CED
Clinical dermatology • Concise report
Clinical and Experimental Dermatology
Successful treatment of generalized granuloma annulare with adalimumab T. Mahmood,1 B. Mansouri2 and A. Menter2 1 Texas A&M Health Sciences Center College of Medicine, Bryan, TX, USA; and 2Department of Dermatology, Baylor University Medical Center, Dallas, TX, USA
doi:10.1111/ced.12598
Summary
We report the case of a 64 year-old woman who demonstrated resolution of recalcitrant, generalized granuloma annulare (GA) following treatment with adalimumab. After showing little response to other treatment techniques, such as steroids and a triple antibiotic regimen, the patient was started on adalimumab. Within 3 months, she showed almost complete resolution of lesions. Within 6 months, she was completely lesion-free, and remained clear following 12 months of adalimumab therapy. This case provides further evidence that tumour necrosis factor-a inhibitors may be a treatment option for patients with recalcitrant, generalized GA.
Granuloma annulare (GA) is a noninfectious, benign skin condition for which the cause and pathogenesis are not well understood. The generalized form of GA is frequently intractable despite the use of multiple topical and systemic therapies. We report a case of GA that was almost fully cleared following 3 months of adalimumab therapy, with complete clearance and no new lesions or recurrences noted after 6 months of therapy. The patient remains clear following 12 months of therapy.
Correspondence: Dr Alan Menter, Department of Dermatology, Baylor University Medical Center, 3900 Junius St. Suite #125, Dallas, TX 75246, USA E-mail: [email protected] Conflict of interest: TM and BM have no conflicts of interest to declare. AM has sat on the advisory boards of AbbVie, Allergan, Amgen, Boehringer Ingelheim, Genentech, Janssen Biotech, Inc., LEO Pharma and Pfizer; has been a consultant for AbbVie, Allergan, Amgen, Convoy Therapeutics, Inc., Ely Lilly, Janssen Biotech, Inc., LEO Pharma, Novartis, Pfizer, Syntrix, Wyeth and XenoPort; has been an investigator for AbbVie, Allergan, Amgen, ApoPharma, Boehringer Ingelheim, Celgene, Convoy Therapeutics, Inc., Ely Lilly, Genentech, Janssen Biotech, Inc., LEO Pharma, Merck, Novartis, Pfizer, Symbio/Maruho, Syntrix and Wyeth; has been a speaker for AbbVie, Amgen, Janssen Biotech, Inc., LEO Pharma and Wyeth; and has received grants and/or honoraria from AbbVie, Allergan, Amgen, ApoPharma, Boehringer Ingelheim, Celgene, Convoy Therapeutics, Inc., Ely Lilly, Genentech, Janssen Biotech, Inc., LEO Pharma, Merck, Novartis, Pfizer, Symbio/Maruho, Syntrix, Wyeth and XenoPort. Accepted for publication 9 September 2014
ª 2015 British Association of Dermatologists
Report A 64-year-old white woman presented with a 3-year history of biopsy-proven GA on her upper and lower extremities, abdomen and back. She had previously been treated with topical and intralesional corticosteroids, with limited improvement. On physical examination, the patient was found to have numerous papules and small GA plaques on her wrist folds, elbows, forearms, knees and lower legs, large confluent plaques on her posterior thighs, and isolated papules on her back and in the right inframammary fold. The combination of rifampicin 600 mg, ofloxacin 400 mg and minocycline 100 mg once monthly was initiated for 3 months, with 50% improvement noted. However, following three additional months of this triple antibiotic regimen, the patient had no further improvement, and new lesions were apparent on her upper and lower extremities (Fig. 1a,b). Therefore, antibiotic therapy was discontinued. Based on previous reports in the literature showing successful treatment of GA with tumour necrosis factor (TNF)-a antagonists,1–7 adalimumab 40 mg every 2 weeks was initiated. After 3 months of adalimumab therapy, there was almost total clearance, with only minor post-inflammatory lesions remaining on the patient’s ankles. After 6 months of therapy, the patient had complete clearance, and remained without
Clinical and Experimental Dermatology
1
Treatment of granuloma annulare with adalimumab T. Mahmood et al.
(a)
(b)
(c)
(d)
Figure 1 Granuloma annulare (GA) lesions on (a) the posterior
left lower leg and (b) anterior right lower leg inferior to the patella. (c,d) The same locations with complete resolution of GA lesions 12 months after initiation of adalimumab.
evidence of new GA lesions after 12 months of therapy (Fig. 1c,d). GA was first described by Colcott Fox in 1895.8 It is a benign skin condition that most often presents with flesh-coloured or erythematous dermal plaques and papules arranged in an annular configuration. This condition is typically asymptomatic, but it can be associated with mild pruritus.9 Lesions can be found anywhere on the body; however, the hands and feet are most commonly involved, while facial lesions are rare. The disease affects patients of all ages, and can follow a self-limiting course or a chronic, relapsing course. In the majority of cases, GA will resolve spontaneously within 2 months to 2 years. Diagnosis is
2
Clinical and Experimental Dermatology
made by clinical examination and biopsy findings. Histologically, GA shows a histiocytic and lymphocytic granulomatous dermal infiltrate, suggesting that delayed-type hypersensitivity reactions and cellmediated immune responses may contribute to the pathogenesis of the disease. The inflammatory infiltrate of GA is composed of CD3+ cells and macrophages, which secrete TNF-a.6 Subtypes of GA include localized, subcutaneous, perforating, patch/macular and generalized/disseminated. Localized GA is the most common subtype, and is typically diagnosed in patients before the age of 30 years, with the condition being about twice as common in women as in men.9 Subcutaneous GA can be present in adults, but is more common in children between the ages of 2 and 10 years. Similarly, perforating GA is also more common in children, and frequently presents with lesions on the lower extremities. Patch or macular GA is the rarest subtype, and is most often present on the trunk and proximal extremities. Generalized or disseminated GA affects patients in a bimodal distribution, most commonly affecting patients younger than 10 years and patients older than 40 years of age. In cases of generalized GA, lesions may persist for up to 10 years with frequent recurrences. Treatment of GA is generally dictated by the distribution of the lesions. Because localized GA is a benign and self-limiting disease, treatment is usually unnecessary, but the condition has been successfully treated for cosmetic purposes with topical steroids, intralesional steroid injections, and cryotherapy.9 However, these techniques are inadequate for generalized GA. Successful systemic treatment with phototherapy, antimalarial drugs, isotretinoin, ciclosporin and dapsone has been documented.9 Marcus et al.10 also reported successful treatment of resistant generalized GA with combination therapy of rifampicin, ofloxacin and minocycline. Seven successful cases of treatment of generalized GA with TNF-a antagonists have been reported.1–7 The efficacy of these drugs is related to the presumed role of TNF-a in GA pathogenesis. Infliximab has shown efficacy in two cases of generalized GA,2,4 while etanercept has been reported to be successful in one case.6 Our case represents the fifth case of a patient with recalcitrant, generalized GA responding well to adalimumab.1,3,5,7 To date, there have been no prospective randomized controlled trials for TNF-a inhibitor use in generalized GA. However, this small collection of case reports provides good evidence that TNF-a
ª 2015 British Association of Dermatologists
Treatment of granuloma annulare with adalimumab T. Mahmood et al.
inhibitors should be considered for the treatment of recalcitrant, generalized GA. 2
Learning points GA is a benign, noninfectious, self-limiting con-
dition that presents with plaques and papules arranged in an annular configuration, frequently on the hands and feet. There are five subtypes of GA, with generalized GA often associated with a chronic, relapsing course compared with the other subtypes. Treatment options for GA include observation, topical or intralesional steroids, antimalarial drugs and cryotherapy. However, generalized GA frequently requires systemic therapy. In cases of recalcitrant, generalized GA, TNF-a inhibitors, such as adalimumab, may be an appropriate treatment option.
3
4
5
6 7
8
References 1 Fanning SB, Chapman G, Yau Y, Leong RW. Education and imaging. Gastrointestinal: improvement of granuloma annulare with anti-tumour necrosis factor
ª 2015 British Association of Dermatologists
9 10
alpha therapy for Crohn’s disease. J Gastroenterol Hepatol 2010; 25: 215. Hertl MS, Haendle I, Schuler G, Hertl M. Rapid improvement of recalcitrant disseminated granuloma annulare upon treatment with the tumour necrosis factor-alpha inhibitor, infliximab. Br J Dermatol 2005; 152: 552–5. Knoell KA. Efficacy of adalimumab in the treatment of generalized granuloma annulare in monozygotic twins carrying the 8.1 ancestral haplotype. Arch Dermatol 2009; 145: 610–11. Murdaca G, Colombo BM, Barabino G et al. Anti-tumor necrosis factor-alpha treatment with infliximab for disseminated granuloma annulare. Am J Clin Dermatol 2010; 11: 437–9. Rosmarin D, LaRaia A, Schlauder S, Gottlieb AB. Successful treatment of disseminated granuloma annulare with adalimumab. J Drugs Dermatol 2009; 8: 169–71. Shupack J, Siu K. Resolving granuloma annulare with etanercept. Arch Dermatol 2006; 142: 394–5. Werchau S, Enk A, Hartmann M. Generalized interstitial granuloma annulare–response to adalimumab. Int J Dermatol 2010; 49: 457–60. Patrascu V, Giurca C, Ciurea RN, Georgescu CV. Disseminated granuloma annulare: study on eight cases. Rom J Morphol Embryol 2013; 54: 327–31. Cyr PR. Diagnosis and management of granuloma annulare. Am Fam Physician 2006; 74: 1729–34. Marcus DV, Mahmoud BH, Hamzavi IH. Granuloma annulare treated with rifampin, ofloxacin, and minocycline combination therapy. Arch Dermatol 2009; 145: 787–9.
Clinical and Experimental Dermatology
3
Clinical dermatology • Concise report
Clinical and Experimental Dermatology
Successful treatment of generalized granuloma annulare with adalimumab T. Mahmood,1 B. Mansouri2 and A. Menter2 1 Texas A&M Health Sciences Center College of Medicine, Bryan, TX, USA; and 2Department of Dermatology, Baylor University Medical Center, Dallas, TX, USA
doi:10.1111/ced.12598
Summary
We report the case of a 64 year-old woman who demonstrated resolution of recalcitrant, generalized granuloma annulare (GA) following treatment with adalimumab. After showing little response to other treatment techniques, such as steroids and a triple antibiotic regimen, the patient was started on adalimumab. Within 3 months, she showed almost complete resolution of lesions. Within 6 months, she was completely lesion-free, and remained clear following 12 months of adalimumab therapy. This case provides further evidence that tumour necrosis factor-a inhibitors may be a treatment option for patients with recalcitrant, generalized GA.
Granuloma annulare (GA) is a noninfectious, benign skin condition for which the cause and pathogenesis are not well understood. The generalized form of GA is frequently intractable despite the use of multiple topical and systemic therapies. We report a case of GA that was almost fully cleared following 3 months of adalimumab therapy, with complete clearance and no new lesions or recurrences noted after 6 months of therapy. The patient remains clear following 12 months of therapy.
Correspondence: Dr Alan Menter, Department of Dermatology, Baylor University Medical Center, 3900 Junius St. Suite #125, Dallas, TX 75246, USA E-mail: [email protected] Conflict of interest: TM and BM have no conflicts of interest to declare. AM has sat on the advisory boards of AbbVie, Allergan, Amgen, Boehringer Ingelheim, Genentech, Janssen Biotech, Inc., LEO Pharma and Pfizer; has been a consultant for AbbVie, Allergan, Amgen, Convoy Therapeutics, Inc., Ely Lilly, Janssen Biotech, Inc., LEO Pharma, Novartis, Pfizer, Syntrix, Wyeth and XenoPort; has been an investigator for AbbVie, Allergan, Amgen, ApoPharma, Boehringer Ingelheim, Celgene, Convoy Therapeutics, Inc., Ely Lilly, Genentech, Janssen Biotech, Inc., LEO Pharma, Merck, Novartis, Pfizer, Symbio/Maruho, Syntrix and Wyeth; has been a speaker for AbbVie, Amgen, Janssen Biotech, Inc., LEO Pharma and Wyeth; and has received grants and/or honoraria from AbbVie, Allergan, Amgen, ApoPharma, Boehringer Ingelheim, Celgene, Convoy Therapeutics, Inc., Ely Lilly, Genentech, Janssen Biotech, Inc., LEO Pharma, Merck, Novartis, Pfizer, Symbio/Maruho, Syntrix, Wyeth and XenoPort. Accepted for publication 9 September 2014
ª 2015 British Association of Dermatologists
Report A 64-year-old white woman presented with a 3-year history of biopsy-proven GA on her upper and lower extremities, abdomen and back. She had previously been treated with topical and intralesional corticosteroids, with limited improvement. On physical examination, the patient was found to have numerous papules and small GA plaques on her wrist folds, elbows, forearms, knees and lower legs, large confluent plaques on her posterior thighs, and isolated papules on her back and in the right inframammary fold. The combination of rifampicin 600 mg, ofloxacin 400 mg and minocycline 100 mg once monthly was initiated for 3 months, with 50% improvement noted. However, following three additional months of this triple antibiotic regimen, the patient had no further improvement, and new lesions were apparent on her upper and lower extremities (Fig. 1a,b). Therefore, antibiotic therapy was discontinued. Based on previous reports in the literature showing successful treatment of GA with tumour necrosis factor (TNF)-a antagonists,1–7 adalimumab 40 mg every 2 weeks was initiated. After 3 months of adalimumab therapy, there was almost total clearance, with only minor post-inflammatory lesions remaining on the patient’s ankles. After 6 months of therapy, the patient had complete clearance, and remained without
Clinical and Experimental Dermatology
1
Treatment of granuloma annulare with adalimumab T. Mahmood et al.
(a)
(b)
(c)
(d)
Figure 1 Granuloma annulare (GA) lesions on (a) the posterior
left lower leg and (b) anterior right lower leg inferior to the patella. (c,d) The same locations with complete resolution of GA lesions 12 months after initiation of adalimumab.
evidence of new GA lesions after 12 months of therapy (Fig. 1c,d). GA was first described by Colcott Fox in 1895.8 It is a benign skin condition that most often presents with flesh-coloured or erythematous dermal plaques and papules arranged in an annular configuration. This condition is typically asymptomatic, but it can be associated with mild pruritus.9 Lesions can be found anywhere on the body; however, the hands and feet are most commonly involved, while facial lesions are rare. The disease affects patients of all ages, and can follow a self-limiting course or a chronic, relapsing course. In the majority of cases, GA will resolve spontaneously within 2 months to 2 years. Diagnosis is
2
Clinical and Experimental Dermatology
made by clinical examination and biopsy findings. Histologically, GA shows a histiocytic and lymphocytic granulomatous dermal infiltrate, suggesting that delayed-type hypersensitivity reactions and cellmediated immune responses may contribute to the pathogenesis of the disease. The inflammatory infiltrate of GA is composed of CD3+ cells and macrophages, which secrete TNF-a.6 Subtypes of GA include localized, subcutaneous, perforating, patch/macular and generalized/disseminated. Localized GA is the most common subtype, and is typically diagnosed in patients before the age of 30 years, with the condition being about twice as common in women as in men.9 Subcutaneous GA can be present in adults, but is more common in children between the ages of 2 and 10 years. Similarly, perforating GA is also more common in children, and frequently presents with lesions on the lower extremities. Patch or macular GA is the rarest subtype, and is most often present on the trunk and proximal extremities. Generalized or disseminated GA affects patients in a bimodal distribution, most commonly affecting patients younger than 10 years and patients older than 40 years of age. In cases of generalized GA, lesions may persist for up to 10 years with frequent recurrences. Treatment of GA is generally dictated by the distribution of the lesions. Because localized GA is a benign and self-limiting disease, treatment is usually unnecessary, but the condition has been successfully treated for cosmetic purposes with topical steroids, intralesional steroid injections, and cryotherapy.9 However, these techniques are inadequate for generalized GA. Successful systemic treatment with phototherapy, antimalarial drugs, isotretinoin, ciclosporin and dapsone has been documented.9 Marcus et al.10 also reported successful treatment of resistant generalized GA with combination therapy of rifampicin, ofloxacin and minocycline. Seven successful cases of treatment of generalized GA with TNF-a antagonists have been reported.1–7 The efficacy of these drugs is related to the presumed role of TNF-a in GA pathogenesis. Infliximab has shown efficacy in two cases of generalized GA,2,4 while etanercept has been reported to be successful in one case.6 Our case represents the fifth case of a patient with recalcitrant, generalized GA responding well to adalimumab.1,3,5,7 To date, there have been no prospective randomized controlled trials for TNF-a inhibitor use in generalized GA. However, this small collection of case reports provides good evidence that TNF-a
ª 2015 British Association of Dermatologists
Treatment of granuloma annulare with adalimumab T. Mahmood et al.
inhibitors should be considered for the treatment of recalcitrant, generalized GA. 2
Learning points GA is a benign, noninfectious, self-limiting con-
dition that presents with plaques and papules arranged in an annular configuration, frequently on the hands and feet. There are five subtypes of GA, with generalized GA often associated with a chronic, relapsing course compared with the other subtypes. Treatment options for GA include observation, topical or intralesional steroids, antimalarial drugs and cryotherapy. However, generalized GA frequently requires systemic therapy. In cases of recalcitrant, generalized GA, TNF-a inhibitors, such as adalimumab, may be an appropriate treatment option.
3
4
5
6 7
8
References 1 Fanning SB, Chapman G, Yau Y, Leong RW. Education and imaging. Gastrointestinal: improvement of granuloma annulare with anti-tumour necrosis factor
ª 2015 British Association of Dermatologists
9 10
alpha therapy for Crohn’s disease. J Gastroenterol Hepatol 2010; 25: 215. Hertl MS, Haendle I, Schuler G, Hertl M. Rapid improvement of recalcitrant disseminated granuloma annulare upon treatment with the tumour necrosis factor-alpha inhibitor, infliximab. Br J Dermatol 2005; 152: 552–5. Knoell KA. Efficacy of adalimumab in the treatment of generalized granuloma annulare in monozygotic twins carrying the 8.1 ancestral haplotype. Arch Dermatol 2009; 145: 610–11. Murdaca G, Colombo BM, Barabino G et al. Anti-tumor necrosis factor-alpha treatment with infliximab for disseminated granuloma annulare. Am J Clin Dermatol 2010; 11: 437–9. Rosmarin D, LaRaia A, Schlauder S, Gottlieb AB. Successful treatment of disseminated granuloma annulare with adalimumab. J Drugs Dermatol 2009; 8: 169–71. Shupack J, Siu K. Resolving granuloma annulare with etanercept. Arch Dermatol 2006; 142: 394–5. Werchau S, Enk A, Hartmann M. Generalized interstitial granuloma annulare–response to adalimumab. Int J Dermatol 2010; 49: 457–60. Patrascu V, Giurca C, Ciurea RN, Georgescu CV. Disseminated granuloma annulare: study on eight cases. Rom J Morphol Embryol 2013; 54: 327–31. Cyr PR. Diagnosis and management of granuloma annulare. Am Fam Physician 2006; 74: 1729–34. Marcus DV, Mahmoud BH, Hamzavi IH. Granuloma annulare treated with rifampin, ofloxacin, and minocycline combination therapy. Arch Dermatol 2009; 145: 787–9.
Clinical and Experimental Dermatology
3
