TSx-Cover

Sarcoidosis

Key Points

  • Sarcoidosis is a multisystem inflammatory disease, characterized by non-caseating granulomas, which occurs in patients of all ages and ethnic groups.
  • Patients require thorough evaluation for multisystem disease and close monitoring for the development of organ inflammation, which can range from asymptomatic to fulminant.
  • Thirty percent of patients will have cutaneous disease, which is protean in its presentations but most commonly presents as papules, plaques, lupus pernio, or scar- or tattoo-associated lesions.

Introduction

Sarcoidosis is a complex multisystem inflammatory disease characterized by noncaseating granulomatous inflammation. The vast majority of patients have lung involvement (90-95%), the skin and eye involvement being the second and third most commonly affected organ systems. Skin involvement occurs in approximately 30% of patients with sarcoidosis, although the incidence and severity can vary by ethnic group. This article will focus on cutaneous sarcoidosis. While sarcoidosis occurs in all ethnic groups and age ranges, with an overall prevalence of 10-40 cases per 100,000 persons, the annual incidence in African Americans is significantly higher, while that in Japanese is markedly lower. Scandinavia has the world’s highest prevalence, but patients of African American ancestry are more likely to have chronic cutaneous disease and present to a dermatologist for evaluation and management. The incidence peaks in patients in their 30s-40s, and some populations displaying a bimodal distribution. The disease is slightly more common in women than in men. The disease phenotype may vary by ethnic group, with African American patients having more chronic cutaneous disease, Northern Europeans/Scandinavians having higher rates of erythema nodosum and acute but self-limited presentations of disease, and Japanese patients having higher rates of ocular and cardiac involvement.

The etiopathogenesis of sarcoidosis remains unknown. The current leading theory speculates that patients inherit a genetic predisposition for an exuberant inflammatory response to an unknown or group of unknown antigens; when exposed, patients mount an inflammatory response, representing the onset of the disease. Putative antigens include an unknown autoantigen, misfolded serum amyloid A proteins, infectious agents (including mycobacteria or Propionibacterium

acnes), particulate matter, or heavy metals/dust/debris. Whatever the inciting exposure, these genetically predisposed patients mount an abnormal immune response. Sarcoidosis is characterized by granulomatous inflammation—affected organs develop infiltrates of macrophages and lymphocytes that aggregate into non-caseating granulomas composed of groups of histiocytes and giant cells, with a sparse rim of lymphocytes (so-called “naked” granulomas). These foci of granulomatous infiltrates may occur throughout the body; the distribution of inflammation determines the disease phenotype. In some patients, the inflammatory response is acute and self-limited; other patients develop persistent inflammation; and some patients develop inflammation that leads to scarring, fibrosis, and permanent organ dysfunction.

Approximately 60% of patients with sarcoidosis will spontaneously remit within the first 2-3 years of disease presentation. Of the remaining patients, some will develop scarring and fibrosis with permanent organ damage, while some patients will have persistent ongoing areas of active inflammation. It is these sites of active disease that are amenable to therapeutic intervention.

Ninety percent or more of patients with sarcoidosis will have lung involvement; this can range from asymptomatic hilar adenopathy picked up incidentally on routine chest imaging, to mild chronic cough or dyspnea, to fulminant pulmonary involvement with massive infiltrates requiring aggressive therapy, oxygen supplementation, and eventual organ transplantation. Ocular involvement can range from asymptomatic disease to significant inflammation putting vision at risk; uveitis is the most common manifestation. Hepatic involvement is common, but rarely clinically relevant. Neurological disease is relatively rare, affecting 5-10% of patients, but can be devastating. Cranial nerve involvement, particularly palsies of the CNVII, is a common presentation. Patients may develop CNS granulomas leading to mass effect, neuroendocrine abnormalities, seizures, and more. Cardiac sarcoidosis is also rare, affecting approximately 5% of patients, but accounts for a significant portion of sarcoidosis-related mortality. Cardiac sarcoidosis is frequently asymptomatic up to the point of critical disease, and the most common presenting sign is sudden cardiac death. Because of this, all patients with sarcoidosis warrant thorough cardiac screening. Symptoms suggestive of cardiac sarcoid can include palpitations, syncope, chest pain, signs of heart failure, or frank arrhythmias. Renal granulomatous inflammation is rare, but renal disease is not uncommon and may be multifactorial. Patients with active sarcoidosis often have granuloma-mediated vitamin D activation and increased levels of 1,25 dihydroxy-vitamin D. They may develop hypercalcemia, and the presence of persistent hypercalcemia and subsequent hypercalciuria can damage the kidneys and lead to renal impairment. Patients may also have lymphadenopathy, fatigue, marrow involvement, endocrinological problems (particularly thyroid disease) and more, making it essential to carefully evaluate of patients with sarcoidosis and monitor them closely on a regular basis. Fatigue is a noteworthy symptom in patients with sarcoidosis, as it may often be crippling and sometimes is the main driver of therapeutic intervention. Patients with sarcoidosis may also be at higher risk of developing lymphoma. While lymphadenopathy may be seen in sarcoidosis, it is important to remember that while sarcoidosis can affect multiple organs, new areas of inflammation warrant thorough evaluation, as patients may have more than one diagnosis.

Cutaneous sarcoidosis generally affects 25-30% of patients with the disease; this number varies depending on the ethnic group. Cutaneous sarcoidosis is generally divided into “specific lesions,” those that display characteristic granulomas on biopsy, and “sarcoid non-specific lesions,” which generally refers to erythema nodosum. Erythema nodosum (EN) is most often seen in patients of Northern European ancestry, presenting with tender red-brown subcutaneous nodules symmetrically distributed on the anterior shins. EN is most often seen in the setting of a specific subtype of sarcoidosis, Löfgren’s syndrome, wherein patients present with fevers, arthritis/arthralgias, hilar adenopathy, and EN. This is almost invariably seen in Caucasian patients and portends a good prognosis; most patients with Löfgren’s syndrome will spontaneously resolve their disease, although they may require symptomatic treatment during the acute inflammatory phase.

Cutaneous sarcoidosis-specific lesions are protean and can present with almost any type of morphology. The most common cutaneous findings are erythematous-to-violaceous papules generally concentrated around the nose, ala, and periorbital, or perioral areas. Plaques are also quite common. Lupus pernio is a specific morphologic pattern of sarcoidosis worth special mention; common in African American patients, patients with lupus pernio have violaceous scaly plaques and nodules of the nose or central cheeks. Patients with lupus pernio are more likely to have chronic, refractory disease that often persists for many years, with some patients having lifelong skin involvement. These patients are often refractory to most standard treatments. Beyond papules, plaques, and lupus pernio, scar- and tattoo-associated lesions are also common. Other morphologic types are less common, but given the widely varied nature of cutaneous sarcoidal lesions and the easy accessibility of skin lesions and low morbidity associated with skin biopsy, dermatologists are often involved in helping make the diagnosis of sarcoidosis by skin biopsy to demonstrate the characteristic granulomas.

Treatment of sarcoidosis depends largely on what organs are affected and the severity of the disease; many patients are asymptomatic or have mild disease, and as 60% of patients will spontaneously resolve within the first few years of disease presentation, treatment is not always necessary. Treatment should be geared towards identifying what organs are affected, and management should be focused on controlling active inflammation in the most critical organs or most severely affected organ systems. This article focuses on cutaneous sarcoidosis treatment; in the setting of significant extracutaneous disease, treatments geared at controlling the granulomatous inflammation in other organs will often improve the skin disease as well. In general, there is limited evidence and a paucity of high quality, large scale, randomized, prospective trials in the treatment of sarcoidosis. Much of the data is based on case series, retrospective studies, and expert opinion. There exist proposed treatment algorithms in the literature.

First-line therapy for limited cutaneous sarcoidosis includes topical corticosteroids (site-specific potency, with lower potency topicals applied to the face and areas of thin skin, and higher potency steroids used for areas of thicker skin or more infiltrative lesions) and intralesional corticosteroid injections. For more widespread skin disease, or cutaneous disease which fails to respond to topical therapy, antimalarials are generally the drug of choice. Most patients will be treated with hydroxychloroquine 400 mg daily (adhering to an ideal body weight dose limit of 6.5 mg/kg/d maximum therapy) with ophthalmological follow up both for the disease itself and potential adverse effects with long-term antimalarial therapy. An alternative option for widespread skin disease is tetracycline class antibiotics, particularly minocycline (dosed at 100 mg twice daily). Minocycline and hydroxychloroquine may be used together for added potency. Notably, hydroxychloroquine and minocycline seem to have little effect on extracutaneous sarcoidosis, although hydroxychloroquine may help some patients’ sarcoidosis-related hypercalcemia. Patients whose cutaneous sarcoidosis fails to respond to topical or intralesional corticosteroids, antimalarials, and/or minocycline may be candidates for treatment with a stronger agent, such as methotrexate (which is widely used for multi-organ sarcoidosis and is highly effective at controlling cutaneous disease) or thalidomide (which generally treats cutaneous sarcoidosis with little effect on extracutaneous disease). Patients who fail to respond to those agents may warrant treatment with an alternate immunosuppressive drug, but emerging evidence suggests that TNF-α inhibitors may be particularly effective at treating refractory cutaneous sarcoidosis. Patients with chronic cutaneous sarcoidosis, particularly those with lupus pernio, may fail to respond to traditional systemic immunosuppressive agents but may demonstrate substantial improvement with TNF-α inhibitors.

Initial Evaluation

Sarcoidosis

Erythema Nodosum

Differential Diagnosis for Sarcoidosis

Urticaria

Psoriasis

Lichen Planus

Differential Diagnosis for Lupus Pernio

Systemic Lupus Erythematosus

Rosacea

Treatment

First-line therapy: For limited cutaneous disease, or scattered residual cutaneous lesions in the setting of existing therapy, topical or intralesional corticosteroids are the treatment of choice. For more widespread disease, antimalarials or minocycline are indicated.

First steps

  • Topical corticosteroids (hydrocortisone 2.5% to the face, triamcinolone 0.1% to the body, clobetasol 0.05% to thick lesions on areas of thick skin such as the elbows or back).
  • Intralesional triamcinolone injections (strength varying by anatomic site, size and depth of lesion).
  • Patients should be evaluated for scar- or tattoo-associated lesions; patients who have tattoo-associated lesions should be counseled to avoid more tattoos.

Subsequent steps

  • Patients who fail to respond to local therapy should be referred to a medical dermatologist with experience in treating cutaneous sarcoidosis, generally at a tertiary care academic medical center.
  • Treatment is a stepwise progression, and multiple treatments may be used together; patients can continue to receive topical and/or intralesional corticosteroids, along with antimalarials and/or tetracycline class antibiotics, while proceeding to more aggressive/suppressive therapy.
  • Methotrexate may be beneficial to patients with widespread skin disease or skin disease that fails to respond to first-line treatment.
  • Thalidomide is an alternate option for patients with widespread skin disease, particularly with recalcitrant facial lesions. Given the teratogenicity of the drug, patients and providers must be registered in the REMS program* to use thalidomide.
  • Patients with the most severe disease, or those who fail to respond to methotrexate, may be candidates for treatment with TNF-α inhibitors, particularly infliximab or adalimumab.

Pitfalls

  • While most patients with sarcoidosis demonstrate their pattern of disease inflammation and organ involvement within the first few years of disease onset, it is important to remain vigilant for new areas of sarcoidal inflammation and to ensure that patients are undergoing routine screening and organ monitoring (in particular, eye and lung screening should be performed regularly).
  • Cardiac sarcoidosis is frequently asymptomatic and may present with sudden death; all patients with sarcoidosis require screening for cardiac sarcoidosis.
  • Vitamin D levels are challenging to monitor and manage in patients with sarcoidosis. The granulomas frequently convert vitamin D from the inactive form (vitamin D 25) to the active form (vitamin D 1,25), and patients may be hypercalcemic as well. When clinicians screen for vitamin D deficiency, they are often only checking vitamin D 25 levels—most patients with sarcoidosis will have low vitamin D 25 levels, but actually their systemic levels of activated vitamin D are generally normal or even high. Care must be taken so as not to over-supplement patients with sarcoidosis with vitamin D supplements, and consider evaluation by a skilled internist or endocrinologist if there are abnormalities.
  • Fatigue is a major issue in patients with sarcoidosis; however, patients with sarcoidosis are also at increased risk for developing thyroid disease, and a thorough, careful evaluation of systemic symptoms is indicated in these patients.

*REMS (Risk Evaluation and Mitigation Strategy), formerly the STEPS program (System for Thalidomide Education and Prescribing Safety), a US Food and Drug Administration program for pharmaceutical risk management.

Clinical Case

Case 1

  • 38-year-old African American man
  • No significant past medical history
  • Review of systems reveals a chronic persistent cough over the past 4-5 months, mild fatigue, with no ocular complaints, no palpitations, and no other systemic complaints
  • Social history is unremarkable
  • Presents for evaluation of multiple, papules concentrated on the nasal tip and around the alar rim. The lesions were first noted about 4 months ago. They are asymptomatic. The patient tried over-the-counter topical corticosteroids without relief

Initial evaluation

  • Healthy appearing male
  • Numerous erythematous-to-slightly violaceous papules on the nasal tip, around the alar rim, and scattered on the cheeks, around the eyes, and around the mouth. Detailed examination reveals a few scaly papules within a tattoo on the arm
  • There is no lymphadenopathy or hepatosplenomegaly on exam
  • The eyes appear red with conjunctival injection
  • The patient has a dry, nonproductive cough occasionally evident during the exam

Diagnosis: Sarcoidosis

  • Recommend patient get chest imaging and pulmonary function testing and see a pulmonologist for suspected pulmonary sarcoidosis
  • Refer patient to ophthalmologist for clinical evidence of active ocular inflammation and the risk of asymptomatic uveitis progressing to visual impairment
  • Refer patient to a dermatologist for a skin biopsy to confirm granulomatous inflammation
  • Routine blood work including complete blood count, comprehensive metabolic profile

Follow-up evaluation

  • The patient has hilar adenopathy on chest x-ray, but normal pulmonary function tests; he is started on a course of oral corticosteroids by his new pulmonologist with significant improvement
  • The patient has uveitis on ocular exam and is treated with topical corticosteroids
  • The patient is sent for additional testing for extracutaneous disease, including cardiac evaluation, vitamin D testing, thyroid testing, hepatic and renal monitoring, all of which come back normal or negative
  • The skin lesions improve somewhat with systemic corticosteroids but recur as the dose is tapered
  • Topical and Intralesional corticosteroid injections are tried with good response
  • The patient should be followed closely by multiple doctors, as African American patients with facial cutaneous lesions tend to have persistent disease which fails to self-resolve

References

Chen ES, Moller DR (2011) Sarcoidosis-scientific progress and clinical challenges. Nat Rev Rheumatol, 7(8):457-467.

Haimovic A, Sanchez M, Judson MA, Prystowsky S (2012) Sarcoidosis: a comprehensive review and update for the dermatologist. Part I: Cutaneous Disease. J Am Acad Dermatol, 66:699 e1-18.

Haimovic A, Sanchez M, Judson MA, Prystowsky S (2012) Sarcoidosis: a comprehensive review and update for the dermatologist. Part I: Extracutaneous Disease. J Am Acad Dermatol, 66:719 e1-10.

Judson MA (2014) The clinical features of sarcoidosis: a comprehensive review. Clinic Rev Allerg Immunol, Oct 2 Epub ahead of print.

Wanat KA, Rosenbach M (2014) A practical approach to cutaneous sarcoidosis. Am J Clin Dermatol, 15:283-297.