Approach

A significant number of asymptomatic patients may not require treatment, despite having an abnormal chest x-ray or abnormal liver enzymes.

Spontaneous remissions occur in 55% to 90% of patients with stage I disease (bilateral hilar lymphadenopathy), 40% to 70% of patients with stage II disease (bilateral hilar lymphadenopathy plus pulmonary infiltrates), and about 20% of patients with stage III disease (pulmonary infiltrates without hilar lymphadenopathy). Remission is not expected in patients with stage IV disease (extensive fibrosis with distortion).[14]

Symptomatic disease

Treatment is primarily indicated in symptomatic disease to avoid danger to life or organs, or to improve quality of life.[68] Corticosteroids are considered first-line treatment for sarcoidosis that requires therapy.

Dosing and route of administration of corticosteroid therapy remain uncertain and vary depending upon the clinical setting. Observational data indicate that there are no additional benefits associated with treating pulmonary disease with higher doses of corticosteroid.[69][70]

Treatment guidelines are available.[14][30]​​​​​​[68] However, management recommendations are informed by relatively few randomized placebo-controlled trials. Therefore, the nonspecialist should consult with a sarcoid specialist, particularly before adding an immunomodulatory agent.

Pulmonary sarcoidosis

No treatment is necessary for stage I disease unless there is progressive adenopathy.

Oral corticosteroids are the mainstay of treatment for symptomatic stages II to IV. Oral corticosteroids improve chest x-ray appearance, symptoms, and spirometry over 3-24 months.[68][71][72]​​ There are limited data beyond 2 years to indicate whether oral corticosteroids have any modifying effect on long-term disease progression (e.g., prevention of pulmonary fibrosis).[71] Inhaled corticosteroids may benefit some patients with pulmonary sarcoidosis, but randomized controlled trials provide limited evidence for efficacy.[71][73][74]

Measures to prevent osteoporosis should be implemented for patients starting corticosteroids. Special care must be taken if vitamin D or calcium is supplemented in patients with sarcoidosis, because the disease may cause hypercalciuria and hypercalcemia by increased endogenous vitamin D. Serum calcium and 24-hour urinary calcium should be monitored before and 1 month after commencing therapy.[75] US guidelines suggest measuring both 25- and 1,25-OH vitamin D levels before vitamin D replacement therapy is started.[31]​​​

Second-line agents

Methotrexate, azathioprine, leflunomide, mycophenolate, hydroxychloroquine, or other emerging/experimental therapies can be used as corticosteroid-sparing agents in patients who do not tolerate high doses of corticosteroids, or as additional treatment in cases of unsatisfactory response to corticosteroids.[14][30]​​​​​[68]

Choice of second-line agent depends on the specialist's experience and individual preference. Subspecialist referral should be considered in cases not responding to first-line treatment or when a second agent is considered. Subsequent lines of therapy include biologic agents, typically infliximab, and should be considered if second-line agents (alone or in combination with corticosteroids) are toxic or insufficiently effective, or if severe or progressive disease is present.[38][68][76]​​​​​

Supportive care

Patients with resting or exercise oxygen saturation ≤88% or PaO₂ ≤55 mmHg on arterial blood gas measurement are given oxygen therapy.

Acute respiratory failure is extremely rare in sarcoidosis. Patients requiring mechanical ventilation or >40% supplemental oxygen require intravenous corticosteroids until oral intake is possible. The switch to oral corticosteroids is usually done within 48 hours if the patient is improving and can tolerate oral intake.

Patients are said to have end-stage lung disease when there are severe reductions in lung volumes, flow rates, and diffusing capacity of the lung for carbon monoxide (DLCO), accompanied by severe symptoms that have exhausted all available treatments. Lung transplant, if desired, is the only therapeutic option for these patients.

Cutaneous sarcoidosis

Topical or intralesional corticosteroids are usually sufficient for mild lesions.[14][68]​ Topical corticosteroids are used for scaly lesions and intralesional for papular or nodular lesions. Oral corticosteroids should be used for large disfiguring lesions or lesions refractory to local therapy. Consider corticosteroid-sparing alternatives (e.g., hydroxychloroquine, methotrexate) whenever possible.[68]

Hydroxychloroquine or methotrexate can be used as third-line agents in patients refractory to oral corticosteroids. These agents lack strong efficacy data and require appropriate monitoring, including for ocular toxicity in patients receiving hydroxychloroquine. Biologic agents, typically infliximab, are generally reserved for later use.[68][77]​​

There is insufficient evidence to support a particular management strategy for patients with lupus pernio with scarring. It is the authors' opinion that a therapeutic trial of corticosteroids is merited in this patient population, with consideration of methotrexate or azathioprine if there is poor response or intolerance to corticosteroids. Subgroup analyses from a clinical trial and observational data suggest that infliximab therapy may be of considerable benefit in patients with lupus pernio.[78][79]

Ocular sarcoidosis

Topical corticosteroids are the mainstay of treatment. Oral corticosteroids are reserved for resistant disease and optic neuritis.

Early referral to an ophthalmologist is suggested for management of complications such as glaucoma, cataracts, vascular retinitis, optic atrophy, and vision loss.

Cardiac sarcoidosis

A multidisciplinary team approach is required to address complex clinical issues that may arise. Higher-dose corticosteroids may be needed. Methotrexate, azathioprine, mycophenolate, or leflunomide are used as corticosteroid-sparing agents or as an alternative to corticosteroids.[38]​[68]​​​​

Patients are typically started on corticosteroids, with immunosuppressive therapy being considered as an alternative if there is intolerance or poor response to corticosteroids. The choice of agent depends on the specialist's experience and individual preference. Infliximab has been shown to benefit patients with refractory cardiac sarcoidosis, although tumor necrosis factor (TNF)-alpha inhibitors should be used with caution because of the potential for cardiotoxicity.[38][80]​​

A patient with cardiac involvement will usually present with arrhythmias or heart block; pulmonary hypertension and congestive heart failure occur later in the course of the condition. Refer these patients early to a cardiologist for appropriate management. Pulmonary hypertension can be comanaged by the pulmonologist and cardiologist.[38]

Neurosarcoidosis

Patients with neurosarcoidosis invariably require corticosteroid therapy; high doses may be prescribed for central nervous system (CNS) involvement. Methotrexate is typically used as a corticosteroid-sparing agent in patients who do not tolerate high doses of corticosteroids or as a second-line treatment in cases of unsatisfactory response to corticosteroids. Other options include azathioprine, mycophenolate, and hydroxychloroquine. Biologics, typically infliximab, are reserved for third-line use.​[2][68]

The physical manifestations of neurosarcoidosis are varied and include neuropathies (including cranial, optic [neuritis]), meningeal disease, CNS parenchymal disease (e.g., endocrinopathy, mass lesions, encephalopathy, seizures), spinal canal disease (e.g., cauda equina syndrome), myopathies, and signs of pituitary disease (e.g., diabetes insipidus).

Renal sarcoidosis

Renal involvement is rare. When it occurs, it is associated with substantial risk of renal failure. A disordered calcium metabolism is the most important cause of renal failure.

Granulomatous interstitial nephritis is the most typical histologic finding.

Corticosteroids remain the cornerstone of treatment. Second-line options for hypercalcemia and hypercalciuria include hydroxychloroquine and ketoconazole. Second-line options for granulomatous interstitial nephritis include azathioprine and mycophenolate mofetil. Third-line options for granulomatous interstitial nephritis include biologics, typically infliximab.[6][81]

Review of immunosuppressive therapies for potential nephrotoxicity and drug interactions with existing medications is required for patients with renal disease.​[30]

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