Oral dapsone for the treatment of generalized granuloma annulare: A retrospective case series

Abstract

To the Editor: Granuloma annulare is a non-infectious granulomatous dermatosis. Although its etiology is unknown, some conditions have been reported in increased frequencies in patients with granuloma annulare compared with the general population, including thyroid disease, diabetes mellitus, dyslipidemia, and viral infections.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 While localized disease tends to spontaneously resolve, generalized granuloma annulare (GGA) cases may persist for decades, and the treatment data are sparse.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 Phototherapy and antimalarials are the first-line treatment for GGA, although retinoids, biologics, and small molecule immunosuppressants can also be used.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 Dapsone may be viable; however, evidence is limited to studies comprising ≤10 patients.2Czarnecki D.B. Gin D. The response of generalized granuloma annulare to dapsone.Acta Derm Venereol. 1986; 66: 82-84PubMed Google Scholar, 3Steiner A. Pehamberger H. Wolff K. Sulfone treatment of granuloma annulare.J Am Acad Dermatol. 1985; 13: 1004-1008Abstract Full Text PDF PubMed Scopus (58) Google Scholar, 4Martín-Sáez E. Fernández-Guarino M. Carrillo-Gijón R. Muñoz-Zato E. Jaén-Olasolo P. Efficacy of dapsone in disseminated granuloma annulare: a case report and review of the literature. Article in Spanish.Actas Dermosifiliogr. 2008; 99: 64-68Crossref PubMed Scopus (19) Google Scholar Here, we evaluate the safety and efficacy of dapsone with a retrospective case series of 26 patients.Institutional review board approval was obtained to review the medical records of patients from a single institution who received oral dapsone for GGA between 2010 and 2020. Patients without pretreatment biopsy and patients lost to follow-up were excluded. Outcomes were categorized as: complete clearance, partial response (fewer, flattened, or faded lesions), or no improvement.Twenty-six patients—primarily Caucasian (100%) women (96%) with a mean age of 64 years—met the inclusion criteria (Table I). Lesions were most commonly plaque-type (24/26; 92%), and involved the lower extremities (23/26; 88%), upper extremities (21/26; 81%), trunk (17/26; 65%), and neck (2/26; 8%); 12 (46%) patients reported pruritus, 4 (15%) patients reported burning pain, and 13 (50%) patients were asymptomatic. The patients had mean disease duration of 5.6 years before initiating dapsone at a median daily dose of 100 mg (25-200 mg) for a mean duration of 9.8 months. Fourteen of 26 (54%) patients improved, and initial responses were observed within a mean of 2.3 months. However, the results were not consistently sustained, and 8 (57%) responders experienced flares following discontinuation. The patients who improved remained on dapsone for longer durations compared with those who did not improve (mean 16.0 vs 2.6 months), and perceived lack of efficacy was the most common discontinuation reason in non-responders (8/12; 67%).Table IPresentation characteristics of 26 patients with generalized granuloma annulare treated with dapsoneAge, y/sex/raceComorbid conditionsGeneralized granuloma annulare disease sitesLesion morphologyPre-dapsone therapiesDapsone maximum daily dose, mg (duration, mo)Adjunctive medicationsOutcome (initial response, mo)Adverse effectsCessation reason74/F/WHypothyroidism, VZVLE, trunkPlaques, patchesClobetasol, topical tacrolimus50 (39)NoneComplete clearance (1)∗Experienced flares after initial response to dapsone.NoneDeath (unrelated)62/F/WHypothyroidism, T2DM, VZVUE, LE, trunkPlaquesNone150 (15)NonePR (0.75)Myelosuppression (3.3 WBC, 11.9 Hg, 137 PLT)Myelosuppression88/F/WNoneUE, LEPlaquesHCQ50 (17)NonePR (1)Myelosuppression (4.6 WBC, 10.5 Hg, 105 PLT)Myelosuppression58/F/WNoneUE, LE, trunkPlaquesColchicine, fluocinonide, MTX, phototherapy, topical tacrolimus100 (13)Clobetasol, topical tacrolimusPR (1)Myelosuppression (4.7 WBC, 10.7 Hg)Myelosuppression76/F/WDLP, hypothyroidismUE, LEPlaques, papulesClobetasol100 (1)PhototherapyPR (1)∗Experienced flares after initial response to dapsone.NauseaNausea59/F/WNoneUE, LE, trunkPlaques, papulesNone100 (10)NonePR (1)NoneUnknown66/F/WHypothyroidismUEPapulesNone150 (39)Clobetasol, pentoxifylline, rifampin/ofloxacin/minocyclinePR (1.5)NoneBenefit plateau66/F/WNoneUEPlaquesMTX, pentoxifylline, phototherapy, prednisone, TCSs150 (13)TACPR (2)∗Experienced flares after initial response to dapsone.UTIUTI44/F/WNoneUE, LEPlaquesNone50 (2)ColchicinePR (2)∗Experienced flares after initial response to dapsone.NoneN/A60/F/WHerpes simplex virusUE, LE, trunkPlaquesNone100 (80)NonePR (3)Myelosuppression (Hg 12.1)Myelosuppression50/F/WT2DM, thyroid nodulesUE, LEPlaquesBetamethasone50 (3)BetamethasonePR (3)∗Experienced flares after initial response to dapsone.Myelosuppression (4.3 WBC, 12.2 Hg, 119 PLT)Myelosuppression51/F/WDLP, hypothyroidism, VZVUE, trunkPlaquesHCQ150 (3)NonePR (3)∗Experienced flares after initial response to dapsone.NoneUnknown63/F/WDLP, hypothyroidism, T2DMUE, LE, trunkPlaquesHCQ, ILK, isotretinoin, MTX, phototherapy75 (22)TACPR (4)∗Experienced flares after initial response to dapsone.NoneBenefit plateau49/F/WNoneUE, LE, trunk, neckPlaques, patchesIsotretinoin, MTX, prednisone, rifampin/ofloxacin/minocycline, TCSs200 (39)PhototherapyPR (8)∗Experienced flares after initial response to dapsone.NoneN/A78/F/WDLP, hypothyroidism, T2DM, VZVLEPlaques, papulesHCQ, TAC100 (1)NoneNIMyelosuppression (4.4 WBC, 11.5 Hg)Myelosuppression80/F/WDLP, T2DMUE, LE, trunkPlaques, papulesFluocinonide50 (1)NoneNIMyelosuppression (10.0 Hg)Myelosuppression61/F/WHypothyroidismUE, LEPlaques, patchesNone150 (1)NoneNINoneLack of efficacy53/F/WNoneUE, LE, trunkPlaquesHalobetasol100 (3)NoneNIDyspnea on exertionLack of efficacy67/M/WT2DMUE, LE, trunkPlaquesHCQ, ILK, phototherapy, TCSs100 (6)NoneNINoneLack of efficacy66/F/WVZVLE, trunkPlaquesTCSs50 (4)NoneNINoneLack of efficacy66/F/WDLP, hypothyroidismUE, LE, trunkPlaquesMTX, TCSs50 (2)NoneNINausea, headache, chills, myalgiasLack of efficacy71/F/WNoneLE, trunkPlaquesAzathioprine, ILK, prednisone, topical pimecrolimus150 (3)NoneNINoneLack of efficacy64/F/WDLP, T2DMLEPlaquesClobetasol, HCQ, pentoxifylline, rifampin/ofloxacin/minocycline25 (0.5)NoneNIUTIUTI55/F/WDLP, hypothyroidism, T2DMUE, LE, trunk, neckPlaques, papulesHCQ, ILK, TCSs25 (6)BetamethasoneNINoneLack of efficacy75/F/WDLPUE, LE, trunkPapules, patchesTCSs100 (0.5)NoneNIMyelosuppression (10.7 Hg)Myelosuppression56/F/WDLPUE, LE, trunkPlaquesAcitretin, prednisone100 (3)NoneNINoneN/ADLP, Dyslipidemia, F, female; HCQ, hydroxychloroquine; Hg, hemoglobin level, g/dL; ILK, intralesional triamcinolone; LE, lower extremities; M, male; MTX, methotrexate; N/A, not applicable; NI, no improvement; PLT, platelet count, ×109/L; PR, partial response; TAC, topical triamcinolone; T2DM, type 2 diabetes mellitus; TCSs, unspecified topical corticosteroids; UE, upper extremities; UTI, urinary tract infection; W, Caucasian; WBC, white blood cell count, ×109/L; VZV, Varicella zoster virus.∗ Experienced flares after initial response to dapsone. Open table in a new tab Seventeen of 26 (65%) patients underwent dapsone monotherapy, including 6 of 13 (46%) responders. The most common concomitant medications in those who improved with dapsone were topical corticosteroids: betamethasone (2/14; 14%), clobetasol (2/14; 14%), and triamcinolone (2/14; 14%). Several agents were attempted before dapsone treatment but failed to yield results or caused unbearable side effects (Table I). Although dapsone was subjectively well-tolerated (2 patients complained of nausea), nearly 1 in 3 patients (8/26; 31%) experienced subclinical myelosuppression (median 12 months after initiating dapsone), which warranted treatment cessation. Dapsone is associated with a variety of local and systemic adverse effects that may preclude its viability.5Ghaoui N. Hanna E. Abbas O. Kibbi A.G. Kurban M. Update on the use of dapsone in dermatology.Int J Dermatol. 2020; 59: 787-795Crossref PubMed Scopus (28) Google ScholarThe management of GGA can be challenging. Granulomatous inflammation can be slow to both form and resolve, and the effects of therapy may not be observed for 3-6 months.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 The evidence to support dapsone for GGA remains debatable as clinical responses may not be durable nor consistently achieved, and the patients may experience treatment-limiting side effects. However, these results contribute to the limited pool of data for a condition which has no definitive treatment option. To the Editor: Granuloma annulare is a non-infectious granulomatous dermatosis. Although its etiology is unknown, some conditions have been reported in increased frequencies in patients with granuloma annulare compared with the general population, including thyroid disease, diabetes mellitus, dyslipidemia, and viral infections.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 While localized disease tends to spontaneously resolve, generalized granuloma annulare (GGA) cases may persist for decades, and the treatment data are sparse.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 Phototherapy and antimalarials are the first-line treatment for GGA, although retinoids, biologics, and small molecule immunosuppressants can also be used.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 Dapsone may be viable; however, evidence is limited to studies comprising ≤10 patients.2Czarnecki D.B. Gin D. The response of generalized granuloma annulare to dapsone.Acta Derm Venereol. 1986; 66: 82-84PubMed Google Scholar, 3Steiner A. Pehamberger H. Wolff K. Sulfone treatment of granuloma annulare.J Am Acad Dermatol. 1985; 13: 1004-1008Abstract Full Text PDF PubMed Scopus (58) Google Scholar, 4Martín-Sáez E. Fernández-Guarino M. Carrillo-Gijón R. Muñoz-Zato E. Jaén-Olasolo P. Efficacy of dapsone in disseminated granuloma annulare: a case report and review of the literature. Article in Spanish.Actas Dermosifiliogr. 2008; 99: 64-68Crossref PubMed Scopus (19) Google Scholar Here, we evaluate the safety and efficacy of dapsone with a retrospective case series of 26 patients. Institutional review board approval was obtained to review the medical records of patients from a single institution who received oral dapsone for GGA between 2010 and 2020. Patients without pretreatment biopsy and patients lost to follow-up were excluded. Outcomes were categorized as: complete clearance, partial response (fewer, flattened, or faded lesions), or no improvement. Twenty-six patients—primarily Caucasian (100%) women (96%) with a mean age of 64 years—met the inclusion criteria (Table I). Lesions were most commonly plaque-type (24/26; 92%), and involved the lower extremities (23/26; 88%), upper extremities (21/26; 81%), trunk (17/26; 65%), and neck (2/26; 8%); 12 (46%) patients reported pruritus, 4 (15%) patients reported burning pain, and 13 (50%) patients were asymptomatic. The patients had mean disease duration of 5.6 years before initiating dapsone at a median daily dose of 100 mg (25-200 mg) for a mean duration of 9.8 months. Fourteen of 26 (54%) patients improved, and initial responses were observed within a mean of 2.3 months. However, the results were not consistently sustained, and 8 (57%) responders experienced flares following discontinuation. The patients who improved remained on dapsone for longer durations compared with those who did not improve (mean 16.0 vs 2.6 months), and perceived lack of efficacy was the most common discontinuation reason in non-responders (8/12; 67%). DLP, Dyslipidemia, F, female; HCQ, hydroxychloroquine; Hg, hemoglobin level, g/dL; ILK, intralesional triamcinolone; LE, lower extremities; M, male; MTX, methotrexate; N/A, not applicable; NI, no improvement; PLT, platelet count, ×109/L; PR, partial response; TAC, topical triamcinolone; T2DM, type 2 diabetes mellitus; TCSs, unspecified topical corticosteroids; UE, upper extremities; UTI, urinary tract infection; W, Caucasian; WBC, white blood cell count, ×109/L; VZV, Varicella zoster virus. Seventeen of 26 (65%) patients underwent dapsone monotherapy, including 6 of 13 (46%) responders. The most common concomitant medications in those who improved with dapsone were topical corticosteroids: betamethasone (2/14; 14%), clobetasol (2/14; 14%), and triamcinolone (2/14; 14%). Several agents were attempted before dapsone treatment but failed to yield results or caused unbearable side effects (Table I). Although dapsone was subjectively well-tolerated (2 patients complained of nausea), nearly 1 in 3 patients (8/26; 31%) experienced subclinical myelosuppression (median 12 months after initiating dapsone), which warranted treatment cessation. Dapsone is associated with a variety of local and systemic adverse effects that may preclude its viability.5Ghaoui N. Hanna E. Abbas O. Kibbi A.G. Kurban M. Update on the use of dapsone in dermatology.Int J Dermatol. 2020; 59: 787-795Crossref PubMed Scopus (28) Google Scholar The management of GGA can be challenging. Granulomatous inflammation can be slow to both form and resolve, and the effects of therapy may not be observed for 3-6 months.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 The evidence to support dapsone for GGA remains debatable as clinical responses may not be durable nor consistently achieved, and the patients may experience treatment-limiting side effects. However, these results contribute to the limited pool of data for a condition which has no definitive treatment option. 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 and 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. Authors Hrin, Bashyam, and Huang have no conflicts of interest to declare.