Effective Treatment of Recalcitrant Generalized Papular Granuloma Annulare With Upadacitinib Monotherapy: A Case Report and Literature Review

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Granuloma annulare (GA) is an inflammatory skin condition with various forms, including localized, generalized, perforating, and subcutaneous types [1]. Generalized GA (GGA) usually appears as skin‐colored, pink, or violaceous papules that merge into annular plaques. A rare variant, known as generalized papular GA (GPGA), is characterized by the presence of distinctive papules without the formation of plaques [2]. Corticosteroids are the first‐line therapy for GA, but corticosteroid‐resistance cases are not uncommon, especially in the GGA [1]. Other options for GGA, such as phototherapy, pentoxifylline, and dapsone, have been reported with varying efficacy [1]. Recently, biologics and Janus kinase inhibitors (JAKis) emerged as potential alternative treatments [1]. Herein, we first present a case of refractory GPGA, successfully treated with upadacitinib (a JAK1 inhibitor) monotherapy, along with a literature review of JAKis for GA treatment.

A 53‐year‐old man presented with a 2‐year history of widespread, symmetrically distributed skin‐colored to violaceous papules on his trunk and limbs (Figure 1A–C). Skin biopsy showed palisading granulomatous inflammation surrounding altered dermal collagen and mucin within the dermis (Figure 2A), with positive staining using alcian blue (Figure 2B). Systemic involvement and family history were both negative. Laboratory tests showed mildly elevated triglycerides, while other examinations were unremarkable. After clinicopathological correlation, a diagnosis of GPGA was made. Prior treatments, including topical and oral corticosteroids, methotrexate, and narrowband ultraviolet B (NB‐UVB), were ineffective. We initiated a daily regimen of upadacitinib at 15 mg. Within 2 weeks, the plaques significantly thinned, and after 4 weeks of therapy, they regressed markedly (Figure 3A–C). Subsequently, we reduced the dose to 15 mg every other day for 4 weeks, and the lesions had completely resolved. We then further reduced the dose to 15 mg every 2 days for an additional 4 weeks before discontinuing the therapy entirely. To date, 6 months after stopping therapy, the patient showed no relapse and experienced no adverse effects.

FIGURE 1.

Representative photographs of the patient displayed skin‐colored and pink to violet papules located on the waist and abdomen (A), the back (B), and the lower limbs (C).

FIGURE 2.

(A) A skin biopsy revealed that the epidermis appears predominantly normal, with lymphocytes and epithelial‐like cells organized in a palisade pattern surrounding the superficial dermal blood vessels and appendages. Additionally, there are central deposits of mucinous material (H&E, ×50). (B) The specimen exhibited positive staining with alcian blue (special staining, ×100).

FIGURE 3.

Representative photographs of the patient demonstrated near‐complete remission of the lesions after 4 weeks of upadacitinib monotherapy treatment (A–C).

1.

JAKis are approved by the FDA in addition to Rx of atopic dermatitis and alopecia areata, and also used off‐label for vitiligo [3, 4]. Recent researches underscored the pivotal roles of both Th1 (IL‐15, TNF‐α, IFN‐γ) and Th2 (IL‐4, IL‐31) cell cytokines in GA pathogenesis, mediated through the JAK‐STAT pathways [1, 5]. These insights have led to the clinical application of JAKis targeting various JAK subtypes for GA treatment [1]. Several case reports documented 14 patients with recalcitrant GA responded favorably to various treatment regimens involving different JAKis (a JAK1 inhibitor upadacitinib, a JAK1 inhibitor abrocitinib, and a JAK1/2 inhibitor baricitinib), as outlined in Table 1. A retrospective case series study on the use of oral tofacitinib (JAK1/3) for the treatment of GA found complete clearance in 11 patients within 4.4 ± 2.1 months of treatment, while four patients exhibited partial clearance within 7.3 ± 2.8 months (Table 1). Unlike typical GA, GPGA is rare and often resistant to standard therapies [2]. Our use of off‐label upadacitinib proved both effective and well‐tolerated. Consistent with previous case reports, our research reinforces the notion upadacitinib, may serve as a promising treatment for refractory GA.

TABLE 1.

Patients with granuloma annulare treated with Janus kinase inhibitors.

Ref	Author/region/year	Cases (N)	Age (y)/sex	GA type	Disease duration (years)	Comorbidities	Previous therapies	JAKis	Treatment Scheme	Clinical remission and time	Adverse events	Follow‐up duration after end of therapy (months)	Relapse
1	De Greef, A. /Belgium/2024	1	50/F	GGA	2	Livedoid vasculopathy	TS, HCQ, MTX, Vit E, Doxycycline	Upa	30 mg/d for 10 months	CR, 24w	Hyperlipidemia	2	No
2	Zheng, J. /Canada/2024	3	52/F 60/F 61/F	GGA GGA GGA	4 5 ND	ND ND ND	TS, NB‐UVB, TCI TS, Dapsone TS, MTX, NB‐UVB	Upa Upa Upa	30 mg/d (reduced to 15 mg/d maint) 30 mg/d (reduced to 15 mg/d maint) 30 mg/d (reduced to 15 mg/d maint)	CR, 32w Near‐CR, 52w Near‐CR, 8w	Weakness Oral lesions, Strep throat, COVID‐19, Bone pains, abdominal cramps Acne	ND ND ND	ND ND ND
3	Coican, A./USA/2024	2	60/F 41/F	GGA GGA	11 21	Hypothyroidism, Type 2 DM ND	ROM, TS, HCQ, Pt, Dapsone, NB‐UVB, TS, SS, MTX, HCQ, Naltrexone, Apremilast	Upa Upa	15 mg/d for 6 months 15 mg/d for 2 months	CR, 16w CR, 8w	No Headache	ND ND	ND ND
4	Slater, K. N./USA/2023	1	57/F	GGA	0.33	Type 2 DM, hypothyroidism, kidney disease	TS, NB‐UVB, ILC, ROM	Upa	15 mg/d for 1 month	Near‐CR, 4w	ND	ND	ND
5	Sondermann, W./Germany/2022	1	61/F	GGA	3	DM, obesity, coronary heart disease, RA	TS, MTX, SS, Etanercept	Upa	Upa 15 mg/d 4 months with low‐dose MTX 7.5 mg/week for a month and TS 6 weeks	CR, 16w	No	ND	ND
6	Michels, A. /Germany/2024	1	77/F	GGA	3	No	TS, PUVA, Oral retinoids	Abr	200 mg/qd for 1 week, 100 mg/qd for 3 months, then 100 mg/qod for 8 weeks	CR, 12w	Nausea, Herpes labialis	6	No
7	Liu, W./China/2024	1	29/F	GGA	1	No	Cs, HCQ, ILC	Abr	150 mg/qd for 6 weeks	Near‐CR, 6w	No	5	No
8	Kim, D. /Korea/2023	2	67/F 40/F	GGA GGA	6 10	Type 2 DM, hypertension No	MTX, Cs, NB‐UVB, TCI Immunosuppressants, TCI	Bar Bar	4 mg/qd for 6 weeks, then 2 mg/qd for 14 weeks. 4 mg/qd for 8 weeks	Near‐CR, 6w Near‐CR, 4w	No No	ND ND	ND ND
9	Yan, T. M. /China/2022	1	67/M	GGA	0.5	No	HCQ, TS, NB‐UVB	Bar	4 mg/qd for 20 weeks	Near‐CR, 20w	No	4	No
10	Jadoul, A. /Belgium/2023	1	66/F	GGA	10	Obesity, hypertension, multinodular goitre, haemochromatosis	TS, UVB, cryotherapy, MTX, Herpes zoster	Bar	4 mg/qd for 7 weeks, stopped due to herpes zoster. One month after the first zoster vaccination, resumed at 4 mg/qd for 2 weeks, then reduced to 2 mg/qd	PR, initiated Bar for 6 weeks, Near‐CR, resumed Bar for 2 weeks	Herpes zoster	ND	ND
11	Dev, A. /India/2024	15	53.9 ± 9.1 /F (n = 13) M (n = 2)	GGA	0.75 ± 0.7	Type 2 DM, hypertension, Mild anemia, depression or no	TC, ILC, TS, HCQ, TCI, doxycycline, acitretin, or no	Tof	5 mg/bid for 5.9 ± 2.4 months	Eleven achieved CR in 4.4 ± 2.1 months, four had PR with 7.3 ± 2.8 months	Hyperlipidemia (N = 2)	7.7 ± 3.7	N = 2 (one at 1 month and another at 3 months)
†	This manuscript	1	53/M	GPGA	2	No	TS, SS, HCQ, NB‐UVB	Upa	15 mg/d for 4 weeks, then 15 mg/qod for 4 weeks, then 15 mg every 2 days for an additional 4 weeks	CR, 8w	No	6	No

Notes: Ref. 1. De Greef, A. et al. Dermatology Ther. 14, 813–817 (2024). Ref. 2. Zheng, J. et al. J Eur Acad Dermatol. (2023). Ref. 3. Coican, A. et al. Case Rep Dermatol Med. 2024, 8859178 (2024). Ref. 4. Slater, K. N. et al. JAAD Case Rep. 34, 12–14 (2023). Ref. 5. Sondermann, W. et al. Dermatol Ther. 35, e15211 (2022). Ref. 6. Michels, A. et al. J DTSCH Dermatol Ges. 22, 841–843 (2024). Ref. 7. Liu, W. et al. J Dermatol Treat. 35, 2313090 (2024). Ref. 8. Kim, D. et al. Clin Exp Dermatol. 48, 375–376 (2023). Ref. 9. Yan, T. M. et al. J Eur Acad Dermatol. 36, e500‐e502 (2022). Ref. 10. Jadoul, A. et al. J Eur Acad Dermatol. (2023). Ref. 11. Dev, A. et al. Indian J Dermatol VE. 1–6 (2024). †The present case.

Abbreviations: Abr, abrocitinib; Bar, Baricitinib; COVID‐19: Corona Virus Disease‐19; CR, complete remission; DM, diabetes mellitus; F, female; GA, granuloma annulare; GGA, generalized granuloma annulare; GPGA, generalized papular granuloma annulare; HCQ, hydroxychloroquine; ILC, intralesional corticosteroids; JAKis, Janus kinase inhibitors; M, male; MTX, methotrexate; N, number; NB‐UVB, narrowband ultraviolet B; ND, No described; PR, partial remission; Pt, pentoxifylline; PUVA, psoralen ultraviolet A; RA, rheumatoid arthritis; Ref, references; ROM, rifampin, ofloxacin, minocyclin; SS, systemic corticosteroids; TCI, topical calcineurin inhibitors; Tof, tofacitinib; TS, topical corticosteroids; UPA, upadacitinib; Vit E, vitamin E; w, week; y, years.

Collectively, future research should aim to validate these findings and explore standardized protocols for JAKi use in GA, along with their long‐term effects and safety profiles for optimal clinical application.

Consent

Consent for the publication of recognizable patient photographs or other identifiable material was obtained by the authors and included at the time of article submission to the journal stating that all patients gave consent with the understanding that this information may be publicly available.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.