Are You Confident of the Diagnosis?
Sarcoidosis is a multisystem granulomatous disease that can impact almost every organ system of the body. While the majority of patients have pulmonary involvement, a significant subset of patients have cutaneous manifestations. In a minority of patients the cutaneous manifestations are the primary organ system affected.
The role of the dermatologist is generally two-fold. First, in cases of suspected sarcoidosis, a thorough cutaneous evaluation can help clinch the diagnosis, with readily accessible skin lesions offering a minimally invasive option for obtaining tissue to identify granulomatous inflammation. Second, due to the protean nature of sarcoidosis and the multiple morphologies with which this disease can manifest, a skilled dermatologist is essential in recognizing, following, and managing patients with cutaneous involvement.
Sarcoidosis can affect patients of any age, both genders, and all ethnic backgrounds. Patients may have different clinical manifestations and different disease presentations based on their geographic or racial background, with certain disease subsets or organ-system involvement being more common in certain populations. In the United States, the rate of sarcoidosis is 10.9/100,000 population in whites, and 35.5/100,000 in blacks. Patients of African-American ancestry with sarcoidosis are more likely to experience a chronic course and have higher rates of complications and death due to sarcoidosis.
Characteristic findings on physical examination
Overall, skin involvement occurs in approximately 25-30% of patients with sarcoidosis; cutaneous disease is frequently under-recognized and may be missed without a careful, total body examination by an experienced dermatologist. Sarcoidosis is truly one of the “great imitators;” the cutaneous manifestations are quite varied and it is important to maintain a high index of suspicion when evaluating patients for presumed sarcoidosis.
Cutaneous manifestations consist of two major categories: lesions specific to sarcoidosis, characterized by granulomatous infiltrates in the skin, and nonspecific lesions resulting from the immunologic response, the classic example being erythema nodosum (EN).
Specific lesions include violaceous macules and papules, plaques (Figure 1, Figure 2, Figure 3), subcutaneous nodules (frequently referred to as Darier-Roussy variant; Figure 4), and lupus pernio—violaceous and variably keratotic papules and plaques involving the nose, nasal ala, and perinasal facial skin (Figure 5). Other, less common presentations of cutaneous sarcoidosis include psoriasiform lesions, alopecia, erythroderma, ulcers, or ichthyosis. Lesions of sarcoidosis may develop preferentially in sites of trauma, including scar- or tattoo-associated lesions (Figure 6).
Sarcoidosis can truly present as almost any primary lesion in the skin (there have not been well defined reports of vesicular, pustular, or bullous variants); when in doubt, or in uncertain cases, skin biopsy to evaluate for non-caseating epithelioid cell granulomas may be necessary to distinguish lesions of sarcoidosis from mimickers.
In general, lesions of sarcoidosis are asymptomatic. Certain patients may complain of pruritus or pain associated with some lesions, but overall patient-related symptoms are of little value in making the diagnosis.
Most commonly patients will present with erythematous-to-violaceous papules or plaques, often involving the nose. In many patients, systemic involvement will manifest as fatigue, and as 90% of patients have pulmonary involvement, it is relatively common to have patients note dyspnea and/or a chronic dry non-productive cough on review of systems. Extracutaneous organ system involvement varies from patient to patient, and a thorough review of systems is essential in evaluating patients and helping direct appropriate referrals to subspecialists.
Expected results of diagnostic studies
The diagnosis of sarcoidosis requires suggestive clinicoradiologic findings and histologic evidence of noncaseating epithelioid cell granulomas, as well as the exclusion of other sources of granulomas.
There are a few rare exceptions to this, where a diagnosis of sarcoidosis may be assumed even in the absence of supportive histology – Löfgren’s syndrome, with bilateral hilar adenopathy on chest imaging, erythema nodosum, fever and arthralgias/arthritis; Heerfort’s syndrome, with uveitis, parotiditis, and fever; asymptomatic bilateral hilar adenopathy on chest imaging, or gallium-67 scan findings of the pathognomonic “Panda” or “Lambda” sign due to specific patterns of uptake on scans.
When evaluating a patient for suspected sarcoidosis, all patients should have a chest x-ray (PA and lateral) to look for hilar adenopathy or interstitial disease (if the findings are nonspecific, a high-resolution non-contrast CT of the chest can further evaluate the lung parenchyma and identify lymphadenopathy). Every patient should see an ophthalmologist for a professional, comprehensive ocular examination.
Every patient with suspected sarcoidosis should have either a tuberculin skin test (PPD) or a serum IFN-γ release assay (e.g., Quantiferon-TB gold™ test) to exclude tuberculosis, which can present with similar radiologic signs as sarcoidosis. Pulmonary function testing, including measurement of the diffusing capacity of the lung for carbon monoxide (DLCO) should be performed on all patients as well, as interstitial disease can be missed on routine radiography.
A tissue diagnosis is generally required for the disease, and the dermatologist can be essential in identifying appropriate suspect lesions and performing a skin biopsy, which in many cases can obviate the need for more invasive and higher risk tissue sampling. (Nevertheless, as cutaneous involvement is only present in a subset of patients, many will require mediastinoscopy, bronchoscopy, or CT-guided biopsy to obtain tissue for diagnostic purposes).
When biopsying a patient with the intent of finding granulomas to help make a diagnosis of sarcoidosis, dermatologists should consider sending a tissue culture along with the histologic sample. Granulomatous infectious processes can be difficult to distinguish from sarcoidosis in certain cases, and a negative tissue culture (grown for 6 weeks, to help rule out atypical mycobacterial infections) and negative special stains can support a diagnosis of sarcoidosis.
The classic histologic findings in sarcoidosis are noncaseating epithelioid cell granulomas, often with a sparse or absent rim of lymphocytes around the granulomas (Figure 7, Figure 8). Granulomas may be present at any level of the dermis, including extension into or isolated lesions within the subcutis. Epidermal changes are less common, but can be present in hyperkeratotic or ulcerative lesions. Granulomas tracking into pilar muscles or dissecting into cutaneous nerves should raise suspicion for an infectious process. Extensive necrosis is rare in sarcoidosis, and should prompt consideration for infection or malignancy.
Special stains for microorganisms, including AFB/Fite and in many cases Gram and fungal stains should be performed. All samples should undergo polarized light examination, although patients with sarcoidosis may have polarizable material within biopsy specimens (some reports note 26%). Granulomas may show formation of asteroid bodies (stellate eosinophilic globules within multinucleated giant cells) or Schaumann bodies (areas of calcification, often within the histiocytes or giant cells), but these are frequently absent, are nonspecific, and not required for the diagnosis (Figure 9).
Basic laboratory testing should be performed in all patients with newly diagnosed or suspected sarcoidosis. A complete blood count (CBC) should be performed, as a small minority of patients will have bone marrow involvement and cytopenias as a result of granulomatous infiltration of the marrow (this is rarely severe, though up to 20% of patients may have mild anemia and up to 40% may have leucopenia, which is rarely clinically relevant).
A comprehensive metabolic panel to evaluate kidney function (actual granulomatous infiltration of the kidneys is rare, but renal disease due to persistent hypercalcemia and hypercalcuria is not uncommon) and hepatic function (again, clinically apparent liver disease is uncommon, but autopsy studies suggest that more than half of patients with sarcoid will have hepatic involvement).
Serum calcium studies should be performed in all patients, as granulomas are frequently metabolically active and may metabolize vitamin D to its active form, with resultant increased serum calcium levels (it is worthwhile to mention that in patients with unexplained hypercalcemia, chest radiography to evaluate for hilar adenopathy or other signs of sarcoidosis may be warranted).
Physicians who primarily manage patients with sarcoidosis should also consider a 24-hour urine calcium measurement, as persistent hypercalcuria may go undiagnosed but lead to kidney stones and renal injury. Measurements of vitamin D levels are often helpful in patients with sarcoidosis; physicians should check both 25-hydroxy vitamin D and 1,25 dihydroxy-vitamin D levels, as the granulomas may convert the 25-hydroxy form to the metabolically active 1,25-dihydroxy form.
Granulomas may also be the source for angiotensin converting enzyme (ACE). Serum ACE levels are neither sensitive nor specific for sarcoidosis, and are not elevated in all patients with sarcoidosis (approximately two thirds of patients will have elevated ACE levels). It is reasonable to check a baseline ACE level; in a subset of patients the ACE level may track with disease activity, but it is not considered a reliable tool on which to base therapeutic management decisions.
Every patient with sarcoidosis should have an electrocardiogram (ECG); while cardiac sarcoidosis is rare (at least in the United States; in Japan, cardiac involvement is actually more common), one of the most common presentations of cardiac sarcoidosis is “sudden cardiac death.” Screening ECGs are indicated in any patient with sarcoidosis; patients with conduction abnormalities or unexplained ECG abnormalities should be referred to a cardiologist. Some suggest that all patients with sarcoidosis should get a baseline trans-thoracic echocardiogram and physicians should consider a 24-hour Holter monitor.
Patients with sarcoidosis who complain of palpitations and have a normal ECG may warrant more intense evaluation and should be referred to a specialist for consideration of either cardiac magnetic resonance imaging (MRI) or cardiac positron emission tomography (PET) scan. These guidelines are in flux, and when faced with a patient with suspected cardiac sarcoidosis, patients may benefit from referral to an experienced cardiologist.
Additionally, due to emerging data suggesting patients with sarcoidosis may be at higher risk of thyroid dysfunction, all patients with sarcoidosis should have a baseline measurement of the thyroid stimulating hormone, and if levels are abnormal a full set of thyroid function tests.
Patients with extensive facial disease, especially patients with severe lupus pernio and numerous perinasal lesions, should be evaluated by an otorhinolaryngologist for sinus or upper airway granulomatous inflammation.
Immunoglobulin abnormalities have been reported in some patients with sarcoidosis, but routine screening of quantitative immunoglobulin levels is not generally necessary.
In sum: all patients should have chest imaging, pulmonary function testing, an ophthalmologic evaluation, and blood work including CBC, complete metabolic panel (CMP), and serum calcium. Evaluation for tuberculosis via tuberculin skin testing (PPD) or IFNγ release assay is indicated in all patients. Measurement of urine calcium (with a 24-hour urine study), vitamin D levels, ACE levels, and thyroid function testing should be considered.
All patients should have a baseline ECG, and any symptomatic patients should be referred for evaluation by a cardiologist familiar with sarcoidosis, for consideration for a cardiac MRI or PET scan to evaluate for cardiac sarcoidosis. Unless there is pathognomonic radiologic evidence of sarcoidosis or a classic clinical presentation of a variant such as Löfgren’s syndrome, tissue diagnosis should be sought.
Many of these tests should be repeated at regular intervals. It is reasonable to share the evaluation and follow-up of patients with sarcoidosis with a skilled primary care doctor or a pulmonologist; dermatologists who are primarily managing patients with sarcoidosis should consider at least annual chest radiographic evaluation, pulmonary function tests (PFTs), and eye examinations, with regular laboratory evaluation.
The disease course can be quite varied; patients with Löfgren’s syndrome often present more acutely, with active systemic inflammation, but usually will resolve within a few years of disease onset. Patients with lupus pernio tend to have a more chronic, protracted course. Patients whose disease persists beyond 3 to 4 years generally continue to have active disease and will rarely self-resolve. African American patients with cutaneous sarcoidosis often have a chronic course. Patients with lupus pernio also tend to have treatment-resistant disease, and managing these patients can be quite challenging.
Patients should be followed by a team of doctors familiar with sarcoidosis and based on each individual patient’s affected organ systems; treatment decisions are often made with an effort to control the granulomatous inflammation in the most severely affected organ system (e.g., in patients’ with neurosarcoidosis, management will be driven by the neurologist; in patients with primarily pulmonary sarcoidosis, the pulmonologist’s role is essential).
Skin involvement frequently tracks with internal organ involvement, but it is not uncommon for patients to achieve adequate disease control internally but have persistent cutaneous involvement, which requires the care of a skilled dermatologist.
The differential diagnosis for patients presenting with suspected sarcoidosis can be broad, and varies depending on the organ systems involved in each individual case. In general, when evaluating patients for cutaneous sarcoidosis, clinicians should attempt to rule out atypical infections such as tuberculosis, leprosy, atypical mycobacterial infections, and deep fungal infections. Foreign body reactions can stimulate granuloma formation, and detailed history and histopathologic examination of tissue specimens is essential.
Other cutaneous granulomatous diseases can occasionally either be confused with or overlap with cutaneous sarcoidosis. Granuloma annulare, necrobiosis lipoidica, and rheumatoid nodules should be considered. In patients presenting with erythema nodosum, it may be challenging to identify the underlying disease, and patients often require an extensive evaluation (see erythema nodosum chapter). Atypical granulomatous diseases (necrobiotic xanthogranuloma, granulomatous vasculitis, granulomatous slack skin) should be excluded in patients with suspected sarcoidosis.
Granulomatous drug reactions are uncommon, but a reaction to medication should always be considered. With the expanded use of IFN and TNFα inhibitors, two drug categories associated with adverse cutaneous granulomatous reactions, granulomatous medication reactions may become more common.
Who is at Risk for Developing this Disease?
Sarcoidosis is a worldwide disease, affecting both sexes, all ages, and every race. The peak age of onset is in patients in their 20s, with most cases occurring before the age of 40. Women may be affected slightly more often than men. In the United States, the lifetime risk of sarcoidosis is about three times higher in US blacks compared with whites (2.4% to 0.8%).
As noted above, African Americans tend to have more severe manifestations and are more likely to experience a chronic course. Overall disease-related mortality is between 1% to 5% of patients, with patients suffering from severe pulmonary disease, cardiac, or neurosarcoidosis. Patients of Northern European ancestry are more likely to present with acute forms of sarcoidosis, including Löfgren’s syndrome; this clinical variant, and the presence of erythema nodosum in general, appears to portend a more benign long-term outcome, with spontaneous disease remission noted more frequently in patients with this initial presentation.
When evaluating a patient with sarcoidosis, it is important to consider their racial/ethnic background, as patients may have higher rates of internal organ involvement depending on their ancestry (for example, both lupus pernio and uveitis are more common in African Americans, whereas erythema nodosum is more common in whites of European descent; cardiac sarcoidosis is generally a rare manifestation, except in Japanese patients with sarcoidosis).
What is the Cause of the Disease?
The cause of sarcoidosis is unknown. Currently most researchers feel that disease occurs in a genetically susceptible individual exposed to an environmental trigger. Familial clusters of sarcoidosis have been reported. Genomic analysis suggests that this complex disease is likely polygenic; HLA-A1, -B8, and –DR3 may contribute to risk for developing sarcoidosis, and HLA-B12 and –DR4 may confer some degree of protection.
Some studies have shown that patients with sarcoidosis are markedly more likely to have known a patient with the disease as compared with control patients, and there have been both familial and seasonal clusters suggesting a possible environmental or infectious agent. “Salem sarcoid” was initially felt to be a cluster of cases of sarcoidosis in women in Salem, Massachusetts; the identification of a common history of beryllium exposure and the recategorization of that disease as berylliosis demonstrates the need for a thorough exposure history in all patients.
It is possible that the causative or triggering agent responsible for activating the inflammatory granulomatous response varies from patient to patient, and further research is necessary and ongoing to attempt to identify triggers. As diagnostic testing has become more sophisticated, a variety of potential causative agents have been identified, ranging from Propionibacterium acnes to mycobacterial species to other infectious agents.
Large, multicentered epidemiologic studies failed to identify a predominant environmental risk factor, although exposure to moldy environments or insecticides may have an impact on increasing risk for developing sarcoidosis. Notably, cigarette smoking appears to offer some small degree of protective effect; the risks of tobacco inhalation greatly outweigh this isolated small potential benefit, however.
Sarcoidosis causes disease through granulomatous inflammatory infiltration of affected organs and resultant organ system dysfunction, as well as through the metabolic activity of the granulomas themselves, which in some patients may lead to hypercalcemia and secondary complications.
Systemic Implications and Complications
Sarcoidosis is a multisystem disease, and internal organ involvement is common. Ninety percent of patients will have some degree of pulmonary involvement, and all patients must be monitored closely for signs and symptoms of lung disease, both through clinical assessment, review of systems, and routine imaging and lung function testing. While the precise rates of systemic disease vary, many patients with sarcoidosis have constitutional symptoms, particularly fatigue. Approximately one-third of patients will have lymphadenopathy.
Cardiac disease is clinically apparent in only about 5% of patients (although autopsy studies suggest the rates may be much higher); notably, the most common clinical manifestation is sudden death – reemphasizing the need for regular screening and highlighting the critical importance of a thorough clinical history and review of systems in all patients. Hepatic involvement is quite common in autopsy studies, ranging from 50% to 80%; this is rarely clinically apparent, but clinicians should consider this when deciding on and monitoring patients during drug therapy, particularly with methotrexate.
Rates of ocular involvement reported in the literature are inconsistent, though general consensus is that the eyes are affected in approximately 25% of patients, with uveitis the most frequently reported symptom. All patients with sarcoidosis should undergo routine ophthalmologic assessment. Neurosarcoidosis is uncommon, affecting fewer than 10% of patients, and may manifest as cranial nerve disease (particularly a facial nerve palsy), peripheral neuropathy, or neuromuscular disease. Endocrine involvement is common, and includes both hypercalcemia/hypercalcuria and thyroid disease.
Patients will frequently have musculoskeletal complaints, but the rates of joint, synovial, or muscular involvement by sarcoidosis are rare. Bone lesions occur in approximately 10% of patients, typically those with chronic disease, and muscle disease occurs in approximately 1% of patients (although autopsy studies, again, suggest the rates of muscle involvement with granulomatous inflammation are higher).
As sarcoidosis can affect almost any organ, clinicians should maintain a high index of suspicion and obtain appropriate diagnostic testing for unexplained symptoms. While direct renal granulomatous infiltration is rare, it can occur, as can gastric, colonic, gonadal, bone marrow, and other rare manifestations.
The focus of this section is on the management of cutaneous sarcoidosis (see Table I).
|Targeted/Local Therapy||Systemic Therapy*|
|– Class I-VII depending on site||– Antimalarial therapy|
|Topical retinoids||Combination therapy|
|Intralesional steroids:||Tetracycline class antibiotics:|
|– 2.5mg/cc to 20mg/cc depending on site||– Minocycline- Doxycycline- Tetracycline|
|– Pulsed-dye laser for individual cosmetically concerning lesions to target erythema||– Systemic corticosteroids|
|Photodynamic therapy||– Adalimumab|
|Alternative intralesional therapies (Excision with or without grafting and dermabrasion have been reported, but are not favored by the author due to risk of induction of scarring and scar-associated granulomas)||– Azathioprine|
|– Mycophenolate mofetil|
|(Leflunomide, chlorambucil, cyclophosphamide,cyclosporine, melatonin, allopurinol, clofazaimine, fumaric acid esters, and other alternative therapies have been reported in case reports and small case series)|
*Note: the order of therapy varies by disease severity and systemic involvement; for example, antimalarial therapy and thalidomide are predominantly active in the skin and would not be appropriate for patients with primarily pulmonary disease.
^Thalidomide and isotretinoin are generally considered more immunomodulatory drugs rather than immunosuppressive
Optimal Therapeutic Approach for this Disease
Given the wide variability in clinical presentation, with patients ranging from isolated and limited cutaneous granulomatous involvement to patients with catastrophic multisystem disease, the optimal therapeutic approach may be very patient-specific. The approach presented herein is designed to aide dermatologists in managing cutaneous sarcoidosis. If patients with multisystem sarcoidosis have active inflammation in extracutaneous, internal organs, discussions with the appropriate specialist and co-management of these challenging patients is appropriate.
Typically, systemic immunomodulatory or immunosuppressive agents targeted at controlling internal organ disease involvement will also beneficially affect the skin. There exists limited data supporting most of the treatment modalities discussed below, with many of the regimens existing in case reports or case series. Sarcoidosis is an orphan disease, with no Food and Drug Administration (FDA)-approved therapies, and all treatments discussed are off-label uses of medications.
Patients with limited cutaneous disease may respond to topical therapies. The low risk of adverse reactions and limited side effect profile of these medications make the use of topical therapy desirable, whether used alone or in conjunction with systemic medications.
Topical steroids alone can control limited skin disease; the strength of the agent prescribed should take into account both the lesion morphologic type and the anatomic location. Relatively small papules, certain macules, and thin plaques will often respond at least somewhat to topical steroids.
Short courses of class I topical steroids on the trunk and extremities can be beneficial; generally patients should avoid prolonged use of potent topical steroids as they can cause atrophy, hypopigmentation, and telangiectasias. Specifically, use of clobetasol 0.05% or halobetasol 0.05% on thick, hyperkeratotic or infiltrated lesions on the trunk or extremities for 2 to 3 weeks can be helpful (Figure 10); lower potency topicals should be used on delicate areas and areas of thin skin, such as flexural creases, the groin, and the face.
While there is little literature evidence to support their use, anecdotally lesions in these areas can be treated with lower-potency topical steroids (such as hydrocortisone 2.5% cream or ointment), or these lesions may respond somewhat to topical tacrolimus (protopic 0.1% ointment twice daily), although therapeutic effect is generally mild.
Intralesional steroid injections with kenalog can produce more dramatic results. Subcutaneous lesions will typically fail to respond to topical therapy due to the depth of the granulomas, but intralesional injections can target the areas of active granulomatous inflammation and lead to dissolution of the lesion and flattening of the nodules. Physicians are advised to inject at the perceived depth of the granuloma to limit atrophy, which may occur more commonly with injections that are too deep, or hypopigmentation, which may occur more often with too-superficial injections.
When injecting large areas or particularly sensitive anatomic sites, such as the nose and ala, diluting kenalog with lidocaine may make the procedure more tolerable to the patients. Generally the concentration of intralesional steroids injected varies by lesion size, morphology, and anatomic location. For facial lesions a starting concentration of 2.5mg /cc injected is appropriate; higher doses can be safely used on the trunk and extremities.
While there are limited case reports of intralesional injections with alternate agents, including intralesional antimalarials, intralesional methotrexate, and more recently intralesional adalimumab, these reports are sporadic and these agents should be reserved for refractory cases or for experienced dermatologists very familiar with the management of cutaneous sarcoidosis.
There have been a few case reports and small series describing the use of either lasers or photodynamic therapy to treat isolated cutaneous sarcoidal lesions. These cases fail to show consistent or persistent responses, and the optimal use of these therapeutic modalities is unclear. It is worth noting that there are also rare reports of areas of sarcoidosis treated with laser therapy which then ulcerated; as ulcerative sarcoidosis can be particularly challenging to treat and leaves behind scarring, lasers should be used with extreme caution.
Specific lesion types, such as the telangiectatic component of angiolupoid sarcoid, may respond somewhat to pulsed-dye laser. Generally, if these modalities are attempted, it is reasonable to try low strengths and attempt to test-treat a small area before proceeding.
While surgical modalities have been reported to be beneficial for a handful of specific lesions and a limited number of cases, the high rates of scar-associated sarcoid and the frequent reports of sarcoidosis growing into and expanding within a surgical site make these invasive approaches less favorable.
When planning to initiate a systemic therapy, the clinician must balance the disease activity, both in the skin and systemically, with the likely benefits and potential adverse effects of the systemic options available. When patients have multisystem disease, therapeutic management should be based on controlling the most severely affected and most critical organ system. This section is geared towards the management of patients with cutaneous sarcoidosis; in patients with skin involvement and internal involvement, treating the internal disease will frequently improve the skin manifestations.
However, in some cases the cutaneous disease is the primary manifestation and the skin is the most affected organ system, and in other cases skin activity may fail to respond while internal organ sarcoidosis is well controlled. Patients should be counseled that response to medications is generally slow, and for almost every agent detailed below, patients require between 3 and 6 months on therapy to see the beneficial effects of the drug.
Antimalarial therapy is relatively benign, generally well tolerated, and effective in treating cutaneous sarcoidosis. Patients with multiple lesions, not amenable to skin-directed therapy, or who fail to respond to topical agents, should be treated with antimalarials as part of their initial therapy. Hydroxychloroquine 200mg twice daily (maximum 6.5mg/kg) is beneficial to many patients with skin sarcoid; generally it can take between 3 and 6 months to see the full beneficial effects.
It is not uncommon for patients to feel they are not responding to hydroxychloroquine and to discontinue treatment, only then to experience more rapid disease progression as the antimalarial is withdrawn. Patients should be counseled to monitor for development of cutaneous adverse effects and should undergo regular eye examinations to monitor for ocular toxicity.
Although there is little in the scientific literature specifically addressing combination antimalarial therapy for patients with cutaneous sarcoidosis, patients who achieve some benefit from hydroxychloroquine may see additional beneficial effects from the addition of quinacrine, compounded as a 100mg tablet taken once daily, and/or a change to chloroquine, which is more potent than hydroxychloroquine but also has a higher risk of ocular toxicity. Although hydroxychloroquine is rarely associated with hematologic or hepatic adverse effects, checking CBC and CMP after initiating treatment is reasonable; some physicians suggest checking a G6PD level prior to treatment, but the rates of hydroxychloroquine-associated toxicity due to G6PD deficiency are incredibly rare.
Tetracycline-class antibiotics have significant anti-inflammatory effects, and minocycline in particular appears to have some anti-granuloma activity. Minocycline 100mg once or twice daily can help a subset of patients with cutaneous sarcoidosis. Combination therapy with minocycline and hydroxychloroquine may have a synergistic effect, and anecdotally the use of both agents appears to be particularly helpful in certain subsets of cutaneous sarcoidosis, such as subcutaneous sarcoid, or the Darier-Roussy variant. Minocycline can induce hyperpigmentation and patients should be counseled to monitor for abnormal pigmentation.
Patients may experience gastrointestinal disturbances and dizziness; slow-release forms of minocycline may have lower rates of those adverse effects. Minocycline has rarely been associated with severe drug reactions, including DRESS and drug-induced lupus, and patients should have intermittent laboratory monitoring and be counseled to report new or changing symptoms. Doxycycline and tetracycline are less potent, but can be substituted for minocycline in patients either reluctant to try minocycline or who experience treatment-limited gastrointestinal or pigmentary complaints.
Pentoxifylline was shown to be helpful in a small case series of patients with pulmonary sarcoidosis; the beneficial effects for cutaneous sarcoidosis may be minor, but treatment with this drug is generally benign and well tolerated. Patients who have cutaneous sarcoidosis and who are reluctant to initiate therapy with systemic immunosuppressive drugs or drugs that require more regular laboratory monitoring or have a potentially more concerning side effect profile may benefit from addition of pentoxifylline to their regimen.
Pentoxifylline also has some mild TNFα inhibitory effects, and patients who may benefit from TNFα inhibitors but whose insurance does not cover those drugs could benefit from a trial of pentoxifylline. This agent may potentially have a role in treating rare cases of ulcerative sarcoidosis, but data are lacking. There is one small series detailing improvements in patients with cutaneous sarcoidosis in response to apremilast, a novel PDE-inhibitor.
A reasonable initial regimen for patients with primarily skin sarcoidosis is hydroxychloroquine and/or minocycline, with adjunctive topical therapy and targeted intralesional injections. Patients who partially respond may benefit from the addition of quinacrine and/or pentoxifylline. Patients who fail to respond to this initial treatment approach, or who have either more extensive skin involvement, more aggressive skin involvement, or extracutaneous disease activity, may require immunosuppressive therapy.
Systemic corticosteroids are very effective in treating sarcoidosis. Prednisone can rapidly control granulomatous inflammation in almost all organ systems. Patients with sarcoidosis will often receive long courses of medium dose steroids for pulmonary sarcoidosis. Skin lesions tend to respond to systemic steroids while being administered, but frequently relapse after steroid tapering.
A subset of patients with sarcoidosis will require chronic maintenance on low dose systemic corticosteroids. A reasonable regimen is 30 to 40mg/d with a taper of 5mg every 2 weeks, with a goal of getting to 10mg every other day; patients often require months on this dose. Patients should be tapered to the lowest possible dose, as the side effects from chronic steroid use are myriad. Systemic steroids should be considered in patients with rapidly progressing, aggressive, or refractory subtypes of cutaneous sarcoidosis.
Patients who are just initiating systemic therapy may benefit from the addition of systemic corticosteroids initially, as often it takes months to respond to alternate treatments.
Methotrexate has long been considered the mainstay of treatment for cutaneous sarcoidosis. Methotrexate is very effective in treating the skin lesions of sarcoidosis, and more than two-thirds of patients will respond to methotrexate – however, it can take up to 6 months to see the effects, and patients must be counseled up front about the lengthy nature required to evaluate the benefits of this regimen.
Patients being treated with methotrexate should abstain from alcohol consumption and have baseline hepatic assessments, including liver function tests and hepatitis serologies, in addition to the evaluations discussed above for all patients with sarcoidosis.
Folic acid is usually prescribed in conjunction with weekly methotrexate dosing. Generally patients are started at a dose of 5mg to 10mg weekly, with slow increase to a target dose of 15mg to 20mg, with frequent laboratory monitoring, particularly early on in the treatment. Patients undergoing methotrexate treatment are at risk of hepatic fibrosis, and as more than 50% of patients with sarcoidosis may have clinically-silent liver involvement of their disease, this patient population may be at higher risk of developing this complication and should be closely monitored.
Methotrexate can also induce pulmonary fibrosis, and distinguishing between methotrexate toxicity and pulmonary involvement of sarcoidosis can be incredibly challenging; patients should undergo a thorough lung evaluation prior to initiating methotrexate therapy.
In patients who are on hydroxychloroquine, it is reasonable to continue that treatment when initiating methotrexate (or systemic steroids), as the mechanism of action is different and patients may benefit from combination therapy.
While high quality, double-blind, comparative data are generally lacking, there is mounting evidence suggesting that the TNFα inhibitors adalimumab and infliximab may be very effective in treating cutaneous sarcoidosis, even traditionally refractory subtypes such as lupus pernio. As it is challenging to get insurance coverage approval for these drugs, and a number of patients will respond to less immunosuppressive regimens, it is reasonable to consider a variety of therapeutic options and choose a regimen based on the individual patient’s disease activity and severity
TNFα inhibitors seem to be one of the few agents that can achieve reasonable clinical responses in patients with particularly challenging forms of cutaneous sarcoidosis, including lupus pernio.
Notably, etanercept does not seem to be effective in treating sarcoidosis; adalimumab appears to be beneficial, but the best data are with the use of infliximab. Patients should be appropriately evaluated for potential complicating underlying diseases or contraindications prior to undergoing TNFα inhibitor therapy, including assessment for neurologic disease, infection (including latent TB, hepatitis, and HIV), or cardiovascular risk factors.
Clinicians should also be aware that all of the TNFα inhibitors have been reported to cause granulomatous inflammation in rare instances, and treating physicians should monitor patients closely for response to therapy.
TNFα inhibitors may be combined with low-dose methotrexate to potentially reduce the rates of neutralizing antibodies, and continuation of ongoing hydroxychloroquine therapy may also be appropriate. Patients with refractory disease may benefit from multi-agent combination therapy, as the mechanisms of action (and side effect profiles) are different among the different classes of agents.
Azathioprine, or mycophenolate, may be an appropriate choice in patients who fail to respond to the above agents. Azathioprine in particular is frequently used by pulmonologists to treat sarcoid in the lungs, but the skin does not appear to respond as well in limited studies. Mycophenolate therapy has been reported to be beneficial in some patients with cutaneous sarcoidosis, but large studies are lacking.
Both azathioprine and mycophenolate therapy are generally well tolerated, and may be appropriate to try in patients who fail to respond to methotrexate and cannot obtain TNFα inhibitors for insurance reasons or because of medical contraindications.
Data supporting the use of other agents is particularly sparse. Thalidomide has TNFα inhibitory effects and is a potent immunomodulatory drug that may be effective at limiting cutaneous inflammation. Isotretinoin has anti-inflammatory effects and can help a small subset of patients, possibly patients with more hyperkeratotic lesion morphologies, although high-quality data are lacking.
Leflunomide, chlorambucil, cyclophosphamide, cyclosporine, melatonin, allopurinol, clofazaimine, fumaric acid esters, and other alternative therapies have been reported in case reports and small case series, but use of these agents for cutaneous sarcoidosis is not well supported by the literature and these drugs should be considered only in patients who fail to respond or cannot tolerate (or obtain) the more traditionally employed therapies discussed above.
Patients who present with cutaneous sarcoidosis require careful evaluation and long-term monitoring. As noted above, the first task is to thoroughly assess the extent of the disease and the organ systems affected. This can be done by the dermatologist, or in conjunction with a primary care doctor or pulmonologist, but should include the initial evaluations detailed above. Patients require lifelong follow-up, and should have a lung and eye evaluation annually, including imaging and pulmonary function testing.
Cutaneous sarcoidosis treatment is challenging, and depends on the patient, the extent of their skin involvement, lesion morphologic type, and internal organ involvement. Treatment options range from relatively safe, well-tolerated immunomodulatory drugs to aggressive, systemic medications that require close clinical follow-up and frequent lab monitoring.
Sarcoidosis may follow a self-limited, short course, and burn out after 2 to 3 years; however, many patients experience a chronic course, particularly African Americans and/or patients with extensive facial cutaneous involvement. These patients often require multiple drugs and long treatment courses, and may develop adverse drug effects as a result.
Sarcoidosis is rarely fatal, but patients with extensive lung disease, neurosarcoidosis, or cardiac sarcoidosis are at risk of dying. All patients with sarcoidosis experience significant disease-related morbidity and decreased quality of life. Patients with cutaneous sarcoid lesions are often asymptomatic, but facial involvement or extensive body or extremity disease, or certain morphologic subtypes such as ulcerative sarcoidosis, can be socially devastating and quite debilitating.
Treatment decisions must be made in the context of the individual patient, weighing extent of disease (both on the skin and internally), comorbidities, laboratory abnormalities, and patient preference. There are no FDA-approved treatments, but there is a wide range of therapeutic options, ranging from skin-directed therapy, to low-risk systemic therapy, to more potent systemic therapy that requires laboratory monitoring, to combinations of all of those treatments.
Patients should be followed closely by doctors comfortable in managing their disease and frequently require multiple physicians who are experts in this disease to manage each affected organ system.
Unusual Clinical Scenarios to Consider in Patient Management
Certain subtypes of cutaneous sarcoidosis are worth discussing separately.
Darier-Roussy, or subcutaneous sarcoidosis, presents with lesions under the skin which can be pea-sized papules, broad subcutaneous plaques, or nodules, with no associated epidermal change. These lesions may be flesh colored and nearly invisible to the eye, or only slightly violaceous; it may be necessary to palpate the skin surface to identify lesions. This disease subtype tends to respond to hydroxychloroquine and minocycline combination therapy in many instances in the author’s opinion.
Ulcerative sarcoidosis is a challenging diagnosis to make, as granulomas may be present at ulcers for a variety of reasons, and it can take numerous biopsies and multiple tissue cultures to feel comfortable with a diagnosis of sarcoidosis and to sufficiently rule out infectious etiologies. Ulcerative sarcoidosis is also challenging to treat; aggressive multiagent systemic therapy is often required, along with meticulous skin care, keeping the ulcer clean, use of compression therapy if possible, and topical therapy to aid in healing. TNFα inhibitors may be helpful to consider earlier on in the course in cases of extensive sarcoidal ulcers, as these are often treatment resistant.
Blau syndrome is an inherited genetic disease caused by mutations in the CARD15 gene. Patients can present with a clinical phenotype in childhood that can be very similar to sarcoidosis, and patients may be mistakenly diagnosed with systemic sarcoid. When evaluating pediatric patients with suspected sarcoidosis, physicians should consider Blau syndrome in the differential diagnosis.
Vitamin D balance is important to consider in managing patients with sarcoidosis. As noted above, metabolically active granulomas can convert 25-hydroxy vitamin D to the 1,25-dihydroxy active form. When patients are treated with systemic corticosteroids, many physicians attempt to prophylax against bone loss by initiating therapy with vitamin D and calcium supplements; it is important to be careful not to do so in patients with sarcoidosis.
Supplementation with vitamin D and calcium should be initiated only after careful assessment of true serum levels (with serum calcium levels normalized based on patient albumin, and with physicians measuring not only the 25-hydroxy form of vitamin D but checking the 1,25-dihydroxy form as well).
Granulomatous reactions to tattoos are not uncommon; in isolation, these do not indicate a diagnosis of sarcoidosis. Indeed, there are sufficient reports of atypical infectious agents transmitted by tattooing inks that one should consider infectious etiologies, particularly atypical mycobacterial infections, when evaluating patients with granulomatous reactions to tattoos. As tattoo pigment is an exogenous substance, some patients may develop granulomatous inflammatory reactions locally without meeting the multisystem criteria for a diagnosis of sarcoidosis.
Nevertheless, infiltrated papules within a tattoo warrant evaluation, as the differential diagnosis of tattoo reactions can be quite broad and, besides sarcoidosis, can include a variety of entities that may present locally but carry systemic implications.
It is reasonable to perform at least a limited evaluation in patients with granulomatous tattoo reactions (including at minimum a thorough history, physical, and review of systems, as well as ideally chest radiography; it is reasonable to consider whether patients with granulomatous tattoo reactions warrant additional sampling for microbiology and tissue culture in laboratories skilled in isolating and identifying mycobacterial pathogens).
What is the Evidence?
Antonelli, A, Fazzi, P, Fallahi, P, Ferrari, SM, Ferrannini, E. “Prevalence of hypothyroidism and Graves disease in sarcoidosis”. Chest. vol. 130. 2006. pp. 526-32. (Discusses the association between sarcoidosis and thyroid disease, co-incidence of which may be more common in female patients.)
Baughman, RP, Costabel, U, du Bois, RM. “Treatment of sarcoidosis”. Clin Chest Med. vol. 29. 2008. pp. 533-48. (Review of available therapies and suggested treatment strategems with algorithms provided; focused primarily on systemic disease but does discuss cutaneous sarcoidosis as well.)
Baughman, RP, Lower, EE. “Evidence-based therapy for cutaneous sarcoidosis”. Clin Dermatol. vol. 25. 2007. pp. 334-40. (Detailed, evidence-based recommendations for a wide range of therapeutic options in treatment of cutaneous sarcoidosis written by an expert in the field.)
Baughman, RP, Lower, EE. “Newer therapies for cutaneous sarcoidosis: the role of thalidomide and other agents”. Am J Clin Dermatol. vol. 5. 2004. pp. 385-94. (This 2004 review focuses on the role of TNF-inhibitors, including thalidomide, and the role of other emerging therapeutic options in the treatment of cutaneous sarcoidosis.)
Doherty, CB, Rosen, T. “Evidence-based therapy for cutaneous sarcoidosis”. Drugs. vol. 68. 2008. pp. 1361-83. (Review of cutaneous sarcoidosis treatments ranging from standard to sparsely reported therapies with little evidence; an excellent discussion of the vast majority of therapeutic options.)
English, JC, Patel, PJ, Greer, KE. “Sarcoidosis”. J Am Acad Dermatol. vol. 44. 2001. pp. 725-43. (A thorough review of sarcoidosis, with an emphasis on the skin manifestation, evaluation, and treatment, with discussion of the etiology, pathogenesis, clinical presentations, systemic evaluation, and treatment options; this is the perfect starting point for a dermatologist beginning to read about this disease.)
Iannuzzi, MC, Fontana, JR. “Sarcoidosis: Clinical presentation, immunopathogenesis, and therapeutics”. JAMA. vol. 305. 2011. pp. 391-9. (An overview of sarcoidosis for the general practitioner; not focused on dermatology but provides a thorough explanation of our understanding of this disease and a broad approach to patient management and treatment.)
Mangas, C, Fernández-Figueras, MT, Fité, E, Fernández-Chico, N, Sàbat, M, Ferrándiz, C. “Clinical spectrum and histological analysis of 32 cases of specific cutaneous sarcoidosis”. J Cutan Pathol. vol. 33. 2006. pp. 772-7. (Discussion of clinical/pathologic correlation and exploration of spectrum of findings in biopsy specimens of known cutaneous sarcoidosis.)
Morgenthau, AS, Iannuzzi, MC. “Recent advances in sarcoidosis”. Chest. vol. 139. 2011. pp. 174-82. (Update on the past decade of advances, including a summary of the ACCESS epidemiologic study, improved diagnostic techniques, genetic understanding, and discussion of possible etiologic agents.)
Stagaki, E, Mountfor, MK, Lackland, DT, Judson, MA. “The treatment of lupus pernio: results of 116 treatment courses in 54 patients”. Chest. vol. 135. 2009. pp. 468-76. (The largest retrospective analysis of lupus pernio with an emphasis on the benefits of the biologics, and infliximab in particular, in the management of lupus pernio. This is a must-read when faced with recalcitrant lupus pernio patients and when considering biologics for cutaneous sarcoidosis.)
Wanat, KA, Rosenbach, M. “A practical approach to cutaneous sarcoidosis”. Am J Clin Derm. vol. 15. 2014. pp. 283-297.
Wanat, KA, Rosenbach, M. “Cutaneous sarcoidosis”. Clin Chest Med. vol. 36. 2015. pp. 685-702.
Govender, P, Berman, JS. “The diagnosis of sarcoidosis”. Clin Chest Med. vol. 36. 2015. pp. 585-602.
Wijsenbeek, MS, Culver, DA. “Treatment of sarcoidosis”. Clin Chest Med. vol. 36. 2015. pp. 751-768.
Mana, J, Marcoval, J, Rubio, M. “Granulomatous cutaneous sarcoidosis: diagnosis, relationship to systemic disease, prognosis and treatment”. Sarcoidosis vasc diffuse lung dis. vol. 30. 2013. pp. 268-281.
Saketkoo, LA, Baughman, RP. “Biologic therapies in the treatment of sarcoidosis”. Exp Rev Clin Immunol. 2016. (A comprehensive overview of cutaneous sarcoidosis including algorithmic outlines for treatments and tables detailing baseline and follow-up screening.)
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