Methotrexate for generalized granuloma annulare: A 60% response rate in a retrospective case series of 15 patients

Abstract

To the Editor: Generalized granuloma annulare (GGA) is a benign granulomatous dermatosis that is plagued by the paucity of high-quality treatment data. The interventions with the most evidence include phototherapy, dapsone, and hydroxychloroquine; however, no regimen appears to produce a reliable response rate.1Wang J. Khachemoune A. Granuloma annulare: a focused review of therapeutic options.Am J Clin Dermatol. 2018; 19: 333-344Crossref PubMed Scopus (37) Google Scholar Methotrexate (MTX) lacks extensive coverage in the treatment of GGA, and a study of 11 patients with GGA (clinically diagnosed) reported 7 responders (3 with complete resolution and 4 with partial resolution; 64% response rate).2Naka F. Strober B.E. Methotrexate treatment of generalized granuloma annulare: a retrospective case series.J Dermatolog Treat. 2018; 29: 720-724Crossref PubMed Scopus (6) Google Scholar Our group sought to further investigate the safety and efficacy of MTX for GGA using a retrospective case series of 15 patients (with biopsy-proven GGA).Upon Wake Forest School of Medicine's institutional review board approval, a retrospective review of patients with GGA treated with MTX between 2011 and 2021 was performed. Patients without biopsies and patients lost to follow-up were excluded. Outcomes were categorized as complete clearance, partial response (fewer, flattened, and faded lesions), or no response.Fifteen patients—primarily White (93%) women (67%) with a mean age of 61.5 ± 11.3 years—met the inclusion criteria (Table I). The lesions were most commonly plaque type (13/15; 87%) and involved the lower extremities (13/15; 87%), trunk (13/15; 87%), and upper extremities (11/15; 73%). Eleven patients (11/15; 73%) reported pruritus, 4 (4/15; 27%) reported burning pain, and 3 (3/15; 20%) were asymptomatic.Table ICharacteristics and outcomes of 15 patients with generalized granuloma annulare treated with MTXAge, y/sex/raceDisease distributionPre-MTX disease duration, yPre-MTX therapiesMTX dose, mg QW (duration, mo)Concomitant medicationsOutcome (time to response [time from flare, if applicable]), moAdverse effects69/M/WLE and trunk0.5Clobetasol, desonide, and halobetasol7.5 (11)NonePR (4), CC (10)None74/F/WUE, LE, and trunk1Dapsone, HCQ, and TCSs7.5 (17)NonePR (2), CC (11)None54/F/WUE, LE, and trunk3Colchicine10 (23)TAC and topical tacrolimusPR (1); flare, CC (13)None72/M/WTrunk0.5Fluocinonide7.5 (20)Prednisone (6-week taper: from 30 mg to 0 mg), fluocinonide, and TACPR (2), CC (10); flare, CC (13)None67/F/WUE, LE, and trunk∗Disease preceded by varicella infection.1.75Colchicine15 (19)Prednisone (5-week taper: from 30 mg to 0 mg) and TACPR (1); flare, CC (10); flare, NRFatigue72/F/WUE, LE, and trunk5Dapsone, pentoxifylline, and ROM10 (8)NonePR (2)None51/F/WUE and trunk10HCQ17.5 (11)Clobetasol and topical tacrolimusPR (4)Alopecia and stomatitis37/F/WLE0.75TCSs7.5 (19)ILK and TCSsPR (9); flare, PR (4)None68/M/WUE, LE, and trunk0.75Doxycycline, ILK, prednisone, and TCSs15 (16)Acitretin and prednisone (5-week taper: from 30 mg to 0 mg)PR (4)Fatigue56/F/WUE, LE, and trunk∗Disease preceded by varicella infection.5HCQ, phototherapy, ROM, and TCSs7.5 (2)Pentoxifylline and clobetasolNRNone80/F/WUE, LE, and trunk2Clobetasol10 (10)NoneNRNone56/F/XUE, LE, trunk, and face3Adalimumab10 (2)NoneNRNone56/F/WUE, LE, and trunk1.5ILK and TCSs15 (3)TCSsNRFatigue55/M/WUE, LE, and trunk0.75Dapsone, HCQ, prednisone, and ROM12.5 (3)NoneNRElevated ALT level (units per liter) (84)55/M/WLE“Years”HCQ10 (1)NoneNRUnspecifiedALT, Alanine aminotransferase; CC, complete clearance; HCQ, hydroxychloroquine; ILK, intralesional triamcinolone; LE, lower extremities; MTX, methotrexate; NR, no response; PR, partial response; QW, once weekly; ROM, rifampin/ofloxacin/minocycline; TAC, topical triamcinolone; TCI, topical calcineurin inhibitor; TCS, unspecified topical corticosteroid; UE, upper extremities; W, Caucasian; X, other race.∗ Disease preceded by varicella infection. Open table in a new tab The patients were diagnosed with GGA at a mean of 2.5 years prior to MTX exposure. None of the patients were treatment naïve, and systemic therapy failed in 10 patients before MTX was commenced at a median weekly dose of 10 mg for a mean duration of 11 months. Nine (9/15; 60%) patients improved (5 had complete clearance and 4 were partial responders), and the most common concomitant medications in MTX responders were prednisone (3/9; 33%) and topical triamcinolone (3/9; 33%). Initial improvements were observed within a mean of 3 months, and the responders remained on MTX longer than nonresponders (mean 16 vs 3.5 months). GGA flared in 4 (4/9; 44%) responders, including 1 patient who failed to improve with subsequent MTX therapy.Of 7 (7/15; 47%) patients who underwent MTX monotherapy, 3 (3/7; 43%) improved, which was a lower response rate compared with that of patients who were treated with concomitant topical and/or systemic medications (6/8; 75%). Six (6/15; 40%) patients reported side effects, and 2 ceased MTX because of the side effects (stomatitis and alopecia, unspecified). One patient experienced elevated alanine aminotransferase levels (84 units per liter) and discontinued MTX due to a lack of efficacy.This study is limited by its sample size and lack of racial diversity. As with dapsone (54% response rate) and hydroxychloroquine (35% response rate), the responses to MTX neither appeared consistent nor were reliably sustained.3Hrin 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.2021.03.045Abstract Full Text Full Text PDF Scopus (4) Google Scholar,4Hrin M.L. Feldman S.R. Huang W.W. Hydroxychloroquine for generalized granuloma annulare: 35% response rate in a retrospective case series of 26 patients.J Am Acad Dermatol. June 30, 2021; https://doi.org/10.1016/j.jaad.2021.06.867Abstract Full Text Full Text PDF Scopus (2) Google Scholar Biologics may be effective options if patients can afford them; in 1 MTX nonresponder, the lesions cleared with adalimumab, but it was discontinued because of its cost.5Chen 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 Identifying a dependable, accessible treatment for GGA can be challenging. However, MTX may be an economical agent to be considered for patients with recalcitrant disease. To the Editor: Generalized granuloma annulare (GGA) is a benign granulomatous dermatosis that is plagued by the paucity of high-quality treatment data. The interventions with the most evidence include phototherapy, dapsone, and hydroxychloroquine; however, no regimen appears to produce a reliable response rate.1Wang J. Khachemoune A. Granuloma annulare: a focused review of therapeutic options.Am J Clin Dermatol. 2018; 19: 333-344Crossref PubMed Scopus (37) Google Scholar Methotrexate (MTX) lacks extensive coverage in the treatment of GGA, and a study of 11 patients with GGA (clinically diagnosed) reported 7 responders (3 with complete resolution and 4 with partial resolution; 64% response rate).2Naka F. Strober B.E. Methotrexate treatment of generalized granuloma annulare: a retrospective case series.J Dermatolog Treat. 2018; 29: 720-724Crossref PubMed Scopus (6) Google Scholar Our group sought to further investigate the safety and efficacy of MTX for GGA using a retrospective case series of 15 patients (with biopsy-proven GGA). Upon Wake Forest School of Medicine's institutional review board approval, a retrospective review of patients with GGA treated with MTX between 2011 and 2021 was performed. Patients without biopsies and patients lost to follow-up were excluded. Outcomes were categorized as complete clearance, partial response (fewer, flattened, and faded lesions), or no response. Fifteen patients—primarily White (93%) women (67%) with a mean age of 61.5 ± 11.3 years—met the inclusion criteria (Table I). The lesions were most commonly plaque type (13/15; 87%) and involved the lower extremities (13/15; 87%), trunk (13/15; 87%), and upper extremities (11/15; 73%). Eleven patients (11/15; 73%) reported pruritus, 4 (4/15; 27%) reported burning pain, and 3 (3/15; 20%) were asymptomatic. ALT, Alanine aminotransferase; CC, complete clearance; HCQ, hydroxychloroquine; ILK, intralesional triamcinolone; LE, lower extremities; MTX, methotrexate; NR, no response; PR, partial response; QW, once weekly; ROM, rifampin/ofloxacin/minocycline; TAC, topical triamcinolone; TCI, topical calcineurin inhibitor; TCS, unspecified topical corticosteroid; UE, upper extremities; W, Caucasian; X, other race. The patients were diagnosed with GGA at a mean of 2.5 years prior to MTX exposure. None of the patients were treatment naïve, and systemic therapy failed in 10 patients before MTX was commenced at a median weekly dose of 10 mg for a mean duration of 11 months. Nine (9/15; 60%) patients improved (5 had complete clearance and 4 were partial responders), and the most common concomitant medications in MTX responders were prednisone (3/9; 33%) and topical triamcinolone (3/9; 33%). Initial improvements were observed within a mean of 3 months, and the responders remained on MTX longer than nonresponders (mean 16 vs 3.5 months). GGA flared in 4 (4/9; 44%) responders, including 1 patient who failed to improve with subsequent MTX therapy. Of 7 (7/15; 47%) patients who underwent MTX monotherapy, 3 (3/7; 43%) improved, which was a lower response rate compared with that of patients who were treated with concomitant topical and/or systemic medications (6/8; 75%). Six (6/15; 40%) patients reported side effects, and 2 ceased MTX because of the side effects (stomatitis and alopecia, unspecified). One patient experienced elevated alanine aminotransferase levels (84 units per liter) and discontinued MTX due to a lack of efficacy. This study is limited by its sample size and lack of racial diversity. As with dapsone (54% response rate) and hydroxychloroquine (35% response rate), the responses to MTX neither appeared consistent nor were reliably sustained.3Hrin 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.2021.03.045Abstract Full Text Full Text PDF Scopus (4) Google Scholar,4Hrin M.L. Feldman S.R. Huang W.W. Hydroxychloroquine for generalized granuloma annulare: 35% response rate in a retrospective case series of 26 patients.J Am Acad Dermatol. June 30, 2021; https://doi.org/10.1016/j.jaad.2021.06.867Abstract Full Text Full Text PDF Scopus (2) Google Scholar Biologics may be effective options if patients can afford them; in 1 MTX nonresponder, the lesions cleared with adalimumab, but it was discontinued because of its cost.5Chen 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 Identifying a dependable, accessible treatment for GGA can be challenging. However, MTX may be an economical agent to be considered for patients with recalcitrant disease. 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. In addition, 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. Drs Bowers and Huang and Author Hrin have no conflicts of interest to declare.