Am J Clin Dermatol DOI 10.1007/s40257-014-0079-3

THERAPY IN PRACTICE

A Practical Approach to Cutaneous Sarcoidosis Karolyn A. Wanat • Misha Rosenbach

Ó Springer International Publishing Switzerland 2014

Abstract Sarcoidosis is a chronic inflammatory disorder that has the potential to affect multiple organs, including the skin. Its cutaneous manifestations are varied and can provide clues to underlying systemic manifestations. Unfortunately, they also can be disfiguring. Therapy is usually directed at the organ system most severely affected, which often may help cutaneous disease. However, cutaneous disease may be recalcitrant to treatment directed at extracutaneous disease, or it may be severe enough to require targeted therapy. This article focuses on the dermatologist’s role in recognizing and diagnosing cutaneous sarcoidosis, evaluating patients for systemic disease involvement, and treating the skin manifestations of sarcoidosis.

Key Points Sarcoidosis is a multisystem, chronic disorder with protean cutaneous manifestations; recognizing the cutaneous involvement is essential Patients require a thorough systemic work-up, with treatment primarily focused on the most severely affected organ system and tailored to treating other organ systems For cutaneous sarcoidosis, a tiered, multistep therapeutic approach should be used, with topical therapies, immunomodulators, and systemic immunosuppressive therapies

1 Introduction

K. A. Wanat Department of Dermatology, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA M. Rosenbach (&) Department of Dermatology, University of Pennsylvania, 2nd Floor Maloney Building, 3400 Spruce Street, Philadelphia, PA 19104, USA e-mail: [email protected]

Sarcoidosis is a chronic, multisystem inflammatory disorder of unknown etiology, which is characterized by noncaseating granulomas impairing tissue function. It is a disease that occurs worldwide and can affect any age group, ethnicity, or race [1–3]. The peak age of presentation is the third to fourth decade of life, although there is a bimodal distribution with a second peak of incidence at the ages of 65–69 years [4, 5]. The geographic incidence varies by country and has racial heterogeneity. In the USA, the annual incidence rates are 35.5 per 100,000 black Americans and 10.9 per 100,000 white Americans, whereas in Japan, the rate is only 1–2 per 100,000 persons [4–6]. Females also have a slighter greater risk than males [5, 7].

K. A. Wanat, M. Rosenbach

sarcoidosis in monozygotic twins versus a 7-fold increase in dizygotic siblings [12]. In addition, multiple human leukocyte antigen (HLA) subtypes and gene mutations (including alterations in tumor necrosis factor [TNF]-a and interferon [IFN], among many other variations) are associated with sarcoidosis in certain populations [13, 14]. Genome-wide susceptibility studies also have identified new susceptibility loci, with potentially associated genes conferring a higher risk of developing sarcoidosis [15–17]. Further investigation into the role of genetics in the risk of susceptibility and phenotypes of sarcoidosis may provide additional clues to the pathogenesis of this complex disease. 2.1 Environmental Exposures

Fig. 1 Histopathology of sarcoidosis: On low power (a), areas of granulomatous inflammation in the dermis with minimal surrounding inflammation are observed (hematoxylin and eosin staining, 94 original magnification). Higher magnification (b) highlights the histiocytes with overall sparse surrounding inflammation and lack of caseation necrosis (hematoxylin and eosin staining, 910 original magnification)

2 Pathophysiology The histopathologic characteristics of sarcoidosis include noncaseating granulomas composed of mononuclear histiocytes, which can form into giant cells and have relatively little surrounding lymphocytic inflammation [‘‘naked granulomas’’] (Fig. 1) [8]. The exact etiology is unknown and is thought to be multifactorial, with numerous genetic, immunologic, and environmental interactions playing a role. Sarcoidosis most likely represents a complex and polygenetic interplay, where an immune response to environmental or infectious exposures leads to disease manifestations in a genetically susceptibility person [9–11]. The role of genetics is supported by familial clustering and increased prevalence among siblings and first-degree relatives [12]. There also are reports of an 80-fold increase in

Environmental exposures, including occupational and infectious etiologies, are also thought to potentially trigger an inflammatory reaction. A mildly increased risk has been associated with exposure to insecticides, pesticides, mildew, mold, and combustible wood; this may be due to the chemicals themselves or to a microbe-rich environment wherein potential triggers may lie [8, 18]. Occupational exposure to heavy metals, and occupations such as firefighting or first response to disasters, also may confer an increased incidence of sarcoidosis [13, 18, 19]. Specifically, patients should be asked about contact with aluminum, zirconium, talc, and beryllium. While beryllium is the cause of chronic berylliosis, patients with chronic berylliosis present with signs and symptoms that closely mimic those seen in patients with systemic sarcoidosis, although patients with berylliosis are much less likely to have cutaneous disease. Numerous infectious triggers have been hypothesized as potential etiologic agents behind sarcoidosis. Mycobacterial organisms are thought to be a possible trigger, and in the laboratory, evidence of mycobacterial infection has been identified in sarcoidal tissues in multiple studies [20–23]. In addition, other infectious agents, including Propionobacterium acnes, Borrelia spp., Mycoplasma, and various viruses, also have been potentially implicated in disease pathogenesis [8, 12, 24]. Some researchers have hypothesized that abnormal or misfolded proteins, such as serum amyloid A, may trigger the granulomatous response in immunologically susceptible patients [25]. 2.2 Immune Response Regardless of the trigger, the immune system response results in granulomatous inflammation and ultimate destruction of the tissues. Both the innate and adaptive immune systems cause a release of cytokines and further

A Practical Approach to Cutaneous Sarcoidosis

proliferation of sarcoidal granulomas, which consist predominately of aggregates of epithelioid macrophages and CD4? T cells [9]. Although not completely elucidated, the role of the T helper (Th)-1 cell in sarcoidal granuloma formation has been established, where macrophages activate CD4? T cells, which subsequently secrete IFN-c and interleukin (IL)-2 cytokines [9, 10, 26–28]. Continued production of the pro-inflammatory cytokines TNF-a, IL12, and IL-18 by macrophages and IFN-c by CD4? T cells continues to promote a Th1 predominant phenotype in sarcoidal granulomas [9, 10, 27, 28]. Recently, the Th17 arm of the immune system has been hypothesized to play a role in the pathogenesis of sarcoidosis. Some studies have demonstrated increased CD4? T cells expressing IL-17, as well as increased levels of IL-17 messenger RNA (mRNA) in bronchoalveolar lavage fluid and peripheral blood from patients with sarcoidosis [24, 26, 29–32]. In addition, genetic analyses have recently identified polymorphisms in the IL-23 receptor and an association with sarcoidosis, especially uveitis, which would further support a role of IL23 and the Th17 pathway in the promotion of sarcoidosis [33]. The innate immune system also is thought to play a role in granulomatous inflammation and sarcoidosis through Toll-like receptors (TLRs) and potential inability of the immune system to clear an infectious antigen, such as in a mycobacterial infection [34–36]. Functional deficits in TLR-9–induced IL-23 production may suggest that this pathway is involved in the pathogenesis of sarcoidosis [35]. The role of the innate immune system also is supported by mutations observed in the nucleotide-binding oligomerization domain containing 2 (NOD2/CARD15) genes in some cases of sarcoidosis, and phenotypic overlap observed between Blau syndrome (a childhood inflammatory disorder affecting the skin, eyes, and joints, with mutations in NOD2) and sarcoidosis [37, 38]. It is possible that sarcoidosis may represent a group of diseases, with a variety of environmental or infectious agents triggering inflammation down multiple pathways, which may vary from patient to patient [39].

3 Clinical Presentation 3.1 Systemic Manifestations Sarcoidosis is a multisystem disease, with the lungs and thoracic lymph nodes being the most commonly affected organs in more than 90 % of cases [12, 40]. However, nearly every other organ can be affected, with the skin and eyes being the other organ systems most commonly involved. Constitutional symptoms of fever, fatigue, and weight loss can occur in one third of patients. Ocular involvement, with uveitis, conjunctivitis, optic neuropathy, and lacrimal gland enlargement, can

occur in approximately 20–30 % of individuals, although series with up to 80 % of patients with eye disease have been reported [12]. The central nervous system may be involved in up to 25 % of patients with sarcoidosis, although as few as 10 % of patients will have symptoms [11, 41, 42]. Neurosarcoidosis is most commonly characterized by cranial nerve or peripheral nerve palsies, meningitis, neuropsychiatric symptoms, seizures, or neuroendocrine dysfunction [42]. While hepatic involvement in sarcoidosis may be more common, sarcoidosis in the liver has clinically relevant manifestations in approximately 10 % of patients and can present with asymptomatic elevations in serum alkaline phosphatase and serum aminotransferase levels, and a cholestatic picture with pruritus, jaundice, portal hypertension, and potentially liver failure [41]. Hypercalciuria, hypercalcemia, and nephrolithiasis can be seen not infrequently in sarcoidosis, so evaluation of kidney involvement is necessary [43]. Cardiac involvement can result in palpitations, heart block, and sudden death, and may be underrecognized and more prevalent than studies have suggested [44, 45]. Other affected organ systems can include the gastrointestinal tract, sinuses, musculoskeletal (arthritis, arthralgias), hematologic (lymphopenia or hypergammaglobulinemia), endocrinologic (pituitary involvement, Heerfordt syndrome), and renal (hypercalcemia, hypercalciuria, or nephrolithiasis) systems [10, 11, 40, 46]. 3.2 Cutaneous Manifestations Cutaneous sarcoidosis is present in 25–30 % of patients and can have protean manifestations, which can provide clues to the overall prognosis, clinical course, and impact of therapeutic decisions [8, 46–48]. Cutaneous manifestations can be broken down into two major categories: lesions specific to sarcoidosis, characterized by granulomatous infiltrates in the skin, and nonspecific lesions resulting from the systemic immunologic response [8, 49, 50]. Specific lesions include violaceous to erythematous to brown macules and papules and plaques [8, 49–52]. Subcutaneous nodules, known as Darier–Roussy sarcoidosis, also can occur and can be best appreciated with palpation [53–58]. One of the most specific manifestations of sarcoidosis is the violaceous, indurated peri-nasal and midfacial plaques of lupus pernio (Fig. 2) [8, 48–52, 59–66]. Scar- and tattoo-associated lesions are also quite common [8, 49, 52, 67, 68]. Less commonly, cutaneous sarcoidosis may manifest as psoriasiform lesions, alopecia (both scarring and nonscarring have been reported), erythroderma, ulcers, or ichthyosis (Fig. 3) [51, 56–58, 69–81]. Erythema nodosum is considered a ‘‘nonspecific’’ skin manifestation, believed to occur as an immunologic response to systemic sarcoidosis (Fig. 4). In erythema nodosum, sarcoidal granulomas are not present in the skin

K. A. Wanat, M. Rosenbach

Fig. 2 Lupus pernio: extensive violaceous plaques with scale on the nose and central face, consistent with classic lupus pernio

but represent a response to granulomatous inflammation present elsewhere in the body [82–84]. Erythema nodosum can present as part of Lo¨fgren’s syndrome (bilateral hilar adenopathy on chest radiography, erythema nodosum skin lesions, fever, and arthritis/arthralgias); a variant of Lo¨fgren’s also can present with periarticular ankle swelling in the absence of actual erythema nodosum lesions [85]. The cutaneous manifestations of sarcoidosis can provide information on the prognosis and potential extracutaneous Fig. 3 Multiple morphologies of cutaneous presentation of sarcoidosis. a Papular sarcoid. b Plaque/lichenoid sarcoid. c Confluent papules around the nasal ala with scaling, slightly verrucous. d Sarcoidal alopecia (scarring) with extensive scaling. e Subcutaneous sarcoid nodules, Darier–Roussy type. f Ichthyosiform sarcoidosis. g Ulcerative sarcoidosis, resembling necrobiosis lipoidica. h Scar-associated sarcoidosis. i Tattoo-associated sarcoidosis, obliterating the tattoo in this case. [Figure 3F courtesy of Jennifer Gardner]

involvement. The frequency of lesion morphology may vary by ethnicity, and systemic involvement may more closely correlate with different lesion types [47, 52]. Erythema nodosum is typically associated with a more acute course and a better prognosis, while lupus pernio is associated with upper respiratory or nasal mucosa involvement, and possibly with bone cysts, and is associated with a more chronic, refractory course [60, 64, 65, 86]. In Scandinavians, approximately one third of patients present with erythema nodosum and associated Lo¨fgren’s syndrome, with lupus pernio reported less frequently in this population [86]. In contrast, lupus pernio is common among African Americans in the USA. In Japan, cutaneous manifestations are less frequent overall, with ocular and cardiac symptoms more commonly being present [47, 52, 87]. Subcutaneous sarcoidosis (Darier–Roussy sarcoidosis) is almost exclusively reported in Caucasians, with underrepresentation in other populations, although the authors have noted multiple African American women with subcutaneous lesions as well [53, 54]. Therapeutic considerations may be tailored to cutaneous involvement, as patients presenting with lupus pernio may have a more refractory

A Practical Approach to Cutaneous Sarcoidosis Fig. 4 Erythema nodosum: erythematous subcutaneous nodules, most often on the anterior legs, which are a nonspecific sign of systemic sarcoidosis

course and require more systemic medications than patients presenting with erythema nodosum. Remission can occur in patients with sarcoidosis, with more than half having resolution of symptoms within 3 years of diagnosis and two thirds having resolution within a decade [10]. However, damage can occur within organ symptoms secondarily to the inflammatory response, so treatment can help prevent long-term fibrosis and scarring in some cases.

4 Diagnosis and Work-Up Because sarcoidosis can have a varied presentation and involve multiple systems, there is no simple, single diagnostic test, and diagnosis depends on clinical presentation, pathologic confirmation of noncaseating granulomas, and supportive laboratory and radiologic evidence of multiorgan disease [3, 11]. Sarcoidosis is a diagnosis of exclusion [88]. When it is clinically suspected, a punch biopsy of the cutaneous lesions is important to establish histopathologic evidence of sarcoidosis and rule out infectious etiologies or other causes of granulomatous disease. Superficial shave biopsies should be avoided because the key pathologic changes are often within the dermis or even within the subcutaneous tissue in some patients. Characteristic histopathologic features include noncaseating granulomas with central, organized collections of epithelioid macrophages and multinucleated giant cells surrounded by an overall sparse infiltrate of lymphocytes and occasionally plasma cells (called ‘‘naked granulomas’’) (Fig. 1). However, sarcoidal granulomas can be seen in multiple entities, including foreign body reactions, infections, and immunodeficiency syndromes. Staining to rule out infectious organisms is important, and polarization for foreign

substances often is performed to help establish a foreign body reaction. However, polarizable foreign material or tattoo ink can be present in sarcoidosis as well (25 % of sarcoidosis biopsies may demonstrate polarizable material), and clinical correlation with further work-up is important [8, 89–91]. Once granulomatous inflammation is confirmed in the skin, evaluation for other organ involvement is important because evidence of the involvement of two organs is required for a formal diagnosis of sarcoidosis by the strictest definition [3, 88]. Patients with sarcoid-like skin lesions and no evidence of extracutaneous disease on comprehensive evaluation may be best diagnosed as having ‘‘sarcoid-like granulomatous disease of unknown significance,’’ although many clinicians traditionally refer to these patients as having isolated cutaneous sarcoidosis. Many of these patients may ultimately develop additional organ system involvement and be diagnosed with sarcoidosis. However, dermatologists need to be aware of cutaneous-limited ‘‘sarcoid-like granulomatous disease of unknown significance’’ when other etiologies of granulomatous inflammation have been excluded (infection, foreign body, etc.) and can use the paradigm discussed below to treat this type of granulomatous disease, which some believe is a type of skin-limited sarcoidosis. When the diagnosis of sarcoidosis is suspected and sarcoidal granulomas are present on skin biopsy, the initial work-up includes laboratory and radiologic evaluation (Table 1) [11, 88, 92]. A thorough history for underlying systemic symptoms and occupational/environment exposures, and a complete physical examination, are important. The initial radiologic work-up includes chest X-rays (posterior–anterior and lateral) for pulmonary and thoracic lymphatic involvement, and pulmonary function tests, including diffusion capacity for carbon monoxide (DLCO), to evaluate for interstitial disease [92, 93]. Evaluation for ophthalmologic involvement also is essential, as asymptomatic disease can be present and in some patients may lead to blindness; most patients with eye involvement will have uveitis [94, 95]. An electrocardiogram also should be included in the work-up to evaluate for underlying arrhythmias, as these may not have symptoms and can lead to cardiac arrest, with a low threshold for additional baseline cardiac screening. Some experts advocate a baseline echocardiogram and 24-hour Holter monitor in all patients with sarcoidosis, and those tests should be performed in patients with any history of palpitations. While controversy exists, cardiac sarcoidosis may be better imaged with either positron emission tomography (PET) scanning or dedicated cardiac magnetic resonance imaging (MRI) [96]. If there are abnormalities or a history of palpitations, referral to cardiology is essential for further

K. A. Wanat, M. Rosenbach Table 1 Recommendations for initial and follow-up examinations in patients with cutaneous sarcoidosis Initial evaluationa

To be performed annuallyb

History (occupational/environmental exposure, complete review of systems)

History

Physical examination

Physical examination

Chest X-ray (posterior–anterior and lateral)

Chest X-ray (posterior–anterior and lateral)

Pulmonary function tests (including diffusion capacity for carbon monoxide)

Pulmonary function tests (including diffusion capacity for carbon monoxide)

Ophthalmologic examination

Ophthalmologic examination

Complete blood count

Complete blood count

Comprehensive serum chemistries (including calcium, liver function tests, creatinine)

Comprehensive serum chemistries (including calcium, liver function tests, creatinine)

Electrocardiogram, transthoracic echocardiogram, Holter monitor (consider additional testing if symptomatic) Urinalysis (if history of stone, then 24-hour urine calcium) Tuberculin skin test or interferon-c release assay Thyroid testing Vitamin D25, Vitamin D1,25 a

Any abnormalities detected on history, review of systems, laboratory tests, or radiologic work-up may warrant further investigation with additional targeted diagnostics and/or expert referral b

Patients should be evaluated more frequently if they are on systemic medications, if there is a change in clinical signs or symptoms, or if their disease is not well controlled

work-up [44, 45, 96–100]. The screening laboratory workup should include a complete blood count, comprehensive metabolic panel (including calcium, liver function tests, and creatinine for kidney function), and urinalysis with 24-hour urine calcium if there is a history of nephrolithiasis [8, 11, 92, 93]. In addition, thyroid testing also should be performed, as thyroid dysfunction can occur with sarcoidosis [101]. Sarcoidal granulomas are metabolically active and can activate vitamin D. Patients with sarcoidosis often have low 25-hydroxyvitamin D levels but elevated 1,25dihydroxyvitamin D3 levels, and screening for both levels is essential, as inappropriate supplementation with calcium and vitamin D can lead to iatrogenic hypercalcemia [102]. Screening for tuberculosis with a tuberculin skin test or an IFN-c release assay also is important, as cutaneous tuberculosis can present with sarcoidal granulomas, and ruling out tuberculosis is important prior to initiation of systemic therapeutics [8, 92, 93, 103]. The use of an IFN-c release assay may be more sensitive, and better at detecting latent tuberculosis infection, because of anergy observed in patients with sarcoidosis [103]. The serum angiotensinconverting enzyme (ACE) level also can be a useful diagnostic test, as elevations can be seen in 40–80 % of patients with sarcoidosis, as it is an enzyme derived from granulomas. However, it is nonspecific; mild levels can be seen in diabetes and osteoarthritis, and high levels can be seen in other granulomatous diseases with infectious causes (such as tuberculosis, leprosy, or fungal infections) or noninfectious causes (such as berylliosis or hyperthyroidism) [11, 92, 104]. Anecdotal evidence suggests that if the

serum ACE level is more than two or three times the upper limit of normal, sarcoidosis may be more likely. Table 1 reviews the initial work-up and monitoring for sarcoidosis patients. Certain clinical presentations are more suggestive of a diagnosis of sarcoidosis, in the absence of an alternative diagnosis (such as infection or lymphoma). These include the presentation of Lo¨fgren’s syndrome (bilateral hilar adenopathy on chest radiography, erythema nodosum skin lesions, fever, and arthritis/arthralgias), Heerfordt syndrome (uveitis, parotitis, and fever), and asymptomatic bilateral hilar lymphadenopathy [88]. Multiorgan system and cutaneous involvement can have a negative impact on the patient’s quality of life, and use of health-related quality-of-life tools to determine baseline disease activity and the clinical response to therapy is important. Health-related quality-of-life metrics have been used previously, and patients with sarcoidosis do have negative quality-of-life indicators, compared with patients who have other disease states and normal patients [105, 106]. In addition, the use of established clinical assessment tools is becoming increasingly important to develop a standardized approach to the assessment of baseline clinical characteristics and the response to therapy. Several clinical assessment tools have been established and can easily be utilized in the evaluation of cutaneous sarcoidosis in clinical practice [66, 107]. Clinicians can use both health-related quality-of-life tools and clinical assessment tools as another measure to determine the response to therapeutic interventions.

A Practical Approach to Cutaneous Sarcoidosis

5 Treatment

5.1 Topical Therapy

There are several therapeutic options for cutaneous sarcoidosis, depending on the extent of involvement, the clinical symptoms and level of disfigurement, and the clinical presentation. Treatment options for extracutaneous sarcoidosis are not discussed here, as they are beyond the scope of this article. All patients should have a thorough evaluation for internal disease, and management of sarcoidosis generally focuses on treating the most severely affected organ system, although combination therapy may be necessary. If patients have severe pulmonary disease and cutaneous involvement, therapy for the lung disease may control the skin, and the skin manifestations may be indicative of how the internal organs are responding to therapy. For patients with primarily cutaneous sarcoidosis, or patients with cutaneous lesions that fail to respond to therapy for systemic sarcoidosis, a stepwise approach is recommended (Fig. 5) [8]. It is important to note that there are no medications approved by the US Food and Drug Administration (FDA) for the treatment of cutaneous sarcoidosis, and there have been few controlled trials. The recommendations are based primarily on retrospective series, small case series, and expert opinion. Clinical trials further evaluating the response of cutaneous sarcoidosis to therapy would be beneficial. Therapeutic options can be divided into local therapies (topical, intralesional, laser), systemic therapies with relatively low risks (immunomodulatory rather than immunosuppressive agents), traditional systemic immunosuppressive agents, and newer ‘‘biologic’’ agents. Granulomatous inflammation is slow to respond, and patients should be advised to maintain a therapeutic regimen for at least 3 months before determining its efficacy. Treatment can be deferred in cases where the skin involvement is limited, stable, or asymptomatic. In addition, certain acute, selflimited presentations (Lo¨fgren’s syndrome) may resolve spontaneously without therapy.

Topical and intralesional therapy should be considered first-line therapy for cutaneous sarcoidosis with limited or mild disease or as an adjunct to help control cutaneous disease when extracutaneous disease is under adequate control. High-potency topical steroids (class 1, such as topical clobetasol or halobetasol) are often the first-line topical therapies used for limited cutaneous sarcoidosis (defined as few papules or plaques) and can be applied once to twice daily, although the evidence for their use is limited [108–110]. Intralesional corticosteroids (triamcinolone 5–40 mg/mL, depending on the individual lesion size and location) also can be injected into papules, plaques, or nodules every 3–4 weeks until resolution [111–113]. The side effects are similar for topical and intralesional steroids, and include atrophy, striae, hypopigmentation, and telangiectasia formation; on facial skin, a lower-potency corticosteroid or combination of a topical corticosteroid and nonsteroidal therapy may be necessary to avoid side effects. Use of topical and intralesional corticosteroids is feasible with limited skin disease but is impractical for widespread or deeper (subcutaneous) involvement of sarcoidosis. In addition to topical steroids, topical tacrolimus (0.03 % or 0.1 %) can be used in limited skin disease, especially for flatter lesions on thinner areas of skin, such as the face [114–117]. Although there is limited evidence for its use, it has a low overall side-effect profile. The combination of topical/intralesional corticosteroids with topical tacrolimus also may be beneficial for limited skin disease. In the authors’ experience, topical retinoids may help cases of sarcoidosis with significant scaling or dyspigmentation. Additional skin-directed therapies that have been reported to be beneficial in limited case studies include photodynamic therapy (PDT), lasers (pulsed-dye lasers and CO2 lasers), and surgical intervention. Various regimens of photodynamic therapy have been utilized in limited case reports, with some improvement [118–121]. Photodynamic therapy with 20 % aminolevulinic acid and blue light (417 nm, 10 J/cm2) treatment every 2 weeks for 10 weeks has resulted in significant improvement in cutaneous sarcoidosis [119]. A 10 % aminolevulinic acid solution with red light (630 nm, 100 J/cm2) over six treatments also demonstrated improvement in one report [122]. Methyl aminolevulinate with red light (630 nm, 37–38 J/cm2) every 1–2 weeks for eight treatments also yielded beneficial results [121]. The side effects of this PDT include burning, pain, photosensitivity, erythema, and potential for hyper- or hypopigmentation and scarring. Many of the PDT reports have noted recurrence of sarcoidal lesions when therapy is stopped. A few case reports have demonstrated

Fig. 5 Stepwise approach to treating cutaneous sarcoidosis. Depending on the severity of the disease and how a patient responds to therapy, medications with additional risk factors or need for monitoring are used

K. A. Wanat, M. Rosenbach

improvement in cutaneous sarcoidal lesions with pulsed dye laser therapy, CO2 laser for laryngeal sarcoidosis, ruby laser, or potassium titanyl phosphate laser, with variable treatment numbers and settings [67, 68, 123–128]. There are anecdotal reports of laser use inducing ulceration within previously stable sarcoidal lesions, and caution is warranted. When the disease is overall under good control and scarring or damage results, surgical reconstruction could be considered for improvement of the disfiguring lesions—with the caveat that sarcoidosis can develop at scars and surgical sites. For limited or more extensive skin disease, ultraviolet A (UVA) phototherapy also can be considered, although there is limited evidence for its use [129–131]. Topical UVA1, medium-dose UVA1, and high-dose UVA1 all have been utilized, with improvement after about 30–50 treatments in total [129–131]. In some cases, UVA was used as sole therapy, and in other cases, it was used as an adjuvant therapy. Side effects of burning, erythema, and pain can occur with phototherapy. 5.2 Systemic Therapy: Immunomodulatory Therapies with Overall Lower Risk When topical or intralesional therapy is not effective for mild disease, or when there is more extensive disease present, then systemic immunomodulators may be considered. This category of therapy also can be used to help stabilize disease while tapering down to lower doses of other more potent immunosuppressants (see below). Therapies in this category include tetracycline-class antibiotics, antimalarials, and other anti-inflammatory agents, such as pentoxifylline and apremilast. Most treatment algorithms for cutaneous sarcoidosis suggest that if patients fail to respond to topical therapy or have more extensive skin disease, antimalarial therapy is the most appropriate first-line systemic agent. Often a combination of these therapies can be used (minocycline and hydroxychloroquine or chloroquine, or the combination of minocycline, hydroxychloroquine, and pentoxifylline) with or without topical therapies. Antimalarials (hydroxychloroquine and chloroquine) are considered to be effective in the treatment of cutaneous sarcoidosis, althoughno randomized controlled trials have been performed [132–137]. These agents can be used as monotherapy or in combination with minocycline, other immunosuppressants, or topical therapies. Chloroquine is dosed at 250 mg daily (maximum dose 3.5 mg/g/day), and hydroxychloroquine is dosed at 200–400 mg daily (maximum dose 6.5 mg/kg/day), and the therapeutic effect is often noted after 2–3 months of therapy. Chloroquine has been more widely studied, although it carries an increased risk of eye toxicity compared with hydroxychloroquine

[132, 135–137]. Both antimalarials are typically well tolerated, although there are risks of ocular toxicity (more with chloroquine), hepatic toxicity, and gastrointestinal upset. Given its overall more favorable safety profile, most clinicians initiate therapy with hydroxychloroquine. Tetracycline-class antibiotics (minocycline, doxycycline, and tetracycline) may be helpful in cutaneous sarcoidosis because of their anti-inflammatory effects and overall low side-effect profile, and they may be used as first-line systemic therapy for moderate sarcoidosis [55, 138–142]. Although these medications are effective against multiple bacteria, it is thought that they are used more for their immunomodulatory properties in sarcoidosis [8, 140]. Minocycline 100 mg twice daily was effective in an open, nonrandomized prospective trial, as well as in a retrospective review, and is considered to be the tetracycline of choice for cutaneous sarcoidosis [139, 142]. In cases when minocycline cannot be tolerated, doxycycline 100 mg twice daily or tetracycline 1000 mg daily may be substituted. Tetracycline antibiotics can have side effects, including headache, dyspigmentation, phototoxicity (doxycycline), and gastrointestinal upset, and they have contraindications in pregnancy and in children less than 8 years of age. Severe but rare side effects of lupus-like reactions, autoimmune hepatitis, and vasculitis also have been reported with minocycline [143]. Other immunomodulators have been used for cutaneous sarcoidosis. Phosphodiesterase type 4 inhibitors, such as pentoxifylline (dosed at 400 mg three times daily) and apremilast (dosed at 20 mg once to twice daily) have been reported to be effective in small reports of pulmonary sarcoidosis and cutaneous sarcoidosis [144–146]. These medications are thought to block cytokines involved in sarcoidosis, including TNF-a, and are generally well tolerated, with some adverse effects of nausea, restlessness, flushing, and drowsiness. 5.3 Systemic Therapy: Immunomodulatory and Immunosuppressive Agents Requiring Close Monitoring Systemic immunosuppressive medications and immunomodulatory medications that require close monitoring and are used in cutaneous sarcoidosis include prednisone, methotrexate, thalidomide, TNF inhibitors and, less commonly, other immunosuppressants, such as mycophenolate mofetil and azathioprine. These medications have greater potential for side effects and infections related to immunosuppression, so often they are used for moderate to severe or recalcitrant disease. Oral corticosteroids are considered first-line systemic immunosuppressive therapy for widespread, disfiguring,

A Practical Approach to Cutaneous Sarcoidosis

ulcerative, or rapidly progressive disease because of their fast onset of action for disease control. Prednisone, or its equivalent, at a dose of 0.5–1 mg/kg/day, often is required to help provide initial disease control, with eventual tapering to the lowest dose possible as tolerated and to prevent disease recurrence [138, 147]. Other immunosuppressants or concomitant topical and oral therapy often are started with severe disease manifestations to help facilitate prednisone tapering, which is important to do given the multiple side effects related to its use, including glucose intolerance, hypertension, cataracts, glaucoma, weight gain, osteopenia, gastrointestinal disturbance, thinning of skin, and difficulty with mood and sleep. Calcium and vitamin D supplementation should be considered in patients treated with oral corticosteroids, but caution should be used in sarcoidosis, given the potential for hypercalcemia and vitamin D excess in these patients [102]. Management of other comorbidities, including diabetes mellitus, osteopenia/osteoporosis and hypertension, also is important. Methotrexate often is used as one of the first immunosuppressant agents for recalcitrant cutaneous disease or as an initial steroid-sparing agent in cases of severe disease [148–151]. Methotrexate is dosed weekly (7.5–25 mg), can be provided either orally or subcutaneously and has been reported to have a greater than 80 % response rate in cutaneous sarcoidosis [148, 149]. In another study, three quarters of the patients (8/12) had complete clearance of their skin lesions with methotrexate, and others had partial improvement [152]. However, side effects can be limiting with methotrexate, including nausea, gastrointestinal intolerance, liver toxicity, leukopenia, hair loss, and oral ulcerations [152]. Laboratory monitoring, including a complete blood count, liver function tests, and creatinine clearance, is important to limit the risks of methotrexate toxicity. In addition, pulmonary fibrosis can occur rarely with methotrexate, so monitoring of pulmonary function is essential. As patients with sarcoidosis frequently have lung involvement, it is important to complete a comprehensive pulmonary evaluation prior to instituting therapy with methotrexate. Although methotrexate can be effective, it can take 3–6 months to reach its full effect [148, 149]. Mycophenolate mofetil and azathioprine are roughly similar to methotrexate in terms of overall immunosuppression, albeit with different mechanisms of action; these drugs are used less commonly in cutaneous sarcoidosis. Mycophenolate mofetil (30–40 mg/kg/day) has been used in small series of patients with cutaneous sarcoidosis as a steroid-sparing and tapering agent [153]. Azathioprine has been used successfully as a second-line agent in pulmonary and chronic sarcoidosis, although more frequent infections were reported; however, its use in cutaneous sarcoidosis is

not well studied and requires further comparative studies to determine if it would be as effective as other agents [154, 155]. In the authors’ experience, neither mycophenolate mofetil nor azathioprine is particularly efficacious in controlling cutaneous sarcoidosis. Thalidomide (50–400 mg/day) has been studied in a small, open-label trial in cutaneous sarcoidosis and has been effective in patients with prolonged and recalcitrant disease [156–160]. It exerts its affect by blocking TNF, and the majority of patients with refractory cutaneous sarcoidosis, including lupus pernio, noted improvement [161– 163]. However, its side-effect profile includes peripheral neuropathy, sedation, nausea, venous thrombosis, and teratogenicity, and requires special monitoring with the STEPs (System for Thalidomide Education and Prescribing Safety) program, which makes this medication impractical for some patients. Lenalidomide may represent a reasonable alternative in select patients, but the data are currently limited [164]. TNF inhibitors have recently been demonstrated to be beneficial for chronic and recalcitrant cutaneous sarcoidosis, including ulcerative sarcoidosis and lupus pernio. Case series and small trials have demonstrated favorable results with infliximab and adalimumab [165–177]. One clinical trial investigating etanercept for pulmonary sarcoidosis was halted early because of lack of efficacy and increased side effects in the treatment group [178]. In a few studies and case series, infliximab (3–7 mg/kg at 0, 2, and 6 weeks, with maintenance therapy every 6–8 weeks) has demonstrated improvement in cutaneous lesions when systemic steroids were inadequate for clinical control [171, 173–176]. Infliximab may be particularly helpful in cases of chronic, refractory lupus pernio [179]. In a small, double-blind, randomized, placebo-controlled trial, adalimumab was found to be an effective and safe medication for the treatment of cutaneous sarcoidosis after 12 weeks [168]. If improvement is noted but lesions are still recalcitrant, dose escalation also may be required to achieve the most beneficial therapeutic response [180]. Adalimumab is generally administered weekly when treating patients with sarcoidosis. The side effects of TNF inhibitors include infusion or injection site reactions, headache, nausea, reactivation of tuberculosis, and increased risks of other infections, lymphoma, solid organ malignancies, and demyelinating disease [8]. Other causes of granulomatous inflammation, including tuberculosis, must be excluded prior to use of these therapies, as reactivation of tuberculosis thought to be sarcoidosis has been reported [181, 182]. Importantly, paradoxical exacerbation of sarcoidosis (or de novo induction of a sarcoid-like granulomatous disease) also has been reported with TNF inhibitors (similar to the phenomenon of TNF-induced psoriasis),

K. A. Wanat, M. Rosenbach Fig. 6 Simplified algorithm in approaching the treatment of cutaneous sarcoidosis. This flow chart provides a framework for how clinicians can think about the therapeutic options for cutaneous sarcoidosis. Certain therapies that are beneficial for the skin may not be beneficial for internal organs, so combination therapy may be necessary. In addition, the inflammation in the skin may help predict how internal organs are responding to therapy

suggesting that more data and understanding of the pathogenesis of the disease are required [183]. Clinicians should be aware of this potential worsening and should consider alternative therapies if worsening disease occurs.

5.4 Additional Reported Therapies: Limited Evidence There are several additional oral therapies that have been tried in cutaneous sarcoidosis but with limited improvement and limited data. These therapies include isotretinoin, melatonin, colchicine, and cyclosporine [109, 184–186]. Leflunomide also has been used in chronic extracutaneous sarcoidosis, but experience in skin is limited [187].

5.5 Emerging Therapeutics There is, as yet, no FDA-approved treatment for sarcoidosis, and therapeutic targets for cutaneous and extracutaneous sarcoidosis are actively being investigated. Physicians managing truly recalcitrant cases should consider consulting the ClinicalTrials.gov web site for clinical trials actively enrolling appropriate patients. Treatment of cutaneous sarcoidosis may draw from the therapeutic options being studied in extracutaneous disease, including pulmonary sarcoidosis. There is active investigation exploring roles for statins, nicotine, and targeted therapies, such as IL-12/IL-23 antagonists, in the treatment of sarcoidosis. A recently completed trial evaluating ustekinumab (an IL-12/IL-23

A Practical Approach to Cutaneous Sarcoidosis

inhibitor) demonstrated no benefit in treating skin or lung disease but, given the potential for the Th17 arm of the immune system to play a role in sarcoidosis, targeted IL-17 inhibitors may be a future target of investigation for treating sarcoidosis. In addition, given the efficacy of thalidomide, further studies with lenalidomide may be reasonable.

6 Therapeutic Approach/Conclusion Sarcoidosis is a multisystem granulomatous disease with protean cutaneous manifestations. In any patient with sarcoidosis affecting the skin, a thorough evaluation for other causes of granulomatous disease, and a thorough work-up for extracutaneous disease, are imperative. Treatment of sarcoidosis should be based upon the most severely affected organ system. For the treatment of cutaneous sarcoidosis, there is limited evidence but significant efficacy in clinical practice. A stepwise approach should be utilized, and generally all patients should receive topical therapies (Fig. 6). First-line systemic agents include antimalarials and other nonimmunosuppressive options, notably minocycline. Patients with more severe disease or those who fail to respond to combination antimalarial and tetracycline-class antibiotics may warrant immunosuppressant therapy with corticosteroids, methotrexate, thalidomide, or TNF inhibitors. Infliximab, in particular, seems to offer great promise to patients who are severely affected by chronic, recalcitrant skin disease. Because sarcoidosis significantly impacts patients’ quality of life, dermatologists should feel comfortable, and be at the forefront, in treating its cutaneous manifestations. Acknowledgments Dr. Rosenbach is supported by a Medical Dermatology Career Development Award through the Dermatology Foundation and has also served as an investigator for a Johnson & Johnson/Centocor clinical trial comparing ustekinumab, golimumab, and placebo. Dr. Wanat has no conflicts of interest that are directly relevant to the content of this review.

References 1. III Italian Conference on Sarcoidosis and Other Granulomatous Disorders. Padua, April 12–13, 1991. Proceedings and abstracts. Sarcoidosis. 1991;8(2):161–202. 2. Proceedings of the 1991 XIIth World Congress on Sarcoidosis. Kyoto, Japan, September 8–13, 1991. Sarcoidosis. 1992;9 Suppl 1:1–683. 3. Statement on sarcoidosis. Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999. Am J Respir Crit Care Med. 1999;160(2):736–55.

4. Rybicki BA, Iannuzzi MC. Epidemiology of sarcoidosis: recent advances and future prospects. Semin Respir Crit Care Med. 2007;28(1):22–35. 5. Rybicki BA, Maliarik MJ, Major M, Popovich J Jr, Iannuzzi MC. Epidemiology, demographics, and genetics of sarcoidosis. Semin Respir Infect. 1998;13(3):166–73. 6. Rybicki BA, Major M, Popovich J Jr, Maliarik MJ, Iannuzzi MC. Racial differences in sarcoidosis incidence: a 5-year study in a health maintenance organization. Am J Epidemiol. 1997;145(3):234–41. 7. Morimoto T, Azuma A, Abe S, Usuki J, Kudoh S, Sugisaki K, et al. Epidemiology of sarcoidosis in Japan. Eur Respiratory J. 2008;31(2):372–9. 8. Haimovic A, Sanchez M, Judson MA, Prystowsky S. Sarcoidosis: a comprehensive review and update for the dermatologist: part I. Cutaneous disease. J Am Acad Dermatol. 2012;66(5):699 e1–18; quiz 717–8. 9. Noor A, Knox KS. Immunopathogenesis of sarcoidosis. Clin Dermatol. 2007;25(3):250–8. 10. Iannuzzi MC, Fontana JR. Sarcoidosis: clinical presentation, immunopathogenesis, and therapeutics. JAMA. 2011;305(4): 391–9. 11. Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. New Engl J Med. 2007;357(21):2153–65. 12. Chen ES, Moller DR. Sarcoidosis—scientific progress and clinical challenges. Nat Rev Rheumatol. 2011;7(8):457–67. 13. Rossman MD, Thompson B, Frederick M, Iannuzzi MC, Rybicki BA, Pander JP, et al. HLA and environmental interactions in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2008;25(2): 125–32. 14. Iannuzzi MC, Iyengar SK, Gray-McGuire C, Elston RC, Baughman RP, Donohue JF, et al. Genome-wide search for sarcoidosis susceptibility genes in African Americans. Genes Immun. 2005;6(6):509–18. 15. Hofmann S, Fischer A, Nothnagel M, Jacobs G, Schmid B, Wittig M, et al. Genome-wide association analysis reveals 12q13.3-q14.1 as new risk locus for sarcoidosis. Eur Respir J. 2013;41(4):888–900. 16. Spagnolo P, Schwartz DA. Genetic predisposition to sarcoidosis: another brick in the wall. Eur Respir J. 2013;41(4):778–80. 17. Franke A, Fischer A, Nothnagel M, Becker C, Grabe N, Till A, et al. Genome-wide association analysis in sarcoidosis and Crohn’s disease unravels a common susceptibility locus on 10p12.2. Gastroenterology. 2008;135(4):1207–15. 18. Newman KL, Newman LS. Occupational causes of sarcoidosis. Curr Opin Allergy Clin Immunol. 2012;12(2):145–50. 19. Reich JM. Sarcoidosis and World Trade Center disaster. J Occup Environ Med. 2012;54(1):2; author reply -3. 20. Gupta D, Agarwal R, Aggarwal AN, Jindal SK. Molecular evidence for the role of mycobacteria in sarcoidosis: a metaanalysis. Eur Respir J. 2007;30(3):508–16. 21. Rutherford RM, Gilmartin JJ. Mycobacteria in pathogenesis of sarcoidosis. Chest. 2004;125(1):354. 22. Brownell I, Ramirez-Valle F, Sanchez M, Prystowsky S. Evidence for mycobacteria in sarcoidosis. Am J Respir Cell Mol Biol. 2011;45(5):899–905. 23. Oswald-Richter KA, Beachboard DC, Seeley EH, Abraham S, Shepherd BE, Jenkins CA, et al. Dual analysis for mycobacteria and propionibacteria in sarcoidosis BAL. J Clin Immunol. 2012;32(5):1129–40. 24. Furusawa H, Suzuki Y, Miyazaki Y, Inase N, Eishi Y. Th1 and Th17 immune responses to viable Propionibacterium acnes in patients with sarcoidosis. Respir Investig. 2012;50(3):104–9. 25. Chen ES, Song Z, Willett MH, Heine S, Yung RC, Liu MC, et al. Serum amyloid A regulates granulomatous inflammation

K. A. Wanat, M. Rosenbach

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43. 44.

in sarcoidosis through Toll-like receptor-2. Am J Respir Crit Care Med. 2010;181(4):360–73. Parisinos CA. Sarcoidosis is a Th1/Th17 multisystem disorder: wider implications. Thorax. 2011;66(11):1011–2; author reply 1012. Zissel G, Prasse A, Muller-Quernheim J. Sarcoidosis—immunopathogenetic concepts. Semin Respir Crit Care Med. 2007;28 (1):3–14. Zissel G, Prasse A, Muller-Quernheim J. Immunologic response of sarcoidosis. Semin Respir Crit Care Med. 2010;31(4): 390–403. Facco M, Cabrelle A, Teramo A, Olivieri V, Gnoato M, Teolato S, et al. Sarcoidosis is a Th1/Th17 multisystem disorder. Thorax. 2011;66(2):144–50. Huang H, Lu Z, Jiang C, Liu J, Wang Y, Xu Z. Imbalance between Th17 and regulatory T-Cells in sarcoidosis. Int J Mol Sci. 2013;14(11):21463–73. Ten Berge B, Paats MS, Bergen IM, van den Blink B, Hoogsteden HC, Lambrecht BN, et al. Increased IL-17A expression in granulomas and in circulating memory T cells in sarcoidosis. Rheumatology. 2012;51(1):37–46. Urbankowski T, Hoser G, Domagala-Kulawik J. Th1/Th2/Th17 related cytokines in the bronchoalveolar lavage fluid of patients with sarcoidosis: association with smoking. Pol Arch Med Wewn. 2012;122(7–8):320–5. Kim HS, Choi D, Lim LL, Allada G, Smith JR, Austin CR, et al. Association of interleukin 23 receptor gene with sarcoidosis. Dis Markers. 2011;31(1):17–24. Schurmann M, Kwiatkowski R, Albrecht M, Fischer A, Hampe J, Muller-Quernheim J, et al. Study of Toll-like receptor gene loci in sarcoidosis. Clin Exp Immunol. 2008;152(3):423–31. Veltkamp M, Van Moorsel CH, Rijkers GT, Ruven HJ, Van Den Bosch JM, Grutters JC. Toll-like receptor (TLR)-9 genetics and function in sarcoidosis. Clin Exp Immunol. 2010;162(1): 68–74. Richmond BW, Drake WP. Vitamin D innate immunity, and sarcoidosis granulomatous inflammation: insights from mycobacterial research. Curr Opin Pulm Med. 2010;16(5):461–4. Gazouli M, Koundourakis A, Ikonomopoulos J, Gialafos EJ, Rapti A, Gorgoulis VG, et al. CARD15/NOD2, CD14, and Tolllike receptor 4 gene polymorphisms in Greek patients with sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2006;23(1): 23–9. Marinis JM, Homer CR, McDonald C, Abbott DW. A novel motif in the Crohn’s disease susceptibility protein, NOD2, allows TRAF4 to down-regulate innate immune responses. J Biol Chem. 2011;286(3):1938–50. Culver DA, Newman LS, Kavuru MS. Gene-environment interactions in sarcoidosis: challenge and opportunity. Clin Dermatol. 2007;25(3):267–75. Haimovic A, Sanchez M, Judson MA, Prystowsky S. Sarcoidosis: a comprehensive review and update for the dermatologist: part II. Extracutaneous disease. J Am Acad Dermatol. 2012;66(5):719 e1–10; quiz 729–30. Baughman RP, Teirstein AS, Judson MA, Rossman MD, Yeager H Jr, Bresnitz EA, et al. Clinical characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Care Med. 2001;164(10 Pt 1):1885–9. Nozaki K, Judson MA. Neurosarcoidosis: clinical manifestations, diagnosis and treatment. Presse Med. 2012;41(6 Pt 2): e331–48. Berliner AR, Haas M, Choi MJ. Sarcoidosis: the nephrologist’s perspective. Am J Kidney Dis. 2006;48(5):856–70. Mantini N, Williams B Jr, Stewart J, Rubinsztain L, Kacharava A. Cardiac sarcoid: a clinician’s review on how to approach the patient with cardiac sarcoid. Clin Cardiol. 2012;35(7):410–5.

45. Kim JS, Judson MA, Donnino R, Gold M, Cooper LT Jr, Prystowsky EN, et al. Cardiac sarcoidosis. Am Heart J. 2009;157(1):9–21. 46. English JC 3rd, Patel PJ, Greer KE. Sarcoidosis. J Am Acad Dermatol. 2001;44(5):725–43; quiz 744–6. 47. Newman LS, Rose CS, Maier LA. Sarcoidosis. New Engl J Med. 1997;336(17):1224–34. 48. Wilson NJ, King CM. Cutaneous sarcoidosis. Postgrad Med J. 1998;74(877):649–52. 49. Marchell RM, Judson MA. Cutaneous sarcoidosis. Semin Respir Crit Care Med. 2010;31(4):442–51. 50. Marchell RM, Judson MA. Chronic cutaneous lesions of sarcoidosis. Clin Dermatol. 2007;25(3):295–302. 51. Mana J, Marcoval J. Skin manifestations of sarcoidosis. Presse Med. 2012;41(6 Pt 2):e355–74. 52. Marcoval J, Mana J, Rubio M. Specific cutaneous lesions in patients with systemic sarcoidosis: relationship to severity and chronicity of disease. Clin Exp Dermatol. 2011;36(7):739–44. 53. Higgins EM, Salisbury JR, Du Vivier AW. Subcutaneous sarcoidosis. Clin Exp Dermatol. 1993;18(1):65–6. 54. Ahmed I, Harshad SR. Subcutaneous sarcoidosis: is it a specific subset of cutaneous sarcoidosis frequently associated with systemic disease? J Am Acad Dermatol. 2006;54(1):55–60. 55. El Sayed F, Dhaybi R, Ammoury A. Subcutaneous nodular sarcoidosis and systemic involvement successfully treated with doxycycline. Leban Med J. 2006;54(1):42–4. 56. Marcoval J, Moreno A, Mana J, Peyri J. Subcutaneous sarcoidosis. Dermatol Clin. 2008;26(4):553–6, ix. 57. Dalle Vedove C, Colato C, Girolomoni G. Subcutaneous sarcoidosis: report of two cases and review of the literature. Clin Rheumatol. 2011;30(8):1123–8. 58. Meyer-Gonzalez T, Suarez-Perez JA, Lopez-Navarro N, Hidalgo A, Herrera-Ceballos E. Subcutaneous sarcoidosis: a predictor of systemic disease? Eur J Intern Med. 2011;22(6): e162–3. 59. Yanardag H, Pamuk ON, Pamuk GE. Lupus pernio in sarcoidosis: clinical features and treatment outcomes of 14 patients. J Clin Rheumatol. 2003;9(2):72–6. 60. Spiteri MA, Matthey F, Gordon T, Carstairs LS, James DG. Lupus pernio: a clinico-radiological study of thirty-five cases. Br J Dermatol. 1985;112(3):315–22. 61. Elgart ML. Cutaneous sarcoidosis: definitions and types of lesions. Clin Dermatol. 1986;4(4):35–45. 62. Elgart ML. Cutaneous lesions of sarcoidosis. Prim Care. 1978;5(2):249–62. 63. Efthimiou P, Kukar M. Lupus pernio: sarcoid-specific cutaneous manifestation associated with chronic sarcoid arthropathy. J Clin Rheumatol. 2011;17(6):343. 64. Neville E, Mills RG, Jash DK, Mackinnon DM, Carstairs LS, James DG. Sarcoidosis of the upper respiratory tract and its association with lupus pernio. Thorax. 1976;31(6):660–4. 65. James DG. Lupus pernio. Lupus. 1992;1(3):129–31. 66. Baughman RP, Judson MA, Teirstein A, Lower EE, Lo K, Schlenker-Herceg R, et al. Chronic facial sarcoidosis including lupus pernio: clinical description and proposed scoring systems. Am J Clin Dermatol. 2008;9(3):155–61. 67. Grema H, Greve B, Raulin C. Scar sarcoidosis—treatment with the Q-switched ruby laser. Lasers Surg Med. 2002;30(5): 398–400. 68. Holzmann RD, Astner S, Forschner T, Sterry G. Scar sarcoidosis in a child: case report of successful treatment with the pulsed dye laser. Dermatol Surg. 2008;34(3):393–6. 69. House NS, Welsh JP, English JC 3rd. Sarcoidosis-induced alopecia. Dermatol Online J. 2012;18(8):4. 70. Douri T, Chawaf AZ, Alrefaee BA. Cicatricial alopecia due to sarcoidosis. Dermatol Online J. 2003;9(1):16.

A Practical Approach to Cutaneous Sarcoidosis 71. Cho HR, Shah A, Hadi S. Systemic sarcoidosis presenting with alopecia of the scalp. Int J Dermatol. 2004;43(7):520–2. 72. Sakemi H, Oiwa H. Psoriasiform plaques of sarcoidosis. Internal Med. 2009;48(5):391. 73. Mittal RR, Singh SP, Gill SS. Psoriasiform sarcoidosis associated with depigmentation. Indian J Dermatol Venereol Leprol. 1996;62(2):103–5. 74. Mitsuishi T, Nogita T, Kawashima M. Psoriasiform sarcoidosis with ulceration. Int J Dermatol. 1992;31(5):339–40. 75. Jun L, Jia-Wei L, Hong-Zhong J. Ulcerative sarcoidosis. Int J Dermatol. 2014;53(4):e315–6. doi:10.1111/ijd.12088 (Epub 2013 Oct 14). 76. Ichiki Y, Kitajima Y. Ulcerative sarcoidosis: case report and review of the Japanese literature. Acta Dermato-Venereol. 2008;88(5):526–8. 77. Hunt RD, Gonzalez ME, Robinson M, Meehan SA, Franks AG Jr. Ulcerative sarcoidosis. Dermatol Online J. 2012;18(12):29. 78. Zhang H, Ma HJ, Liu W, Yuan XY. Sarcoidosis characterized as acquired ichthyosiform erythroderma. Eur J Dermatol. 2009;19(5):516–7. 79. Vasaghi A, Kalafi A. Unusual manifestation of cutaneous sarcoidosis: a case report of morpheaform sarcoidosis. Acta Med Iran. 2012;50(9):648–51. 80. Kelley BP, George DE, LeLeux TM, Hsu S. Ichthyosiform sarcoidosis: a case report and review of the literature. Dermatol Online J. 2010;16(8):5. 81. Gangopadhyay AK. Ichthyosiform sarcoidosis. Indian J Dermatol Venereol Leprol. 2001;67(2):91–2. 82. Rampin L, Musto A, Marzola MC, Tadayyon S, Ferretti A, Chondrogiannis S, et al. Diagnosis of unknown sarcoidosis associated to erythema nodosum with 18F-FDG PET/CT. Revista Espanola de Medicina Nuclear e Imagen Mol. 2013;32(3): 190–2. 83. Ohta H, Tazawa R, Nakamura A, Kimura Y, Maemondo M, Kikuchi T, et al. Acute-onset sarcoidosis with erythema nodosum and polyarthralgia (Lofgren’s syndrome) in Japan: a case report and a review of the literature. Intern Med. 2006;45 (9):659–62. 84. O’Connor TM, Cagney D, Jahangir A, Brady A, Fitzgibbon J, Lee G, et al. Characteristics of patients presenting with erythema nodosum and sarcoidosis. Ir Med J. 2009;102(6):181–4. 85. Donmez S, Kisacik B, Pamuk ON, Pehlivan Y, Aydogdu E, Yurekli OA, et al. Are clinical features in Lofgren’s syndromerelated erythema nodosum different from idiopathic erythema nodosum? Sarcoidosis Vasc Diffuse Lung Dis. 2012;29(2): 128–31. 86. Hillerdal G, Nou E, Osterman K, Schmekel B. Sarcoidosis: epidemiology and prognosis. A 15-year European study. Am Rev Respir Dis. 1984;130(1):29–32. 87. Pietinalho A, Ohmichi M, Hiraga Y, Lofroos AB, Selroos O. The mode of presentation of sarcoidosis in Finland and Hokkaido, Japan. A comparative analysis of 571 Finnish and 686 Japanese patients. Sarcoidosis Vasc Diffuse Lung Dis. 1996; 13(2):159–66. 88. Judson MA. The diagnosis of sarcoidosis. Clin Chest Med. 2008;29(3):415–27, viii. 89. Ivemark BI. Observations on the histopathology of sarcoidosis. Acta Med Scand Suppl. 1956;312:438–42. 90. Takahashi M. Histopathology of sarcoidosis and its immunological bases. Acta Pathol Jpn. 1970;20(2):171–82. 91. Marcoval J, Mana J, Moreno A, Gallego I, Fortuno Y, Peyri J. Foreign bodies in granulomatous cutaneous lesions of patients with systemic sarcoidosis. Arch Dermatol. 2001;137(4):427–30. 92. Costabel U, Guzman J, Baughman RP. Systemic evaluation of a potential cutaneous sarcoidosis patient. Clin Dermatol. 2007;25(3):303–11.

93. Costabel U, Hunninghake GW. ATS/ERS/WASOG statement on sarcoidosis. Sarcoidosis Statement Committee. American Thoracic Society. European Respiratory Society. World Association for Sarcoidosis and Other Granulomatous Disorders. Eur Respir J. 1999;14(4):735–7. 94. Bodaghi B, Touitou V, Fardeau C, Chapelon C, LeHoang P. Ocular sarcoidosis. Presse Med. 2012;41(6 Pt 2):e349–54. 95. Rothova A. Ocular involvement in sarcoidosis. Br J Ophthalmol. 2000;84(1):110–6. 96. Dubrey SW, Falk RH. Diagnosis and management of cardiac sarcoidosis. Prog Cardiovasc Dis. 2010;52(4):336–46. 97. Chapelon-Abric C. Cardiac sarcoidosis. Curr Opin Pulm Med. 2013;19(5):493–502. 98. Martusewicz-Boros MM, Piotrowska-Kownacka D, Domagala J, Kowalewski M, Wiatr E. Cardiac sarcoidosis mimicking ischaemic infarct. Kardiol Pol. 2014;72(1):86. 99. Nakamura S, Hashimoto Y, Nishi K, Takeda K, Mizumoto T, Demitsu T, et al. High rate of cardiac sarcoidosis presenting with cutaneous plaque type sarcoidosis in 18F-fluorodeoxyglucose positron emission tomography-computed tomography: a case series. J Med Case Rep. 2014;8(1):17. 100. Rosenbach M. Practice gaps. The dermatologist’s role in sarcoidosis. JAMA Dermatol. 2013;149(6):760–1. 101. Anolik RB, Schaffer A, Kim EJ, Rosenbach M. Thyroid dysfunction and cutaneous sarcoidosis. J Am Acad Dermatol. 2012;66(1):167–8. 102. Sage RJ, Rao DS, Burke RR, Lim HW. Preventing vitamin D toxicity in patients with sarcoidosis. J Am Acad Dermatol. 2011;64(4):795–6. 103. Gupta D, Kumar S, Aggarwal AN, Verma I, Agarwal R. Interferon gamma release assay (QuantiFERON-TB Gold In Tube) in patients of sarcoidosis from a population with high prevalence of tuberculosis infection. Sarcoidosis Vasc Diffuse Lung Dis. 2011;28(2):95–101. 104. Studdy PR, Bird R. Serum angiotensin converting enzyme in sarcoidosis—its value in present clinical practice. Ann Clin Biochem. 1989;26(Pt 1):13–8. 105. Cox CE, Donohue JF, Brown CD, Kataria YP, Judson MA. The Sarcoidosis Health Questionnaire: a new measure of healthrelated quality of life. Am J Respir Crit Care Med. 2003;168(3): 323–9. 106. Victorson DE, Choi S, Judson MA, Cella D. Development and testing of item response theory-based item banks and short forms for eye, skin and lung problems in sarcoidosis. Qual Life Res. 2014;23(4):1301–13. doi:10.1007/s11136-013-0567-6 (Epub 2013 Nov 9). 107. Rosenbach M, Yeung H, Chu EY, Kim EJ, Payne AS, Takeshita J, et al. Reliability and convergent validity of the cutaneous sarcoidosis activity and morphology instrument for assessing cutaneous sarcoidosis. JAMA Dermatol. 2013;149(5):550–6. 108. Khatri KA, Chotzen VA, Burrall BA. Lupus pernio: successful treatment with a potent topical corticosteroid. Arch Dermatol. 1995;131(5):617–8. 109. Wise RD. Clinical resolution of facial cutaneous sarcoidosis with systemic colchicine and a topical corticosteroid ointment. Compr Ther. 2008 Summer;34(2):105–10. 110. Volden G. Successful treatment of chronic skin diseases with clobetasol propionate and a hydrocolloid occlusive dressing. Acta Dermato-Venereol. 1992;72(1):69–71. 111. Bersani TA, Nichols CW. Intralesional triamcinolone for cutaneous palpebral sarcoidosis. Am J Ophthalmol. 1985;99(5):561–2. 112. Callen JP. Intralesional corticosteroids. J Am Acad Dermatol. 1981;4(2):149–51. 113. Singh SK, Singh S, Pandey SS. Cutaneous sarcoidosis without systemic involvement: response to intralesional corticosteroid. Indian J Dermatol Venereol Leprol. 1996;62(4):273–4.

K. A. Wanat, M. Rosenbach 114. Green CM. Topical tacrolimus for the treatment of cutaneous sarcoidosis. Clin Exp Dermatol. 2007;32(4):457–8. 115. Gutzmer R, Volker B, Kapp A, Werfel T. [Successful topical treatment of cutaneous sarcoidosis with tacrolimus]. Hautarzt. 2003;54(12):1193–7. 116. Katoh N, Mihara H, Yasuno H. Cutaneous sarcoidosis successfully treated with topical tacrolimus. Br J Dermatol. 2002;147(1):154–6. 117. Vano-Galvan S, Fernandez-Guarino M, Carmona LP, Harto A, Carrillo R, Jaen P. Lichenoid type of cutaneous sarcoidosis: great response to topical tacrolimus. Eur J Dermatol. 2008;18 (1):89–90. 118. Hasegawa T, Suga Y, Mizuno Y, Haruna K, Ikeda S. Photodynamic therapy using intense pulsed light for cutaneous sarcoidosis. J Dermatol. 2012;39(6):564–5. 119. Penrose C, Mercer SE, Shim-Chang H. Photodynamic therapy for the treatment of cutaneous sarcoidosis. J Am Acad Dermatol. 2011;65(1):e12–4. 120. Karrer S, Abels C, Wimmershoff MB, Landthaler M, Szeimies RM. Successful treatment of cutaneous sarcoidosis using topical photodynamic therapy. Arch Dermatol. 2002;138(5):581–4. 121. Wilsmann-Theis D, Bieber T, Novak N. Photodynamic therapy as an alternative treatment for cutaneous sarcoidosis. Dermatology. 2008;217(4):343–6. 122. Kondo C, Watanabe D, Nakaseko H, Morishita M, Tsuboi T, Tamada Y, et al. Photodynamic therapy for recurrent sarcoid flexor tenosynovitis of the finger. J Am Acad Dermatol. 2006;55(5 Suppl):S99–101. 123. Green JJ, Lawrence N, Heymann WR. Generalized ulcerative sarcoidosis induced by therapy with the flashlamp-pumped pulsed dye laser. Arch Dermatol. 2001;137(4):507–8. 124. Roos S, Raulin C, Ockenfels HM, Karsai S. Successful treatment of cutaneous sarcoidosis lesions with the flashlamp pumped pulsed dye laser: a case report. Dermatol Surg. 2009;35(7):1139–40. 125. Frederiksen LG, Jorgensen K. Sarcoidosis of the nose treated with laser surgery. Rhinology. 1996;34(4):245–6. 126. Hocar O, Faye O, Wolkenstein P, Goldzal S, Revuz J, Cosnes A. Cutaneous sarcoidosis: efficacy of KTP laser. Ann Dermatol Venereol. 2007;134(2):174–5. 127. James JC, Simpson CB. Treatment of laryngeal sarcoidosis with CO2 laser and mitomycin-C. Otolaryngol Head Neck Surg. 2004;130(2):262–4. 128. Ruff T, Bellens EE. Sarcoidosis of the larynx treated with CO2 laser. J Otolaryngol. 1985;14(4):245–7. 129. Gleeson CM, Morar N, Staveley I, Bunker CB. Treatment of cutaneous sarcoid with topical gel psoralen and ultraviolet A. Br J Dermatol. 2011;164(4):892–4. 130. Graefe T, Konrad H, Barta U, Wollina U, Elsner P. Successful ultraviolet al treatment of cutaneous sarcoidosis. Br J Dermatol. 2001;145(2):354–5. 131. Mahnke N, Medve-Koenigs K, Berneburg M, Ruzicka T, Neumann NJ. Cutaneous sarcoidosis treated with medium-dose UVA1. J Am Acad Dermatol. 2004;50(6):978–9. 132. Jones E, Callen JP. Hydroxychloroquine is effective therapy for control of cutaneous sarcoidal granulomas. J Am Acad Dermatol. 1990;23(3 Pt 1):487–9. 133. Marchetti M, Baker MG, Noland MM. Treatment of subcutaneous sarcoidosis with hydroxychloroquine: report of 2 cases. Dermatol Online J. 2014;20(1):21250. 134. Meyersburg D, Schon MP, Bertsch HP, Seitz CS. Uncommon cutaneous ulcerative and systemic sarcoidosis. Successful treatment with hydroxychloroquine and compression therapy. Hautarzt. 2011;62(9):691–5.

135. Modi S, Rosen T. Micropapular cutaneous sarcoidosis: case series successfully managed with hydroxychloroquine sulfate. Cutis Cutan Med Pract. 2008;81(4):351–4. 136. Siltzbach LE, Teirstein AS. Chloroquine therapy in 43 patients with intrathoracic and cutaneous sarcoidosis. Acta Med Scand Suppl. 1964;425:302–8. 137. Zic JA, Horowitz DH, Arzubiaga C, King LE Jr. Treatment of cutaneous sarcoidosis with chloroquine. Review of the literature. Arch Dermatol. 1991;127(7):1034–40. 138. Badgwell C, Rosen T. Cutaneous sarcoidosis therapy updated. J Am Acad Dermatol. 2007;56(1):69–83. 139. Bachelez H, Senet P, Cadranel J, Kaoukhov A, Dubertret L. The use of tetracyclines for the treatment of sarcoidosis. Arch Dermatol. 2001;137(1):69–73. 140. Miyazaki E, Ando M, Fukami T, Nureki S, Eishi Y, Kumamoto T. Minocycline for the treatment of sarcoidosis: is the mechanism of action immunomodulating or antimicrobial effect? Clin Rheumatol. 2008;27(9):1195–7. 141. Schmitt CE, Fabi SG, Kukreja T, Feinberg JS. Hypopigmented cutaneous sarcoidosis responsive to minocycline. J Drugs Dermatol. 2012;11(3):385–9. 142. Steen T, English JC. Oral minocycline in treatment of cutaneous sarcoidosis. JAMA Dermatol. 2013;149(6):758–60. 143. Kircik LH. Doxycycline and minocycline for the management of acne: a review of efficacy and safety with emphasis on clinical implications. J Drugs Dermatol. 2010;9(11):1407–11. 144. Park MK, Fontana JR, Babaali H, Gilbert-McClain LI, Stylianou M, Joo J, et al. Steroid-sparing effects of pentoxifylline in pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2009;26(2):121–31. 145. Zabel P, Entzian P, Dalhoff K, Schlaak M. Pentoxifylline in treatment of sarcoidosis. Am J Respir Crit Care Med. 1997;155(5):1665–9. 146. Baughman RP, Judson MA, Ingledue R, Craft NL, Lower EE. Efficacy and safety of apremilast in chronic cutaneous sarcoidosis. Arch Dermatol. 2012;148(2):262–4. 147. Veien NK. Cutaneous sarcoidosis: prognosis and treatment. Clin Dermatol. 1986;4(4):75–87. 148. Baughman RP, Lower EE. Evidence-based therapy for cutaneous sarcoidosis. Clin Dermatol. 2007;25(3):334–40. 149. Baughman RP, Nunes H. Therapy for sarcoidosis: evidence-based recommendations. Expert Rev Clin Immunol. 2012;8(1):95–103. 150. Doherty CB, Rosen T. Evidence-based therapy for cutaneous sarcoidosis. Drugs. 2008;68(10):1361–83. 151. Mosam A, Morar N. Recalcitrant cutaneous sarcoidosis: an evidence-based sequential approach. J Dermatol Treat. 2004;15 (6):353–9. 152. Veien NK, Brodthagen H. Cutaneous sarcoidosis treated with methotrexate. Br J Dermatol. 1977;97(2):213–6. 153. Kouba DJ, Mimouni D, Rencic A, Nousari HC. Mycophenolate mofetil may serve as a steroid-sparing agent for sarcoidosis. Br J Dermatol. 2003;148(1):147–8. 154. Muller-Quernheim J, Kienast K, Held M, Pfeifer S, Costabel U. Treatment of chronic sarcoidosis with an azathioprine/prednisolone regimen. Eur Respir J. 1999;14(5):1117–22. 155. Vorselaars AD, Wuyts WA, Vorselaars VM, Zanen P, Deneer VH, Veltkamp M, et al. Methotrexate vs azathioprine in secondline therapy of sarcoidosis. Chest. 2013;144(3):805–12. 156. Carlesimo M, Giustini S, Rossi A, Bonaccorsi P, Calvieri S. Treatment of cutaneous and pulmonary sarcoidosis with thalidomide. J Am Acad Dermatol. 1995;32(5 Pt 2):866–9. 157. Hoch O, Muller S, Buttner G, Mensing H. [Thalidomide in the treatment of cutaneous and systemic sarcoidosis]. Hautarzt. 2001;52(10 Pt 2):962–5.

A Practical Approach to Cutaneous Sarcoidosis 158. Lee JB, Koblenzer PS. Disfiguring cutaneous manifestation of sarcoidosis treated with thalidomide: a case report. J Am Acad Dermatol. 1998;39(5 Pt 2):835–8. 159. Nguyen YT, Dupuy A, Cordoliani F, Vignon-Pennamen MD, Lebbe C, Morel P, et al. Treatment of cutaneous sarcoidosis with thalidomide. J Am Acad Dermatol. 2004;50(2):235–41. 160. Rousseau L, Beylot-Barry M, Doutre MS, Beylot C. Cutaneous sarcoidosis successfully treated with low doses of thalidomide. Arch Dermatol. 1998;134(8):1045–6. 161. Baughman RP, Lower EE. Newer therapies for cutaneous sarcoidosis: the role of thalidomide and other agents. Am J Clin Dermatol. 2004;5(6):385–94. 162. Fazzi P, Manni E, Cristofani R, Cei G, Piazza S, Calabrese R, et al. Thalidomide for improving cutaneous and pulmonary sarcoidosis in patients resistant or with contraindications to corticosteroids. Biomed Pharmacother. 2012;66(4):300–7. 163. Oliver SJ, Kikuchi T, Krueger JG, Kaplan G. Thalidomide induces granuloma differentiation in sarcoid skin lesions associated with disease improvement. Clin Immunol. 2002;102(3): 225–36. 164. Dalm VA, van Hagen PM. Efficacy of lenalidomide in refractory lupus pernio. JAMA Dermatol. 2013;149(4):493–4. 165. Burns AM, Green PJ, Pasternak S. Etanercept-induced cutaneous and pulmonary sarcoid-like granulomas resolving with adalimumab. J Cutan Pathol. 2012;39(2):289–93. 166. Field S, Regan AO, Sheahan K, Collins P. Recalcitrant cutaneous sarcoidosis responding to adalimumab but not to etanercept. Clin Exp Dermatol. 2010;35(7):795–6. 167. Heffernan MP, Smith DI. Adalimumab for treatment of cutaneous sarcoidosis. Arch Dermatol. 2006;142(1):17–9. 168. Pariser RJ, Paul J, Hirano S, Torosky C, Smith M. A doubleblind, randomized, placebo-controlled trial of adalimumab in the treatment of cutaneous sarcoidosis. J Am Acad Dermatol. 2013;68(5):765–73. 169. Philips MA, Lynch J, Azmi FH. Ulcerative cutaneous sarcoidosis responding to adalimumab. J Am Acad Dermatol. 2005;53(5):917. 170. Fok KC, Ng WW, Henderson CJ, Connor SJ. Cutaneous sarcoidosis in a patient with ulcerative colitis on infliximab. J Crohns Colitis. 2012;6(6):708–12. 171. Heffernan MP, Anadkat MJ. Recalcitrant cutaneous sarcoidosis responding to infliximab. Arch Dermatol. 2005;141(7):910–1. 172. Meyerle JH, Shorr A. The use of infliximab in cutaneous sarcoidosis. J Drugs Dermatol. 2003;2(4):413–4. 173. Rosen T, Doherty C. Successful long-term management of refractory cutaneous and upper airway sarcoidosis with periodic infliximab infusion. Dermatol Online J. 2007;13(3):14.

174. Sene T, Juillard C, Rybojad M, Cordoliani F, Lebbe C, Morel P, et al. Infliximab as a steroid-sparing agent in refractory cutaneous sarcoidosis: single-center retrospective study of 9 patients. J Am Acad Dermatol. 2012;66(2):328–32. 175. Tu J, Chan J. Cutaneous sarcoidosis and infliximab: evidence for efficacy in refractory disease. Aust J Dermatol. 2013. doi:10. 1111/ajd.12056 (Epub ahead of print). 176. Tuchinda P, Bremmer M, Gaspari AA. A case series of refractory cutaneous sarcoidosis successfully treated with infliximab. Dermatol Ther. 2012;2(1):11. 177. Wanat KA, Rosenbach M. Case series demonstrating improvement in chronic cutaneous sarcoidosis following treatment with TNF inhibitors. Arch Dermatol. 2012;148(9):1097–100. 178. Utz JP, Limper AH, Kalra S, Specks U, Scott JP, Vuk-Pavlovic Z, et al. Etanercept for the treatment of stage II and III progressive pulmonary sarcoidosis. Chest. 2003;124(1):177–85. 179. Stagaki E, Mountford WK, Lackland DT, Judson MA. The treatment of lupus pernio: results of 116 treatment courses in 54 patients. Chest. 2009;135(2):468–76. 180. Thielen AM, Barde C, Saurat JH, Laffitte E. Refractory chronic cutaneous sarcoidosis responsive to dose escalation of TNFalpha antagonists. Dermatology. 2009;219(1):59–62. 181. Fraser SJ, Hill AT, McKay DA, Reid WA, Mathers ME, MacDougall G, et al. Cutaneous tuberculosis revealed by infliximab therapy for presumed sarcoidosis. Clin Exp Dermatol. 2010;35(4):e141–2. 182. Dhaille F, Viseux V, Caudron A, Dadban A, Tribout C, Boumier P, et al. Cutaneous sarcoidosis occurring during anti-TNF-alpha treatment: report of two cases. Dermatology. 2010;220(3): 234–7. 183. Santos G, Sousa LE, Joao AM. Exacerbation of recalcitrant cutaneous sarcoidosis with adalimumab—a paradoxical effect? A case report. An Bras Dermatol. 2013;88(6 Suppl 1):26–8. 184. Georgiou S, Monastirli A, Pasmatzi E, Tsambaos D. Cutaneous sarcoidosis: complete remission after oral isotretinoin therapy. Acta Dermato-Venereol. 1998;78(6):457–9. 185. Pignone AM, Rosso AD, Fiori G, Matucci-Cerinic M, Becucci A, Tempestini A, et al. Melatonin is a safe and effective treatment for chronic pulmonary and extrapulmonary sarcoidosis. J Pineal Res. 2006;41(2):95–100. 186. York EL, Kovithavongs T, Man SF, Rebuck AS, Sproule BJ. Cyclosporine and chronic sarcoidosis. Chest. 1990;98(4): 1026–9. 187. Sahoo DH, Bandyopadhyay D, Xu M, Pearson K, Parambil JG, Lazar CA, et al. Effectiveness and safety of leflunomide for pulmonary and extrapulmonary sarcoidosis. Eur Respir J. 2011;38(5):1145–50.