Sarcoidosis

What every physician needs to know:

Sarcoidosis is a rare (incidence of 10-40/100,000) multi-organ, granulomatous disease of unknown etiology. While the lungs and hilar and mediastinal lymph nodes are usually involved, any organ system may be effected. The disease manifestations depend upon the duration of disease, site and extent of organ involvement and the activity of the granulomatous process. Given the diverse manifestations of the disease, patients may present to clinicians of different specialties.

The disease affects all ethnic groups and is slightly more common in females. While about 70 percent of individuals will resolve the disease in about two years, 30 percent may develop chronic disease. African Americans appear to have a worse prognosis than do Americans of European ancestry.

Classification on Clinical Manifestations:

Because of the multi-organ involvement of the disease, patients may present with nonspecific constitutional manifestations, findings related to specific organ involvement as discussed below, or both (1). Approximately one-third of patients experience nonspecific constitutional symptoms of low grade fever, fatigue, malaise, or weight loss.

Pulmonary sarcoidosis is the most common manifestation of sarcoidosis as the lungs and/or hilar and mediastinal nodes are involved in about 90 percent of patients. Dyspnea, dry cough, and chest pain are the most common pulmonary symptoms. Pulmonary complications that may develop include a restrictive or, less commonly, an obstructive lung disease, pulmonary fibrosis, cavitary lung disease or pulmonary hypertension. Pulmonary sarcoidosis is traditionally classified via chest radiograph findings (see section on imaging studies below).

Cardiac involvement is the second leading cause of death in patients with sarcoidosis in the United States and is seen in approximately 5 percent of patients. It can manifest as high grade atrioventricular heart block, lethal ventricular arrhythmias, or heart failure. Subclinical cardiac involvement has been detected in approximately 25-50 percent of patients on autopsy studies.

Skin involvement, which can occur in 25 percent of individuals, can manifest as maculopapular or nodular lesions. Involvement of the face is known as lupus pernio and is more common in chronic sarcoidosis. Erythema nodosum is a non-granulomatous lesion of the lower legs that is usually more common in Europeans than in Americans and usually represents acute sarcoidosis as part of Lofgren’s syndrome.

Ocular lesions occur in 11-83 percent of individuals and may involve all parts of the eye with uveitis the most common manifestation.

Neurologic involvement, which can occur in 5 percent of individuals, can involve the peripheral or central nervous system. Facial nerve palsies, hypothalamic, and pituitary lesions are common when neurologic involvement is present.

Liver involvement is frequent (up to 80 percent) but rarely severe. Mild abnormalities in liver function testing are the most common manifestation.

Musculoskeletal involvement is also frequent (~50 percent) and most commonly involves the knees, ankles, elbows, wrists, and small joints of the hands and feet. Joint deformity is rare.

Endocrine manifestations can occur in up to 10 percent of individuals, usually presenting as hypercalcemia or hypercalciuria that can lead to nephrocalcinosis. Involvement of the hypothalamus and pituitary can also lead to thyroid and adrenal dysfunction.

Granulomatous involvement of the kidney is rare. Extrathoracic lymph nodes may be involved in 20 percent of individual, with the cervical lymph nodes the most common site. Splenic involvement in also frequent but rarely severe. Bone marrow involvement may occur occasionally. Salivary involvement usually involves the parotid glands. Gastrointestinal involvement occurs in less than 1 percent of individual and usually involves the esophagus or stomach. Involvement of the reproductive organs can occur in both males and females.

Two clinical syndromes that have been identified are Lofgren’s syndrome and Heerfordt’s syndrome. Lofgren’s syndrome presents acutely and is characterized by erythema nodosum, ankle swelling, fever and bilateral hilar and mediastinal adenopathy. Involvement of the parotid glands, facial nerve, and anterior uveitis, along with fever, has been called Heerfordt’s syndrome.

Are you sure your patient has sarcoidosis? What should you expect to find?

The diagnosis of sarcoidosis is established when the clinicoradiographic findings are supported by the histological finding of non-caseating granulomas on tissue biopsy and alternative granulomatous processes are excluded. In special circumstances, such as the finding of a bilateral hilar adenopathy in an asymptomatic individual, Lofgren’s syndrome, and Heerfordt’s syndrome, the diagnosis of sarcoidosis can be made by clinicoradiographic data alone.

The diagnosis of cardiac sarcoidosis deserves special mention. There are two distinct pathways in which cardiac sarcoidosis can be established.

1. Histological diagnosis from myocardial tissue: This requires the finding of non-caseating granulomas on direct myocardial biopsy.

2. Clinical diagnosis from invasive and non-invasive studies: This requires histological diagnosis of extra-cardiac sarcoidosis with either clinical cardiac disease, as described above, or advanced non-invasive cardiac imaging consistent with myocardial involvement, as described below.

Beware: there are other diseases that can mimic sarcoidosis.

Because sarcoidosis is a disease of unknown etiology, other causes of granulomatous diseases must be ruled out, including mycobacterial diseases, fungal disease, and other infectious granulomatous diseases. In addition, granulomatous involvement can be seen in hypersensitivity reactions and in response to neoplastic diseases or foreign bodies. Immunodeficiencies, such as hypogammaglobulinemia or chronic granulomatous disease, which are due to neutrophil disorders must also be ruled out. Lymphoma must always be ruled out as a cause of lymph node enlargement.

How and/or why did the patient develop sarcoidosis?

How and why patients develop sarcoidosis is unknown. While the peak incidence of the disease occurs at ages 35-45 years, about a third of patients may present after age 55. Teenagers can also present with sarcoidosis, but sarcoidosis in children younger than ten years is usually associated with Blau syndrome.

While sarcoidosis can occur in all racial and ethnic groups, the incidence appears to be higher in African Americans and in women of Irish and Italian descent. The ratio of female-to-male involvement appears to be about 2:1, which is especially true in the elderly. Seasonal variation has been reported, as most cases are reported in the spring. Differences in disease manifestations have been shown, with a higher incidence of cardiac and eye involvement in those of Japanese descent, erythema nodosum in Northern Europeans, and multi-organ involvement in African Americans.

Familial clustering of sarcoidosis has been used to support both a genetic and an environmental cause of sarcoidosis. Studies of twins have shown that concordance of sarcoidosis is far more common among monozygotic than it is among dizgotic twins, supporting a genetic predisposition. Supporting an environmental cause is the observation of clusters of cases of sarcoidosis among firefighters, World Trade Center first responders, and US Navy service persons in special job categories. Exposure to bioaerosols or microbiologic agents may also be associated with sarcoidosis.

Genetic associations with sarcoidosis have been noted in genome-wide association studies, suggesting that sarcoidosis is associated with multiple small or moderate genetic effects. HLA Class II genes have had the strongest association with sarcoidosis; this association may be relevant since these genes present environmental antigens to T lymphocytes. The strongest association has been noted with HLA-DRB1*0301 and erythema nodosum in Northern Europeans. These individuals also have an increased expression of the T-cell-specific antigen chain AV2S3, suggesting that a specific antigen may be associated with this form of sarcoidosis.

Immunologic studies in sarcoidosis have shown that there is an oligoclonal T cell response, suggesting a specific antigen stimulation. CD4 T cells have been shown to be increased at the site of disease activity, and there is an increase in TH1 cytokines (TNF and gINF). However, the increase in TH1 cytokines may switch to a TH2 phenotype in fibrotic sarcoidosis.

Studies of etiologic triggers in sarcoidosis have centered on mycobacterial antigens and propionibacterial organisms. Mycobacterial nucleic acids have been found in the tissues of some patients with sarcoidosis, and the mycobacterial proteins (mKatG, ESAT-6, mycobacterial superoxide dismutase A, antigen 85A, and heat shock protein 70) may elicit TH1 responses in up to 50 percent of patients with sarcoidosis. Propionibacterial DNA has been found in more than 90 percent of sarcoidosis tissue in Japan and Europe, but high recovery rates (~60%) were also found in the control. Specific T cell responses to proprionibacterial antigens in sarcoidosis have not been demonstrated, although some cases of skin sarcoidosis have responded to antibiotics that are effective against propionibacteria. Whether these agents are the cause of certain subsets of sarcoidosis remains uncertain.

Which individuals are at greatest risk of developing sarcoidosis?

Adults between the ages of twenty and fifty have the greatest risk of developing sarcoidosis. African Americans and women of Italian or Irish descent are also at increased risk for developing sarcoidosis. Non-smokers are at risk for developing sarcoidosis since a number of studies have shown that smoking is associated with protection from sarcoidosis.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Although blood studies cannot be used to confirm a diagnosis of sarcoidosis, several blood tests are recommended as part of the initial evaluation of patients with sarcoidosis and merit discussion.

All patients with suspected sarcoidosis should have a complete blood count (CBC), serum chemistries, including calcium, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase, creatinine, and blood-urea-nitrogen (BUN) obtained. Of these, the most common abnormalities include a mild anemia of chronic disease (4 to 20 percent of patients), leukopenia (up to 40 percent), an elevated alkaline phosphatase, and hypercalcemia (up to 10 percent). The mechanism for the hypercalcemia is due to dysregulated production of calcitriol by the macrophages of the granuloma.

Angiotensin converting enzyme (ACE), produced by cells within the granuloma complex, reflects the total body granuloma burden in the disease. Although it may help support the diagnosis of sarcoidosis, it is neither sensitive nor specific to make the diagnosis of sarcoidosis. One study demonstrated a sensitivity of 57 percent, specificity of 90 percent, positive predictive value of 90 percent, and negative predictive value of only 60 percent.

Other blood tests that may be abnormal in patients with sarcoidosis include elevations in the erythrocyte sedimentation rate and c-reactive protein (CRP). Like ACE, these tests are neither sensitive nor specific.

All patients with newly diagnosed or suspected sarcoidosis should also receive an interferon-gamma release assay (IGRA) or a tuberculin skin test both to exclude mycobacterium tuberculosis as the cause of the granulomatous disease and prior to initiation of immunosuppressive therapy for the sarcoidosis.

What imaging studies will be helpful in making or excluding the diagnosis of sarcoidosis?

Because of the frequency of lung involvement, the chest x-ray may be the most important screening test once sarcoidosis is suspected. The chest x-ray may also be the first test to suggest a diagnosis of sarcoidosis. Chest radiograph findings in sarcoidosis are classically divided into 5 stages:

• Stage 0: no adenopathy or infiltrates
• Stage I: bilateral hilar adenopathy alone
• Stage II: bilateral hilar adenopathy and diffuse reticulonodular opacities
• Stage III: reticulonodular pattern alone
• Stage IV: fibrosis

The pulmonary infiltrates in patients with sarcoidosis typically have a mid to upper-zone predominance. As discussed later, these radiographic stages also have prognostic and therapeutic significance. Chest CT may be normal or show a variety of abnormalities including adenopathy, thickening along the bronchovascular bundles, nodularity, fibrosis or fibrocavitary disease.

Positron emission tomography (PET) with fluoro-deoxy-glucose (FDG) may be used to help identify an area of active inflammation for tissue biopsy.

Two imaging tests, cardiac MRI (CMR) and PET with FDG, can be used to assist in the diagnosis of cardiac sarcoidosis, as described above. Patchy uptake on a dedicated cardiac PET and positive gadolinium enhancement on MRI support the diagnosis.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of sarcoidosis?

There are no non-invasive tests that can exclude the diagnosis of sarcoidosis. Pulmonary function studies may be normal, show a restrictive process with depressed transfer factor (Dlco), or can occasionally show evidence of small airway disease or obstruction. Exercise studies may show evidence of oxygen desaturation, but only in severe cases.

Ophthalmologic examination, which should be performed in all patients with suspected or confirmed diagnosis of sarcoidosis, may find conjunctivitis, lacrimal glade blockage, and/or anterior and posterior uveitis.

What diagnostic procedures will be helpful in making or excluding the diagnosis of sarcoidosis?

In the presence of a compatible clinical picture, tissue biopsy to rule out infectious and neoplastic disease and to demonstrate non-caseating granuloma is the best means to confirm a diagnosis of sarcoidosis. If present, biopsy of skin lesions, conjunctival nodules, enlarged peripheral lymph nodes, or an enlarged lacrimal or parotid gland is preferable to an intra-thoracic biopsy due to the less invasive nature of the procedure. A notable exception is erythema nodosum, which should not be biopsied to confirm disease as non-caseating granulomas are not present.

Oftentimes, however, an extra-thoracic site for biopsy is not available and an intra-thoracic biopsy is necessary. The gold standard for the diagnosis is a surgical lung biopsy and cervical mediastinoscopy. Due to a high diagnostic yield approaching 90 percent in carefully selected patients of an endoscopic approach consisting of a combination of endobronchial biopsy (EBB), transbronchial lung biopsy (TBLB), and ultrasound guided transbronchial needle aspiration (EBUS-TBNA), surgical approaches are usually not required.

Characteristic findings on bronchoalveolar lavage (BAL) can help support the diagnosis of sarcoidosis. A lymphocytic predominance greater than 15 percent on BAL cellular differential is highly sensitive (>90 percent) but nonspecific for sarcoidosis. A lymphocyte CD4:CD8 ratio of greater than 3.5 has a sensitivity of 53 percent and specificity of 94% for the diagnosis.

Endomyocardial biopsy is not sensitive for the diagnosis of cardiac sarcoidosis and is positive in only about 30 percent of cases.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of sarcoidosis?

The diagnosis of sarcoidosis is most secure in the presence of a compatible clinical condition and the presence of non-caseating granulomas on biopsy. Special stains and cultures should be done to rule out bacterial, fungal, and mycobacterial infections, and there should be no evidence of any neoplastic process. To date, genetic studies have not been useful in making or excluding the diagnosis of sarcoidosis.

If you decide the patient has sarcoidosis, how should the patient be managed?

Once a diagnosis of sarcoidosis has been confirmed, the next step includes assessments of the extent of the disease, severity of the disease, activity of the disease, and its impact on the patient. Extent of organ involvement should be determined by means of a complete history to look for symptoms of pulmonary, cardiac, eye, neurologic, or systemic symptoms. Next, the patient should have a complete physical examination to look for organ involvement (e.g., skin lesions, hepatosplenomegaly, neurologic signs, adenopathy, pulmonary rales, abnormal cardiac rhythms, and any signs of cardiac failure). All patients should be referred to an ophthalmologist to rule out eye involvement.

Minimal laboratory studies to assess for extent and severity of disease should include a chest x-ray and pulmonary function test (spirometry, lung volumes, and Dlco) for lung involvement, EKG for cardiac involvement, CBC for bone marrow or splenic involvement, and a comprehensive metabolic panel for renal, liver, or endocrine involvement. All patients should then be followed at 3 to 6 month intervals to monitor for both new organ involvement and disease activity. The ACCESS study demonstrated that new organ involvement was noted in 25 percent of patients within two years. If there is significant organ involvement or debilitating symptoms attributed to sarcoidosis, treatment with immunosuppressive drugs should be considered.

Except for the possibility of splenectomy for severe splenic involvement that has not responded to therapy, surgery does not have a role in the treatment of sarcoidosis. Indications for drug therapy usually depend on the organ involved, the severity of the impairment, and whether there is progressive disease.

Indications for treatment of pulmonary sarcoidosis include symptomatic disease, progressive disease, and severe disease. All patients with significant symptoms attributed to sarcoidosis should be considered for treated. In the absence of symptoms, deterioration of lung function such as a reduction of total lung capacity, forced vital capacity, or diffusing capacity, or radiographic progression such as new pulmonary infiltrates or reticular fibrotic changes, are indications for initiation of therapy.

Prednisone or its equivalent is usually started at 20-40 mg/day and slowly tapered over 6-12 months. Inhaled steroids can be used for patients with cough that is due to bronchial sarcoidosis and those with a reactive airway syndrome. Methotrexate, azathioprine and leflunomide have been used successfully as steroid-sparing drugs when patients have been intolerant of corticosteroid therapy or the disease relapses with corticosteroid tapering and chronic immunosuppression is necessary. In rare cases, anti-TNF monoconal antibodies have been used in patients with pulmonary sarcoidosis. In severe, fibrotic, end-stage disease, lung transplantation may be an option.

Patients with cardiac sarcoidosis may suffer from heart block, sudden arrhythmias, or heart failure. If the patient has cardiac symptoms (palpitations, chest pain, or shortness of breath) or an abnormal EKG, then further work-up of cardiac sarcoidosis should include a holter monitor, cardiac echocardiogram, and a cardiac MRI or 18-FDG PET scanning. Cardiac mapping may be useful to determine the patient’s risk for a sudden arrhythmia. Because of the risk of sudden death, an electrophysiologist should be involved and AICD should be considered if there is confirmation of significant cardiac involvement. A pacemaker-ICD is usually placed if the patient has significant heart block.

A trial of immunosuppression is generally recommended in a patient diagnosed with cardiac sarcoidosis. Prednisone is the initial drug of choice but there is no evidence that dosages greater than 30 mg a day are any more effective than dosages less than 30 mg a day. Methotrexate and azathioprine are used if the patient is intolerant of prednisone. In addition, plaquenil may have some utility in cardiac sarcoidosis. The anti-TNF antibodies have been successful in anecdotal reports, but they should be avoided in the presence of severe heart failure (EF < 30%), in which case heart transplantation may be successful.

Eye involvement can often be treated with steroid eye drops if there is only anterior involvement. Posterior involvement should be treated with systemic steroids or intraocular injection of steroids, but methotrexate and azathioprine have been used in patients who are intolerant of steroids. The anti-TNF monoclonal antibodies have been used in individuals with severe recalcitrant disease.

Peripheral nerve or cranial nerve involvement with sarcoidosis often does not need to be treated, or it will respond to a short course of steroids. On the other hand, CNS involvement often involves high-dose, long-term steroids, with the dose and duration of treatment depending on the acuity and severity of the involvement. Acute, severe syndromes are often treated with IV pulse steroids at 1 gram a day for 3 to 5 days, followed by a steroid taper. These patients are often treated with methotrexate, azathioprine, or mycophenate mofitil as steroid-sparing agents. The anti-TNF monoclonal antibodies have been most useful in this subset of patients, and plaquenil has also been reported to be of some use. Severe CNS involvement with sarcoidosis is a rare and devastating complication of the disease.

Skin involvement in sarcoidosis often does not need to be treated unless it is cosmetically important. Erythema nodosum, which usually has a good prognosis, responds well to non-steroidal anti-inflammatory therapy or a short course of steroids. In contrast, lupus pernio can be very difficult to treat, and systemic steroids, methotrexte, and azathioprine have all been used with limited success. Recently, the anti-TNF monoclonal antibodies have been shown to be possibly useful in this syndrome.

Hypercalcemia in sarcoidosis often responds to low-dose corticosteroids. Because of it low toxicity, plaquenil may be especially useful in this syndrome.

The risks of treatment in sarcoidosis are significant. The side effects of corticosteroids, which are related to dose and duration, include: hyperglycemia, hypertension, significant weight gain, adrenal insufficiency, infection, fluid retention, pancreatitis, cataracts, myopathy, Cushing’s syndrome, hypokalemic alkalosis, insomnia, depression, osteoporosis, ischemic necrosis of the hip, acne, heartburn, nausea, or skin fragility. Even the steroid-sparing drugs can be associated with bone marrow failure, liver toxicity, pulmonary fibrosis, and an increased risk of neoplasia.

What is the prognosis for patients managed in the recommended ways?

The natural history of sarcoidosis is variable. Seventy percent of patients may spontaneously resolve without the need for medication while 30 percent may progress. An individual patient’s course is difficult to predict. Patients with erythema nodosum usually have a good prognosis, while the prognosis of patients with cardiac or CNS involvement is usually poor. Multi-organ involvement also has a worse prognosis. Patients with severe organ involvement are also less likely than other patients to resolve their disease.

Therefore, the clinician is faced with a significant problem: watchful waiting may lead to spontaneous resolution but it also carries the risk that the patient will develop irreversible fibrosis. Early treatment may cause significant side effects that are due to corticosteroid therapy or to the steroid-sparing drugs when patients may have resolved spontaneously without them. Treatment must be tailored to each individual patient, as there are no studies that document long-term beneficial effects of treatment in sarcoidosis. While short-term, clinically significant benefit can be achieved, patients must be continually monitored to ensure appropriate response and that the benefit of the medication outweighs the side effects.

What other considerations exist for patients with sarcoidosis?

Despite the genetic associations with sarcoidosis, genetic counseling is not advised because the risk of a first-degree relative’s having the disease is small (~ 1% in European Americans and ~10% in African Americans).

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