Cutaneous sarcoidosis: Management

INTRODUCTION — Sarcoidosis is a multisystem granulomatous disease characterized by the presence of noncaseating granulomas in organ tissue (picture 1). Skin involvement is common and may present with a wide variety of clinical manifestations (picture 2A-E).

Treatment of cutaneous sarcoidosis is not always necessary. Common reasons for proceeding with treatment include disfiguring, symptomatic, ulcerating, or worsening skin disease. Scientific support for most treatments is limited; accepted therapeutic options include various local and systemic therapies.

The treatment of the cutaneous manifestations of sarcoidosis will be reviewed here. The clinical manifestations and diagnosis of cutaneous sarcoidosis and the suggested evaluation for extracutaneous sarcoidosis in patients with cutaneous involvement are discussed separately.

●(See "Cutaneous manifestations of sarcoidosis", section on 'Specific lesions'.)

●(See "Cutaneous manifestations of sarcoidosis", section on 'Diagnosis'.)

●(See "Cutaneous manifestations of sarcoidosis", section on 'Evaluation for systemic disease'.)

The management of extracutaneous sarcoidosis is also reviewed separately.

●(See "Treatment of pulmonary sarcoidosis: Initial approach".)

●(See "Treatment of pulmonary sarcoidosis refractory to initial therapy".)

●(See "Gastrointestinal, hepatic, pancreatic, and peritoneal sarcoidosis".)

●(See "Management and prognosis of cardiac sarcoidosis".)

●(See "Neurologic sarcoidosis".)

●(See "Sarcoid arthropathy".)

●(See "Kidney disease in sarcoidosis".)

●(See "Sarcoidosis of bone".)

●(See "Sarcoid myopathy".)

DECISION TO TREAT — Although cutaneous sarcoidosis is not life threatening and leads to physical impairment in only a minority of patients, the disease can be disfiguring, and the psychologic and social impact can be devastating. Primary indications for treatment include cosmetically disfiguring, symptomatic, ulcerating, or progressively worsening skin disease. The lupus pernio variant of sarcoidosis has a particularly destructive and disfiguring nature; therefore, treatment of this variant is almost always indicated. For patients with stable, asymptomatic disease that is not cosmetically concerning for the patient, deferring treatment is reasonable. (See "Cutaneous manifestations of sarcoidosis", section on 'Lupus pernio'.)

The decision to treat is complicated by the unpredictable course of cutaneous sarcoidosis, which includes the possibility for eventual spontaneous remission in up to two-thirds of patients [1,2], as well as a paucity of high-quality studies evaluating treatments. Few randomized trials have evaluated therapies, and evidence on most treatments is primarily limited to small uncontrolled prospective studies, retrospective analyses, and case reports [3-5]. In addition, the response to treatment varies, and some therapies have the potential for serious adverse effects. Thus, when cutaneous involvement is the only indication for treatment, the risks and benefits must be considered carefully.

For patients requiring systemic treatment for concomitant extracutaneous sarcoidosis (often systemic glucocorticoid therapy), a separate approach to treatment for skin manifestations is not always necessary. Often, these patients experience simultaneous improvement in cutaneous disease. Patients with insufficient responses may benefit from the addition of a skin-directed approach to treatment. (See 'Initial therapy' below.)

INITIAL THERAPY — Selection of an initial therapy begins with assessment of the extent and severity of disease to determine the most appropriate treatment pathway. The approach can be divided into interventions for localized, extensive, and rapidly progressing or progressively disfiguring disease.

Localized disease — The definition of localized disease is not strict but may be considered as limited skin involvement (eg, partial involvement of one or two body areas or a few small lesions in multiple body areas) and skin involvement for which topical or intralesional treatment would not be impractical. Typically, skin involvement is less than 5 percent of the total body surface area.

General approach — Intralesional or topical corticosteroid therapy is our preferred first-line treatment for localized cutaneous sarcoidosis. Although high-quality evidence to support efficacy is lacking, extensive clinical experience supports a potential for partial or complete clinical improvement.

The efficacy of topical and intralesional corticosteroid therapy has not been compared. In our experience, intralesional therapy tends to yield better responses (particularly for lupus pernio and other thick or nodular lesions for which penetration of a topical drug may be insufficient) and is our preferred option for treatment. However, other factors may influence selection between these therapies. For example, intralesional injection can be painful and difficult for some patients to tolerate.

Sarcoidosis in sites at greatest risk for corticosteroid-induced skin atrophy (eg, facial, intertriginous, or genital skin) requires a cautious approach to local corticosteroid therapy. (See 'Facial, intertriginous, or genital involvement' below and "Topical corticosteroids: Use and adverse effects", section on 'Adverse effects'.)

Intralesional corticosteroid injection — Intralesional corticosteroid injection offers the advantage of delivery of high corticosteroid concentrations into the dermis, where granulomas are present:

●Administration – We typically initiate treatment with injection of approximately 0.1 mL of a 5 mg/mL concentration of triamcinolone acetonide diluted in saline into each injection site. Injections into lesions larger than 1 cm in diameter are placed approximately 1 cm apart. (See "Intralesional corticosteroid injection".)

Treatment is repeated every three to four weeks until lesion resolution, provided noticeable clinical improvement continues. If noticeable improvement does not occur after a treatment with the 5 mg/mL concentration, we increase the concentration to 10 mg/mL at the following treatment session. If progressive improvement is not evident after three or four injection sessions, we typically discontinue this treatment. (See 'Failure of initial therapy' below.)

The pain associated with intralesional injection may be difficult for some patients to tolerate, particularly if the lesions are located in sensitive areas or multiple lesions are present. Potential adverse effects of intralesional corticosteroid therapy include cutaneous atrophy, hypopigmentation, and suppression of the hypothalamic-pituitary-adrenal axis. In order to reduce the risk of the latter, we try not to administer more than 20 mg of triamcinolone acetonide per treatment session [6]. (See "Intralesional corticosteroid injection", section on 'Adverse effects and pitfalls'.)

●Efficacy – Literature support for intralesional corticosteroid injection for cutaneous sarcoidosis is primarily limited to benefit documented in case series and case reports [7-9].

Topical corticosteroids — Superpotent (group 1) topical corticosteroids, such as clobetasol propionate, are typically used for cutaneous sarcoidosis (table 1) [10-13]. Advantages of topical corticosteroid therapy include relative safety, ease of use, and lack of pain associated with administration. A disadvantage of topical therapy may be lower ability to penetrate into the dermis compared with intralesional injections:

●Administration – We typically instruct patients to apply the corticosteroid to the affected areas either twice daily or once daily under an occlusive dressing. We re-examine patients approximately every two weeks to assess response and to evaluate for adverse effects. If there is no improvement after four weeks of treatment, we discontinue topical corticosteroids and initiate alternative therapy, typically intralesional corticosteroid injections or systemic therapy. In our experience, topical corticosteroid monotherapy often fails to achieve complete lesion resolution without simultaneously inducing cutaneous atrophy. (See 'Intralesional corticosteroid injection' above and 'Failure of initial therapy' below.)

In addition to cutaneous atrophy, hypopigmentation, purpura, and acne can develop with prolonged use of topical corticosteroids, or even with short-term use, when potent corticosteroids are used. Percutaneous absorption of topical corticosteroids is rarely high enough to suppress the hypothalamic-pituitary-adrenal axis, except when high-potency agents are applied over large areas of skin. The local and systemic adverse effects of topical corticosteroids are discussed in greater detail separately. (See "Topical corticosteroids: Use and adverse effects", section on 'Adverse effects'.)

●Efficacy – Studies evaluating topical corticosteroid therapy are limited. In an uncontrolled study that included patients with a variety of chronic skin diseases, once-weekly application of clobetasol propionate lotion under a hydrocolloid dressing led to improvement in sarcoidal papules in all three patients with cutaneous sarcoidosis within three to five weeks [14]. In a separate case report, application of halobetasol propionate 0.05% ointment twice daily for 10 weeks led to considerable flattening of lesions of lupus pernio [15].

Facial, intertriginous, or genital involvement — Our approach to localized cutaneous sarcoidosis on facial, intertriginous, or genital skin differs from disease in other sites because of increased risk for corticosteroid-induced skin atrophy in these areas. In general, we opt for medium-potency (group 4 (table 1)) rather than superpotent topical corticosteroids and often incorporate topical calcineurin inhibitors (tacrolimus or pimecrolimus) as corticosteroid-sparing drugs in the treatment regimen. Of note, early systemic therapy is preferred for patients with unstable disease resulting in worsening facial disfigurement or with extensive skin involvement. (See 'Topical corticosteroids' above and 'Rapid progression or worsening disfigurement' below and 'Extensive disease' below.)

In our practices, we typically use topical or intralesional corticosteroids as initial therapy and utilize topical calcineurin inhibitors as a method to reduce corticosteroid use in patients requiring long-term or frequent use to maintain remission. Tacrolimus 0.1% ointment or pimecrolimus 1% cream is usually applied twice daily, and signs of efficacy are expected within one to three months [16,17]. Topical calcineurin inhibitors are also used in conjunction with local corticosteroids (eg, application of a topical calcineurin inhibitor and topical corticosteroid on alternate weeks). Like topical corticosteroids, limited ability to penetrate into the dermis may inhibit efficacy for thick or nodular lesions.

Data on the efficacy of topical calcineurin inhibitors are limited. Successful treatment of cutaneous sarcoidosis with tacrolimus 0.03% or 0.1% ointment has been documented in case reports, including one patient who failed to respond to doxycycline or fumaric acid esters and a second who did not improve with topical or systemic corticosteroids [16,18-22]. Treatment with pimecrolimus 1% cream has been associated with improvement of papular sarcoidosis and lichenoid cutaneous sarcoidosis in case reports [17,23].

Topical tacrolimus and pimecrolimus are generally well tolerated and do not induce cutaneous atrophy. A transient burning sensation after application is a common side effect. Tacrolimus 0.03% ointment can be substituted for tacrolimus 0.1% ointment if the former is not tolerated. (See "Treatment of atopic dermatitis (eczema)", section on 'Topical calcineurin inhibitors'.)

Extensive disease — Systemic agents commonly used for extensive skin involvement (loosely defined as an extent of disease for which topical or intralesional therapy is not practical) or localized involvement that fails to adequately respond to local therapy include antimalarial drugs (hydroxychloroquine or chloroquine), methotrexate, and tetracyclines (minocycline or doxycycline).

Oral glucocorticoids are another treatment option. However, due to a broad side effect profile, we generally reserve oral glucocorticoids for rapid disease spread or worsening disfigurement. In contrast to the slower onset of effect of antimalarial drugs, methotrexate, and tetracyclines (typically weeks to months), responses to oral glucocorticoids can be rapid. Systemic glucocorticoids are used more routinely in the treatment of pulmonary sarcoidosis [24], but prolonged treatment with these drugs may be associated with lower quality of life [25]. (See 'Rapid progression or worsening disfigurement' below.)

Although antimalarial drugs, methotrexate, and tetracyclines are widely used, supporting data are limited and efficacies have not been directly compared. Because of a relatively greater amount of efficacy data on antimalarials and methotrexate, we tend to favor initial treatment with these drugs over tetracyclines, particularly for patients with more severe disease. Treatment selection is also based upon factors such as patient comorbidities, contraindications, adverse effects, and patient comfort with treatment and monitoring regimens.

Antimalarials — Benefit of hydroxychloroquine and chloroquine in cutaneous sarcoidosis is thought to be related to immunomodulatory effects. Antimalarials impede the presentation of antigenic peptides to CD4+ helper T cells and interfere with the release of cytokines and other mediators associated with granuloma formation [26]:

●Administration – Typical dosing for adults is 200 to 400 mg per day for hydroxychloroquine and 250 mg per day for chloroquine. Signs of improvement generally appear after four to six weeks, but treatment should be continued for at least three months to evaluate efficacy.

Once satisfactory improvement is achieved, the antimalarial drug can be tapered and discontinued, as tolerated. Tapering regimens are not standardized. In patients who improve on 400 mg of hydroxychloroquine, we often reduce the dose to 200 mg per day following satisfactory improvement. We reassess patients approximately once monthly and continue to taper by reducing the frequency of dosing if the response to treatment is maintained (eg, to 200 mg every other day).

Hydroxychloroquine is often preferred over chloroquine because of a lower risk for antimalarial-induced ocular toxicity, though responses to hydroxychloroquine may be less consistent [4]. To minimize this risk, it is suggested that doses of hydroxychloroquine and chloroquine should not exceed 5 mg/kg and 2.3 mg/kg of real body weight per day, respectively [27]. In addition, patients require baseline and subsequent ophthalmologic examinations. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Adverse effects' and "Antimalarial drugs in the treatment of rheumatic disease", section on 'Routine eye examinations'.)

Other adverse effects of hydroxychloroquine and chloroquine include gastrointestinal distress, ocular toxicity, and neurologic or hematologic abnormalities. Administration with food may help to minimize nausea. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Adverse effects' and "Antimalarial drugs in the treatment of rheumatic disease", section on 'Routine eye examinations'.)

●Efficacy – Efficacy data are limited to a few small uncontrolled studies, most of which indicate a favorable effect of antimalarials in the majority of treated patients [4,28]. A systematic review of study data prior to 2004 found that 84 of 103 patients (82 percent) treated with chloroquine or hydroxychloroquine for cutaneous sarcoidosis had a favorable response to therapy [4]. In one uncontrolled study in which 12 of 17 patients improved during hydroxychloroquine therapy, treatment responses were first observed after four weeks; most patients had maximum treatment responses at 12 weeks [29]. Discontinuation of treatment may result in disease relapse [30].

Methotrexate — The anti-inflammatory properties of methotrexate are believed to contribute to suppression of granuloma formation in sarcoidosis:

●Administration – Doses of methotrexate typically range from 10 to 25 mg given once weekly for adults. A therapeutic response usually is not evident for four to eight weeks and occasionally occurs as long as six months after initiation of treatment [31,32]. In our experience, treating with maximum dosing (25 mg per week) for at least three months is important prior to assuming inefficacy of methotrexate.

Upon achievement of satisfactory improvement, the dose of methotrexate can be tapered. The best regimen for tapering is unknown. We taper methotrexate in 2.5 mg increments weekly, biweekly, or monthly, with the speed of tapering guided by the clinical scenario. Slow tapers may be more appropriate for patients with more severe disease or a history of rapid relapses. Some patients maintain improvement with only 2.5 mg per week of methotrexate [33].

Adverse effects include gastrointestinal upset, stomatitis, leukopenia, hepatotoxicity, and pulmonary fibrosis. Folic acid (1 mg daily) or folinic acid (2.5 mg weekly) supplementation reduces the likelihood of some adverse effects [34]. In addition to numerous drug interactions that increase the risk of methotrexate toxicity, pre-existing liver disease and alcohol abuse are contraindications to methotrexate due to the risk for hepatotoxicity. Dosing of methotrexate must be adjusted in patients with renal disease. (See "Major side effects of low-dose methotrexate" and "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Folic acid supplementation'.)

Methotrexate is teratogenic and should not be given to pregnant women. Precautions for both men and women are also indicated prior to attempts to conceive. (See "Major side effects of low-dose methotrexate", section on 'Pregnancy risk'.)

●Efficacy – The efficacy of methotrexate for cutaneous sarcoidosis has been documented in small uncontrolled studies and case reports [31,35-38]. In an uncontrolled study of 16 patients with cutaneous sarcoidosis who were treated with methotrexate (25 mg per week) followed by a taper to 5 to 15 mg per week upon improvement, lesions completely resolved in 12 patients (75 percent), and the remaining 4 patients had partial improvement [33]. In a case series that included 50 patients with sarcoidosis treated with methotrexate at doses between 10 and 15 mg per week for at least two years, skin lesions improved in 16 of 17 patients with cutaneous sarcoidosis [35]. Relapse was common after the discontinuation of therapy. In a retrospective analysis of 26 patients treated only with 7.5 mg methotrexate weekly, 37 percent of 11 patients with cutaneous sarcoidosis reported improvement in skin lesions [39].

Tetracyclines — The mechanism of action of tetracyclines (eg, minocycline, doxycycline) in sarcoidosis is not fully understood but is thought to involve immunomodulatory inhibition of granuloma formation rather than an antimicrobial effect [40-42].

Although tetracyclines are given for cutaneous sarcoidosis, data to support efficacy are weak. The relatively favorable side effect profiles of these drugs contribute to their status as alternative systemic medications for cutaneous sarcoidosis:

●Administration – The typical dose of minocycline and doxycycline used in adults is 100 mg twice daily. In our experience, responses are typically seen within one to three months. Upon achievement of a satisfactory response, the dose can be tapered. The best method of tapering is unclear. Tapering to 100 mg per day and lower daily doses based upon maintenance of response is reasonable.

Potential adverse effects of tetracyclines include photosensitivity, pigment changes in teeth and skin (picture 3), and gastrointestinal distress. Minocycline is less likely to cause photosensitivity but has been associated with dizziness and a lupus-like syndrome. (See "Tetracyclines", section on 'Adverse reactions'.)

●Efficacy – The efficacy of minocycline is supported by an uncontrolled study in which 12 patients with cutaneous sarcoidosis (9 of whom had previously failed treatment with antimalarials) were treated with minocycline 100 mg twice daily for a median of 12 months [43]. Skin lesions completely resolved in eight patients (67 percent) and partially improved in two patients (17 percent). Most of the responders (seven patients) showed initial signs of improvement within one month, and the time to achieve maximal improvement ranged from one to six months. Patients remained in remission for an average of 15.3 months (range 1 to 33 months) after the discontinuation of therapy. The three patients who relapsed after the cessation of minocycline subsequently responded to doxycycline 100 mg twice daily.

A benefit of minocycline for cutaneous sarcoidosis is also suggested by a retrospective study that found that 20 of 27 patients with non-lupus pernio cutaneous sarcoidosis achieved complete remission (6 patients) or partial improvement (14 patients) after treatment with minocycline [44]. In addition, improvement in subcutaneous and tattoo sarcoidosis with doxycycline has been reported [45,46].

Rapid progression or worsening disfigurement — A more aggressive approach is indicated for patients experiencing rapid spread of skin involvement or worsening disfigurement due to cutaneous sarcoidosis (algorithm 1).

Systemic glucocorticoids — Systemic glucocorticoid therapy is not used for most patients with isolated cutaneous sarcoidosis because of the potential for serious side effects with long-term glucocorticoid therapy. However, because systemic glucocorticoid therapy may induce rapid improvement, it is the initial treatment of choice for rapidly progressive or progressively disfiguring sarcoidosis. It is important to lower the dose of glucocorticosteroids as rapidly as possible to minimize exposure, so treatment is often combined with a glucocorticoid-sparing agent:

●Administration – The optimal regimen for systemic glucocorticoid therapy is unknown, and various regimens have been described [12,47]. In our practice, we begin with 0.5 mg/kg per day of prednisone. Clinically significant improvement usually occurs within two weeks, and marked improvement is expected within three to four weeks. Tapering of prednisone by 5 mg per week can be attempted in patients who respond well to the initial 0.5 mg/kg per day dose. If disease activity recurs, we return to the lowest effective dose of prednisone and add a glucocorticoid-sparing agent (usually hydroxychloroquine or methotrexate) prior to additional attempts at tapering.

If clinically significant improvement is not evident after two weeks of 0.5 mg/kg per day of prednisone, we increase the dose to 1 mg/kg per day and initiate simultaneous treatment with a glucocorticoid-sparing agent (usually hydroxychloroquine or methotrexate). Improvement is expected within three to four weeks. Once satisfactory improvement is attained, we taper the dose of prednisone by 10 mg per week.

Calcium and vitamin D supplementation for prevention of osteoporosis are generally recommended for patients who receive long-term glucocorticoids; however, because patients with sarcoidosis may have associated hypercalcemia, caution is indicated in this population. (See "Hypercalcemia in granulomatous diseases" and "Calcium and vitamin D supplementation in osteoporosis", section on 'Granulomatous diseases'.)

The adverse effects of systemic glucocorticoid therapy are discussed separately. (See "Major adverse effects of systemic glucocorticoids".)

●Efficacy – Although systemic glucocorticoids are considered the standard of care for rapidly progressive or progressively disfiguring sarcoidosis, no randomized trials have evaluated efficacy for cutaneous sarcoidosis [48-53]. In a retrospective study of 116 treatment courses in 54 patients with lupus pernio, monotherapy with systemic glucocorticoids was associated with complete or near resolution of lupus pernio lesions in 20 percent of treatment courses and at least some improvement in 72 percent [50]. In addition, a 1997 systematic review of published reports found that skin lesions resolved in 12 of 16 patients with ulcerative sarcoidosis who were treated with prednisone as monotherapy [48], and a small retrospective study and case series have documented improvement in subcutaneous sarcoidosis during treatment with systemic glucocorticoids [49,51]. (See "Treatment of pulmonary sarcoidosis: Initial approach", section on 'Efficacy of glucocorticoids'.)

FAILURE OF INITIAL THERAPY — Patients who fail to respond to one of the suggested initial therapies may benefit from trials of other first-line therapies prior to proceeding to treatments for refractory disease. For example, patients with inadequate responses of localized disease to topical or intralesional corticosteroid therapy are candidates for systemic treatment with antimalarial drugs, methotrexate, or tetracyclines, and patients who respond poorly to one of these systemic drugs may achieve a better response to one of the other systemic agents [4]. (See 'Extensive disease' above.)

In addition, topical or intralesional corticosteroid therapy may be used as an adjunctive intervention in patients who achieve only partial responses to systemic therapy [40].

REFRACTORY DISEASE — Some patients, especially those with eruptive skin lesions, rapidly progressive cutaneous disease, or lupus pernio, may fail to respond to systemic glucocorticoids, antimalarials, methotrexate, and tetracyclines. Tumor necrosis factor (TNF)-alpha inhibitors (infliximab or adalimumab) and thalidomide are our preferred next-line therapies for these patients. However, efficacy data are limited, and further study is necessary to confirm the effects of these interventions. Infliximab is the most studied agent [5].

TNF-alpha plays an important role in the pathogenesis of sarcoidosis [54]. Agents that suppress TNF are thought to contribute to the inhibition of granuloma formation in sarcoidosis [54]. Paradoxically, multiple occurrences of TNF-alpha inhibitor-induced sarcoidosis have been reported, contributing to reservation of these drugs for refractory cases [55-64].

Efficacy of different TNF-alpha inhibitors for cutaneous sarcoidosis does not appear to be equivalent. Limited data suggest etanercept may be less effective than infliximab and adalimumab [65,66]. Additional study is necessary to clarify the effects of other TNF-alpha inhibitors, including golimumab and certolizumab [5,67].

Infliximab — Infliximab is an intravenously administered, chimeric, monoclonal antibody directed against TNF-alpha. Optimal dosing for cutaneous sarcoidosis has not been established. Often, 3 to 5 mg/kg is given at weeks 0, 2, and 6, and then every six weeks [50,68]. A panel of sarcoidosis experts suggested maintenance dosing every four weeks rather than every six weeks; however these recommendations were not specific for cutaneous sarcoidosis, and consideration of other maintenance doses was suggested based upon disease activity [69].

Data on infliximab therapy are limited [70]. A randomized trial of 138 patients with pulmonary sarcoidosis compared the efficacy of 5 mg/kg of infliximab, 3 mg/kg of infliximab, or placebo given at 0, 2, 6, 12, 18, and 24 weeks [68]. Analyses of the trial data revealed no significant differences in the response of lupus pernio (n = 19) or all forms of cutaneous sarcoidosis (n = 36) among the three groups [68,71]. However, in a subset analysis in which the response of patients with chronic facial sarcoidosis was assessed with an alternative scoring tool, infliximab therapy was superior to placebo for improving desquamation and induration but not erythema, area of involvement, or photographic assessment at 24 weeks [72]. Also, a systematic review of nonrandomized studies found an overall complete or partial response rate of 89 percent among 84 patients [70].

The onset of action of infliximab may be delayed. In one of the largest observational studies that included 46 patients with sarcoidosis and skin involvement (primarily lupus pernio, nodules, or plaques), the overall cutaneous response rate (including complete and partial responses) to anti-TNF therapy was 24 percent after 3 months, 46 percent after 6 months, and 79 percent after 12 months [55]. Patients received infliximab with or without concomitant systemic glucocorticoids or immunosuppressants.

Improvement in extracutaneous sarcoidosis has been reported during treatment with biosimilars for infliximab; however, efficacy of biosimilars for infliximab for cutaneous sarcoidosis is unclear [73-75].

Adverse effects of infliximab include infusion reactions and an increased risk for infections. The side effects of biologic TNF inhibitors are discussed in greater detail separately. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects" and "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections" and "Tumor necrosis factor-alpha inhibitors: Risk of malignancy".)

Adalimumab — Adalimumab is an anti-TNF human monoclonal antibody that may be effective for cutaneous sarcoidosis. Optimal dosing specifically for cutaneous disease has not been established. Our typical regimen consists of an initial 80 mg dose at week 0 followed by 40 mg given at week 1 and then once weekly.

Favorable results have been observed in a small randomized trial, case reports, and a case series [65,76-81]. Benefit has also been reported in extracutaneous sarcoidosis. (See "Treatment of pulmonary sarcoidosis refractory to initial therapy", section on 'Tumor necrosis factor-alpha antagonists'.)

In the randomized trial, 10 patients with cutaneous sarcoidosis were treated with either adalimumab (80 mg at week 0 followed by 40 mg once weekly) or a placebo agent for 12 weeks [80]. Continuation of other systemic medications was allowed provided the dose remained relatively stable. The trial found that 5 of 10 patients in the adalimumab group versus 1 of 5 patients in the placebo group achieved at least a two-grade improvement in the physician global assessment score, a difference that was not statistically significant. However, at the end of the additional 12-week, open-label phase, statistically significant improvement was found in the target lesion area among patients given adalimumab. This study has been criticized because of its small size, lack of statistical significance in its primary and secondary outcomes studied, miscalculation of statistical analysis of the primary outcome, and failure to include an intent-to-treat analysis [82].

Case reports have described use of other adalimumab regimens for cutaneous sarcoidosis, including the exclusion of an 80 mg loading dose, the administration of 40 mg every other week rather than once weekly, and the administration of 80 mg once weekly [65,76-81]. Larger, randomized trials are necessary to confirm the efficacy of adalimumab for cutaneous sarcoidosis [83].

Thalidomide — Thalidomide inhibits TNF-alpha and interferon (IFN)-gamma, the major cytokines that drive granuloma formation in sarcoidosis, as well as other factors [84-86]. Uncontrolled studies and case reports suggest that thalidomide may be effective for cutaneous sarcoidosis [86-91]. Although beneficial effects of 100 mg per day of thalidomide were not confirmed in a small, randomized trial that evaluated thalidomide in a dose of 100 mg per day [92], benefit has been reported in uncontrolled studies using thalidomide doses higher than 100 mg per day.

When treating refractory cutaneous sarcoidosis with thalidomide, we initiate therapy with a dose of 100 mg per day and gradually escalate the dose to 200 mg. However, sedation and neuropathy increase with higher doses. Because of safety concerns, we generally limit thalidomide therapy to three months. Further study is necessary to clarify the efficacy of thalidomide and its derivatives. (See "Management of discoid lupus erythematosus and subacute cutaneous lupus erythematosus refractory to antimalarial therapy", section on 'Thalidomide'.)

In the three-month, randomized, investigator-masked, multicenter trial, patients with chronic (≥12 months) and disfiguring or extensive cutaneous sarcoidosis were randomly assigned to receive thalidomide 100 mg once daily (20 patients) or oral placebo (19 patients) [92]. Three target skin lesions were assessed for area and infiltration monthly; patients were classified as responders if they exhibited at least 50 percent reductions in both the area and infiltration of all three target skin lesions as well as no new lesions and a lack of marked deterioration of nontarget lesions. After three months, there was no difference in the response rate between the two groups. In the thalidomide group, 4 of 20 patients (20 percent) were responders versus 4 of 19 patients (21 percent) in the placebo group. No patients achieved a complete response, and four patients in the thalidomide group discontinued treatment early because of adverse effects. Patients who discontinued treatment were analyzed as treatment failures. Limitations of this trial include the short duration, relatively low dose of thalidomide, and limited power.

Larger trials are necessary to confirm these findings and to determine whether better results may be obtained with different thalidomide regimens. Analysis of an open-label, follow-up phase that followed the randomized trial suggests a beneficial effect of thalidomide doses above 100 mg daily [92]. After an additional three months of open-label thalidomide therapy (up to 200 mg per day), 6 of the 14 patients who had been in the thalidomide arm of the study and were available for clinical evaluation achieved complete healing and four achieved lesser improvement, according to the investigator assessment. Among the 14 patients from the original placebo arm of the study available for evaluation after three months of thalidomide, two had complete responses and eight had lesser degrees of improvement.

Thalidomide is teratogenic. In the United States, patient and provider participation in the THALOMID Risk Evaluation and Mitigation Strategy (REMS) program (www.thalomidrems.com) is mandatory in order for this drug to be prescribed and dispensed. Other adverse effects associated with thalidomide include somnolence, peripheral neuropathy, thrombosis, constipation, endocrine dysfunction, and neutropenia. (See "Thalidomide: Drug information".)

Lenalidomide (a thalidomide analog with a safer adverse effect profile) was reported to markedly improve lupus pernio in a patient who had not responded to systemic corticosteroids and hydroxychloroquine and had not been able to tolerate methotrexate or thalidomide [93].

Biosimilar anti-TNF-alpha agents appear to be promising but have not been studied in sarcoidosis [24].

OTHER THERAPIES — Multiple other interventions, including systemic and intralesional agents, phototherapy, laser therapy, and surgical excision, have been used for patients with refractory cutaneous sarcoidosis; however, the limited data to support efficacy of these agents precludes recommendations for their routine use.

Janus kinase inhibitors — Limited data suggest that Janus kinase (JAK) inhibitors may be effective treatments for cutaneous and systemic organ sarcoidosis. These agents eradicate signal transducer and activator of transcription (STAT) 1 and 3, as well as normalize cytokines that are associated with the formation of granulomas in sarcoidosis.

Complete and partial responses of cutaneous sarcoidosis to oral JAK inhibitors have been documented in case reports, including several patients with prolonged disease that had responded poorly to other therapeutic agents [94-97]. Most patients have been treated with the JAK1, JAK2, and JAK3 inhibitor tofacitinib, but some patients have been treated with ruxolitinib, a JAK1 and JAK2 inhibitor.

A steroid-sparing effect was observed in a small, 16-week, open-label, prospective study [98]. After four weeks on tofacitinib, the dose of prednisone could be gradually reduced by at least 50 percent to less than 5 mg in three of five patients (one was lost to follow-up, and the other withdrew due to deteriorating, neurologic complications).

Compounded tofacitinib 2% ointment applied to lesions twice daily has appeared partially effective in case reports. In one patient, treatment of scalp sarcoidosis was associated with a partial response, with improvement in erythema, scaling, and induration [99]. In another report, improvement of erythema and induration was noted in angiolupoid sarcoidosis of the nose beginning at 10 weeks, with minimal activity present at 18 months [100]. Telangiectasias were treated with a pulsed dye laser (PDL).

Other — Examples of additional systemic agents for which uncontrolled studies, case series, or case reports have suggested benefit in patients with sarcoidosis include allopurinol [101-108], apremilast [109], chlorambucil [110], dimethyl fumarate [111], isotretinoin [112-114], leflunomide [115-117], melatonin [118,119], mycophenolate mofetil [120], and tranilast [121]. Intralesional therapies have included intralesional chloroquine [122] and intralesional fluorouracil [123]. A single-blind randomized trial suggested benefit of an oral antimycobacterial regimen with concomitant levofloxacin, ethambutol, azithromycin, and rifampin [124].

There are case reports that describe improvement in cutaneous sarcoidosis associated with ultraviolet A1 (UVA1; 340 to 400 nm) phototherapy [125,126]. In addition, successful treatment with topical psoralen plus ultraviolet A (PUVA) therapy has been documented in a case report and small case series [127,128].

Various lasers have been used for cutaneous sarcoidosis [129]. Improvements in lesions of lupus pernio, nodular sarcoidosis, and scar sarcoidosis have been reported in patients treated with PDLs [130-134]. Moreover, responses to treatment with a 532 nm frequency-doubled neodymium-doped:yttrium aluminium garnet (Nd:YAG) laser [135,136], Q-switched ruby laser [137], ablative carbon dioxide laser [138-140], and erbium:yttrium aluminum garnet (Er:YAG) laser have been documented [136].

Improvements have been noted in several patients after treatment with photodynamic therapy [141-145]. In our experience, relapses are common after this treatment.

Surgical excision of cutaneous sarcoidosis lesions is rarely performed due to the potential for sarcoidosis to recur in surgical scars. However, improvement in cosmetic appearance has been reported in patients with severely disfiguring lesions on the nose after reconstructive surgery [146,147]. (See "Cutaneous manifestations of sarcoidosis", section on 'Scar sarcoidosis'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sarcoidosis".)

SUMMARY AND RECOMMENDATIONS

●Overview – Sarcoidosis is a multisystem granulomatous disorder that can present with skin involvement (picture 2A-E). Although a variety of therapies have been used for cutaneous sarcoidosis, high-quality evidence to support the efficacy of these treatments is limited. Treatment can be challenging and is individualized because of the variability of clinical presentations, diversity of systemic organ involvement, variability of the risk for adverse effects among patients, and financial factors. (See 'Introduction' above and 'Initial therapy' above.)

●Decision to treat – Treatment is not required for all patients with cutaneous sarcoidosis. Spontaneous resolution is possible. In the absence of extracutaneous indications for the treatment of sarcoidosis, treatment should be considered for patients with cosmetically disfiguring, symptomatic, ulcerating, or progressively worsening skin disease. Patients with stable disease that is not bothersome do not require therapy. Treatment is usually required for lupus pernio due to the disfiguring nature of this variant. (See 'Decision to treat' above.)

●Treatment of localized disease – Patients with a limited number of skin lesions may benefit from local therapies. For patients with localized disease on the trunk or extremities, we suggest initiating treatment with superpotent topical corticosteroids or intralesional corticosteroid injections (Grade 2C). Increased risk for corticosteroid-induced skin atrophy warrants a more cautious approach to local corticosteroid therapy in patients with facial or intertriginous skin involvement. (See 'Localized disease' above.)

●Treatment of extensive or resistant disease – Some patients do not respond sufficiently to local therapy or have widespread disease that makes local therapy impractical. For these patients, we suggest initial treatment with antimalarial agents or methotrexate (Grade 2C). Minocycline and doxycycline are alternative systemic therapies. (See 'Extensive disease' above.)

●Treatment of rapidly progressing or disfiguring disease – For patients experiencing rapid disease progression or worsening disfigurement, we suggest a systemic glucocorticoid as initial therapy (algorithm 1) (Grade 2C). (See 'Rapid progression or worsening disfigurement' above.)

●Refractory disease – For patients who fail to improve with the suggested initial therapies for cutaneous sarcoidosis, we suggest a trial of anti-tumor necrosis factor (TNF) therapy (Grade 2C). Therapeutic options include infliximab, adalimumab, and thalidomide. (See 'Refractory disease' above.)