Variable therapeutic outcomes with baricitinib in refractory generalised granuloma annulare - Need for type specific cytokine data

Dear Editor,

Granuloma annulare (GA) is an idiopathic granulomatous inflammatory skin disorder that presents as erythematous papules and annular plaques in elderly females. Skin lesions are localised in most patients and self-resolving. However, around 15% of patients have generalised (>10) lesions that are usually treatment unresponsive.¹ Various treatment modalities have been used like steroids, psoralen plus ultraviolet A (PUVA), isotretinoin, dapsone, pentoxifylline, hydroxychloroquine, cyclosporine, interferon-gamma (IFN-γ), potassium iodide, nicotinamide, niacinamide, salicylic acid, dipyridamole, fumaric acid ester, etanercept, infliximab, adalimumab but with limited evidence.²

Understanding of the pathogenetic mechanisms of GA is insufficient, which precludes the use of targeted therapy. With evidence from recent immunological studies suggesting the role of Janus kinase (JAK) pathways and related cytokines, JAK inhibitors (JAKi) such as abrocitinib, tofacitinib, baricitinib, and upadacitinib have been successfully used in the treatment of GA.^1,3-5 We report outcomes of treatment with baricitinib in three patients with generalised GA, one having undergone lesional cytokine mRNA analysis. We retrospectively analysed records of three patients who were diagnosed with refractory generalised GA with the diagnosis confirmed histologically and were treated with baricitinib monotherapy (4 mg orally once daily). Lesional and non-lesional skin biopsies were also sent for cytokine (mRNA levels) analysis before initiation of baricitinib in patient 1 and were analysed as per previously defined methods.⁶ The comparison between lesional and non-lesional skin showed upregulation of IL-21 (2.33-fold) and downregulation of IFN-γ (0.08-fold) and IL-15 (0.96-fold) in the former. Clinical and therapeutic details of patients are elaborated in Table 1.

Baricitinib monotherapy gave a favourable response in the treatment of three patients with generalised GA for whom conventional treatment had previously failed. Response was noted as early as within four weeks of treatment. The best response was seen in disseminated papular GA, which responded within a short span of time [Figure 1]. The plaque variant took longer to respond (12-14 weeks vs six weeks) and did not show complete clearance in one patient. Relapse post discontinuation was observed in patient 1 with generalised plaques, while no relapse was observed in generalised papular GA patient (patient 3).

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Figure 1a,1b:

Generalised erythematous papules on the trunk and limbs of Patient 1, suggestive of generalised papular GA.

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Figure 1c,1d:

Complete resolution of papules at 8-weeks of baricitinib.

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IFN-γ, a crucial cytokine in the development of GA, as well as other molecular mediators - oncostatin M (OSM), IL-15, and IL-21 operate via the JAK-STAT pathway.⁵ GA is believed to be a T-cell dependent cutaneous inflammatory disorder involving T helper 1 (Th1) and Th2 polarisation, but the literature on Th17 or T regulatory (Treg) cytokine profiles is still inadequate. Recent RNA sequencing data, however, suggests upregulation of only Th1 cytokines in GA lesions, predominantly IFN-γ and IL-21.⁵ IFN-γ signals via JAK 1, JAK2, and TYK-2, while IL-21 signals via JAK1/JAK3 thus making GA amenable to treatment with JAK inhibitors [Table 2].^1,3-5,7 In patient 1, a two-fold increase was observed in IL-21 levels (in lesional versus non-lesional skin) but none in IFN-γ, suggesting likely differences in cytokine responses between patients, possibly translating to varied clinical response.

There is little data on type-specific GA polarisation.However, while Wang et al.⁵ reported greater suppression of pathogenic cytokine activity in complete responders to tofacitinib versus partial responders, with increased IFN-γ, IL-21, IL-15, and OSM, we did not find significantly high IFN-γ activity, while IL-21 was raised twice above the normal skin level. However, while we compared the levels with the patient’s uninvolved skin, Wang et al. compared levels with normal skin biopsies from healthy controls.⁵ The lack of an IFN- γ signal may suggest a lower likelihood of response to baricitinib. Tofacitinib, which inhibits JAK1/JAK3 (and thus IL-21 signalling) may be a better option in such cases.

Baricitinib was well tolerated in our patients with only minor side effects. Lack of a consistent response in our series suggests that there is a need for tissue-based cytokine studies across the varied CD4 T cell profiles to effectively individualise treatment in this refractory disorder.