Resolution of refractory generalized granuloma annulare after treatment with alitretinoin

Abstract

IntroductionGranuloma annulare (GA) is an inflammatory skin disease that can be divided into localized, generalized, subcutaneous, perforating, and patch subtypes. Generalized granuloma annulare (GGA) is defined as GA that affects at least the trunk and the upper and/or lower extremities.1Dabski K. Winkelmann R.K. Generalized granuloma annulare: clinical and laboratory findings in 100 patients.J Am Acad Dermatol. 1989; 20: 39-47Abstract Full Text PDF PubMed Scopus (238) Google Scholar Multifactorial causes, including infection, sun exposure, drugs, and trauma, seem to contribute to the disease development. A histopathologic examination may reveal changes in mainly the papillary and mid dermis with lymphohistiocytic granuloma. Inflammatory infiltrates may show palisaded or interstitial patterns or a mixture of both. Herein, we report a case of GGA that was refractory to multiple drugs but successfully treated with alitretinoin.Case reportA 72-year-old man with an 8-year history of widespread, asymptomatic, erythematous papules and plaques on the arms, legs, and trunk visited the clinic. The lesions were discrete, pinpoint-to-pinhead–sized, and confluent (Fig 1, A). He had been prescribed medicine for 4 years at a local clinic without improvement. His past medical history included acute myeloid leukemia that had been in complete remission for 19 years, anti–hepatitis C virus antibody positivity, and cerebral stroke. He was taking levetiracetam for epilepsy and antihypertensive drugs. Laboratory findings, including antinuclear antibodies and rheumatic factor, showed no abnormalities. A punch biopsy was done, and the histopathology showed chronic granulomatous inflammation in the papillary dermis with mostly perivascular lymphohistiocytic and neutrophilic infiltration (Fig 2). He was diagnosed with GGA; 30 mg of oral alitretinoin daily, antihistamines, and topical tacrolimus ointment were started. After 7 months of treatment, partial remission was achieved, but several new lesions appeared on his extremities. The alitretinoin was discontinued, and 200 mg of hydroxychloroquine twice daily was started. Two months later, he returned with the exacerbation of skin lesions (Fig 1, B, C), with lesions extending to his neck and the greater part of his trunk. The hydroxychloroquine was switched back to alitretinoin with no washout period. Within 8 months, all lesions flattened, some with postinflammatory hyperpigmentation, and no new lesions were seen (Fig 1, D-F). Topical tacrolimus was continued throughout the whole period. Alitretinoin was administered for a total of 15 months to achieve remission, and the aggravation of GGA was present only in the first break in medication. The posttreatment laboratory results showed no abnormalities, and there were no adverse events.Fig 2Punch biopsy from the upper portion of the arm revealing chronic granulomatous inflammation in the papillary dermis without necrosis, perivascular lymphohistiocytic infiltration, and a few polymorphonuclear leukocyte infiltrates. Multinucleated giant cells are also present. (Hematoxylin-eosin stain; original magnification: ×100.)View Large Image Figure ViewerDownload Hi-res image Download (PPT)DiscussionThe pathogenesis of GA is not well understood. Many case reports have described relationships between GGA and systemic diseases; few large series have been published, and these associations have been debated.2Ehret M. Lenormand C. Scrivener J.N. Gusdorf L. Lipsker D. Cribier B. Generalized granuloma annulare: a clinicopathological study. Article in French.Ann Dermatol Venereol. 2020; 147: 271-278Crossref PubMed Scopus (5) Google Scholar Multifactorial causes, including infection, sun exposure, drugs, and trauma, seem to contribute to the disease development. Activation of T cell–mediated immune response is thought to be the pathologic mechanism of GGA.3Garcia-Gil M.F. Alvarez-Salafranca M. Martinez Garcia A. Ara-Martin M. Generalized granuloma annulare after pneumococcal vaccination.An Bras Dermatol. 2021; 96: 59-63Crossref PubMed Scopus (4) Google Scholar In this case of GGA, there was no definite cause of the disease. The history of malignancy may have had an impact, but it is known that myeloid leukemias are less commonly associated with GGA compared to other lymphomas.4Li A. Hogan D.J. Sanusi I.D. Smoller B.R. Granuloma annulare and malignant neoplasms.Am J Dermatopathol. 2003; 25: 113-116Crossref PubMed Scopus (84) Google Scholar Moreover, the fact that the leukemia had been in complete remission for 19 years before the occurrence of GGA makes the association of the 2 conditions highly unlikely.While localized GA often resolves spontaneously or responds to topical glucocorticoids, GGA may last for years. Various treatments, such as topical or systemic steroids, antimalarial drugs, immunosuppressants, isotretinoin, photodynamic or psoralen plus UV-A therapy, and adalimumab, have been reported to successfully treat GGA (Table I), but most of these reports were case reports or small case series, with an absence of randomized controlled trials.5Lukacs J. Schliemann S. Elsner P. Treatment of generalized granuloma annulare - a systematic review.J Eur Acad Dermatol Venereol. 2015; 29: 1467-1480Crossref PubMed Scopus (42) Google Scholar Most of these treatment options’ mechanisms of action are not well known, but T cell inhibition, immune modulation, and anti-inflammation are regarded as key factors. Among retinoids, etretinate, and isotretinoin have been used to treat GGA, as they inhibit delayed hypersensitivity responses, cellular immunity, and the proliferation of fibroblasts.5Lukacs J. Schliemann S. Elsner P. Treatment of generalized granuloma annulare - a systematic review.J Eur Acad Dermatol Venereol. 2015; 29: 1467-1480Crossref PubMed Scopus (42) Google Scholar Etretinate (0.8 mg/kg/day) was given for 7 months to achieve resolution, although the patients suffered from hair loss.6Botella-Estrada R. Guillen C. Sanmartin O. Aliaga A. Disseminated granuloma annulare: resolution with etretinate therapy.J Am Acad Dermatol. 1992; 26: 777-778Abstract Full Text PDF PubMed Scopus (36) Google Scholar Patients with GGA treated with isotretinoin were between 0.5 to 1 mg/kg/day and 40 to 80 mg/day for a treatment duration of 2 to 14 months. Two of the 7 patients showed relapses of GGA after the discontinuation of the drug. Adverse effects, such as cheilitis, dryness of mucosae, and moderate increases in cholesterol and triglyceride serum levels or abnormal liver function tests were reported.7Pasmatzi E. Georgiou S. Monastirli A. Tsambaos D. Temporary remission of disseminated granuloma annulare under oral isotretinoin therapy.Int J Dermatol. 2005; 44: 169-171Crossref PubMed Scopus (17) Google Scholar Alitretinoin, a 9-cis-retinoic acid, is a pan-retinoid receptor agonist that has been approved for chronic hand eczema because of its immunomodulatory and anti-inflammatory effects; it halts chemokine-induced leukocyte recruitment and inhibits dendritic cell–mediated T cell activation. The action mechanism of alitretinoin is believed to involve the regulation of the expression of genes that control cellular differentiation and proliferation.8Napolitano M. Potestio L. De Lucia M. Nocerino M. Fabbrocini G. Patruno C. Alitretinoin for the treatment of severe chronic eczema of the hands.Expert Opin Pharmacother. 2021; 23: 159-167Crossref PubMed Scopus (2) Google Scholar The shortest half-life among the retinoids and the nonaccumulating nature of metabolites make alitretinoin a safer alternative than isotretinoin or acitretin.9Letule V. Herzinger T. Ruzicka T. Molin S. Treatment of Darier disease with oral alitretinoin.Clin Exp Dermatol. 2013; 38: 523-525Crossref PubMed Scopus (33) Google Scholar Compared to isotretinoin and acitretin, alitretinoin exerts stronger anti-inflammatory and immune-modulatory effects without suppressing the activity of the sebaceous glands, leading to fewer side effects (eg, xerosis or mucosal dryness).10Tietze J.K. Heppt M.V. Flaig M.J. Thomas P. Successful treatment of lichen amyloidosus with oral alitretinoin.J Eur Acad Dermatol Venereol. 2016; 30: 884-885Crossref PubMed Scopus (6) Google Scholar In this case of GGA, we started alitretinoin at 30 mg/day, which is a common dosage for hand eczema. Before alitretinoin treatment, a lipid panel test, complete blood cell count, and liver function test—and, in women, pregnancy testing—are necessary. A follow-up liver function test and complete blood cell count were done after 1 year of alitretinoin administration. If abnormal laboratory results are anticipated, follow-up tests might be needed. In this case, despite the strong anti-inflammatory properties of alitretinoin, the slow therapeutic response may have been due to advanced age, a long disease duration, and extensive disease activity. Since alitretinoin acts as an anti-inflammatory agent, the treatment response may be monitored by the fading and flattening of erythematous lesions. When alitretinoin was discontinued and the patient was switched to hydroxychloroquine, he suffered from GGA aggravation. This could be supporting evidence that the improvement of the disease was not a part of its natural course. Although alitretinoin shares common molecular structures with other retinoids, there have been no reports of GGA successfully treated with alitretinoin to our knowledge.Table IPracticable treatments for GGA and their regimens and levels of evidenceTreatmentRegimenLevel of evidenceAntimicrobials Amoxicillin/clavulanic acidAmoxicillin/clavulanic acid875/125 mg twice dailyD Dapsone25-200 mg (mean 100 mg) dailyC Doxycycline100 mg twice dailyD Minocycline + ofloxacin + rifampinOnce monthly single dose of 600 mg rifampicin, 400 mg ofloxacin, and 100 mg minocycline hydrochlorideD ApremilastInitial dose of 10 mg, increasing by an increment of 10 mg daily until maintenance dosage of 30 mg twice dailyDBiologic agents Adalimumab80 mg subcutaneously, followed by 40 mg every other week, 1 week after initiationD Infliximab5 mg/kg at weeks 0, 2, 6, 14, and 24D DupilumabLoading dose of 600 mg subcutaneously at week 0 and then decreased to 300 mg every 2 weeksDCorticosteroids Intralesional corticosteroidsC Topical corticosteroidsCHydroxychloroquine200 mg twice dailyCMethotrexate12.5-15 mg weeklyOral isotretinoin0.5 mg to 1 mg/kg daily or 40-80 mg dailyDPentoxifylline400 mg 3 times dailyCPhototherapy Narrowband-UVBC psoralen plus UV-AC UV-A1CPotassium iodide150-450 mg daily, gradually increased to 900-1500 mg dailyDRadial Pulse therapyDSulfasalazine500 mg daily to 1.5 g twice daily depending on tolerance and efficacyCTacrolimus ointmentDTofacitinibOral: 5 mg twice dailyTopical: 2% ointment twice dailyDGGA, Generalized granuloma annulare. Open table in a new tab Herein, we report a case of GGA that was refractory to multiple drugs but successfully treated with alitretinoin, and we suggest that alitretinoin can be a treatment option for this frustrating condition since it exerts anti-inflammatory effects without immunosuppression. Compared to other retinoids, alitretinoin is better suited for elderly patients because it is less drying and less desquamative. IntroductionGranuloma annulare (GA) is an inflammatory skin disease that can be divided into localized, generalized, subcutaneous, perforating, and patch subtypes. Generalized granuloma annulare (GGA) is defined as GA that affects at least the trunk and the upper and/or lower extremities.1Dabski K. Winkelmann R.K. Generalized granuloma annulare: clinical and laboratory findings in 100 patients.J Am Acad Dermatol. 1989; 20: 39-47Abstract Full Text PDF PubMed Scopus (238) Google Scholar Multifactorial causes, including infection, sun exposure, drugs, and trauma, seem to contribute to the disease development. A histopathologic examination may reveal changes in mainly the papillary and mid dermis with lymphohistiocytic granuloma. Inflammatory infiltrates may show palisaded or interstitial patterns or a mixture of both. Herein, we report a case of GGA that was refractory to multiple drugs but successfully treated with alitretinoin. Granuloma annulare (GA) is an inflammatory skin disease that can be divided into localized, generalized, subcutaneous, perforating, and patch subtypes. Generalized granuloma annulare (GGA) is defined as GA that affects at least the trunk and the upper and/or lower extremities.1Dabski K. Winkelmann R.K. Generalized granuloma annulare: clinical and laboratory findings in 100 patients.J Am Acad Dermatol. 1989; 20: 39-47Abstract Full Text PDF PubMed Scopus (238) Google Scholar Multifactorial causes, including infection, sun exposure, drugs, and trauma, seem to contribute to the disease development. A histopathologic examination may reveal changes in mainly the papillary and mid dermis with lymphohistiocytic granuloma. Inflammatory infiltrates may show palisaded or interstitial patterns or a mixture of both. Herein, we report a case of GGA that was refractory to multiple drugs but successfully treated with alitretinoin. Case reportA 72-year-old man with an 8-year history of widespread, asymptomatic, erythematous papules and plaques on the arms, legs, and trunk visited the clinic. The lesions were discrete, pinpoint-to-pinhead–sized, and confluent (Fig 1, A). He had been prescribed medicine for 4 years at a local clinic without improvement. His past medical history included acute myeloid leukemia that had been in complete remission for 19 years, anti–hepatitis C virus antibody positivity, and cerebral stroke. He was taking levetiracetam for epilepsy and antihypertensive drugs. Laboratory findings, including antinuclear antibodies and rheumatic factor, showed no abnormalities. A punch biopsy was done, and the histopathology showed chronic granulomatous inflammation in the papillary dermis with mostly perivascular lymphohistiocytic and neutrophilic infiltration (Fig 2). He was diagnosed with GGA; 30 mg of oral alitretinoin daily, antihistamines, and topical tacrolimus ointment were started. After 7 months of treatment, partial remission was achieved, but several new lesions appeared on his extremities. The alitretinoin was discontinued, and 200 mg of hydroxychloroquine twice daily was started. Two months later, he returned with the exacerbation of skin lesions (Fig 1, B, C), with lesions extending to his neck and the greater part of his trunk. The hydroxychloroquine was switched back to alitretinoin with no washout period. Within 8 months, all lesions flattened, some with postinflammatory hyperpigmentation, and no new lesions were seen (Fig 1, D-F). Topical tacrolimus was continued throughout the whole period. Alitretinoin was administered for a total of 15 months to achieve remission, and the aggravation of GGA was present only in the first break in medication. The posttreatment laboratory results showed no abnormalities, and there were no adverse events. A 72-year-old man with an 8-year history of widespread, asymptomatic, erythematous papules and plaques on the arms, legs, and trunk visited the clinic. The lesions were discrete, pinpoint-to-pinhead–sized, and confluent (Fig 1, A). He had been prescribed medicine for 4 years at a local clinic without improvement. His past medical history included acute myeloid leukemia that had been in complete remission for 19 years, anti–hepatitis C virus antibody positivity, and cerebral stroke. He was taking levetiracetam for epilepsy and antihypertensive drugs. Laboratory findings, including antinuclear antibodies and rheumatic factor, showed no abnormalities. A punch biopsy was done, and the histopathology showed chronic granulomatous inflammation in the papillary dermis with mostly perivascular lymphohistiocytic and neutrophilic infiltration (Fig 2). He was diagnosed with GGA; 30 mg of oral alitretinoin daily, antihistamines, and topical tacrolimus ointment were started. After 7 months of treatment, partial remission was achieved, but several new lesions appeared on his extremities. The alitretinoin was discontinued, and 200 mg of hydroxychloroquine twice daily was started. Two months later, he returned with the exacerbation of skin lesions (Fig 1, B, C), with lesions extending to his neck and the greater part of his trunk. The hydroxychloroquine was switched back to alitretinoin with no washout period. Within 8 months, all lesions flattened, some with postinflammatory hyperpigmentation, and no new lesions were seen (Fig 1, D-F). Topical tacrolimus was continued throughout the whole period. Alitretinoin was administered for a total of 15 months to achieve remission, and the aggravation of GGA was present only in the first break in medication. The posttreatment laboratory results showed no abnormalities, and there were no adverse events. DiscussionThe pathogenesis of GA is not well understood. Many case reports have described relationships between GGA and systemic diseases; few large series have been published, and these associations have been debated.2Ehret M. Lenormand C. Scrivener J.N. Gusdorf L. Lipsker D. Cribier B. Generalized granuloma annulare: a clinicopathological study. Article in French.Ann Dermatol Venereol. 2020; 147: 271-278Crossref PubMed Scopus (5) Google Scholar Multifactorial causes, including infection, sun exposure, drugs, and trauma, seem to contribute to the disease development. Activation of T cell–mediated immune response is thought to be the pathologic mechanism of GGA.3Garcia-Gil M.F. Alvarez-Salafranca M. Martinez Garcia A. Ara-Martin M. Generalized granuloma annulare after pneumococcal vaccination.An Bras Dermatol. 2021; 96: 59-63Crossref PubMed Scopus (4) Google Scholar In this case of GGA, there was no definite cause of the disease. The history of malignancy may have had an impact, but it is known that myeloid leukemias are less commonly associated with GGA compared to other lymphomas.4Li A. Hogan D.J. Sanusi I.D. Smoller B.R. Granuloma annulare and malignant neoplasms.Am J Dermatopathol. 2003; 25: 113-116Crossref PubMed Scopus (84) Google Scholar Moreover, the fact that the leukemia had been in complete remission for 19 years before the occurrence of GGA makes the association of the 2 conditions highly unlikely.While localized GA often resolves spontaneously or responds to topical glucocorticoids, GGA may last for years. Various treatments, such as topical or systemic steroids, antimalarial drugs, immunosuppressants, isotretinoin, photodynamic or psoralen plus UV-A therapy, and adalimumab, have been reported to successfully treat GGA (Table I), but most of these reports were case reports or small case series, with an absence of randomized controlled trials.5Lukacs J. Schliemann S. Elsner P. Treatment of generalized granuloma annulare - a systematic review.J Eur Acad Dermatol Venereol. 2015; 29: 1467-1480Crossref PubMed Scopus (42) Google Scholar Most of these treatment options’ mechanisms of action are not well known, but T cell inhibition, immune modulation, and anti-inflammation are regarded as key factors. Among retinoids, etretinate, and isotretinoin have been used to treat GGA, as they inhibit delayed hypersensitivity responses, cellular immunity, and the proliferation of fibroblasts.5Lukacs J. Schliemann S. Elsner P. Treatment of generalized granuloma annulare - a systematic review.J Eur Acad Dermatol Venereol. 2015; 29: 1467-1480Crossref PubMed Scopus (42) Google Scholar Etretinate (0.8 mg/kg/day) was given for 7 months to achieve resolution, although the patients suffered from hair loss.6Botella-Estrada R. Guillen C. Sanmartin O. Aliaga A. Disseminated granuloma annulare: resolution with etretinate therapy.J Am Acad Dermatol. 1992; 26: 777-778Abstract Full Text PDF PubMed Scopus (36) Google Scholar Patients with GGA treated with isotretinoin were between 0.5 to 1 mg/kg/day and 40 to 80 mg/day for a treatment duration of 2 to 14 months. Two of the 7 patients showed relapses of GGA after the discontinuation of the drug. Adverse effects, such as cheilitis, dryness of mucosae, and moderate increases in cholesterol and triglyceride serum levels or abnormal liver function tests were reported.7Pasmatzi E. Georgiou S. Monastirli A. Tsambaos D. Temporary remission of disseminated granuloma annulare under oral isotretinoin therapy.Int J Dermatol. 2005; 44: 169-171Crossref PubMed Scopus (17) Google Scholar Alitretinoin, a 9-cis-retinoic acid, is a pan-retinoid receptor agonist that has been approved for chronic hand eczema because of its immunomodulatory and anti-inflammatory effects; it halts chemokine-induced leukocyte recruitment and inhibits dendritic cell–mediated T cell activation. The action mechanism of alitretinoin is believed to involve the regulation of the expression of genes that control cellular differentiation and proliferation.8Napolitano M. Potestio L. De Lucia M. Nocerino M. Fabbrocini G. Patruno C. Alitretinoin for the treatment of severe chronic eczema of the hands.Expert Opin Pharmacother. 2021; 23: 159-167Crossref PubMed Scopus (2) Google Scholar The shortest half-life among the retinoids and the nonaccumulating nature of metabolites make alitretinoin a safer alternative than isotretinoin or acitretin.9Letule V. Herzinger T. Ruzicka T. Molin S. Treatment of Darier disease with oral alitretinoin.Clin Exp Dermatol. 2013; 38: 523-525Crossref PubMed Scopus (33) Google Scholar Compared to isotretinoin and acitretin, alitretinoin exerts stronger anti-inflammatory and immune-modulatory effects without suppressing the activity of the sebaceous glands, leading to fewer side effects (eg, xerosis or mucosal dryness).10Tietze J.K. Heppt M.V. Flaig M.J. Thomas P. Successful treatment of lichen amyloidosus with oral alitretinoin.J Eur Acad Dermatol Venereol. 2016; 30: 884-885Crossref PubMed Scopus (6) Google Scholar In this case of GGA, we started alitretinoin at 30 mg/day, which is a common dosage for hand eczema. Before alitretinoin treatment, a lipid panel test, complete blood cell count, and liver function test—and, in women, pregnancy testing—are necessary. A follow-up liver function test and complete blood cell count were done after 1 year of alitretinoin administration. If abnormal laboratory results are anticipated, follow-up tests might be needed. In this case, despite the strong anti-inflammatory properties of alitretinoin, the slow therapeutic response may have been due to advanced age, a long disease duration, and extensive disease activity. Since alitretinoin acts as an anti-inflammatory agent, the treatment response may be monitored by the fading and flattening of erythematous lesions. When alitretinoin was discontinued and the patient was switched to hydroxychloroquine, he suffered from GGA aggravation. This could be supporting evidence that the improvement of the disease was not a part of its natural course. Although alitretinoin shares common molecular structures with other retinoids, there have been no reports of GGA successfully treated with alitretinoin to our knowledge.Table IPracticable treatments for GGA and their regimens and levels of evidenceTreatmentRegimenLevel of evidenceAntimicrobials Amoxicillin/clavulanic acidAmoxicillin/clavulanic acid875/125 mg twice dailyD Dapsone25-200 mg (mean 100 mg) dailyC Doxycycline100 mg twice dailyD Minocycline + ofloxacin + rifampinOnce monthly single dose of 600 mg rifampicin, 400 mg ofloxacin, and 100 mg minocycline hydrochlorideD ApremilastInitial dose of 10 mg, increasing by an increment of 10 mg daily until maintenance dosage of 30 mg twice dailyDBiologic agents Adalimumab80 mg subcutaneously, followed by 40 mg every other week, 1 week after initiationD Infliximab5 mg/kg at weeks 0, 2, 6, 14, and 24D DupilumabLoading dose of 600 mg subcutaneously at week 0 and then decreased to 300 mg every 2 weeksDCorticosteroids Intralesional corticosteroidsC Topical corticosteroidsCHydroxychloroquine200 mg twice dailyCMethotrexate12.5-15 mg weeklyOral isotretinoin0.5 mg to 1 mg/kg daily or 40-80 mg dailyDPentoxifylline400 mg 3 times dailyCPhototherapy Narrowband-UVBC psoralen plus UV-AC UV-A1CPotassium iodide150-450 mg daily, gradually increased to 900-1500 mg dailyDRadial Pulse therapyDSulfasalazine500 mg daily to 1.5 g twice daily depending on tolerance and efficacyCTacrolimus ointmentDTofacitinibOral: 5 mg twice dailyTopical: 2% ointment twice dailyDGGA, Generalized granuloma annulare. Open table in a new tab Herein, we report a case of GGA that was refractory to multiple drugs but successfully treated with alitretinoin, and we suggest that alitretinoin can be a treatment option for this frustrating condition since it exerts anti-inflammatory effects without immunosuppression. Compared to other retinoids, alitretinoin is better suited for elderly patients because it is less drying and less desquamative. The pathogenesis of GA is not well understood. Many case reports have described relationships between GGA and systemic diseases; few large series have been published, and these associations have been debated.2Ehret M. Lenormand C. Scrivener J.N. Gusdorf L. Lipsker D. Cribier B. Generalized granuloma annulare: a clinicopathological study. Article in French.Ann Dermatol Venereol. 2020; 147: 271-278Crossref PubMed Scopus (5) Google Scholar Multifactorial causes, including infection, sun exposure, drugs, and trauma, seem to contribute to the disease development. Activation of T cell–mediated immune response is thought to be the pathologic mechanism of GGA.3Garcia-Gil M.F. Alvarez-Salafranca M. Martinez Garcia A. Ara-Martin M. Generalized granuloma annulare after pneumococcal vaccination.An Bras Dermatol. 2021; 96: 59-63Crossref PubMed Scopus (4) Google Scholar In this case of GGA, there was no definite cause of the disease. The history of malignancy may have had an impact, but it is known that myeloid leukemias are less commonly associated with GGA compared to other lymphomas.4Li A. Hogan D.J. Sanusi I.D. Smoller B.R. Granuloma annulare and malignant neoplasms.Am J Dermatopathol. 2003; 25: 113-116Crossref PubMed Scopus (84) Google Scholar Moreover, the fact that the leukemia had been in complete remission for 19 years before the occurrence of GGA makes the association of the 2 conditions highly unlikely. While localized GA often resolves spontaneously or responds to topical glucocorticoids, GGA may last for years. Various treatments, such as topical or systemic steroids, antimalarial drugs, immunosuppressants, isotretinoin, photodynamic or psoralen plus UV-A therapy, and adalimumab, have been reported to successfully treat GGA (Table I), but most of these reports were case reports or small case series, with an absence of randomized controlled trials.5Lukacs J. Schliemann S. Elsner P. Treatment of generalized granuloma annulare - a systematic review.J Eur Acad Dermatol Venereol. 2015; 29: 1467-1480Crossref PubMed Scopus (42) Google Scholar Most of these treatment options’ mechanisms of action are not well known, but T cell inhibition, immune modulation, and anti-inflammation are regarded as key factors. Among retinoids, etretinate, and isotretinoin have been used to treat GGA, as they inhibit delayed hypersensitivity responses, cellular immunity, and the proliferation of fibroblasts.5Lukacs J. Schliemann S. Elsner P. Treatment of generalized granuloma annulare - a systematic review.J Eur Acad Dermatol Venereol. 2015; 29: 1467-1480Crossref PubMed Scopus (42) Google Scholar Etretinate (0.8 mg/kg/day) was given for 7 months to achieve resolution, although the patients suffered from hair loss.6Botella-Estrada R. Guillen C. Sanmartin O. Aliaga A. Disseminated granuloma annulare: resolution with etretinate therapy.J Am Acad Dermatol. 1992; 26: 777-778Abstract Full Text PDF PubMed Scopus (36) Google Scholar Patients with GGA treated with isotretinoin were between 0.5 to 1 mg/kg/day and 40 to 80 mg/day for a treatment duration of 2 to 14 months. Two of the 7 patients showed relapses of GGA after the discontinuation of the drug. Adverse effects, such as cheilitis, dryness of mucosae, and moderate increases in cholesterol and triglyceride serum levels or abnormal liver function tests were reported.7Pasmatzi E. Georgiou S. Monastirli A. Tsambaos D. Temporary remission of disseminated granuloma annulare under oral isotretinoin therapy.Int J Dermatol. 2005; 44: 169-171Crossref PubMed Scopus (17) Google Scholar Alitretinoin, a 9-cis-retinoic acid, is a pan-retinoid receptor agonist that has been approved for chronic hand eczema because of its immunomodulatory and anti-inflammatory effects; it halts chemokine-induced leukocyte recruitment and inhibits dendritic cell–mediated T cell activation. The action mechanism of alitretinoin is believed to involve the regulation of the expression of genes that control cellular differentiation and proliferation.8Napolitano M. Potestio L. De Lucia M. Nocerino M. Fabbrocini G. Patruno C. Alitretinoin for the treatment of severe chronic eczema of the hands.Expert Opin Pharmacother. 2021; 23: 159-167Crossref PubMed Scopus (2) Google Scholar The shortest half-life among the retinoids and the nonaccumulating nature of metabolites make alitretinoin a safer alternative than isotretinoin or acitretin.9Letule V. Herzinger T. Ruzicka T. Molin S. Treatment of Darier disease with oral alitretinoin.Clin Exp Dermatol. 2013; 38: 523-525Crossref PubMed Scopus (33) Google Scholar Compared to isotretinoin and acitretin, alitretinoin exerts stronger anti-inflammatory and immune-modulatory effects without suppressing the activity of the sebaceous glands, leading to fewer side effects (eg, xerosis or mucosal dryness).10Tietze J.K. Heppt M.V. Flaig M.J. Thomas P. Successful treatment of lichen amyloidosus with oral alitretinoin.J Eur Acad Dermatol Venereol. 2016; 30: 884-885Crossref PubMed Scopus (6) Google Scholar In this case of GGA, we started alitretinoin at 30 mg/day, which is a common dosage for hand eczema. Before alitretinoin treatment, a lipid panel test, complete blood cell count, and liver function test—and, in women, pregnancy testing—are necessary. A follow-up liver function test and complete blood cell count were done after 1 year of alitretinoin administration. If abnormal laboratory results are anticipated, follow-up tests might be needed. In this case, despite the strong anti-inflammatory properties of alitretinoin, the slow therapeutic response may have been due to advanced age, a long disease duration, and extensive disease activity. Since alitretinoin acts as an anti-inflammatory agent, the treatment response may be monitored by the fading and flattening of erythematous lesions. When alitretinoin was discontinued and the patient was switched to hydroxychloroquine, he suffered from GGA aggravation. This could be supporting evidence that the improvement of the disease was not a part of its natural course. Although alitretinoin shares common molecular structures with other retinoids, there have been no reports of GGA successfully treated with alitretinoin to our knowledge. GGA, Generalized granuloma annulare. Herein, we report a case of GGA that was refractory to multiple drugs but successfully treated with alitretinoin, and we suggest that alitretinoin can be a treatment option for this frustrating condition since it exerts anti-inflammatory effects without immunosuppression. Compared to other retinoids, alitretinoin is better suited for elderly patients because it is less drying and less desquamative. None disclosed.