Sarcoidosis

Definition:

    • Inflammatory disease characterized by the presence of noncaseating granulomas.

    • Multisystem involvement and requires the presence of 2 or more organs for a specific diagnosis.

    • Patients usually present before 40 years of age. Highest prevalence rates in African Americans and Scandinavians descent.

    • Finding of noncaseating granuloma is not specific for sarcoidosis. Rule out other conditions also known to cause granulomas:

      • mycobacterial and fungal infections

      • malignancy

      • environmental agents like beryllium.

    • Sarcoidosis can affect all organs. Lungs are the most commonly affected. Others are liver, spleen, skin, and eyes.

    • Clinical outcome is variable, remission occurs in over half of the patients within a few years of dx; however, the remaining half develop chronic disease lasting for years/decades.

Etiology:

    • Unknown

    • Hypothetical likely etiology is some infectious or noninfectious environmental agent triggers an inflammatory response in a genetically susceptible host.

      • Propionibacter acnes in LN of sarcoid

      • Atypical mycobacterium

      • Mycobacterium TB catalase-peroxidase (mKatG)

      • Insecticides, mold.

      • HCW have higher risk

Incidence and Prevalence:

    • Worldwide

    • High prevalence in Nordic population

    • African-American

    • Women > men

    • Young adults but uncommon in persons <18 years

    • Another peak occurs around age 60

      • 1/2 of patients are >40

    • Sporadic or familial form. Familial form common in American blacks and Irish.

Patholophysiology and immunopathogenesis:

Granuloma is the pathologic hall mark of sarcoidosis. Lofgren's syndrome a form of sarcoidosis characterized by hilar LAD on CXR, uveitis, and erythema nodosum. Associated with good prognosis. >90% resolve in <2 yrs. Associated with HLA-DQB1*0201

Pts with lupus pernio, cardiac, or neurologic involvement rarely experience disease remission.

Macrophage/Helper T cells cluster → cytokines.

IL-2 released by T cells

IF-gamma and TNF released by macrophages

Advance untreated HIV rarely develop sarcoidosis, becomes unmaksed as HIV is Tx and immune system is restored.

Cyclosporine has little impact on treatment of sarcoidosis

Chronic form of disease associated with high level of IL-8 and excess amounts of TNF.

Clinical manifestations:

    • Fever, fatigue, malaise, weight loss, dyspnea, dry cough, chest pain, rash, or visual complaints.

    • Sarcoidosis ranges from asymptomatic to those with organ failure.

    • CXR screening, 20–30% of pulmonary cases are detected in asymptomatic individuals.

    • Respiratory complaints including cough and dyspnea are the most common presenting symptoms. In many cases, the patient presents with a 2–4 week history of these symptoms. As it is nonspecific it takes a long time to suspect a diagnosis. Often the diagnosis of sarcoidosis is usually only suggested when a CXR is done.

    • Eye disease is more common among blacks. < 40, it occurs more frequently in women. > 40, eye disease is more common in men.

    • Skin and eye lesions.

      • Erythema nodosum over anterior legs, lupus pernio (indurated plaques with associated discoloration of the nose, cheeks, lips, and ears).

      • Uveitis is the most common eye lesion in sarcoidosis.

    • Peripheral lymphadenopathy and splenomegaly.

    • Lofgren's syndrome is defined as an acute presentation of sarcoidosis characterized by arthritis, erythema nodosum, and bilateral hilar lymphadenopathy.

    • Myocardial involvement is becoming increasing recognized in patients with sarcoidosis and may result in cardiomyopathy, arrhythmia, and sudden death.

Diagnosis:

    • H & P, CXR (PA and lat views), PFTs, CBC, CMP, UA, ECG, and ophthalmological exam.

    • Patient with clinical and radiographic characteristics suggestive of sarcoidosis.

    • Histologic evidence of noncaseating granulomas, in the absence of an alternate etiology of graunolomatous disease (e.g., mycobacterial or fungal infection, berylliosis, granulomatous vasculitis, cancer with local sarcoid reaction).

    • Lung involvement occurs in >90% of sarcoidosis patients.

      • CXR: bilateral hilar adenopathy.

      • CT scan feature, peribronchial thickening and reticular nodular changes, predominantly subpleural. Peribronchial thickening seen on CT scan suggest high yield of granulomas from bronchial biopsies performed for diagnosis.

    • Biopsy is not required in all patients, such as patients with stage 1 or stage 2 pulmonary sarcoidosis or patients with Lofgren's syndrome.

    • Chose an easy accessible peripheral target for bx. If not possible do transbronchial lung bx +/- transbronchial needle aspiration of mediastinal lymph node. Transbronchial bx is 70% accurate.

    • PET scan, a positive scan may be due to the granulomas from sarcoidosis and not to disseminated malignancy.

    • Sr ACE levels can be helpful in the diagnosis of sarcoidosis. However, the test has somewhat low sensitivity and specificity. Elevated levels of ACE >50% of the upper limit of normal are seen in only a few conditions including sarcoidosis, leprosy, Gaucher's disease, hyperthyroidism, and disseminated granulomatous infections such as miliary tuberculosis.

      • Because the ACE level is determined by a biologic assay, the concurrent use of an ACE inhibitor such as lisinopril will lead to a very low ACE level.

Diagnostic approach.

    • Needs both compatible clinical features and pathologic findings.

    • Pts evaluated for possible sarcoidosis are based on two scenarios).

      • In the first scenario, a patient may undergo a biopsy revealing a noncaseating granuloma in either a pulmonary or an extrapulmonary organ. If the clinical presentation is consistent with sarcoidosis and there is no alternative cause for the granulomas identified, then the patient is felt to have sarcoidosis.

      • In the second scenario, si or sx suggest sarcoidosis such as the presence of b/l LAD in an otherwise asymptomatic patient or a patient with uveitis or a rash consistent with sarcoidosis. Dxtic procedure should be performed. For the patient with a compatible skin lesion, a skin bx should be considered. Other biopsies to consider could include liver, extrathoracic lymph node, or muscle. In some cases, a biopsy of the affected organ may not be easy to perform (such as a brain or spinal cord lesion). In other cases, such as an endomyocardial biopsy, the likelihood of a positive biopsy is low. Because of the high rate of pulmonary involvement in these cases, the lung may be easier to approach by bronchoscopy. During the bronchoscopy, a transbronchial biopsy, bronchial biopsy, or transbronchial needle aspirate of an enlarged mediastinal lymph node can be performed.

        • If the biopsy reveals granulomas, an alternative diagnosis such as infection or malignancy must be excluded.

        • Bronchoscopic washings can be sent for cultures for fungi and tuberculosis. For the pathologist, the more tissue that is provided, the more comfortable is the diagnosis of sarcoidosis. A needle aspirate may be adequate in an otherwise classic case of sarcoidosis, but may be insufficient in a patient in whom lymphoma or fungal infection is a likely alternative diagnosis. Since granulomas can be seen on the edge of a lymphoma, the presence of a few granulomas from a needle aspirate may not be sufficient to clarify the diagnosis.

        • Mediastinoscopy remains the procedure of choice to confirm the presence or absence of lymphoma in the mediastinum. Alternatively, for most patients, evidence of extrathoracic disease (e.g., eye involvement) may further support the diagnosis of sarcoidosis.

      • For patients with negative pathology, positive supportive tests may increase the likelihood of the diagnosis of sarcoidosis. These tests include an elevated ACE level, which can also be elevated in other granulomatous diseases but not in malignancy. A positive gallium scan can support the diagnosis if increased activity is noted in the parotids and lacrimal glands (Panda sign) or in the right paratracheal and left hilar area (lambda sign).

      • A BAL is often performed during the bronchoscopy. An increase in the percentage of lymphocytes supports the diagnosis of sarcoidosis. The use of the lymphocyte markers CD4 and CD8 can be used to determine the CD4/CD8 ratio of these increased lymphocytes in the BAL fluid. A ratio of > 3.5 is strongly supportive of sarcoidosis but is less sensitive than an increase in lymphocytes alone. Although in general, an increase in BAL lymphocytes is supportive of the diagnosis, other conditions must be considered.

      • These supportive tests when combined with commonly associated clinical features of the disease, which are not diagnostic of sarcoidosis, can enhance the diagnostic probability. These nondiagnostic features include uveitis, renal stones, hypercalcemia, seventh cranial nerve paralysis, or erythema nodosum.

      • Because the diagnosis of sarcoidosis can never be certain, over time other features may arise that lead to an alternative diagnosis. On the other hand, evidence for new organ involvement may eventually confirm the diagnosis of sarcoidosis.

Standard scoring system described by Scadding in 1961

    • Upper and middle lobe are usually involved.

    • Stage I:

      • CXR: Hilar or mediastinal LAD

    • Stage II:

      • CXR: Hilar or mediastinal LAD + lung parenchymal involvement shows as infiltrates.

    • Stage III:

      • CXR: Lung parenchymal involvement alone, infiltrates

    • Stage IV:

      • CXR: Pulmonary fibrosis, honeycombing appearance.

Other conditions with upper lobe predominance:

    • Hypersensitivity pneumonitis

    • Silicosis

    • Langerhans cell histiocytosis

    • Tuberculosis

    • Pneumocystis pneumonia

HRCT: perilymphatic nodules, patchy ground-glass opacities, reticular infiltrates, traction bronchiectasis, progressive massive fibrosis, hilar or mediastinal LAD.

PFTs

    • DLCO is the most sensitive test for an interstitial lung disease.

    • Reduced lung volumes typical of restrictive lung disease seen in sarcoidosis.

      • Many patients presenting with sarcoidosis still have lung volumes within the normal range, despite abnormal chest roentgenograms and dyspnea.

    • 1/2 of patients present with obstructive disease, reduced ratio (FEV1/FVC).

    • Airway hyperreactivity determined by methacholine challenge will be positive in some of these patients. Few patients with cough will respond to bronchodilators as the only form of treatment. In some cases, high-dose inhaled glucocorticoids alone are useful.

    • Pulmonary arterial hypertension reported in at least 5% of sarcoidosis patients.

Skin involvement

1/3 patients get it.

Erythema nodosum, maculopapular lesions, hyper- and hypopigmentation, keloid formation, and subcutaneous nodules.

Lupus pernio a specific complex of involvement of the bridge of the nose, the area beneath the eyes, and the cheeks is referred to as lupus pernio and is diagnostic for a chronic form of sarcoidosis.

Skin lesions are caused by noncaseating granulomas, the diagnosis of sarcoidosis can be readily made by a skin biopsy.

Eye

    • Frequency of eye involvement is high in Japan.

    • United States 30% eye involvement, more common in blacks than whites.

      • Anterior uveitis

      • Posterior uveitis: retinitis and pars planitis.

      • All patients with sarcoidosis receive a thorough ophthalmologic examination.

      • Sicca is seen in over half of the chronic sarcoidosis patients, due to lacrimal gland disease. Although the patient may no longer have active inflammation, the dry eyes may require natural tears or other lubricants.

Liver

    • Bx can identify liver involvement in > 1/2 of sarcoidosis patients.

    • LFTs:

      • Most common abnormality is ▲ALP consistent with an obstructive pattern.

      • ▲ ALT, AST can occur.

      • ▲ bilirubin level is a marker for more advanced liver disease.

      • Portal hypertension from extensive intrahepatic cholestasis casuing ascites and esophageal varices can occur.

      • Pts with both sarcoidosis and HepC should avoid therapy with interferon because of its association with the development or worsening of granulomatous disease.

Bone Marrow and Spleen

    • Lymphopenia, due to sequestration of the lymphocytes into the areas of inflammation.

    • Anemia, leukopenia is less common.

    • Bone marrow examination will reveal granulomas in about a third of patients.

    • Splenomegaly can be detect 5–10% of patients, but splenic bx reveals granulomas in 60% of patients.

Calcium Metabolism

    • Hypercalcemia and/or hypercalciuria.

    • ▲ production of 1,25-dihydroxyvitamin D by the granuloma itself, causes an ▲ intestinal absorption of calcium → to hypercalcemia with a suppression of PTH level. ▲ exogenous vit D from diet or sunlight exposure may worsen this problem.

    • Sr calcium should be determined as part of the initial evaluation of all sarcoidosis patients, and a repeat determination may be useful during the summer months with increased sun exposure.

    • In pts with a h/o of renal calculi, a 24-h urine calcium measurement should be obtained. If a sarcoidosis patient with a history of renal calculi is to be placed on calcium supplements, a follow-up 24-h urine calcium level should be measured.

Renal Disease

    • <5% of sarcoidosis pts affected.

    • Hypercalcemia is most likely cause of sarcoidosis-associated renal disease.

    • Acute renal failure has been encountered as a result of hypercalcemia.

    • Treatment of the hypercalcemia with glucocorticoids and other therapies often improves, but does not totally resolve, the renal dysfunction.

Nervous System

    • Neurologic disease is reported in 5–10% of sarcoidosis patients and appears to be of equal frequency across all ethnic groups.

    • Any part of the central or peripheral nervous system can be affected.

    • The presence of granulomatous inflammation is often visible on MRI studies. The MRI with gadolinium enhancement may demonstrate space-occupying lesions, but the MRI can be negative due to small lesions or the effect of systemic therapy in reducing the inflammation.

    • Cerebral spinal fluid (CSF) findings include a lymphocytic meningitis with a mild increase in protein. The CSF glucose is usually normal but can be low.

    • Certain areas of the nervous system are more commonly affected in neurosarcoidosis. These include cranial nerve involvement, basilar meningitis, myelopathy, and anterior hypothalamic disease with associated diabetes insipidus).

    • Seizures and cognitive changes also occur.

    • Cranial nerve seven paralysis can be transient and can be mistaken for Bell's palsy (idiopathic seventh nerve paralysis). Often resolves within weeks and does not recur, it may have occurred prior to a definitive diagnosis of sarcoidosis.

    • Optic neuritis is another cranial nerve manifestation of sarcoidosis. This manifestation is more chronic and usually requires long-term systemic therapy. It can be associated with both anterior and posterior uveitis.

    • Multiple enhancing white matter abnormalities may be detected by MRI, suggesting multiple sclerosis. In such cases, the presence of meningeal enhancement or hypothalamic involvement suggests neurosarcoidosis, as does evidence of extraneurologic disease such as pulmonary or skin involvement, which also suggests sarcoidosis. Since the response of neurosarcoidosis to glucocorticoids and cytotoxic therapy is different from that of multiple sclerosis, differentiating between these disease entities is important.

Cardiac

    • Cardiac involvement common in Japanese, rare in pts in U.S

    • CHF or cardiac arrhythmias. Both manifestations result from infiltration of the heart muscle by granulomas.

    • Diffuse granulomatous involvement of the heart muscle can lead to ejection fractions below 10%.

      • Even in this situation, improvement in the ejection fraction can occur with systemic therapy.

    • Arrhythmias can also occur with diffuse infiltration or with more patchy cardiac involvement. If the AV node is infiltrated, heart block can occur. This can be detected by routine electrocardiography. Ventricular arrhythmias and sudden death due to ventricular tachycardia are common causes of death. Arrhythmias are best detected using 24-h ambulatory monitoring. Because ventricular arrhythmias are usually multifocal due to patchy multiple granulomas in the heart, ablation therapy is not useful. Patients with significant ventricular arrhythmias should be considered for an implanted defibrillator, which appears to have reduced the rate of death in cardiac sarcoidosis.

    • While systemic therapy can be useful in treating the arrhythmias, patients may still have malignant arrhythmias up to 6 months after starting successful treatment, and the risk for recurrent arrhythmias occurs whenever medications are tapered.

Musculoskeletal System

    • Direct granulomatous bone and muscle involvement as documented by x-ray, gallium scan, or biopsy can be seen in about 10% of sarcoidosis patients.

    • Fatigue associated with sarcoidosis may be overwhelming for many patients. Recent studies have demonstrated a link between fatigue and small peripheral nerve fiber disease in sarcoidosis.

Other Organ Involvement

    • Sarcoidosis can affect any organ of the body, rarely does it involve the breast, testes, ovary, or stomach.

    • Because of the rarity of involvement, a mass in one of these areas requires a biopsy to rule out other diseases including cancer.

Complications

    • Sarcoidosis is usually a self-limited, non-life-threatening disease.

    • Organ-threatening disease can occur.

    • Blindness, paraplegia, or renal failure.

    • Death from sarcoidosis occurs in about 5% of patients seen in sarcoidosis referral clinics. The usual causes of death related to sarcoidosis are from lung, cardiac, neurologic, or liver involvement. In respiratory failure, an elevation of the right atrial pressure is a poor prognostic finding.

    • Lung complications can also include infections such as mycetoma, which can subsequently lead to massive bleeding.

    • In addition, the use of immunosuppressive agents can increase the incidence of serious infections.

Treatment:

    • Treatment is not usually required as the disease regresses in most patients. With more advance stages, chances of remission diminishes. In general patient's with acute disease presentation (e.g., Lofgren's syndrome) have a favorable prognosis, while patients with a chronic presentation are more likely to develop progressive disease and organ dysfunction.

    • Corticosteroids are usually first-line therapy. If chronic steroids are required, second-line agents such as methotrexate and azathioprine can be used as steroid-sparing agents. The data suggests infliximab may improve lung function in chronic sarcoidosis.

    • Lung transplant considered in select patients.

Indications for therapy should be based on symptoms.

    • ▲LFT and an abnormal CXR. Wait and watch

    • Acute disease:

    • Sx confined to only one organ, topical therapy is preferable.

    • Multiorgan disease or disease too extensive for topical therapy:

      • Glucocorticoids remain the drugs of choice for this disease. However, the decision to continue to treat with glucocorticoids or to add steroid-sparing agents depends on the tolerability, duration, and dosage of glucocorticoids. Dosage of glucocorticoids is usually higher for neurosarcoidosis and lower for cutaneous disease.

Erythema nodosum

Bilateral hilar lymphadenopathy

Common organ involvement is sarcoidosis

Lupus pernio a specific complex of involvement of the bridge of the nose, the area beneath the eyes, and the cheeks is referred to as lupus pernio and is diagnostic for a chronic form of sarcoidosis.

Lupus pernio

Prognosis

    • Risk of death or loss of organ function remains low in sarcoidosis. Poor outcomes usually occur in patients who present with advanced disease in whom treatment seems to have little impact. In these cases, irreversible fibrotic changes have frequently occurred.

    • Majority of patients, have resolurtion their disease within 2–5 years. These patients are felt to have acute, self-limiting sarcoidosis. On the other hand, there is a form of the disease that does not resolve within the first 2–5 years. These chronic patients can be identified at presentation by certain risk factors at presentation such as fibrosis on chest roentgenogram, presence of lupus pernio, bone cysts, cardiac or neurologic disease (except isolated seventh nerve paralysis), and presence of renal calculi due to hypercalciuria. Recent studies also indicate that patients who require glucocorticoids for any manifestation of their disease in the first 6 months of presentation have a >50% chance of having chronic disease. In contrast, <10% of patients who require systemic therapy in the first 6 months will require chronic therapy.

Management of sarcoidosis