Off-Label Management Strategies for Generalized Granuloma Annulare: What’s New?

Granuloma annulare (GA) is a benign, inflammatory granulomatous skin disease with an estimated annualized prevalence of ~0.06% in the United States.¹ The most common subtypes are localized and generalized GA (GGA), which affect about 75% and 15% of patients, respectively.² While localized GA responds well to topical and intralesional corticosteroids, GGA responds poorly to topical therapies and can be challenging to manage, even with systemic treatments. While multiple treatment modalities have been employed in the management of GGA, effective and safe options are still lacking. This review will discuss limitations of traditional therapies and explore emerging treatment modalities for GGA. Traditional Treatments Antimalarials, tetracycline antibiotics, and phototherapy have historically been mainstays of GGA management, although varying levels of evidence support their efficacy. In a 2021 claims database study (n=11,608), tetracycline antibiotics (n=820) and hydroxychloroquine (n=268) were the most frequently prescribed systemic therapies in the 6 to 12 months following diagnosis of any GA subtype.¹ Although tetracyclines were prescribed three times more often, evidence supporting their use in GGA is inferior to that of hydroxychloroquine. While one retrospective study found that only 2 of 7 patients responded to oral doxycycline and 0 of 9 responded to oral minocycline, a systematic review (n=35) of hydroxychloroquine for GGA demonstrated that 71.4% of patients experienced partial or complete clearance.³ Of note, however, in a more recent case series (n=26), only 35% of patients experienced partial or complete clearance, suggesting variable efficacy.³ In the aforementioned claims database study, phototherapy was rarely utilized despite being cited as the most well-studied treatment in a review article on GGA’s therapeutic options.² The largest retrospective study evaluating psoralen and ultraviolet A (n=33) in GGA found that 66% of patients achieved complete clearance or “good” improvement, though only 32% of patients who achieved clearance remained in remission 1 year post-treatment.⁴ While other phototherapy modalities, such as narrowband ultraviolet B, have also demonstrated similar efficacy rates, phototherapy is limited by logistical constraints.³ Altogether, these data underscore the inadequacy of traditional treatments and the need for more effective GGA management strategies. Emerging Treatments Tumor Necrosis Factor-α Inhibitors (TNFis) TNFis are among the newer treatment classes being employed in the management of GGA. TNF-α has been found at high levels in the skin and serum of patients with GGA.5 Further, it plays an active role in both granuloma formation and maintenance, underpinning its utility in GGA management.^6,7 In a systematic review (n=24) of TNFis for GGA, adalimumab and infliximab exhibited higher efficacy rates than etanercept. The most common dosing regimen for adalimumab (n=16) was 80 mg the first week, followed by 40 mg injections every other week, and 87.5% of patients experienced improvement or complete remission.^5,8 Seven of the patients treated with adalimumab came from a single case series, in which improvement was appreciated in all patients at the first follow-up visit, occurring at a mean duration of 13.9 ± 9.5 weeks.⁸ Infliximab (n=3) was administered at 5 mg/kg at weeks 0, 2, and 6, then at monthly intervals, and all patients experienced complete remission.⁵ Lastly, etanercept (n=5) was administered at 50 mg twice weekly, resulting in complete resolution in one case and no improvement in the remaining four cases.^7,9 Etanercept’s suboptimal efficacy compared to adalimumab and infliximab is likely due to its inability to bind transmembrane TNF-α and ultimately aid in granuloma destruction.⁷ Across case reports and series, TNFis have demonstrated a favorable safety profile in GGA management. Alopecia and loss of energy have each been reported, however, neither resulted in treatment cessation.⁷ Additionally, while there have been no reports of paradoxical GA exacerbation in GGA patients treated with TNFis, there is some concern for this potential adverse effect due to case reports of TNFis paradoxically inducing GA when used to treat other inflammatory conditions.³ Janus Kinase Inhibitors (JAKis) JAKis are the newest treatment class being explored in the management of GGA. One of the first studies investigating their efficacy and mechanistic evidence was an open-label clinical trial in which 5 patients with GGA were treated with tofacitinib 5 mg twice daily for 6 months.10 Before treatment initiation, the investigators identified increased mRNA expression of interferon-γ, oncostatin M,

IL-15, and IL-21 – integral mediators of the JAK-STAT pathway – in GA lesions.10 Within 1 to 3 months of treatment initiation, all patients experienced improvement, and, after 6 months, 3 patients achieved complete clearance, while 2 experienced partial but significant improvement, further supporting involvement of the JAK-STAT pathway in GA pathogenesis.¹⁰ In another 15-patient case series of tofacitinib 5 mg twice daily, patients exhibited similar results after a mean duration of 4.4 ± 2.1 months, with 11 experiencing complete and 4 experiencing partial responses. In this study, tofacitinib was tapered to 5 mg daily for 1 month before cessation. Only 2 patients experienced lesion recurrence 1 month and 3 months after tofacitinib discontinuation, which resolved with re-administration of tofacitinib 5 mg twice daily for 1 month.¹¹ Upadacitinib has also demonstrated efficacy in GGA treatment at various doses, including 15 mg three times weekly, 15 mg daily, and 30 mg daily. Upadacitinib resulted in complete clearance in most case reports, with one patient experiencing clearance in as little as 8 weeks.¹² Baricitinib has also been effective in a handful of cases when dosed at 2 to 4 mg daily. Finally, abrocitinib, the latest JAKi to be employed in GGA management, has successfully treated two cases at doses of 150 to 200 mg daily.¹² JAKis have largely been well-tolerated in patients with GGA. However, some adverse effects have been reported, including limited reports of herpes infections and hyperlipidemia.¹² Additionally, in a 3-patient case series of upadacitinib in GGA, therapy was tapered from 30 to 15 mg daily in two patients due to various adverse effects at the higher dose, including generalized weakness, a nonpainful linear lesion in the oral cavity, and respiratory illnesses.¹² Phosphodiesterase-4 Inhibitors (PDE4is) PDE4is are another emerging treatment option under investigation for GGA management, with inconsistent results supporting their efficacy. As GA is presumed to be a Th1-type delayed hypersensitivity reaction to unidentified antigens and PDE4 inhibition downregulates Th1 cytokines including TNF-α and interferon-γ, the role of PDE4is in GGA is mechanistically logical.^3,13 Apremilast’s success in treating GGA was first reported in a two-patient case series in which both patients were treated with apremilast 30 mg daily. The first patient achieved significant improvement of all lesions after 3 months of treatment and sustained improvement after 18 months of treatment. The second patient achieved clearance of all chest lesions and improvement of upper extremity lesions after 4 months of treatment.¹³ However, a more recent case series of 8 patients treated with apremilast 30 mg twice daily demonstrated less promising results with only 3 patients experiencing complete clearance, 3 failing to respond, and 1 having a partial response.¹⁴ The last patient initially experienced complete clearance; however, down-titration led to flares and, ultimately, discontinuation. Though its efficacy was variable, apremilast was well-tolerated except for one patient experiencing diarrhea.¹⁴

TNFis and JAKis are both promising emerging therapies shown to be effective and safe in GGA management. Although there is still a lack of high-quality, head-to-head trials, both TNFis and JAKis have demonstrated higher rates of efficacy than traditional GGA therapies in the limited existing case series. Notably, while both TNFis and JAKis have demonstrated rapid onset of action in GGA management, JAKis appear to outperform TNFis.¹² Despite their advantages, a major prohibitive factor of TNFis and JAKis is their high cost. Ultimately, while this may prevent them from being used as first-line therapies at this time, both TNFis and JAKis should actively be considered as second-line therapies for GGA.

NM’s work is funded through independent research grants from Incyte and Johnson & Johnson. SIV’s work is funded through an independent research grant from Galderma. AF has served as a consultant for AbbVie and a speaker and consultant for Pfizer.

Adam Friedman MD FAAD ajfriedman@mfa.gwu.edu