Introduction

Epidemiology

Since the 1960s, most studies have estimated the annual incidence of granuloma annulare (GA) to range from 0.1% to 0.4%, with a female-to-male ratio of approximately 2:1 [1,2,3,4,5]. GA may occur at any age, although it is reported most commonly in the first 3 to 5 decades of life [5, 6]. Subcutaneous GA is predominantly observed in children, whereas generalized GA is more common among elderly patients [6,7,8,9]. Most recent study conducted on 11,608 patients with incident GA and 17,862 patients with prevalent GA, found the incidence of GA to be 0,04% and prevalence to be 0,06%, with a female-to-male ratio of 3:1 [10].

Pathogenenesis

It is hypothesized that GA involves an immunologically mediated reaction leading to inflammation around the blood vessels [11, 12•].

Recently, two studies have aimed to explain the pathogenesis of GA. Both studies describe the role of lymphocytes T and cytokines produced by them. One study reported the upregulation of Th1 and Th2 pathways in GA lesions. Cytokines associated with the Th1 pathway include TNF-α, IL-1β, IFN-γ, and IL-12/23p4, while IL-4 and IL-31 are linked to the Th2 pathway.

Another research group similarly identified activation of the Th1 pathway, however without concurrent upregulation of the Th2 pathway. They emphasized the significance of four cytokines: IFN-γ, IL-21, OSM, and IL-15 in GA lesions. Both research groups pay attention to the fact that cytokines involved in GA pathogenesis, signal through the JAK-STAT pathway [12•, 13•].

Etiology/Co-occurrence/Triggers

Although GA is often considered idiopathic, many associations and co-morbidities have been observed (Table 1). The most frequently described connections appear to be between GA and both types of diabetes mellitus or between GA and thyroid diseases [14].

Table 1 GA co-occurrences and triggers most described in case reports and other studies
Full size table

Clinical Presentation

Granuloma annulare primarily presents as annular groups of skin-colored to erythematous papules and plaques, which are mostly asymptomatic; however, some individuals report pruritus and pain. In most cases, the course of GA is self-limiting; nevertheless, some subtypes of GA are less likely to subside. Due to the skin symptoms polymorphism, several variants of the disease have been identified, including localized, disseminated, or generalized, subcutaneous and perforating (Fig. 1). In addition, depending on the author, there are a few less prevalent GA subtypes which were published as case reports or small case series (Table 2).

Fig. 1
figure 1

Localized granuloma annulare may present as singular (a) or plural (b) erythematous ring-like plaques

Full size image
Table 2 Subtypes of GA
Full size table

Pathohistology and Diagnosis

Although GA can be diagnosed through physical examination of the lesions and the overall clinical presentation, due to the wide range of possible differential diagnosis, a skin biopsy remains the definitive diagnostic method and should be performed in all cases where diagnosis is uncertain. The presence of mucin deposition, palisading histiocytes and lymphocytes and necrobiotic collagen in histologic examination confirms the diagnosis of GA and appears to be consistent across all subtypes of the disease [39].

Additional Diagnostic Tests

Sonography has been reported to play a contributory role, especially in diagnosis of subcutaneous GA type, aiding in differentiation from other conditions like rheumatoid nodules and soft tissue malignancies [40,41,42]. Dermoscopy may assist in distinguishing between granulomatous skin conditions and in locating lesions [43]. While it remains controversial, GA can be associated with an underlying hematological or solid organ malignancy. Patients presenting with generalized or atypical GA may require a thorough examination including lymph node palpation, evaluation for B symptoms as well as complete blood count and chest radiograph. In cases of high clinical suspicion, computed tomography of chest, pelvis and abdomen may be considered. Furthermore, patients should complete their age-appropriate cancer screening [4, 15]. Although a definitive correlation between GA and laboratory blood tests has not been established, clinicians should consider screening for the most widely documented chronic comorbidities associated with GA: diabetes mellitus, hyperlipidemia, and thyroid diseases due to its cost-effectiveness, particularly in individuals presenting with additional risk factors [4].

Differential Diagnosis

Commonly, GA must be differentiated from other non-infectious granulomatous skin conditions, including necrobiosis lipoidica, rheumatic nodules, foreign body granulomas, cutaneous sarcoidosis, and interstitial granulomatous dermatitis [43]. Increased mucin deposits in the centers of granuloma are an important histological finding which helps in differentiating GA from other granulomatous skin conditions [4, 44]. In these cases, a skin biopsy is essential for the diagnosis of GA. The differential diagnosis of perforating GA includes reactive perforating collagenosis/dermatosis, perforating folliculitis, elastosis perforans serpiginosa, perforating calcific elastosis, psoriasis and interstitial variant of mycosis fungoides [45, 46]. Cases of subcutaneous GA mimicking dermatomyositis, rheumatoid nodules and sarcoidosis have been reported [4, 47, 48]. Infectious granulomatous skin conditions such as Hansen’s disease and tuberculosis should also be considered during patient assessment [49].

Treatment

Owing to the fact that GA encompasses a spectrum of disease of varying severity, it becomes essential to determine whether a diagnosis should consistently prompt treatment. Nevertheless, concern regarding the undetermined time to remission or psychological discomfort associated with the formation of lesions frequently causes a desire to proceed with therapy.

Topical Treatment

Steroids

Although high potency corticosteroids and intralesional corticosteroids appear to be the first step therapeutic approach, particularly in individuals with localized GA, there is no agreement on the optimal dosage and duration of treatment. While these therapies are generally well tolerated, patients should be informed about the risks of atrophy, telangiectasia, hypopigmentation, and striae. The efficacy of topical corticosteroids is mostly limited to clinical experience with few case studies concerning usage of halobetasole, clobetasol propionate, mometasone furoate. Halobetasole 0,05% has demonstrated significant improvement in the auricular form of GA, whereas clobetasol propionate 0.05% and mometasone furoate 0.1% applied in children, led to disease remission on hands and feet after failure of tacrolimus 0.1% treatment [57, 58]. High potency corticosteroids may be especially beneficial in thick-skinned areas such as the dorsal surfaces of hands and feet which are less permeable to topical corticosteroids, and therefore less vulnerable to side effects. According to clinicians intralesional corticosteroids injections have a higher likelihood of a satisfactory response; however, no study comparing topical and intralesional corticosteroids has been conducted. Injections of intralesional corticosteroid with 2.5 to 5.0 mg per mL triamcinolone have shown effectiveness in localized GA, but all of the studies come from the second half of the twentieth century [59, 60]. There is also evidence suggesting that scarification might be an individual treatment option. This raises a question: whether intralesional glucocorticosteroids are effective due to glucocorticosteroids’ potency alone, or as an additive effect of glucocorticosteroids and skin damage [61].

Calcineurin Inhibitors

Topical tacrolimus and pimecrolimus are frequently regarded as a safe option due to low number of side-effects. Furthermore, unlike corticosteroids, which are considered the first-line therapy for GA, they do not cause skin atrophy. The reported therapies comprise topical application of 1% pimecrolimus or 0,1% tacrolimus ointments twice a day to the lesion site [62]. The duration of the therapy ranges from 1 to 3–4 months, with the recommendation for individualization. A report involving 4 GA patients treated with 0,1% tacrolimus ointment for 8 weeks showed limited benefits, with only two patients responding to the treatment [63]. Another study on 3 children presenting with localized GA found topical tacrolimus treatment to be ineffective [58]. Conversely, a case report of 4 female patients presenting with disseminated GA showed complete clearance of lesions in two of them and a marked improvement in the other two within 6 weeks of therapy [64]. Tacrolimus also proved effective in treating a GA lesion in a sensitive periorbital area, resulting in a complete remission without adverse effects [65]. Additionally, topical tacrolimus treatment showed promise in cases of PGA, particularly on damaged and ulcerated skin [66]. In one report, a combination therapy of systemic isotretinoin and topical pimecrolimus 1% cream was administered to treat generalized GA in a patient with MDS with full remission obtained after 4 months of therapy [67].

Topical Vitamin E

While further research regarding the role of topical vitamin E is needed its efficacy may stem from its antioxidative potential and the ability to neutralize free oxygen radicals [68]. Unfortunately, the authors did not specify the type or dosage of the applied material, using only the term "topical vitamin E". Topical application of vitamin E has shown promising results in localized GA, leading to complete healing of lesions within 1–3 weeks without recurrence in one-year follow-up [69]. Furthermore, there is a study comparing oral and topical vitamin E, with more satisfactory results in favor of topical administration [68]. Topical vitamin E may be associated with various side effects such as contact urticaria, eczematous dermatitis, and erythema multiform-like reactions [70].

Imiquimod

Imiquimod is a drug with a unique mechanism of action. It stimulates the innate immune system by promoting the synthesis and release of several proinflammatory cytokines - most importantly TNF-α, IFN and IL-6 [71]. The proposed treatment regimen in GA generally requires the patient to apply 5% imiquimod cream daily to lesions overnight for 10-12 h and to wash it afterwards [72, 73]. No side-effects of the treatment, apart from mild postinflammatory hyperpigmentation, have been reported. However, one case in which inadvertent application of imiquimod cream to GA lesion resulted in significant inflammation and expansion of the annular plaques [74]. There is no agreement on the duration of the treatment, with durations ranging from 4 to 12 weeks [72, 73, 75, 76].

Topical Dapsone

Although use of oral dapsone in treatment of GA is common, topical usage has not been thoroughly examined. A single case report describes a patient with periocular GA treated with topical dapsone 5% gel, applied twice daily to the lesion. After 3 weeks of treatment, significant clinical improvement has been observed [77].

Phototherapy

In a retrospective study involving 33 patients, phototherapy with additional psoralen (PUVA) resulted in 50% clearance rate after 22 sessions, 16% showed good improvement after 29 courses, and a moderate benefit was observed after 33 courses. Follow-up data were obtained for 19 patients, however only 6 of them (32%) reported being clear 12 months after therapy, with only 3 maintaining clearance of lesions at 2 years [78]. In another retrospective analysis, 13 patients were treated with narrowband UVB phototherapy (NB-UVB), with 54% of them responding to the treatment, including 23% with complete response and 31% with partial response. The mechanism by which UVB phototherapy benefits patients with GA remains unclear, as UVB is known to penetrate the skin up to the epidermis and papillary dermis, while GA granulomas are located deeper in the dermis. However, authors suggest that despite PUVA being more effective method for GA treatment, NB-UVB should be considered as legitimate first line therapy for generalized GA, due to wider therapeutic index and less side effects [79]. Photodynamic therapy (PDT) has been lately proposed as an alternative treatment modality, offering a safer therapeutic option, without risk of PUVA-induced non-melanoma cancers. In fact, PDT is widely used in aforementioned malignancies. In a prospective study of 7 patients, photodynamic therapy was performed on the most cosmetically bothersome GA lesions, up to a total of 3 sessions, depending on the lesions’ responses. The complete remission was acquired in 2 patients, some improvement was obtained in 2 patients, and 3 patients did not benefit from PDT [80].

Lasers

Numerous studies support the effectiveness of lasers, including Pulsed Dye Laser (PDL), excimer laser and Fractional Photothermolysis (FP)in the treatment of GA, especially localized type [81]. Among the benefits of laser treatment are: avoidance of the negative effects of steroids, low systemic toxicity, and low levels of associated morbidity [81].

Pulsed Dye Laser

Multiple authors discuss cases of individuals who had long-lasting GA lesions resistant to conventional forms of therapy, which only improved significantly after PDL [82, 83]. Lesional changes after treatment included decrease in erythema and flattening [81]. While limited response to PDL treatment with high recurrence rates was observed in generalized GA, localized forms showed significant improvement in over half of the treated lesions. The most frequently used wavelengths were 585 and 595 nm, allowing for a maximum penetration depth of 1.5 mm, limiting application to superficial structures [84]. The laser fluences ranged from 6.75 J/cm2 to 15.0 J/cm2 for 1 to 3 treatments performed at 4–6 weeks intervals [81, 85]. In the majority of cases, transient hypo- and hyperpigmentation were observed. Other side effects include erythema, purpura, edema, blistering, crusting, pigmentary changes, and, rarely scarring [81].

Excimer Laser

Only a few cases present the use of excimer laser in GA lesions, however the results are encouraging. The first study describes a case of a patient with refractory, long-lasting GA affecting trunk and extremities. Following 15 treatment sessions with excimer laser, complete resolution was observed with no residual scarring [86]. Another study reports 2 cases of generalized GA; both patients' lesions completely vanished after a few months of consistent excimer laser treatments [87]. Fluence values ranged from 0.3 J/cm2 to 1.0 J/cm2 for 6 to 15 treatment sessions with 5 doses per session [81, 86]. While some patients tolerate the procedure well and report no side effects, mild erythema and transient hyperpigmentation may occur [81].

Fractional Photothermolysis

Another type of laser treatment that may serve as an alternative in GA lesions is FP using a 1,440-nm Nd:YAG laser. A single study reports a case of disseminated GA in which FP was the first line of treatment due to patient’s preferences. Following 2 to 3 treatment sessions, test areas showed significant clinical improvement expressed by reduction of both height and the diameter of lesions, while the control regions remained unchanged or even progressed [88]. Another case report describes a patient with a 5-year history of disseminated GA, who opted for FP using 1,550 nm Er:YAG laser as the preferred treatment. Successfully, 11 laser sessions with 1-month intervals resulted in clearance of 80–90% lesions [89]. Parameters varied from 6,0 J/cm2 to 70,0 J/cm2 for 2 to 11 treatments [81].

Procedural Methods

Due to the benign nature of localized GA, procedural methods have been marginalized in favor of less invasive approaches. In a prospective study from 1994, cryosurgery with nitrous oxide and liquid nitrogen was successful in 25 of 31 patients with a localized form of GA. Cryotherapy with ethyl chloride has also been described as successful, although the evidence regarding the treatment is scarce [90]. Cases of treatment with hyperthermia and electrodessication have been reported; however, they remain isolated and/or obsolete reports [91]. Procedural methods can lead to permanent scarring and are typically avoided due to importance of the cosmetic effect in GA treatment.

Oral Treatment

Isotretinoin

Oral isotretinoin is best recognized for treating severe acne, although it has been demonstrated in multiple case studies to be successful in treating granuloma annulare [67, 92]. A systematic review enrolled 12 case reports or series with 16 patients who received 0.5–1 mg/kg/day oral isotretinoin, concluded that it effectively cleared lesions by at least 90% in all patients, regardless of GA variant type [93].

Oral Vitamin E

Patients generally demonstrate favorable tolerance to oral vitamin E treatment, frequently choosing it for its perceived natural origin [94]. In a case of refractory generalized GA resistant to multiple therapies, a patient voluntarily discontinued hydroxychloroquine and minocycline and initiated oral vitamin E therapy at a dose of 180 mg once daily along with topical tea tree oil, resulting in promising improvements within 3 weeks [94]. Furthermore, oral administration of vitamin E demonstrates a positive risk-to-benefit ratio compared to several treatment modalities associated with various adverse effects [95]. The therapeutic effects of vitamin E on GA are likely attributed to its anti-inflammatory properties [94]. Recent studies have reported various treatment approaches, including oral vitamin E alone [95] or combination of oral vitamin E with pentoxifylline [96], zileuton[97] and even topical tea tree oil [94]. Treatment durations ranged from 3 to 12 month, with a daily vitamin E intake of 400 to 600 IU. One 7-year-old was given 200 IU per day for 6 months [95]. The majority of patients mentioned in case reports showed no improvement with prior conventional treatment, although they demonstrated objective healing or improvement in their lesions after administration of oral vitamin E. No cases of patients experiencing progression while using vitamin E have been recorded [94,95,96,97].

Fumaric Acid Esters

The immunomodulatory characteristics of Fumaric Acid Esters (FAE) render them a feasible choice for managing GA, similar to their incorporation into conventional therapeutic regimens for psoriasis [98]. Despite the distinct pathogenic mechanisms underlying psoriasis and GA, both conditions exhibit the common feature of inflammatory dermatoses [98]. Recently few studies have investigated the efficacy of oral FAE in GA cases, mostly regarding the disseminated type of this disease [98,99,100,101,102]. The majority of case studies discussed persistent GA previously managed with conventional techniques [98, 100, 101]. FAE in form of tablets were administered to all patients, starting with 120 mg and subsequently increased to 480–720 mg per day[99, 101], with a maximum dose of 1.2 g per day recommended [103]. While the typical length of therapy is 2–3 months, some patients may benefit from maintenance care for 2–3 years [101, 103].

Elevation and color of skin lesions significantly improved clinically as a result of systemic FAE therapy along with remission or partial remission in the majority of cases [98]. Another trial showed better results of photochemotherapy combined with oral FAE in comparison to photochemotherapy alone. Furthermore, such a combination enables the use of a lower mean dose of UVA radiation [104]. However, study groups reported FAE discontinuation due to adverse effects, thus individual dosage adjustment may be required [98, 99, 104]. Adverse reactions may include diarrhea, dizziness, nausea, flush and stomach pain [98].

Antimalarials

The presumed mechanism of action involves immune and inflammatory response suppression in GA [105]. Case studies of antimalarial treatment for GA demonstrated improvement in 25 out of 35 patients treated with hydroxychloroquine, and all 12 patients treated with chloroquine, experienced improvement, with an overall efficacy rate of 79.6%. Mean time of therapy ranged from 2.0 to 22.1 months and dosage ranged between 200 and 400 mg, once or twice daily [106]. Since the publication of aforementioned review, a few case reports and one retrospective analysis have described 2 patients, 1 of which was a pediatric patient, who had complete remission; 2 who had partial resolution, and 1 with persistent GA lesions treated with hydroxychloroquine [107,108,109]. Nevertheless, more recent studies report less satisfactory response to antimalarial therapy. Retrospective review showed improvement in only 5 of 12 patients after the course of hydroxychloroquine [110]. Another retrospective analysis of 26 patients treated with hydroxychloroquine describes improvement of GA lesions in only 35% [111]. Side effects of antimalarial drugs may include gastrointestinal symptoms, hyperpigmentation, non-specific cutaneous drug reactions, neurological changes, corneal deposits, retinopathy and aplastic anemia [112].

Dapsone

Dapsone suppresses non-specific inflammatory effects and has been reported as a successful treatment of GA [113]. Earlier small prospective studies report efficacy of 100 mg oral dapsone per day with improvement of lesions after 4–12 months of treatment [114,115,116,117]. More recent retrospective case series involving 26 GA patients treated with dapsone at a median dose of 100 mg per day for mean duration of 9,8 months observed regression of lesions in 14 of 26 (54%) patients. However, 8 of them (57%) experienced flares after completing treatment. Moreover, in 31% patients subclinical myelosuppression was noticed, which warranted discontinuation of treatment [118]. Similarly, another study showed improvement of GA lesions in 3 of 5 patients treated with dapsone [110].

Doxycycline

The abundance of T-helper cells in GA makes its pathogenesis similar to other systemic non-infectious granulomatous diseases such as sarcoidosis. Doxycycline, a successful therapeutic option for sarcoidosis, has been reported in treatment of GA, as evidenced by a case study, wherein an individual achieved almost complete remission after a 10-week course of doxycycline (100 mg per day) [119]. In another retrospective study improvement was observed in 2 of 7 patients treated with doxycycline [110]. In one case of generalized GA associated with interstitial lung disease, lesions resolved almost completely after 2 months of treatment with 100 mg of doxycycline twice per day [120].

Antituberculous Agents

In addition to tubercular granuloma, antituberculous agents have been investigated for management of GA. Several case reports describe 13 patients treated with monthly dosage of rifampicin 600 mg, ofloxacin 400 mg, and minocycline 100 mg (ROM) in combination therapy for 3 to 8 months. Patients showed complete remission of lesions after pulsed ROM. Although some patients experienced postinflammatory hyperpigmentation, most of them reported no side effects [121,122,123]. However, a prospective study indicated less sufficient response to 6 months ROM therapy and suggested that monthly triple antibiotic therapy may improve but not clear GA [124]. A single case study reports complete clinical resolution after rifampicin, pyrazinamide and isoniazid combination therapy in patient with necrobiotic GA of the penis [125]. In retrospective study 2 of 5 patients treated with a daily dosage of rifampicin 600 mg, minocycline 100 mg, and ofloxacin 400 mg experienced improvement, but only one total remission [126].

Amoxicillin/Clavulanic Acid

A single case report describes significant improvement of GA after treatment with amoxicillin/clavulanic acid 875/125 mg twice per day. After a month, to maintain control of GA, a regimen of amoxicillin/clavulanic acid 875/125 mg twice daily for one week every month was initiated and proved successful [127].

Allopurinol

Allopurinol, a xanthine oxidase inhibitor, has been demonstrated to be an effective drug in various granulomatous diseases such as sarcoidosis. Oral allopurinol has been evaluated in a singular case series of 3 patients with a long-lasting therapy refractory DGA. The patients received a daily dose of 300 mg allopurinol, resulting in diseases remission for 2 of them [128].

Methotrexate

Two retrospective case series evaluating the efficacy of management of GGA with methotrexate (MTX) have been conducted. In a case series of 15 patients, who received a median weekly dose of 10 mg MTX for a mean duration of 11 months, 60% of patients responded with complete clearance or partial improvement [129]. In another study 7 out of 11 patients (64%) experienced either complete or partial resolution of lesions [130]. Additionally, a singular case of successful treatment of DGA with MTX has been reported [131].

Cyclosporin A

In a case series of 4 patients with DGA receiving cyclosporine A (CyA) therapy for a total of 6 weeks starting with a dose of 4 mg/kg/day, all patients achieved resolution within 3 weeks of therapy. The medication was well tolerated, and no relapses were recorded in the following 12 months [132]. Another small case series of 2 patients with an unspecified form of GA responded favorably to treatment with 3 mg/kg/day CyA, with complete resolution of the lesions and no recurrence of the disease within following 12 months [133].

Apremilast

Apremilast, a phosphodiesterase-4 inhibitor, has been successfully utilized in treatment of severe plaque psoriasis and psoriatic arthritis [134]. Most recently, a few case reports have been published with encouraging effects not only in patients suffering from both psoriasis and GA, but also in individuals exclusively affected by GA. In these case studies, patients experienced total or partial improvement with a 60 mg apremilast regimen, and the positive response was sustained after at least a 4-month follow-up period. The majority of patients reported mild side effects like short-term diarrhea and myalgia [135,136,137].

Others

There are several oral therapeutic options with limited evidence of single case studies, including calcitriol, pentoxifylline, and chlorambucil [53, 96, 138, 139]. Patients who received calcitriol and pentoxifylline observed little improvement, mostly in conjunction with other treatments [53, 96, 138]. Conversely, chlorambucil 2 mg/day resulted in complete remission of GA with a prolonged resolution of skin lesions at a 9 month follow-up [139]. A recent case series suggest sulphasalazine as a treatment option in GA and related granulomatous diseases, with 14 of 16 patients reporting at least significant improvement. However, it is noteworthy that discontinuation or tapering of sulfasalazine in 12 patients led to disease recurrence or exacerbation in 5 patients [140].

Biological treatment

JAK-1/2- Inhibitors

Given the function of Janus kinase (JAK) as a signal transducer and activator of transcription pathway in the development of GA, JAK inhibitors appear to be a promising treatment [13•]. However, according to the recent Oral Rheumatoid Arthritis Trial (ORAL) Surveillance study, JAK inhibitors have been associated with higher risk of experiencing major adverse.

cardiovascular events (MACEs) and developing cancer compared with patients on TNF-α inhibitors [141]. As a result, the US Food and Drug Administration issued black box warnings for all approved JAK inhibitor drugs [142].

Tofacitinib

Patients with severe, refractory GA were the focus of recently described studies [13•, 143]. Over a period of 4 to 8 months, all patients received 5 mg of tofacitinib twice daily [13•, 143]. In the clinical trial, each patient exhibited rapid response to tofacitinib, with visible alleviation of the lesions within 1 to 3 months. Additionally, after 6 months of treatment, 3 of the 5 patients presented complete resolution of GA, whereas the remaining 2 patients experienced clinical improvement with disappearance of many lesions, but not all of them. Although tofacitinib was favorably tolerated, one patient developed uncomplicated urinary tract infections while receiving treatment [13•]. Following a course of tofacitinib, other studies similarly indicate complete or nearly complete remission [13•, 143]. Two studies also investigated the application of 2% ointment-based topical tofacitinib [144, 145]. After using tofacitinib 2% ointment twice daily, significant improvement was noted, with lesions nearly disappearing after 15 weeks [144]. In another study, a patient with generalized GA was instructed to apply tofacitinib to limited lesions on the right arm and after 12 weeks these have almost entirely cleared. Furthermore, lesions on the left arm and in other body areas improved as well [145].

Upadacitinib

A single case study describes a patient with rheumatoid arthritis (RA) and disseminated patch-type GA. Skin condition deteriorated during etanercept therapy for RA, and as a result upadacitinib 15 mg was administered alongside low-dose MTX for approximately a month at a dosage of 7.5 mg per week. After 6 weeks of upadacitinib treatment, which was well tolerated by the patient, skin lesions improved, with complete clearance noted by the patient after 4 months [146]. Another case report describes a patient with treatment-resistant generalized GA. Within 4 weeks of initiating upadacitinib at 15 mg per day, clinical examination revealed almost complete remission of lesions [147].

Baricitinib

Few case reports describe 4 patients with GA treated with oral baricitinib 4 mg per day, however 2 of them were tapered to 2 mg after complete remission. In all cases lesions started rapidly improving after 4–8 weeks of treatment [108, 148, 149].

Dupilumab

Dupilumab, a human monoclonal antibody that suppresses both interleukin-4 (IL-4) and interleukin-13 (IL-13), seems to be a potential treatment for GA since numerous cytokines play a role in its development [150•]. Recent two studies, demonstrated the efficacy of dupilumab in patients who had previously failed other treatments, including adalimumab [150•, 151]. At week 0, patients received a loading dose of 600 mg dupilumab subcutaneously, followed by 300 mg every other week. In both cases, the initial favorable results, in the form of lesions flattening or partial clearance, were observed 2–4 weeks after the treatment was administered for the first time [150•, 151]. One patient demonstrated nearly complete resolution of her widespread GA at the 12-week follow up [151]. Although generally well-tolerated, possible side effects of dupilumab include: injection site responses, conjunctivitis, blepharitis, oral herpes, keratitis, eye pruritus, and dry eye [150•, 151]. A case of generalized GA following dupilumab therapy has also been reported, with enduring symptoms despite cessation of dupilumab [28].

Tildrakizumab

The efficacy of tildrakizumab, a selective IL-23 inhibitor, is tentative. The off-label use of the monoclonal antibody has been reported in two isolated case reports [152]. In one of them, subcutaneous 100 mg tildrakizumab proved to be effective in treatment of GGA, resulting in a significant reduction of lesions in a patient. Conversely, a report of a patient presenting with GGA showed no improvement at the 28-week follow-up [153].

TNF-α Inhibitors

TNF-α inhibitors, including adalimumab, etanercept, golimumab, and infliximab, represent a therapeutic option for all types of granuloma annulare (GA), with adalimumab having the strongest evidence of efficacy [154]. In a case series,7 adults with disseminated or generalized GA were treated with 80 mg of adalimumab, administered subcutaneously for 3 months or until total remission. All endpoints were successfully addressed, involving GA Investigator Global Assessment Score, body surface area, erythema, and induration. All patients achieved at least two points improvement in GA Investigator Global Assessment Score and average improvement of 87%, 88%, and 95%, in following body surface area, erythema, and induration [155]. Similarly, case reports have also demonstrated the therapeutic effect of infliximab 5 mg/kg for GA skin lesions with a variety of administration schedules ranging from 6 to 24 weeks [156, 157]. A single case report proved that GA can be successfully treated with golimumab [3]. There is inconsistency in the data about the use of etanercept for GA skin lesions; a case from 2006 with 4 patients showed either no change or deterioration, whilst a case from 2020 reported a patient with complete resolution [160, 161].

Conclusions

The majority of the medical literature on the therapy of GA is restricted to individual case reports or short series of patients without a control group, which restricts their ability to demonstrate therapeutic efficacy, particularly in GA with a self-limiting course (Table 3).

High-potency corticosteroids, whether topical or intralesional, should be tried as the first-line therapy. Although intralesional corticosteroids have a better possibility of producing a favorable response, no study comparing topical and intralesional corticosteroids has been conducted. Calcineurin inhibitors should be used alternatively in patients with localized GA, especially in areas of sensitive skin, as they do not increase the risk of skin atrophy.

Table 3 Summary of reported therapies for GA and their level of evidence
Full size table

If first-line therapy fails, then phototherapy may be considered as it is the most well-studied form of GA treatment; however, it remains more effective in localized GA. Laser therapy including Pulsed Dye Laser, Excimer Laser and Fractional Photothermolysis can be a useful therapeutic option for GA. Among the benefits of laser treatment are avoidance of the negative effects of steroids and low systemic toxicity.

In case of failure of both topical corticosteroid treatment and phototherapy, systemic treatment should be proposed. Among the most researched oral treatment options; isotretinoin, dapsone, hydroxychloroquine seem to be the most appropriate, regarding the efficacy to adverse effects ratio. Despite promising results of the use of immunosuppressants such as MTX and CyA, the necessity of patient monitoring due to numerous side effects of these medications may hinder their use, narrowing down the number of eligible patients.

If long-lasting GA remains recalcitrant to conventional treatment, application of biological therapies should be considered. The use of JAK inhibitors seems to be a logical course of treatment, given the significance of Janus kinase in the pathophysiology of GA. Tofacitinib, upadacitinib, or baricitnib administration significantly improves lesions while displaying nearly no side effects. Another group of biological substances contains monoclonal antibodies suppressing interleukins, such as dupilumab and tildrakizumab. Even in cases when GA was resistant to prior treatments, the use of dupilumab produced a valid response. Among TNF-α inhibitors, adalimumab has the most shown efficacy in GA, while infliximab, golimumab, and etanercept may also provide some promising effects, but further research is needed.

We are still lacking the ideal management for GA that consistently demonstrates long-term efficacy without the risk of relapse after treatment, while also ensuring satisfactory cosmetic outcomes, and minimal need for treatment monitoring. Therefore, the therapy should be tailored to individual patients, with comprehensive education provided regarding all available treatment modalities and associated side effects.