Granuloma annulare: modern concepts of pathogenesis and pathogenetically based therapy (literature review)

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INTRODUCTION

Granuloma annulare (GA) is a benign skin condition characterized by skin-colored or pinkish papules, often forming annular rings [1]. Morphologically, the papules represent granulomatous inflammation with collagen degradation, mucin deposition, and histiocytic infiltration [1].

The disease was first described in 1895 by Thomas Colcott Fox under the name ringed eruptions [2], and the term granuloma annulare became generally accepted after the publications of Henry Radcliffe Crocker and Sir Ernest Graham-Little in the first decade of the 20th century [3, 4].

The GA lesions are most frequently localized on the dorsal and lateral surfaces of the hands and feet, and in approximately 75% of cases, the process is confined to these areas [5]. Disseminated variants include generalized, papular, and atypical generalized GA [6], with clinical and morphological manifestations varying substantially. In addition to typical forms, GA may present as palmoplantar, subcutaneous, perforating, patch-type, or plaque-type variants [7]. Rare forms of GA affecting the eyes have also been reported [8, 9].

Morphologically, the disease may differ in the extent of collagen necrobiosis, the arrangement of histiocytes (palisading or interstitial pattern), the presence of elastophagocytosis, and the composition of the infiltrate, which may include giant cells and, in some cases, eosinophilic and neutrophilic granulocytes [10, 11].

GA is considered a relatively rare dermatosis, with an estimated prevalence of 0.04%, occurring slightly more frequently in women [1]. GA usually develops in patients in their fifties [12], although according to some reports, more than two-thirds of patients are younger than 30 years [5].

In recent years, an increasing incidence of GA has been noted, which may be related to the high prevalence of infectious diseases [13, 14], including infections caused by SARS-CoV-2 [15]. Vaccination may also act as a triggering factor. Among noninfectious triggers of GA, certain dietary supplements and medications have been reported [16–18], whereas predisposing factors include immune and inflammatory disorders such as diabetes mellitus, dyslipidemia, lupus erythematosus, Sjögren syndrome [12, 19], hypothyroidism [20], and others.

The increasing incidence of GA and its associations with other diseases have stimulated interest in its pathogenesis and therapeutic approaches [1, 21, 22]. In recent years, new data have emerged regarding the mechanisms of GA development, the roles of T-helper type 1 (Th1) and type 2 (Th2) cells and distinct macrophage subpopulations [21, 22]. These insights into GA pathogenesis have provided a rationale for expanding therapeutic strategies for this dermatosis [1]. Two reviews published in 2018 and 2022 analyzed the effectiveness of various treatments [1, 23]. The authors noted the lack of a standardized approach and the limited number of evidence-based publications; they also proposed a stepwise algorithm incorporating topical and systemic therapies depending on disease form and extent, and highlighted prospects for further therapeutic development.

The review aimed to systematize current concepts of the molecular and cellular mechanisms underlying GA, its infectious and noninfectious triggers, the role of endocrine, immune, and oncologic disorders as predisposing factors, and pathogenetically based therapeutic approaches.

PATHOGENESIS OF GRANULOMA ANNULARE: CURRENT CONCEPTS

The pathogenesis of GA remained unclear for a long time. Certain progress has been achieved in recent years owing to studies focused on the cellular and molecular mechanisms underlying GA development.

Comparative analysis of a wide range of biomarkers in skin biopsy specimens from GA lesions revealed differences in the expression of genes involved in the regulation of innate immunity, Th1 and Th2 lymphocytes, and Janus kinases (JAK) [21]. GA was characterized by activation of Th1/TNF-α (tumor necrosis factor-alpha; p < 0.01) and IFN-γ (interferon-gamma; p < 0.01) signaling pathways, Th2/IL-4 (interleukin 4; p < 0.001), and JAK3 (p < 0.001). Thus, the authors emphasized the involvement of both Th1 and Th2 lymphocytes in GA pathogenesis, whereas previous investigations had focused mainly on Th1-mediated mechanisms [1]. Increased messenger ribonucleic acid (RNA) expression of cytokines representing both T-cell axes (TNF-α, IL-1β, IFN-γ, IL-12/23p4, IL-4, and IL-31), along with Th17 and Th22 lymphocytes, and activation of the JAK-signal transducer and activator of transcription (JAK-STAT) was demonstrated. These findings, on the one hand, explain the high efficacy of adalimumab in patients with disseminated GA [24]; on the other hand, they provide a rationale for the use of dupilumab and tofacitinib in treatment-resistant forms of the disease.

GA represents an immune cell infiltration composed of macrophages and lymphocytes. However, the nature of interactions among T-lymphocytes, macrophages, and fibroblasts underlying these changes became clear only in 2021. Using single-cell RNA sequencing (scRNAseq) and cytokine/chemokine/receptor expression modeling, Wang et al. [22] demonstrated that JAK–STAT–dependent cytokines—IFN-γ, oncostatin M, IL-21, and IL-15—play a pivotal role in these processes. Th1 cells were identified as the source of IFN-γ and IL-21; they also secrete chemokine C-C motif ligand 3 (CCL3, or macrophage inflammatory protein 1α) and CCL4 (macrophage inflammatory protein 1β), which recruit monocytes into the skin. According to the authors, Th1 cells are a major source of CCL3 and CCL4, promoting monocyte migration to lesional sites, whereas IFN-γ induces their polarization into activated macrophages (M). GA is characterized by macrophage polarization toward both proinflammatory (M1) and anti-inflammatory (M2) phenotypes [25]. The apparent paradox may reflect a biphasic process in which collagen degradation mediated by M1 macrophages is followed by tissue remodeling and mucin deposition mediated by M2 macrophages. Furthermore, IFN-γ and oncostatin M are likely to induce fibroblast polarization toward a proinflammatory phenotype with secretion of matrix metalloproteinases, their inhibitors, noncanonical collagens, and periostin, all contributing to extracellular matrix remodeling. Finally, activated macrophages, particularly of the M1 phenotype, and fibroblasts produce IL-15 and chemokine C-X-C motif ligands 9, 10, and 11 (CXCL9, CXCL10, CXCL11), which sustain T-lymphocyte activation and promote chemotaxis of proinflammatory cells to the lesion site. The clear dependence of GA-associated inflammation on T-cells led Wang et al. [22] to hypothesize that GA has an autoimmune nature.

A specific antigen has not yet been identified; however, it may be expressed by fibroblasts. Recently, vimentin epitopes recognized by CD4⁺ lymphocytes in another granulomatous process—sarcoidosis, which also affects the skin—have been considered potential autoantigens [26]. In any case, recent investigations provide a foundation for a deeper understanding of GA pathogenesis and for the development of targeted therapeutic strategies.

RISK FACTORS FOR GRANULOMA ANNULARE

Despite advances in understanding the molecular mechanisms underlying GA, its etiology remains unknown. In most cases, the disease appears to be sporadic. However, its associations with endocrine, immune, and autoimmune disorders, malignant neoplasms, and the triggering role of infections and vaccination have been subjects of discussion and research for many years [5].

Granuloma Annulare, Diabetes Mellitus, and Dyslipidemia

The association between GA and diabetes mellitus has been studied for decades [27–30]. However, most cohort investigations were based on small patient samples, and their findings were often inconsistent [31]. In a recent retrospective cohort investigation including 5137 patients with GA and a control group of 51,169 volunteers without GA, diabetes mellitus at the time of lesion onset was present in 21.1% of patients with GA versus 13.3% in controls, with an odds ratio (OR) of 1.75 [12]. In addition, hyperlipidemia was slightly more frequent among patients with GA than in controls (32.5% vs 28.4%; OR = 1.21). The authors emphasized that both diabetes mellitus and dyslipidemia in most cases preceded the development of skin lesions rather than occurring during the follow-up period, suggesting that these conditions may represent predisposing factors for GA. The pathogenetic basis of this association involves activation of shared cytokine-mediated signaling pathways, particularly those involving IL-6, T-cell dysregulation, and macrophage activation [21, 32].

A relationship between GA, diabetes mellitus, and dyslipidemia was also confirmed in a case–control study including 177 patients with GA and 708 controls from the US National Institutes of Health database [20]. The analysis showed a 63% higher likelihood of hyperlipidemia among individuals with GA. The authors emphasized that the analysis of the electronic database did not allow assessing the clinical features of GA or other diseases; however, the identified association supports and extends the current understanding of the relationship between GA, diabetes mellitus, and dyslipidemia.

Granuloma Annulare, Autoimmune Diseases, and Malignant Neoplasms

The prevalence of GA in patients with autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, Crohn disease, and others may be higher than in the general population. Evidence supporting this association includes published case reports [19, 33–37] and cohort studies [12]. However, data on the frequency and clinical characteristics of GA in this patient population remain limited and do not permit definitive conclusions.

The association between GA and malignant neoplasms also remains uncertain. Although several case reports and small case series have described GA occurring in association with hematologic malignancies or solid organ tumors [38–43], cohort studies have failed to confirm this relationship [12, 44, 45], casting doubt on its existence. Nevertheless, one of the most recent large multicenter studies did not exclude a possible link between GA and hematologic malignancies [46]. Therefore, this issue remains open, and further large-scale investigations are needed to clarify potential associations.

Granuloma Annulare and Medications

A wide range of pharmacologic agents have been implicated as potential triggers of GA, including hydroxychloroquine, allopurinol, amlodipine, interferon preparations, intranasal calcitonin, levetiracetam, paroxetine, thalidomide, immune checkpoint inhibitors, and many others [5, 47]. The exact mechanisms underlying these associations remain unclear.

In recent years, cases of GA have been reported in patients receiving genetically engineered biologic agents or phosphodiesterase-4 inhibitors for the treatment of other conditions. Specifically, a few cases of GA have been reported in association with treatment using TNF-α (infliximab, adalimumab, and etanercept) [48, 49], IL-17 inhibitors (ixekizumab and secukinumab) [50, 51], and the IL-4 inhibitor (dupilumab) [52]. One case of particular interest involved a patient with psoriasis who developed GA during apremilast therapy, with further lesion dissemination following initiation of secukinumab [18]. The authors suggested that the link between GA and agents targeting IL-17–mediated signaling pathways may result from enhanced Th1-cell activity secondary to Th17 blockade [53]. The activation of Th1 lymphocytes is associated with the development of GA in predisposed individuals.

Infections as a Trigger of Granuloma Annulare

Infections have traditionally been considered a risk factor for GA. Indeed, the dermatosis may develop in patients following tuberculosis, leprosy, fungal diseases, bacterial and viral infections, or vaccination [5, 54]. Among viral triggers, Epstein–Barr virus [13], human immunodeficiency virus [55], and varicella-zoster virus [56] have been reported. Vaccines against hepatitis B, measles-mumps-rubella, tetanus, pneumococcus, and others [5, 57], and immunotherapy [58], have also been implicated.

In recent years, attention has focused on the association between GA and COVID-19 or SARS-CoV-2 vaccination. During the pandemic, cases of GA occurring after COVID-19 or SARS-CoV-2 vaccination were reported [15, 59–62]; the authors noted that GA following vaccination was generalized in 76.92% of cases, developing within 8 weeks after vaccine administration [59]. Reports of GA after SARS-CoV-2 vaccination have continued to appear over the past two years [63–65]. It is suggested that the SARS-CoV-2–induced cytokine cascade may trigger GA, including generalized subcutaneous forms, either as a manifestation of reactive inflammation or through immune complex deposition in damaged vessels [61].

Granuloma Annulare and Genetic Predisposition

It is believed that the development of GA in response to the aforementioned triggering factors occurs in individuals with a genetic predisposition, the nature of which has not yet been established. In 1987, Friedman et al. [27] described 11 families in which at least two first-degree relatives were diagnosed with GA. Familial cases of dermatosis have also been reported by other authors [66].

An association between GA and certain histocompatibility antigens, including HLA-B35 and HLA-AH8.1, has been postulated [27, 67]. HLA-B35 may also be linked to autoimmune thyroiditis, which has been reported among diseases associated with GA [68]. HLA-AH8.1, in turn, is a marker of increased TNF-α secretion. The presence of this antigen was demonstrated in twin sisters who responded well to adalimumab therapy for generalized GA.

THERAPEUTIC APPROACHES TO GRANULOMA ANNULARE

Treatment of GA, particularly its deep and disseminated forms, remains challenging. Topical corticosteroids are traditionally considered as first-line therapy [69] and may be effective in limited disease forms. Overall, improvement is observed in 41% of patients, with complete resolution in 24% [70]. Calcineurin inhibitors, primarily tacrolimus, can be used in combination with topical corticosteroids [69, 71]. In cases unresponsive to topical therapy or in disseminated disease, narrowband UVB phototherapy (311 nm), PUVA therapy with oral photosensitizers, and excimer UV light therapy (308 nm) are employed [69, 72, 73]. Publications describe the use of antibacterial agents, particularly dapsone, and antimalarial drugs. In a retrospective analysis of dapsone efficacy (100 mg daily for a median of 9.8 months) in 26 patients with generalized GA, lesion regression was observed in 54% [74]. Although similar therapeutic efficacy has been reported by other investigators [75], dapsone use is limited by potential adverse effects. Myelosuppression, observed in 31% of patients, frequently necessitated treatment discontinuation [74]. Additionally, the therapeutic effect may be transient, with recurrence occurring in 57% of patients after treatment cessation. Regarding hydroxychloroquine, a 2020 analysis showed promising results, with improvement or resolution of lesions in 79.6% of cases [76]; however, subsequent clinical and retrospective publications have not confirmed such high efficacy [1].

Thus, the development of effective therapeutic approaches for GA, particularly disseminated and treatment-resistant forms, remains an important task. Based on recent advances in understanding the pathogenesis of the disease, targeted therapies have been proposed, including JAK inhibitors (tofacitinib, baricitinib, upadacitinib), apremilast, dupilumab, and TNF-α inhibitors (adalimumab, etanercept, infliximab). It should be noted that GA is not an approved indication for these agents; therefore, their inclusion in therapeutic algorithms requires justification. Targeted therapies are most frequently used in patients with widespread or treatment-resistant GA.

JAK inhibitors in the treatment of Granuloma Annulare

JAK inhibitors may be particularly promising for patients with granulomatous diseases [77, 78]. Tofacitinib has been the most commonly used agent for generalized, severe, and treatment-resistant GA (Table 1 [22, 77–81]). High clinical efficacy was accompanied by resolution of characteristic histopathologic changes, reduction of inflammatory infiltrate, and decreased expression of genes regulated by JAK-STAT–dependent cytokines (IFN-γ, TNF-α, IL-6) and JAK-STAT–independent cytokines (TNF-α, mTORC1) and oncostatin M [22, 78].

 

Table 1. Effectiveness of pharmacological agents in patients with GA according to various authors

Author, year	GA, form	Patients, n	Previous therapy	Intervention	Outcomes
JAK inhibitors in the treatment of GA
Damsky et al., 2020	Generalized		Hydroxychloroquine, phototherapy, systemic GC, doxycycline, cyclosporine, isotretinoin	Tofacitinib, 5 mg twice daily	Clinical: complete resolution of lesions. Histology: resolution of granulomatous inflammation. RNA sequencing: decreased expression of genes regulated by JAK-STAT–dependent cytokines (IFN-γ, TNF-α, IL-6) and JAK-STAT–independent cytokines (TNF-α, mTORC1).
Damsky et al., 2019	Localized		None	Tofacitinib, 2% ointment twice daily	Almost complete resolution of treated lesions at week 15 (one untreated lesion showed no improvement).
Durgin et al., 2020	Generalized		Hydroxychloroquine, dapsone	Tofacitinib, 2% ointment twice daily	Complete resolution of lesions on the extremities, almost complete resolution of lesions on the trunk (from 10% to 1% of affected BSA) at week 12 of therapy. No recurrence during the 2-month follow-up period.
Wang et al., 2021	Generalized		Systemic GC, pentoxifylline	Tofacitinib, 5 mg twice daily	Clinical: complete resolution in 3 patients by month 6; significant improvement (70% BSA reduction) in 2 patients. Histology: resolution of granulomatous inflammation, significant decrease in CD3+ lymphocytes and CD68+ macrophages. RNA sequencing: suppression of IFN-γ, oncostatin M, IL-15, IL-21 expression
McPhie et al., 2021	Generalized		Intralesional GC, topical calcineurin inhibitors, methotrexate, phototherapy, ustekinumab	Tofacitinib, 5 mg twice daily	Patient 1: improvement at 4 weeks, almost complete resolution of lesions by month 9 of therapy. Patient 2: improvement at 4 weeks; treatment stopped for other reasons.
Bosch-Amate et al., 2022	Generalized		Oral GC, hydroxychloroquine, retinoids, pentoxifylline, dapsone, phototherapy, methotrexate, adalimumab	Tofacitinib, 5 mg twice daily (1 patient); tofacitinib, 2% ointment twice daily (2 patients)	Complete resolution at 4, 6, and 8 months of therapy.
De Greef et al., 2024	Disseminated		Topical GC, hydroxychloroquine, doxycycline, methotrexate, vitamin E	Upadacitinib, 30 mg/day	Significant improvement at 2 months of therapy, complete resolution of lesions by month 6 of therapy.
Slater et al., 2023	Disseminated		Topical GC, intralesional GC, narrowband UVB phototherapy, rifampicin, ofloxacin, minocycline, ruxolitinib 2%	Upadacitinib, 15 mg/day	Almost complete resolution of lesions by month 4 of therapy; therapy planned to continue up to 1 year at the time of publication.
Sondermann et al., 2022	Plaque	1 (patient with RA)	Topical GC. RA therapy: methotrexate 15 mg/week, oral prednisolone 2 mg/day, then etanercept	Upadacitinib, 15 mg/day Methotrexate, 7.5 mg/week	Significant improvement at 6 weeks of therapy; complete resolution of lesions by month 4 of therapy.
Zheng et al., 2023	Generalized		Topical GC, tacrolimus, narrowband UVB phototherapy, dapsone	Upadacitinib, 30 mg/day initial, then 15 mg/day	Significant improvement of skin condition. Adverse events in 1 patient included acneiform eruptions.
Coican et al., 2024	Generalized		Topical GC, oral GC, methotrexate, hydroxychloroquine, apremilast	Upadacitinib, 15 mg/day	Complete resolution of lesions by month 2 in the first patient and by month 4 in the second patient. No recurrence during the 6-month follow-up period.
Yan et al., 2022	Generalized		Hydroxychloroquine, topical GC, narrowband UVB phototherapy	Baricitinib, 4 mg/day	Improvement after 2 months of therapy; almost complete resolution of lesions by month 5 of therapy. No recurrence during the 4 months after discontinuation of baricitinib.
Jadoul et al., 2023	Generalized		No response to standard therapy (drug names not specified)	Baricitinib, 4 mg/day	Improvement at week 12, clinical status remained improved during the 12-week follow-up period.
Kim et al., 2023	Generalized		Topical GC, oral GC, methotrexate	Baricitinib, 4 mg/day	Significant improvement within 2 weeks. No recurrence during the 6-month follow-up period.
Piontkowski et al., 2024	Generalized		Topical GC, intralesional GC, tacrolimus, hydroxychloroquine	Ruxolitinib, 1.5% cream twice daily	Complete skin clearance by week 12 of therapy.
Dupilumab in the treatment of GA
Song at al., 2023	Generalized	1 (patient with DM)	Topical GC, antihistamines, glycyrrhizin, narrowband UVB phototherapy, intramuscular GC	Dupilumab, 600 mg initial, then 300 mg every 2 weeks	Pre-treatment: pruritus, multiple histiocytes in infiltrate. Reduction of pruritus intensity at week 4 of therapy. Significant improvement by week 2, with further positive response over 16 weeks of follow-up.
Song at al., 2020	Generalized		Topical GC, rifampicin, ofloxacin, minocycline, hydroxychloroquine, methotrexate, adalimumab	Dupilumab, 600 mg initial, then 300 mg every 2 weeks	Complete resolution of most lesions by week 4 of therapy. Some lesions on extremities did not fully resolve, but showed marked improvement. No recurrence during 12 weeks of follow-up.
Paganini et al., 2023	Generalized		Infliximab, doxycycline, methotrexate	Dupilumab, 600 mg initial, then 300 mg every 2 weeks	Significant improvement at week 4 of therapy, complete resolution with minor residual hyperpigmentation by week 24 of therapy.
Apremilast in the treatment of GA
Blum et al., 2019	Generalized		Topical GC, intralesional GC	Apremilast, 10 mg/day	Significant improvement of erythema and lesion induration over 3 months of follow-up.
Bishnoi et al., 2019	Generalized	4 (2 patients post-BC treatment, 1 with bipolar personality disorder)	Topical GC, hydroxychloroquine, isotretinoin, dapsone	Apremilast, initial dose 30 mg twice daily, then reduced to 30 mg/day	Significant improvement by weeks 6–8 of therapy. Adverse events in 1 patient included nausea and myalgia (managed with medications).
Joshi et al., 2023	Generalized		Not specified	Apremilast, 30 mg twice daily	In 3 patients, complete resolution; in 1 patient, 90% resolution over 6 months of therapy, with sustained remission over 2 years. 1 patient had lesion resolution but recurrence on dose reduction. 3 patients had no significant effect: initial improvement followed by new lesions. 1 patient showed no change. Adverse events in 1 patient included diarrhea, leading to treatment discontinuation.
Hansel et al., 2021	Generalized	2 (first patient: psoriasis + post-BC treatment, second patient: post-BC treatment)	Topical GC, systemic GC	Apremilast, initial dose 10 mg/day, increased to 30 mg twice daily	Complete resolution of truncal lesions, improvement of lesions on extremities. In patient with psoriasis, PASI75 achieved by week 8 of therapy.
Joshi et al., 2021	Generalized	1 (patient with psoriasis and arthritis)	Not specified	Apremilast, 30 mg twice daily	Complete resolution of truncal and extremity lesions by month 6 of therapy, lesions on the feet improved. Minor new lesions observed over 7 months of follow-up.
TNF-α inhibitors in the treatment of GA
Chen et al., 2019	Generalized	27 (22 studies)	Topical GC, systemic GC, PUVA, narrowband UVB phototherapy, methotrexate, mycophenolate mofetil, hydroxychloroquine, minocycline, dapsone, clofazimine	Adalimumab, etanercept, infliximab, combination of adalimumab and infliximab	Significant improvement of skin condition in the majority of patients: 14/16 receiving adalimumab, 1/5 receiving etanercept, 3 receiving infliximab. Residual pigmentation in fewer than 11 patients, 1 patient had erythema. Adverse events: fatigue in 1 patient on adalimumab.
Antoñanzas et al., 2020	Generalized	1 (patient with chronic autoimmune gastritis)	Cyclosporine	Etanercept, 50 mg twice weekly	Complete resolution of lesions by month 2 of therapy.
Kozic et al., 2011	Generalized		Prednisolone, doxycycline, methotrexate	Adalimumab, 40 mg initial, then 40 mg every 2 weeks in combination with methotrexate 15 mg/week	Complete resolution of lesions by week 6 of therapy. Adalimumab continued for 1 more month, methotrexate discontinued. No recurrence by month 2 of follow-up period.
Horoub et al., 2024	Generalized		Hydroxychloroquine, methotrexate, intralesional GC, narrowband UVB phototherapy	Adalimumab, 40 mg every 2 weeks, intradermal Kenalog injections. Methotrexate 20 mg/week added due to new lesions	Significant improvement by month 2 of therapy. New lesions at month 10. After inclusion of methotrexate in combination therapy, lesions resolved with residual pigmentation.
Bürgler et al., 2019	Disseminated		Topical GC, hydroxychloroquine, doxycycline, PUVA	Infliximab, 5 mg/kg, repeated at weeks 2, 6, 14, and 24	Clinical: significant improvement by week 2, complete resolution by week 24 of therapy. No recurrence during 23 months of follow-up period. Histology: decreased inflammatory infiltrate, reduction in myeloid (CD11c) dendritic cells, decreased macrophages (M1: CD68, CD32; M2: CD163), reduced CD1a+ dendritic cells and CD8+ lymphocytes. Noticeable decrease in CD183+ cells expressing CXCR3.
IL-23 inhibitors in the treatment of GA
Awad et al., 2022	Generalized		Not specified	Tildrakizumab, 100 mg subcutaneously	Significant improvement. No adverse events were reported.

Note: BC, breast cancer; BSA, body surface area; DM, diabetes mellitus; GA, granuloma annulare; GC, glucocorticoids; RA, rheumatoid arthritis; UV, ultraviolet.

 

Upadacitinib [82–85], baricitinib [86–88], and ruxolitinib [89] have been used in a smaller number of patients with GA, but initial results also indicate high clinical efficacy. Notably, in one case, upadacitinib was administered to a patient with rheumatoid arthritis concurrently receiving methotrexate for her primary disease [90]. Upadacitinib has also shown effectiveness in cutaneous sarcoidosis [78]. These findings, on the one hand, confirm the importance of JAK-mediated signaling pathways in the pathogenesis of granulomatous disorders and, on the other, underscore the therapeutic potential of JAK inhibitors in these conditions.

Dupilumab in the Treatment of Granuloma Annulare

Dupilumab is a monoclonal antibody that specifically binds to the α-subunit of the IL-4 receptor (IL-4Rα), a shared component of the IL-4 and IL-13 heterodimeric receptors, thereby blocking the effects of these cytokines [91]. Two main observations prompted its use in GA. First, IL-4 and IL-13 secretion may induce macrophage polarization toward the M2 phenotype [92]; second, a recent retrospective study analyzing 47 children with GA [93] and a case–control study [94] suggested a potential association between GA and atopy.

To date, three publications describe dupilumab use in three patients with generalized GA resistant to other therapies [95–97]. The first of these reports was published in 2020 [95]. In one reported case, generalized GA developed in a patient with long-standing type 2 diabetes mellitus [96]. Additionally, a case has been described in which dupilumab, prescribed for severe atopic dermatitis, acted as a trigger for widespread GA [52]. Therefore, conclusions regarding the role of dupilumab in GA management remain preliminary, and further data on its efficacy in this patient population are required.

Apremilast in the Treatment of Granuloma Annulare

Apremilast, a phosphodiesterase-4 inhibitor, is approved for the treatment of psoriasis, psoriatic arthritis, and Behcet disease [26]. The drug suppresses the production of proinflammatory cytokines by Th1 lymphocytes and macrophages [98], which served as the rationale for its use in patients with generalized GA.

To date, publications have reported the use of apremilast in 16 patients (Table 1 [99–102]), including those with concomitant psoriasis and psoriatic arthritis [100, 101], patients previously treated for breast cancer [101, 102], and one patient with bipolar disorder receiving lithium therapy [102]. The reported outcomes are highly heterogeneous: some patients achieved a marked therapeutic response and long-term remission; others experienced lesion recurrence, whereas the third category of patients showed no improvement. Such variability in treatment outcomes may be explained by Th2 activation, which is believed to be a component in GA pathogenesis [21, 94], and by an emerging imbalance of competing cytokine pathways in certain patients [1].

TNF-α Inhibitors in the Treatment of Granuloma Annulare

In 2019, Chen et al. [103] analyzed the efficacy of TNF-α inhibitors in patients with disseminated GA. The authors demonstrated the effectiveness of this drug class in disseminated and treatment-resistant forms of the disease (Table 1). More recent publications have reported successful use of adalimumab [18, 104], etanercept [105], and infliximab [106] in patients with GA. The long-term clinical effects of infliximab may be explained by significant suppression of immune inflammation, including a decrease in cutaneous myeloid dendritic cells, macrophage subpopulations, and CXCR3⁺ T-cells.

However, cases of GA developing in patients receiving adalimumab for psoriasis [17] or rheumatoid arthritis [107] have also been described.

IL-23 Inhibitors in the Treatment of Granuloma Annulare

Among genetically engineered agents, tildrakizumab, an IL-23 inhibitor, has been used for disseminated GA [21, 22]. A favorable clinical response was reported in one patient [108] and lack of improvement in another [109]. According to the authors, the limited efficacy of IL-23 inhibitors in GA and the ability of IL-17 inhibitors to induce GA [50, 51] are not unexpected. The mechanisms of cutaneous injury in GA are primarily mediated by Th1 cytokines, IFN-γ, and TNF-α; therefore, selective inhibition of the IL-23/Th17 signaling pathway may not result in adequate suppression of inflammation.

PRACTICAL TREATMENT ALGORITHMS FOR GRANULOMA ANNULARE

Based on the available data, several practical algorithms for the management of GA have been proposed. According to one such algorithms, at the first step, a combination of narrowband UVB phototherapy or antimalarial agents with topical glucocorticoids or intralesional corticosteroid injections is used; at the second step, doxycycline or pentoxifylline is added, and if these are ineffective, the use of TNF-α inhibitors may be considered [110]. This stepwise algorithm has been shown to achieve improvement in more than 80% of patients.

CONCLUSION

Our analysis of published reports reveals that much about the etiopathogenesis of GA and its treatment approaches remains unknown, despite certain progress in this field. In recent years, it has become clear that GA pathogenesis is complex and involves activation not only of Th1 cells and their signaling pathways but also of Th2 lymphocytes. These lymphocytes, through the secretion of chemokines CCL3 and CCL4, and IFN-γ initiate a series of events that result in monocyte accumulation in the dermis and their polarization into activated macrophages (M) of both M1 and M2 phenotypes. The consequences of these events include inflammation, collagen degradation, and mucin deposition. However, the precise nature of the intercellular interactions between T lymphocytes, macrophages, and fibroblasts underlying these changes has not been fully elucidated. The identity of the antigen that initiates the process also remains unclear. Some authors suggest that it may be an autoantigen, such as certain vimentin epitopes, in which case the disease could be considered autoimmune.

Data regarding predisposing factors and triggers of GA remain contradictory. The initiating role of diabetes mellitus and hypertriglyceridemia, infectious agents, particularly COVID-19 or SARS-CoV-2 vaccination, and genetically engineered biologic agents, primarily TNF-α, IL-17, IL-4, and IL-23 inhibitors, has not been excluded; however, the true contribution of these triggers and predisposing factors is still being investigated.

Issues related to treatment selection for patients with widespread GA resistant to conventional therapy, including topical glucocorticoids, narrowband UVB phototherapy, or antimalarial agents, also remain unresolved. The analysis of publications evaluating the effects of targeted therapies in such patients suggests that JAK inhibitors (tofacitinib) and TNF-α inhibitors (adalimumab) may represent alternative options. Nevertheless, reports on the efficacy of these drug classes are limited, and their broader clinical use is restricted by the absence of GA among approved indications and by potential adverse effects.

ADDITIONAL INFORMATION

Authors' contributions. I.O. Smirnova ― development of the publication concept, reviewing, approving the final version of the article before submitting it for publication; C.A. Pahalage ― systematization of information, collection and analysis of literary sources, writing the first version of the article, editing the article; P.D. Ptashnikova ― collection and analysis of literary sources, writing the first version of the article, editing the article. Thereby, all authors provided approval of the version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Funding sources. No funding.

Disclosure of interests. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Statement of originality. The authors did not use previously published information (text, illustrations, data) in conducting the research and creating this paper.

Generative AI. Generative AI technologies were not used of this article creation.

Provenance and peer-review. This paper was submitted to the journal on an unsolicited basis and reviewed according to the usual procedure. Two external reviewers and the scientific editor of the publication participated in the review.

About the authors

Chanilka A. Pahalage

Saint-Petersburg State University; Leningrad Regional Center for Specialized Types of Medical Care

Author for correspondence.
Email: chanilka92@hotmail.com
ORCID iD: 0000-0002-1713-4123
SPIN-code: 2828-8975
Russian Federation, Saint Petersburg; Saint Petersburg

Irina O. Smirnova

Saint-Petersburg State University; City Dermatological and Venereological Dispensary

Email: driosmirnova@yandex.ru
ORCID iD: 0000-0001-8584-615X
SPIN-code: 5518-6453

MD, Dr. Sci. (Medicine), Professor

Russian Federation, Saint Petersburg; Saint Petersburg

Polina D. Ptashnikova

Saint-Petersburg State University

Email: enternita7@yandex.ru
ORCID iD: 0000-0003-4699-1746
SPIN-code: 8715-3940
Russian Federation, Saint Petersburg

References

Supplementary files