Granuloma Annulare: An Updated Review of Epidemiology, Pathogenesis, and Treatment Options

Tejas P. Joshi; Madeleine Duvic

Disclosures

Am J Clin Dermatol. 2022;23(1):37-50. 

In This Article

Review of Management Options

Topical and Intralesional Corticosteroids

Topical and intralesional corticosteroids are considered first-line therapies for GA and can induce partial or complete GA regression in some patients, although several cases of GA remain recalcitrant to corticosteroid treatment.[8,10] Recent single-center retrospective studies of GA treatments further seem to suggest that corticosteroids may have efficacy in the management of GA in some but not all patients. In a retrospective of study of 133 GA patients, 17 of the 55 patients treated with topical triamcinolone and 10 of the 25 patients treated with intralesional triamcinolone experienced improvement.[58] Another retrospective study of 49 generalized GA patients showed similar response rates, with topical corticosteroid treatment leading to stable disease in 46.6% of patients, partial remission in 19% of patients, complete remission in 10.3% of patients, and disease progression in 8.6% of patients. In the same study, of five other patients treated with intralesional triamcinolone, two achieved partial remission and three achieved total remission.[59] A 2021 retrospective study investigated the efficacy of topical corticosteroids alone, intralesional triamcinolone alone, and combination topical and intralesional corticosteroid therapy. All three treatment groups had similar response rates, with partial resolution being seen in 21 (41%) patients treated with topical corticosteroids alone, 7 (50%) patients treated with intralesional triamcinolone alone, and 14 (48%) patients treated with a combination of topical and intralesional corticosteroids. Complete resolution was achieved in 12 (24%) patients treated with topical corticosteroids alone, 2 (14%) patients treated with intralesional triamcinolone alone, and 8 (28%) patients treated with combination topical and intralesional corticosteroids.[60] A recent case series of patients with patch type GA showed a slightly lower response rate to corticosteroids, with 5 of the 20 patients treated with topical corticosteroids showing improvement.[13]

Altogether, considering their modest efficacy, relative safety, and low cost, corticosteroids remain viable first-line therapies. However, GA refractory to corticosteroids is common, such that it may become necessary to resort to second-line therapies.

Antimicrobials Revisited

Isolated case reports have shown antimicrobials to be effective in the management of GA, although larger retrospective studies conducted more recently fail to establish their efficacy. One case of generalized GA occurring in the setting of interstitial lung disease was observed to resolve almost completely in response to a 2-month course of doxycycline 100 mg twice daily.[61] A twice-daily regimen of amoxicillin/clavulanic acid 875/125 mg was shown to result in durable control of GA in another patient.[62] However, in a retrospective study of 133 GA patients, of whom eight were treated with minocycline, seven with doxycycline, two with ofloxacin, and two with rifampin, only two of the seven patients treated with doxycycline showed improvement.[58] In another retrospective study of 127 GA patients, only two of the five patients treated with a daily cocktail of rifampin (600 mg), minocycline (100 mg), and ofloxacin (400 mg) responded: one experienced complete resolution and the other experienced partial resolution.[60] As already mentioned, eight GA patients with confirmed positive biopsies for Chlamydiales DNA did not respond to doxycycline, and of the seven patients with confirmed positive biopsies for Borrelia DNA, only two responded to a 9-month course of antibiotic therapy.[43]

Larger retrospective studies do suggest some efficacy for dapsone. In a recent retrospective review of 26 generalized GA patients treated with a median daily dose of dapsone 100 mg for a mean duration of 9.8 months, 54% experienced regression of lesions. However, the remissions were not durable in 57% of responders, who experienced lesion relapse. In addition, subclinical myelosuppression was observed in 31% of patients, warranting discontinuation of treatment.[63] Two other case series reported similar response rates to dapsone: three of seven patients treated with dapsone experienced partial remission in the study by Visconti et al.,[60] and three of five patients treated with dapsone showed improvement in the study by Rubin and Rosenbach.[58] Given the concern for myelosuppression, dapsone should be used cautiously, especially in immunocompromised at-risk individuals.

Antimalarials Revisited

A 2019 review pooling together the reported cases of antimalarial treatment for GA showed that 25 of 35 patients treated with HCQ, and all of the 12 patients treated with chloroquine, experienced improvement, with an overall response rate of 79.6%.[64] Since the publication of this review, additional reports have emerged that are more mixed. Megna et al. reported complete clearance of disseminated GA in one patient with an 8-week course of HCQ 200 mg twice daily,[65] and Xu et al. reported a pediatric patient who experienced complete remission of disseminated GA after 6 months of treatment with HCQ 25 mg once daily.[66] In a retrospective review by Nordmann et al., of the five patients who were treated with HCQ, one patient achieved complete clearance, two achieved partial clearance, and one showed stable disease.[59] However, in the retrospective review conducted by Rubin and Rosenbach, only five of the 12 patients who were treated with HCQ showed improvement.[58] A recent retrospective review of 26 GA patients treated with a median daily dosage of HCQ 400 mg for a mean duration of 10 months showed an even poorer response rate, with only 35% of patients improving with treatment.[67] The poor response reported to HCQ in more recent studies is unfortunate, as HCQ is a cheap and generally well-tolerated drug.

Apremilast

Apremilast is a phosphodiesterase-4 inhibitor that has been licensed for the treatment of psoriasis, psoriatic arthritis, and oral ulcers associated with Behcet's disease.[68] Several recent case reports recommend further investigation of apremilast in the management of GA. Blum and Altman reported the first two cases of GA treated with apremilast: one patient experienced durable improvement in erythema and induration of lesions in 3 months and the other patient had near complete remission of lesions at 4 months.[69] Bishnoi et al. then reported a case series of four GA patients treated with apremilast, three of whom experienced a reduction in lesion number and one patient who experienced decreased erythema and pruritus; in all four patients, response to apremilast was seen within 6–8 weeks of initiating treatment.[70] Joshi and Tschen reported an additional case where apremilast led to near total resolution of lesions in seven months.[71] Most recently, Hansel et al. reported two patients who also experienced marked improvement of their GA within 8 weeks of treatment.[72] Notably, all patients treated with apremilast for their GA tolerated the medication well. Only two patients in the case series by Bishnoi et al. reported myalgia and mild gastrointestinal symptoms, which were managed with treatment.[70]

While the current reported cases are compelling, a paradoxical case of GA induction after starting apremilast therapy for psoriasis has also been reported.[51] Clearly, further randomized studies are needed to evaluate the safety and efficacy of apremilast in the management of GA.

Biologic Therapies Revisited

In 2019, Chen et al. reviewed the role of biologic therapies in the treatment of chronic GA. Based on their pooled analysis, TNFα inhibitors in particular show some promise: 14 of 16 patients treated with adalimumab, one of five patients treated with etanercept, and all three patients treated with infliximab experienced improvement. One patient treated with combination adalimumab and infliximab also experienced improvement.[73] More recently, three separate cases of GA responsive to adalimumab,[51] etanercept,[74] and infliximab[75] have been added to the literature. The most recent report on infliximab is particularly interesting. The authors also investigated the molecular milieu of the GA lesion microenvironment. They observed expansion of CD183+ cells in GA that was blunted by infliximab treatment.[75] Thus, downregulation of CD183+ cells could explain the role of infliximab in GA. However, this is likely only one piece of the puzzle, as infliximab, along with adalimumab and etanercept, have also been reported to paradoxically induce GA.[49] Knowledge of the association between anti-TNFα agents and GA, then, still remains incomplete and further molecular studies are needed to elucidate this relationship. Altogether, TNFα inhibitors may show efficacy in some GA patients, although patients should be monitored for paradoxical GA exacerbation.

Recently, Song reported that dupilumab, an IL-4 and IL-13 inhibitor, could successfully control GA,[76] and also reported that tildrakizumab, an IL-23 inhibitor, was actually ineffective in the management of GA in another patient.[77]

Methotrexate

Two retrospective studies suggest methotrexate to be a promising second-line therapy for GA. In a study of 15 patients treated with a median weekly dose of methotrexate 10 mg for a mean duration of 11 months, 60% of patients responded to treatment.[78] Another study of 11 patients reported a similar response rate: 64% of patients witnessed improvement, of whom 43% achieved complete clearance and 57% achieved partial clearance. While the majority of patients tolerated methotrexate well, two patients experienced gastrointestinal adverse effects and hair loss that warranted treatment cessation.[79] Additionally, one patient in the retrospective review by Rubin and Rosenbach was treated with methotrexate, and responded to treatment.[58] Given its immunomodulatory function and low cost, methotrexate may be considered a second-line therapy for GA, although continuous monitoring for adverse effects (e.g. myelosuppression) is crucial.

Pentoxifylline Revisited

Pentoxifylline is a methylxanthine derivative that has anti-inflammatory properties, although its mechanism of immunomodulation is not fully understood.[80] Recent studies suggest that pentoxifylline may be a viable therapy for the management of GA in some patients. In a three-patient case series, all patients treated with pentoxifylline witnessed complete clearance of their GA lesions; however, two patients experienced GA flare-ups: one was managed by transiently increasing pentoxifylline dosage and the other was managed with intralesional corticosteroids.[81] In the 127-patient retrospective study conducted by Visconti et al., of the 27 patients treated with pentoxifylline 400 mg thrice daily, 56% experienced partial remissions and 15% experienced complete resolution.[60] Indeed, while the response rate to pentoxifylline was high, not all patients experienced improvement and it is likely that pentoxifylline may not be efficacious in all patients. Both patients treated with pentoxifylline in the retrospective review by Rubin and Rosenbach experienced lesion persistence.[58] Nevertheless, pentoxifylline, like HCQ, is a cheap and relatively well tolerated small molecule that may merit further study in randomized controlled trials.

Phototherapy Revisited

In their 2018 review, Wang and Khachemoune identified phototherapy to be the most well-studied and efficacious management option for GA.[8] Recent studies lend further support to the efficacy of phototherapy, yet not all patients treated with phototherapy respond robustly and some fail to respond altogether.

Of all the phototherapy modalities, photodynamic (PD) therapy seems to be supported by the most evidence.[8] A 2020 retrospective review of 13 GA patients treated with a mean of three PD therapy sessions adds to this evidence base. In all patients, methyl aminolevulinate or aminolevulinic acid was applied for 3 h, illuminated with LED 635 nm with a fluence of 37 J/cm2. Seven patients experienced complete regression of their GA and four patients experienced partial improvement. PD treatment was well tolerated in all patients, with only two experiencing slight hyperpigmentation.[82]

Ultraviolet A1 (UVA1) also appears to be an effective phototherapy modality. In a retrospective review of nine patch GA patients, Aichelburg et al. reported four patients to be treated with UVA1 phototherapy, of whom two experienced complete remission while the other two experienced partial remissions.[83] In another case series of five GA patients treated with UVA1, two experienced complete clearance, two experienced partial clearance, and one patient did not respond to treatment.[84] In the retrospective study by Nordmann et al., of the 20 patients receiving UVA1 therapy, three experienced full remission, six achieved partial remission, seven had stable disease, and one experienced disease progression.[59]

Narrowband UVB (NB-UVB) also appears promising. In the retrospective review by Aichelburg et al., of the two individuals treated with NB-UVB, one achieved complete regression of GA while the other achieved partial regression.[83] Another case of patch GA showing excellent response to NB-UVB has been reported.[13] Furthermore, two recent isolated case reports demonstrate the efficacy of NB-UVB in the management of generalized GA.[85,86] However, in the study by Visconti et al., a low response rate to NB-UVB therapy was observed, with only one of the four patients treated experiencing partial resolution.[60] A similarly low response rate was observed by Nordmann et al.: of the eight patients treated with NB-UVB, none achieved full remission, three showed partial clearance, four had stable disease, and one patient had disease progression.[59]

Aichelburg et al. reported oral psoralen plus UVA (PUVA) to be effective in all three patients who were treated.[83] Moreover, of the 11 patients treated with PUVA in the study by Nordmann et al., three patients experienced complete remission, four experienced partial remission, three had stable disease, and one experienced disease progression.[59]

In the study by Rubin and Rosenbach, four of the eight patients treated with phototherapy responded. Unfortunately, the investigators did not specify the phototherapy subtype used.[58]

Altogether, phototherapy continues to appear as an effective option for some patients. Considering its relative safety profile and moderate efficacy, phototherapy is a reasonable second-line treatment for GA. However, it may be worth noting that phototherapy is expensive and may not be an affordable option for all patients. Additionally, phototherapy use has declined in recent years in favor of targeted therapies.[87,88] Thus, despite its evidence base, phototherapy may not be as practical as oral therapies.

Tofacitinib

Tofacitinib is a JAK inhibitor that is quickly gaining popularity in dermatology for a wide range of applications, and has shown some off-label efficacy in inflammatory conditions such as alopecia areata, atopic dermatitis, psoriasis, and vitiligo.[89] In a case series of five GA patients treated with oral tofacitinib, three patients experienced complete involution of lesions while two others experienced marked improvement.[36] An additional case of GA responding to oral tofacitinib was recently reported by Damsky et al..[90] The report by Damsky et al. is particularly interesting because the investigators also characterize the molecular changes induced by tofacitinib treatment. Of note, they report a reduction in not only the cytokines involved in the JAK-STAT pathway but also a reduction in non-JAK-STAT pathway-dependent cytokines, such as TNFα. The investigators therefore propose that JAK-STAT pathway dysregulation may be the proximal pathogenic event that incites the immune dysregulation that is observed in GA.[90]

Two patients with near total resolution of their GA in response to topical tofacitinib have also been described, suggesting that the topical formulation of the drug may also be efficacious.[91,92] It is worth noting though that JAK-STAT inhibitors are expensive and may not be covered by insurance for off-label applications. Thus, JAK-STAT inhibitors may need to be reserved as treatments of last resort.

Other Therapies

In addition to the therapies discussed above, a diverse assortment of other therapies for GA have been reported, highlighting the lack of an established paradigm of care for GA. Sulphasalazine has shown a modicum of efficacy in the management of GA. A retrospective study of 13 GA patients treated with sulphasalazine found that 11 patients responded to treatment. Sulphasalazine was generally well tolerated, although three patients discontinued therapy due to adverse effects (elevated liver function tests, gastrointestinal distress, neutropenia, and xerostomia).[93]

Potassium iodide (KI) is another treatment that has been suggested for GA, although recent studies yield disappointing results. An 11-patient retrospective study found that KI led to improvement in only four patients.[94] Furthermore, in the retrospective study by Nordmann et al., of the 12 patients treated with KI, none experienced complete resolution, three experienced partial resolution, two had stable disease, and two had GA progression.[59]

The larger retrospective studies previously cited also report small numbers of individual patients treated with a myriad of other therapies. In the 133-patient retrospective study by Rubin and Rosenbach, the following additional therapies were reported: local radiation (with only one patient being treated, who did show improvement), niacinamide (with neither of the two patients treated showing improvement), oral isotretinoin (with one of the two patients treated showing improvement), oral corticosteroid (with three of the six patients treated showing improvement), tacrolimus cream (with one of the five patients treated showing improvement), and zileuton (with none of the three patients treated showing improvement).[58] In the 127-patient retrospective study by Visconti et al., three patients were treated with isotretinoin 20 mg twice daily, of whom only one showed partial improvement; one patient was also treated with cyclosporine 100 mg daily but did not show improvement.[60]

In 2018, a report of radial pulse therapy (a form of extracorporeal shock wave therapy) was found to improve GA in one patient.[95] While novel, radial pulse therapy is impractical for disseminated GA and no further reports have emerged that validate its efficacy in localized GA.

Control of common comorbidities (diabetes and hyperlipidemia) may also be an indirect therapy for GA. Indeed, both diabetes and hyperlipidemia have been associated with T-cell dysregulation[96,97] and control of these comorbidities may dampen overactive T-cell reactions that are central to GA pathogenesis. In 2020, Patrun and Hadžavdić reported a diabetic patient with disseminated GA who experienced complete resolution of lesions after starting insulin treatment.[98] Another GA patient with hyperglycemia and hyperlipidemia was reported to experience partial resolution of GA after 2 months of treatment with atorvastatin, fenofibrate, glimepiride, and metformin.[99] These case studies suggest that management of comorbid diabetes and hyperlipidemia may, in and of itself, be a therapeutic strategy to address GA. We summarize the recently reported treatments for GA in Table 3 and indicate the level of evidence for each therapeutic strategy.

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