Treatment of Generalized Granuloma Annulare with JAK Inhibitors: Systematic Review

Introduction

Granuloma annulare (GA) is a rare granulomatous inflammatory skin condition characterized by annular, skin-colored to erythematous or violaceous plaques.¹ The localized form is the most common, appearing as isolated plaques, however approximately 15–25% of cases manifest as generalized GA (GGA), defined by at least 10 widespread annular plaques. Other variants include subcutaneous GA, commonly seen in children as firm, painless nodules; perforating GA, which presents with umbilicated papules that may drain fluid; and patch GA, characterized by erythematous patches, typically on the lower extremities.²

In the United States, the incidence of GA is approximately 0.04%, with a prevalence of around 0.06%. It is most frequently diagnosed in the fifth decade of life and is more common in women, with a female-to-male ratio of 3:1.³ GA is also more prevalent in Caucasians, occurring at up to twice the rate seen in Hispanic and Asian populations.

Several studies have explored the association between GA and various comorbidities. A large cohort study and a case-control study confirmed an association between GA and diabetes, hyperlipidemia, hypothyroidism, and rheumatoid arthritis.^3,4 Among these, diabetes and hyperlipidemia are the most frequently reported. Hypothyroidism and rheumatoid arthritis were also found to be associated with GA but occurred less frequently.^3,4 Although there have been reports of GA occurring in patients with malignancies, a definitive relationship remains unproven.³

Although the exact pathogenesis of GA remains unclear, histopathological and molecular studies revealed key immune mechanisms. Both localized and generalized GA share key histologic features, including dermal lymphohistiocytic infiltrates and collagen degeneration.⁵ A delayed-type hypersensitivity reaction appears central, with Th1 lymphocytes stimulating macrophages to release IFN-γ and matrix metalloproteinases (MMPs), resulting in collagen degradation.⁶ Recent studies demonstrate upregulation of Th1 and JAK-STAT signaling pathways, with increased expression of cytokines such as TNF-α, IL-1β, IFN-γ, IL-12/23p4, oncostatin M, IL-15, and IL-21, underscoring the role of these pathways in GA pathogenesis.⁷

GGA remains a treatment challenge for many clinicians due to the lack of FDA-approved therapies and the unpredictable success rate of many reported therapies.⁷ Unlike localized GA, which often resolves spontaneously within 1–2 years, generalized GA often follows a more chronic course with lower rates of spontaneous resolution. This often necessitates systemic treatment or phototherapy, as therapies effective for localized disease like topical or intralesional corticosteroids, are frequently ineffective for GGA.^5,7 Systemic treatments include dapsone, antimalarials (hydroxychloroquine, chloroquine), tetracycline antibiotics, isotretinoin, and fumaric acid esters.^5,8 Phototherapy, such as UVB or PUVA, has shown promising results in case reports.^9–11

Given the limited and inconsistent efficacy of conventional therapies, there has been growing interest in immunomodulatory approaches. Recent insights highlighting the role of Th1 activation and JAK-STAT pathway upregulation in GA pathogenesis, support therapeutic rationale for JAK inhibition. Molecular studies demonstrate that JAK blockade normalizes both JAK-STAT-dependent (ie IFN-γ) and JAK-STAT-independent cytokines (ie TNF-α), underscoring JAK-STAT signaling as a key pathogenic driver.¹²

In this systematic review, we will assess the efficacy and safety of different JAK inhibitors in treating GGA.

Materials and Methods

PRISMA Flowchart

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines.¹³ The protocol was registered with PROSPERO under the registration number CRD420251029012 A flowchart diagram is presented in Figure 1.

Figure 1 PRISMA 2020 flowchart describing the inclusion methodology applied in review process.

Search Strategy

A comprehensive search was conducted on the following electronic databases: MEDLINE/Pubmed, Web of Science, and Embase. To mitigate publication bias, we implemented a comprehensive, systematic search across multiple databases to reduce the likelihood of missing relevant studies. All databases were searched from inception to April 2025. The specific search strategy used the following terms: “granuloma annulare” OR “generalized granuloma annulare” [Article title/Abstract/Keywords] AND “JAK inhibitor” OR “tofacitinib” OR “ruxolitinib” OR “baricitinib” OR “abrocitinib” OR “Upadacitinib” [Article title/Abstract/Keywords]. Only study types including case reports, case series, observational studies, and clinical trials published in the English-language were considered. Review articles, conference abstracts, preprint papers, books, and book chapters were omitted. To integrate the results from MEDLINE/Pubmed, Web of Science, and Embase, we exported all records into a quality evidence synthesis and management software (Covidence). During this process, duplicate records were removed both automatically by the Covidence software and manually by the reviewers. Titles and abstracts were first screened based on predefined inclusion and exclusion criteria, after which full-text reviews were conducted for the articles that met initial eligibility.

Study Population–Selection

The following PICO (Population, Intervention or exposure, Comparison, Outcome) elements were applied as inclusion criteria for this systematic review: (i) Population: patients diagnosed with GGA of any age or sex, excluding patients with localized GA only, (ii) Intervention: any JAK inhibitor, such as abrocitinib, baricitinib, tofacitinib, upadacitinib, or ruxolitinib (iii) Comparison: This review does not have any comparators, (iv) Outcome: clinical improvement or complete resolution of symptoms, the occurrence of adverse effects, and the timing of treatment response.

Data Extraction

For all studies that met the inclusion criteria, two independent reviewers (D.J. and S.J.) extracted data using a standardized, predefined form. Any discrepancies were resolved by a third reviewer (B.G). The following information was collected for each study: first author, year of publication, study type, number of patients, patient demographics (age, sex), medical comorbidities, prior treatments, JAK inhibitor used, dosage, route of administration, time to initial response, clinical outcome, achievement of complete clearance, reported adverse effects, and presence of relapse (Table 1). Risk of bias was assessed using appropriate tools based on study type: the JBI Critical Appraisal Tool for Case Series, the JBI Critical Appraisal Tool for Case Reports, and the ROBINS-I tool for the clinical trial. Full appraisal results are presented in the appendix (Tables A1–A3).

Table 1 Characteristics of Included Studies Evaluating JAK Inhibitors for Generalized Granuloma Annulare

Results

The initial search using the predefined criteria identified 159 publications. After removing 89 duplicates, 70 studies remained for screening. Of these, 22 met inclusion criteria and were included in this review (Figure 1). Most studies had a high risk of bias due to their design (case reports or case series), lack of randomization, and limited blinding. Only one included study was a randomized controlled trial, which was assessed as having a moderate risk of bias due to potential issues in outcome measurement. This trial relied on clinical assessments of BSA involvement, histology, and cytokine levels, with unblinded outcome assessors, raising concerns about measurement bias, particularly for subjective outcomes like BSA and quality of life (Skindex-16). Full risk-of-bias assessments are available in the appendix (Tables A1–A3). Figure 2 demonstrates the total number of patients treated with each JAK Inhibitor and Figure 3 illustrates the overall response to each JAK inhibitor across included studies. Across all included studies, the median time to initial clinical response was 5 weeks (IQR 2.75–8 weeks) and for patients with complete response, time to clearance was 17.6 weeks (IQR 15.5–19.2 weeks). Table 1 summarizes detailed information on dosing regimens, time to response, time to clearance, and relapse following treatment discontinuation for individual studies.

Figure 2 Pooled Number of Patients Treated with Each JAK Inhibitor.

Figure 3 Pooled Treatment Response to JAK Inhibitors in Generalized Granuloma Annulare: Complete vs Partial Clearance.

Abrocitinib

One case report evaluated the efficacy of abrocitinib in a 77-year-old female with GGA who had previously failed prior therapy with a topical steroid and bath PUVA. The patient experienced fading of lesions after 2 weeks, with complete resolution by 3 months. Treatment began with 200 mg/day for 1 week, followed by 100 mg/day for 3 months, then tapered to 100 mg every other day for 2 months. No relapse was observed 6 months after treatment cessation.¹⁴

Baricitinib

A total of 11 patients across 4 case reports and 3 case series were treated with baricitinib for GGA, with doses ranging from 2–4 mg/day. All patients had failed at least one prior therapy. Time to initial clinical response ranged from 2 to 14 weeks, with a median of 6 weeks (IQR 4.5–7.5 weeks). Most patients demonstrated significant improvement, with 3 patients achieving complete response. Relapse was noted in 2 patients following treatment discontinuation. One patient relapsed just 3 days after stopping baricitinib, another after 1 month. Adverse effects were generally minimal, though one patient experienced systemic symptoms including fever, sore throat, gastrointestinal upset, and insomnia. Herpes zoster was reported in another case, leading to temporary treatment interruption.^15–21

Tofacitinib

A total of 27 patients across 1 case report, 1 clinical trial, and 4 case series were treated with tofacitinib for GGA. All patients had previously failed one or more therapies. Of these patients, 26 were given 5 mg oral tofacitinib twice daily and one patient was given topical 2% ointment twice daily. Time to initial response occurred between 1 week and 3 months, all patients showing significant clinical improvement and 18 showing complete clearance. For patients with complete response, median time to clearance was 17.6 weeks (IQR 17.6–24 weeks). Relapse was reported in two patients following discontinuation of tofacitinib after 1 and 3 months. In both cases lesions resolved after re-initiation of treatment. Adverse events were uncommon. Two patients developed hyperlipidemia, and one patient experienced two uncomplicated urinary tract infections.^12,22–26

Upadacitinib

A total of 10 patients across 6 case reports and 1 case series were treated with Upadacitinib for GGA. All patients had recalcitrant disease and had failed multiple previous therapies. Patients were prescribed oral upadacitinib with dosages ranging from 15 mg twice a week to 30 mg twice daily. Time to initial response occurred between 3 and 8 weeks for these patients, with a median of 5 weeks (IQR 3.25–7.5 weeks). In patients with complete response, median time to clearance was 8 weeks (IQR 8 −16 weeks). 60% of patients (6/10) achieved complete response, and the remaining 40% (4/10) showed near complete response. No relapses were reported. Adverse effects were generally mild and included weakness, oral lesions, infections, bone pain, abdominal cramps, acne, hyperlipidemia, and mild headaches. Most patients did not experience any adverse effects.^27–33

Ruxolitinib

One case report described a healthy 51-year-old female who was treated with topical ruxolitinib 1.5% cream twice daily for GGA that was recalcitrant to previous therapies. The patient achieved complete resolution after 12 weeks of twice-daily application. She remained mostly clear beyond 12 weeks, requiring topical therapy with ruxolitinib two to three times per week to manage minor flares.³⁴

Discussion

Granuloma annulare, particularly its generalized form (GGA), continues to present a significant therapeutic challenge due to its often refractory nature and the absence of FDA-approved treatments. Our systematic review, encompassing 22 studies, highlights the emerging role of JAK inhibitors as a promising targeted therapy for GGA.

Our findings indicate that JAK inhibitors consistently demonstrate clinical improvement in patients with GGA, often leading to complete or near-complete lesion clearance. Complete response was reported in 58.0% (29/50) and partial or near complete response in 42.0% (21/50) of patients. Tofacitinib, with 27 patients across various study types, showed significant clinical improvement in all cases, with (18/27) 66.7% achieving complete clearance. Similarly, baricitinib treatment resulted in significant improvement for most patients across 11 cases, while upadacitinib led to improvement in all 10 reported cases, with (6/10) 60% achieving complete clearance. One patient on Abrocitinib had complete response. Even topical ruxolitinib showed complete resolution in one reported case. These results are particularly encouraging given that most included patients had a history of refractory disease, having failed numerous conventional systemic and topical therapies. The median time to initial response was 5 weeks (IQR 2.75–8 weeks) suggesting a relatively rapid therapeutic effect compared to some traditional treatments. For patients with complete response, median time to clearance was 17.6 weeks (IQR 15.5–19.2 weeks).

The safety profile of JAK inhibitors in this GGA cohort appears acceptable, with most reported adverse effects being mild and consistent with the known side effects of these agents in other dermatologic conditions. Importantly, no new safety signals were identified. Reported side effects mirrored those of larger trials of JAK inhibitors, primarily hyperlipidemia and infections (eg herpes labialis, urinary tract infections, respiratory infections, and herpes zoster).³⁵ Relapse was observed in a subset of patients upon discontinuation or tapering of the JAK inhibitor, underscoring the potential need for long-term or maintenance therapy, similar to other chronic inflammatory conditions.

Molecular studies previously indicated that JAK blockade not only normalizes JAK-STAT pathway associated cytokines like IFN-γ but also non-JAK-STAT-dependent cytokines such as TNF-α, suggesting a pivotal role for JAK-STAT pathway upregulation as a key driver in GA pathogenesis.¹² The clinical efficacy demonstrated by JAK inhibitors in this review provides further evidence supporting this hypothesized mechanism. By targeting this inflammatory pathway, JAK inhibitors offer a more targeted approach, potentially leading to a more predictable efficacy for patients with GGA.

This review is limited by the quality of the available evidence, as included studies were primarily case reports and case series. Additionally, heterogeneity among the included studies, including differences in study design, dosing regimens, treatment duration, and outcome definitions limits the interpretability of pooled findings. Most case reports lacked detailed information on patient follow-up and specific outcome measurements, while case series often did not include control groups. This limits our ability to draw definitive conclusions regarding efficacy and safety. Only one included study was a randomized controlled trial, which, despite its higher methodological rigor, was assessed as having a moderate risk of bias due to potential issues in outcome measurement. This absence of larger, well-controlled clinical trials limits the generalizability of our findings. Lastly, our review was limited to English-language literature, which might introduce language bias.

Conclusions

JAK inhibitors show promise as a targeted therapy for GGA, offering a novel and often effective approach for patients with refractory disease who have exhausted traditional treatment options. Their ability to induce clinical improvement and complete clearance in a notable proportion of patients, coupled with a manageable safety profile, makes them a valuable addition to the limited therapeutic options for GGA. JAK inhibitors may be considered for patients with refractory GGA who have not responded to standard therapies, with careful shared decision making regarding their off-label use. However, further high-quality, randomized controlled trials are needed to establish long-term efficacy, safety, optimal dosing regimens, and long-term safety outcomes for JAK inhibitors in the management of GGA.