Successful Treatment of Refractory Generalized Granuloma Annulare with Upadacitinib

Granuloma annulare is a poorly understood dermatosis that, when generalized, can occur in up to 15 percent of patients. In these cases, treatment is frustrating and experimental. We report a case of a 60-year-old woman and a 41-year-old woman who demonstrated resolution of recalcitrant, generalized granuloma annulare (GA) following oral treatment with upadacitinib. After showing little to no response to other various treatments, such as steroids, antibiotic regimens, and systemic therapies, each patient was started on 15 mg of daily upadacitinib. At 2 months, one patient had complete clearance of all lesions while the other patient experienced noticeable improvement. Within 4 months, the other patient reached total resolution of her lesions. These cases provide evidence of a therapeutic option that may shorten disease duration and provide relief from cutaneous disease.


Introduction
Granuloma Annulare (GA) is a benign, cutaneous condition characterized by granulomatous infammation of the dermis.GA presents as erythematous, annular plaques or papules and may be localized, disseminated, or subcutaneous.It is thought that GA is the result of a delayed-type hypersensitivity reaction, although the exact etiology of GA is unknown.However, the disease has been associated with thyroid disease, diabetes, certain infections (Epstein-Barr Virus, Varicella Zoster Virus, Human Immunodefciency Virus, and tuberculosis), vaccinations, malignancy, and medications (TNF-α inhibitors, apremilast, and secukinumab) [1,2].Studies have shown upregulation of infammatory pathways such as T1 and T2 in GA lesions compared to healthy skin.Additionally, expression of the Janus Kinase-signal transducer and activator of transcription (JAK-STAT) pathway, a driver of IFN-mediated infammation, was also upregulated and implicated in the disease [3].Although a multitude of treatment options exist, physicians lack a standardized, evidence-based treatment regimen for their patients with GA due to poor understanding of the pathogenesis of this disease.Without a better understanding of the disease, our patients are left with a condition that can persist for months to years.Recently, JAK inhibitor (JAKI) immunomodulation has gained popularity in treating cutaneous diseases including atopic dermatitis and psoriasis.Importantly, JAKIs have also shown promising efects when used of-label for other debilitating conditions such as alopecia areata, vitiligo, and even sarcoidosis [4].Topical tofacitinib, a JAK1 and JAK3 inhibitor, has been reported to successfully treat both localized and generalized GA in a limited number of reports [4,5].To our knowledge, there are fve reported cases of generalized GA responsive to upadacitinib, a selective JAK1 inhibitor [6][7][8].Our case series documents two presentations of refractory disseminated GA that had complete resolution on treatment with upadacitinib.

Case 1.
A 60-year-old Caucasian female presented to the clinic with refractory GA for eleven years.Her past medical history includes hypothyroidism and diabetes mellitus type 2. At the time of presentation, the patient had inadequate responses to "ROM" therapy (rifampin, ofoxacin, and minocycline), ultrapotent topical steroids, dapsone, hydroxychloroquine, narrowband UVB, and pentoxifylline.Te patient did achieve clearance with adalimumab; however, she had to switch treatment regimens due to lack of insurance coverage.Clinical examination revealed mildly pruritic pink to erythematous dermal papules and annular plaques involving the neck, chest, and difusely throughout her back, inner arms, and inner thighs (Figures 1 and 2).Te patient was agreeable to a trial of upadacitinib 15 mg once daily and all other treatments were discontinued.Eight weeks after the initiation of upadacitinib, clinical examination showed a noticeable improvement in redness and induration.Four months into treatment, her exam demonstrated complete clearance of all lesions with no adverse efects reported (Figures 1 and 2).Te patient remains clear on 15 mg daily, six months later.If she continues to maintain clearance, attempts to taper of upadacitinib will be discussed after one-year total of daily therapy.

Case 2.
A 41-year-old female with a 21-year history of localized GA presented to the clinic with worsening, generalized GA.She had previously been treated with escalating potencies of topical steroids, oral steroids, methotrexate, hydroxychloroquine, low-dose naltrexone, and apremilast without signifcant improvement.In the three preceding months, she had been treated with apremilast with no improvement.On exam, she demonstrated mildly pruritic, erythematous, disseminated papules and nonscaly plaques around most of her joints, including bilateral knees, knuckles, and elbows (Figures 3 and 4).After discussion of treatment options, the patient elected to try a sample of oral upadacitinib 15 mg daily and discontinue other treatments.Follow-up evaluation at three weeks showed partial improvement in her condition, with 30% of the papules and plaques cleared and only mild headaches reported.At her two-month follow-up, the patient reached complete clearance of all lesions (Figures 3 and 4).

Discussion
Granuloma Annulare (GA) is a noninfectious, granulomatous disease with clinical variants including generalized or disseminated, perforating, patch, and subcutaneous.Localized GA is typically self-limiting and may resolve by itself or within months to a few years with traditional therapies; however, generalized granuloma annulare (GGA) may persist for decades and be unresponsive to traditional agents.Various therapeutic options exist for the treatment of GA, including corticosteroids, systemic therapies (methotrexate, hydroxychloroquine, apremilast, and TNF inhibitors), dapsone, pentoxifylline, and antimicrobials (rifampin, ofoxacin, and minocycline).In a systematic review of efcacious agents used to treat GGA, TNF-α inhibitors had the highest reported efcacy [9].Interestingly, GGA has also been reported, although rarely, as an adverse class efect of TNF-α therapy in patients with rheumatoid arthritis (RA) that ceases once the medication is discontinued [10,11].We present two cases of refractory, disseminated GA to call attention to upadacitinib as a promising therapeutic avenue.To date, we know of only fve GGA cases reporting the robust efects of upadacitinib.Slater et al. demonstrated a case of refractory disseminated GA, with concomitant diabetes and hypothyroidism, that completely resolved with upadacitinib treatment in just four weeks [6].In a report by Sondermann et al., daily upadacitinib in a patient with diabetes and RA led to remission of both her RA and recalcitrant GA [7].Zheng et al. recently documented a series of three cases of long-standing generalized GA responsive to and maintaining clearance with upadacitinib [8].
Although the exact etiology of GA is unknown, some clinical triggers and associations provide hints as to the mechanism behind the disease.As mentioned previously, GA lesions tend to have an upregulation of T1 and T2 pathways, as well as JAK-STAT.A recent study reported by Min et al. showed a 5400-fold increase in interleukin-4 Case Reports in Dermatological Medicine 4 Case Reports in Dermatological Medicine (IL-4) in GA lesions compared to normal skin which inspired an investigation into the association of GA with atopic comorbidities [3].Interestingly, patients with GA were signifcantly more likely to have experience with allergic rhinitis, asthma, and eczema [12].Terefore, it could be suggested that the mechanistic culprit responsible for GA is T2 dysregulation.Having demonstrated complete clearance of GGA with upadacitinib, our case series provides further insight into this valuable therapeutic option.In Table 1, we summarize the case reports available to date, to our knowledge, using upadacitinib for the treatment of GGA.Tese four cases, including two from this paper, all reported near-complete or complete clearance of GGA lesions within 13 months.
While upadacitinib exhibits efects of a favorable treatment option, our series possesses fundamental limitations.A larger, more inclusive cohort of patients is required in order to validate the long-term efcacy and safety profle.Additionally, longer observational periods are essential to adequately study the permanency of results.As more GGA patients are treated with JAKI, we will gain insight into the disease course after treatment tapering in regard to fare-ups and JAKI tolerance.Te two new cases reported here show a quick onset, successful treatment with upadacitinib in the setting of refractory, longstanding GGA, eleven years in case one and twenty-one years in case two.Our fndings provide further support that JAKIs, specifcally upadacitinib, show promise as a potential frst-line option for disseminated GA given the positive responses and treatment toleration in reported cases.

Figure 2 :Figure 1 :
Figure 2: Left arm before (a) and 4 months after (b) treatment with upadacitinib.Images demonstrate resolution of pink to erythematous dermal papules and plaques.

Figure 4 :Figure 3 :
Figure 4: Left elbow before (a) and after (b) treatment with upadacitinib for 2 months.Images show resolution of pink dermal papules.