Pulmonary Medicine

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, site, and extent of organ involvement and the activity of the granulomatous process, and because of 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:

The lungs and/or hilar and mediastinal nodes are involved in about 90 percent of patients, and cardiac involvement as either arrhythmias or heart failure may be seen in 5-25 percent, although cardiac involvement may be as high as 60 percent in Japanese patients.

Skin involvement, which can occur in 25 percent of individuals, may be maculopapularor nodular lesions. Involvement of the face is known as lupus pernio. Erythema nodosum is a non-granulomatous lesion of the lower legs that is usually more common in Europeans than in Americans. Ocular lesions occur in 10-15 percent of individuals and may involve all parts of the eye.

Neurologic involvement, which can occur in 5 percent of individuals, involves the peripheral or central nervous system. Liver involvement is frequent (~50%) but rarely severe. Musculoskeletal involvement is also frequent (~50%), but joint deformity is rare. Endocrine manifestations can occur in up to 10 percent of individuals, usually manifested in hypercalcemia or hypercalciuria that can lead to nephrocalcinosis.

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 and infrequently 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. Pulmonary hypertension is due to a variety of granulomatous lesions.

Lofgren's syndrome is 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?

Because of the varied manifestations of the disease, patients may present with a variety of symptoms. Fever, joint pain, fatigue, and shortness of breath are the most common symptoms; while red eye, facial weakness, new skin lesions, or neck swelling may also be presenting complaints, physical findings are usually rare. New maculopapular skin lesions are helpful, as is presentation with erythema nodosum (raised painful lesions that are usually on the shins and that are often associated with ankle swelling). Lupus pernio (plaque-like lesions of the cheeks and nose) can also be seen.

Occasionally, palpable, moveable lymph nodes can be felt in the neck or groin, and enlargement of the liver or spleen can occasionally be palpated or felt. While joint complaints are common, rarely is there joint redness or swelling. Pulmonary findings are not common but may include rales and wheezing.

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 causes of infectious granulomatous diseases. In addition, granulomatous involvement can be seen in hypersensitivity and in reaction to neoplastic diseases. Granulomas can also be due to foreign bodies. Immunodeficiency, 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 is children younger than ten years is usually associated with the 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?

Blood studies cannot be used to confirm a diagnosis of sarcoidosis. An elevated angiotensin converting enzyme (ACE) may raise suspicion, but it is not specific for sarcoidosis and it may be negative in the presence of the disease. A slight anemia and elevated liver enzymes are not uncommon, and occasionally the sedimentation rate is elevated.

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. The finding of bilateral hilar and mediastinal adenopathy with or without upper lobe infiltrates should raise suspicion for a granulomatous disease process. A chest CT would be helpful to confirm these findings. While up to 10 percent of patients with sarcoidosis may have a negative chest x-ray, a negative chest CT can also be seen in sarcoidosis.

An asymptomatic patient with bilateral hilar and mediastinal adenopathy has been considered by many as diagnostic of sarcoidosis. MRI is useful for the diagnosis of cardiac and CNS sarcoidosis when the diagnosis has been confirmed in other tissues. PET scanning with fluoro-deoxy-glucose has been useful in making the diagnosis of cardiac sarcoidosis and may be helpful in determining the extent of organ involvement. In most institutions, the PET scan has replaced Gallium scanning.

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 frequently show a restrictive process and a depressed transfer factor (Dlco), and sarcoidosis can occasionally present with 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?

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. Skin lesions are readily accessible but can sometimes be misleading. Trans-bronchial lung biopsy during bronchoscopy used to be the preferred procedure for making the diagnosis when there is obvious pulmonary involvement, but e-bus bronchoscopy with trans-bronchial needle aspiration of mediastinal nodes under ultrasound guidance has proven a safe and effective means of confirming granulomatous inflammation. Mediastinoscopy and open lung biopsy can also provide diagnostic material.

Conjunctival biopsy is useful when there is obvious conjunctival involvement. Endomyocardial biopsy is useful in diagnosis cardiac sarcoidosis in only about 30 percent of cases. Extra-thoracic lymph node biopsy may also be used to confirm the diagnosis if well-formed granulomatous inflammation is present and foreign bodies are not, and stains and cultures for routine, fungal, and mycobacterial organisms are negative.

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 granulomatous inflammation 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 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 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 3-6-month intervals to monitor any organ involvement that was detected, as in the ACCESS study, new organ involvement was noted in 25 percent of patients within two years. If there is significant organ involvement, treatment with immunosuppresive 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.

Patients with pulmonary sarcoidosis should be treated if they have chest x-ray that demonstrates parenchymal abnormalities in conjunction with significant respiratory symptoms (dyspnea or severe cough) and significant impairment in pulmonary function. 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 and azathioprine have been used successfully as steroid-sparing drugs when patients have been intolerant of corticosteroid therapy. 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 arrythmias, or heart failure. Because of the risk of sudden death, a pacemaker-ICD is frequently implanted if there is confirmation of significant cardiac involvement. 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 echo, and possibly a cardiac MRI or 18-FDG PET scanning. Cardiac mapping may be useful to determine the patient's risk for a sudden arrythmia. A pacemaker-ICD is usually placed if the patient has significant heart block or arrythmia or evidence of heart failure.

Prednisone is the drug of choice for patients with cardiac sarcoidosis, 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 3-5 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 as possibly particularly 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. Corticosteroids' side effects, which are related to dose and duration, may cause patients to develop diabetes, 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: 70 percent of patients may resolve without the need for medication, while 30 percent may progress, and it is difficult to predict which patients will fall into which group. Patients with erythema nodosum usually have a good prognosis, while the prognoses 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 carry 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 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).

What’s the evidence?

Judson, M. "Sarcoidosis: clinical presentation, diagnosis, and approach to treatment". Am J Med Sci. vol. 335. 2008. pp. 26-33.

A brief review of sarcoidosis.

Grutters, JC, Borch, JMM. "Corticosteroid treatment in sarcoidosis". Eur Respir J. vol. 28. 2006. pp. 627-636.

An excellent review of steroids in sarcoidosis.

Yousesef, G, Beanlands, RSB, Birnie, DH, Nery, PB. "Cardiac sarcoidosis: applications of imaging in diagnosis and directing treatment". Heart. vol. 97. 2011. pp. 2078-2087.

An excellent review of the diagnosis and treatment of cardiac sarcoidosis.

"ATS statement on Sarcoidosis". Am J Respir Crit Care Med. vol. 160. 1999. pp. 736-755.

A somewhat dated but still excellent review. A new statement should be out shortly.

Marchell, RM, Judson, MA. "Cutaneous sarcoidosis". Seminars in Respiratory and Critical Care Medicine. vol. 31. 2010. pp. 442-451.

Excellent review with a good selection of pictures and discussion of therapy.

Herbort, CP, Rao, NA, Mochizuki, M. "International criteria for the diagnosis of ocular sarcoidosis: results of the First International Workshop on Ocular Sarcoidosis". Ocular Immunology and Inflammation. vol. 17. 2009. pp. 160-169.

Excellent pictures and discussion of ocular sarcoidosis.
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