granuloma annulare [GGA]).1Wang J. Khachemoune A. Granuloma annulare: a focused review of therapeutic options.Am J Clin Dermatol. 2018; 19: 333-344Crossref PubMed Scopus (38) Google Scholar GGA tends to be resistant to therapy, and the challenges surrounding its management are exacerbated by the paucity of data.1Wang J. Khachemoune A. Granuloma annulare: a focused review of therapeutic options.Am J Clin Dermatol. 2018; 19: 333-344Crossref PubMed Scopus (38) Google Scholar Antimalarials have been suggested as a first-line systemic treatment for GGA, and the use of hydroxychloroquine (HCQ) has been supported by a 14-patient case series (64% improvement rate).2Grewal S.K. Rubin C. Rosenbach M. Antimalarial therapy for granuloma annulare: results of a retrospective analysis.J Am Acad Dermatol. 2017; 76: 765-767Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar Here, we evaluated the effect of HCQ on patients with GGA using a 26-patient case series. Institutional review board approval was obtained to conduct a retrospective medical record review of GGA patients who received HCQ between 2011 and 2020. Patients without biopsies and those lost to follow-up were excluded. Outcomes were classified as follows: complete clearance, partial response (flattening, fading, and reduction in the number of lesions), or no response. Twenty-six patients—primarily Caucasian (100%), women (92%), and with a mean age of 59 years—met the inclusion criteria (Table I). The most common co-morbid conditions at the time of presentation were dyslipidemia (11/26; 42%), hypothyroidism (10/26; 38%), and type 2 diabetes mellitus (6/26; 23%). Six (6/26; 23%) patients had a history of viral infections (4 with varicella zoster and 2 with herpes simplex). Lesions presented as plaques (18/26; 69%), papules (13/26; 50%), and patches (5/26; 19%), most commonly affecting the upper extremities (23/26; 88%), lower extremities (19/26; 73%), and trunk (19/26; 73%). Twenty (20/26; 77%) patients reported pruritus.Table ITwenty-six patients with biopsy-proven generalized granuloma annulare treated with hydroxychloroquineAge, y/sex/raceLesion distributionPre-HCQ therapiesHCQ duration, mo∗200 mg twice daily unless otherwise specified.Concomitant medicationsResponse (initial response; time from flare, if applicable), moAdverse effects50/F/WFace, neck, and UE†Pretreatment biopsy.Hydrocortisone and terbinafine4NoneCC (4)None67/F/WUE and trunk†Pretreatment biopsy.Selenium sulfide19NonePR (5); CC (7)None70/M/WUE and trunk†Pretreatment biopsy.Pentoxifylline16FluocinonidePR (3); flared, CC (12)None69/F/WUE, LE, and trunk†Pretreatment biopsy.Clobetasol and prednisone16NoneCC (4); flared, PR (6); flared, NRNone57/F/WUE and LE†Pretreatment biopsy.Clobetasol6ClobetasolPR (3)None52/F/WUE and trunk†Pretreatment biopsy.Doxycycline, ILK, TCIs, and TCSs6CalcipotriolPR (6)None46/F/WUE and LE†Pretreatment biopsy.Fluocinonide, ILK, minocycline, MTX, phototherapy, and topical pimecrolimus6FluocinonidePR (1.5); flared, NRNone51/F/WUE, LE, trunk, and neck†Pretreatment biopsy.Colchicine, dapsone, isotretinoin, minocycline, prednisone, and TCSs42DapsonePR (2); flared, no follow-up evaluation at time of analysisNone70/F/WUE, LE, and trunk†Pretreatment biopsy.Minocycline, MTX, prednisone, and TAC48Pentoxifylline and phototherapyPR (3); flared, PR (5)None57/F/WUE, LE, and trunk†Pretreatment biopsy.,‡Post-treatment biopsy.ILK, MTX, and ROM3NoneNRNone74/F/WFace, LE, and trunk†Pretreatment biopsy.Betamethasone, clobetasol, and TAC9TCSsNRPhotosensitivity54/M/WLE†Pretreatment biopsy.TCSs2NoneNRGI upset76/F/WUE and trunk†Pretreatment biopsy.TCSs13TACNRNone36/F/WUE, LE, and trunk†Pretreatment biopsy.TCSs1NoneNRPruritus75/F/WUE, LE, and trunk†Pretreatment biopsy.Cyclosporine, dapsone, and prednisone1NoneNRNone66/F/WUE, LE, and trunk†Pretreatment biopsy.Dapsone6NoneNRNone39/F/WUE, LE, and trunk†Pretreatment biopsy.Clobetasol and TAC8Clobetasol and TACNRHair loss46/F/WFace, UE, and trunk†Pretreatment biopsy.ROM and TCSs2§200 mg once daily.NoneNRGI upset and fatigue65/F/WLE†Pretreatment biopsy.Clobetasol and ROM10PentoxifyllineNRHair loss61/F/WUE and trunk†Pretreatment biopsy.Unknown11TACNRNone55/F/WUE, LE, trunk, and neck‡Post-treatment biopsy.Dapsone, ILK, and TCSs5NoneNRNone57/F/WUE, LE, and trunk†Pretreatment biopsy.Clobetasol, ILK, and phototherapy2NoneNRNone74/F/WUE and LE†Pretreatment biopsy.Hydrocortisone3NoneNRNone55/F/WUE, LE, and trunk†Pretreatment biopsy.Clobetasol, pentoxifylline, and ROM7NoneNRNone54/F/WUE, LE, and trunk†Pretreatment biopsy.Fluocinonide and TAC3Fluocinonide and TACNRDiffuse rash58/F/W‖CLL (3 months preceding GGA).UE and LE†Pretreatment biopsy.Clobetasol, ILK, ROM, and pentoxifylline11ClobetasolNRNoneCC, Complete clearance; CLL, chronic lymphocytic leukemia; GGA, generalized granuloma annulare; GI, gastrointestinal; HCQ, hydroxychloroquine; ILK, intralesional triamcinolone; LE, lower extremities; MTX, methotrexate; NR, no response; PR, partial response; ROM, rifampin/ofloxacin/minocycline; TAC, topical triamcinolone; TCI, topical calcineurin inhibitors; TCS, unspecified topical corticosteroids; UE, upper extremities; W, Caucasian.∗ 200 mg twice daily unless otherwise specified.† Pretreatment biopsy.‡ Post-treatment biopsy.§ 200 mg once daily.‖ CLL (3 months preceding GGA). Open table in a new tab CC, Complete clearance; CLL, chronic lymphocytic leukemia; GGA, generalized granuloma annulare; GI, gastrointestinal; HCQ, hydroxychloroquine; ILK, intralesional triamcinolone; LE, lower extremities; MTX, methotrexate; NR, no response; PR, partial response; ROM, rifampin/ofloxacin/minocycline; TAC, topical triamcinolone; TCI, topical calcineurin inhibitors; TCS, unspecified topical corticosteroids; UE, upper extremities; W, Caucasian. Disease activity existed for a mean of 3 years before the commencement of HCQ dosed at a median 400 mg daily for a mean duration of 10 months. Nine (9/26; 35%) patients improved (4 had complete clearance and 5 were partial responders), and initial responses were observed within a mean of 3.5 months. Five responders (5/9; 56%) flared, including 2 who failed to respond to subsequent HCQ therapy. Thirteen (13/26; 50%) patients underwent HCQ monotherapy. Three (3/26; 12%) patients were administered concomitant systemic treatments (2 responders and 1 nonresponder). Of the HCQ responders, 6 (6/9; 67%) received adjunctive topical (fluocinonide in 2, clobetasol in 1, and calcipotriol in 1) and systemic medications (pentoxifylline in 1 and dapsone in 1). No patient received biologic therapy, which may be effective in patients with GGA.3Chen A. Truong A.K. Worswick S. The role of biologics in the treatment of chronic granuloma annulare.Int J Dermatol. 2019; 58: 622-626Crossref PubMed Scopus (13) Google Scholar Although all the patients were counseled to undergo baseline and annual ophthalmologic evaluations upon HCQ commencement, 13 (13/26; 50%) patients underwent eye examinations. No patient experienced retinal toxicity, and HCQ was generally well tolerated; 19 (19/26; 73%) patients underwent therapy, without adverse effects. The most common discontinuation reason was the perceived lack of efficacy (11/21; 52%). While this study cited a lower response rate (9/26; 35%) than previous studies (9/14; 64%), our case series is not a broadly applicable population (100% Caucasian), and the lack of racial diversity may have attest to the challenges and disparities associated with diagnosing GGA in patients with skin of color.2Grewal S.K. Rubin C. Rosenbach M. Antimalarial therapy for granuloma annulare: results of a retrospective analysis.J Am Acad Dermatol. 2017; 76: 765-767Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar This study is also limited by a lack of a control group and standardized outcome measures. Nevertheless, our results challenge the strength of HCQ as a first-line systemic treatment for GGA; our group recently published data suggesting that improvements are observed more quickly (2.3 months vs 3.5 months) and in higher proportions (54% vs 35%) with dapsone.4Hrin M.L. Bashyam A.M. Feldman S.R. Huang W.W. Oral dapsone for the treatment of generalized granuloma annulare: a retrospective case series.J Am Acad Dermatol. March 20, 2021; (https://doi.org/10.1016/j.jaad.2021.03.045)Google Scholar Small-molecule drugs can be cost-effective treatment options, and additional studies of systemic agents for GGA are warranted. Dr Feldman has received research, speaking and/or consulting support from a variety of companies, including Galderma, GSK/Stiefel, Almirall, Leo Pharma, Boehringer Ingelheim, Mylan, Celgene, Pfizer, Valeant, Abbvie, Samsung, Janssen, Lilly, Menlo, Merck, Novartis, Regeneron, Sanofi, Novan, Qurient, National Biological Corporation, Caremark, Advance Medical, Sun Pharma, Suncare Research, Informa, UpToDate, and National Psoriasis Foundation. He is the founder and majority owner of www.DrScore.com and the founder and part owner of Causa Research, a company dedicated to enhancing patients' adherence to treatment. Dr Huang and Author Hrin have no conflicts of interest to declare.