Sarcoidosis

Disease Overview

Sarcoidosis is a disease that affects multiple organs of the body. It develops when groups of cells in the immune system form red and swollen (inflamed) lumps called granulomas in various organs in the body.¹

The inflammation that leads to these granulomas can be caused either by infections or by exposure to some environmental factors.¹

This disorder affects the lungs in approximately 90% of affected people, but it can affect almost any organ in the body. Disease presentation and severity varies widely.² Because it can affect any organ, symptoms are very variable. Most often it affects the lungs and lymph nodes in the chest.^1,2

Treatment depends on the specific symptoms and on which organs are affected. Many people recover with few or no long-term problems, but in some people the disease causes permanent scarring (fibrosis) in the lungs or in other organs and can lead to life-threatening heart or lung problems.¹

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Synonyms

• sarcoid of Boeck
• Schaumann's disease

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Subdivisions

• acute sarcoidosis; Heerferdt-Waldenstrom and Lofgren's syndromes (included)
• chronic sarcoidosis
• subacute sarcoidosis

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Signs & Symptoms

Sarcoidosis may be acute, subacute, or chronic in its presentation. The acute form may present as Löfgren’s syndrome, characterized by skin problems (erythema nodosum), bilateral enlarged lymph nodes (lymphadenopathy) and inflammation of multiple joints (polyarthritis). People with subacute sarcoidosis have nonspecific signs such as fever, weight loss, frailty along with joint pain and enlarged lymph nodes. Chronic sarcoidosis is linked with persistent lung problems and with problems in other organs of the body.³

In more than half of the people with Löfgren’s syndrome, the disease resolves spontaneously (i.e., without the need for treatment) within 2 years, on average. After five years, recovery is much less likely. Acute disease with rapid onset usually resolves spontaneously and has an excellent prognosis. Non-Löfgren’s syndrome is mostly associated with the chronic form trend of >2 years of duration.⁴

Sarcoidosis can also be classified into acute and chronic according to the course of the disease and the outcome, acute (≤2 years) and chronic (≥3–5 years) when the disease follows a waxing and waning course over many years.⁵

Many people with subacute sarcoidosis have no apparent symptoms (asymptomatic). In these people the disorder may be discovered during a routine chest X-ray in which lymph node and/or lung involvement may be seen.⁶

In some people with sarcoidosis, symptoms develop gradually and subtly over a period of months. Initially, there may be respiratory difficulties that are most often associated with lung involvement. In some people, other organ systems may eventually become involved. This type of onset suggests that a person is affected with the chronic form of sarcoidosis.⁵

Symptom onset usually occurs in individuals aged 20 to 40 years, particularly between the ages of 20 and 29.

At the time of diagnosis most people only have lung problems and only about 7% of the affected people have problems in other organs of the body outside the lungs (extrapulmonary disease) such as of the liver, heart and/or brain and spinal cord (central nervous system). However, as time goes by and the disease progresses, more affected people with sarcoidosis may develop extrapulmonary involvement.^2,5,6

The signs and symptoms that may occur in sarcoidosis vary with the extent and severity of organ involvement as follows:^1,4,5,6,7

• People with no symptoms (asymptomatic) when the disease is detected on chest imaging incidentally – approximately 5% of cases
• People with no specific systemic complaints (fever, anorexia and other) – 45% of cases
• Lofgren’s syndrome (a classic set of symptoms of sarcoidosis) is an acute form of sarcoidosis, usually self-limited, and especially common in Scandinavian patients, but uncommon in African American and Japanese patients. It includes:
  • Swollen lymph nodes in the chest, neck, chin, armpits, or groin
  • A rash of small, itchy, or painful bumps called erythema nodosum that most commonly appear on the head, neck, or legs
  • Blurred vision, eye pain or redness, light sensitivity, or watery eyes
  • Pain, stiffness, or swelling of several joints
  • Fever
• Heerferdt-Waldenstrom syndrome, also an acute form of sarcoidosis, describes another specific combination of symptoms that includes:
  • Fever
  • Enlargement of the salivary glands located near the ears (parotid glands)
  • Inflammation of the front portion of the middle layer of the eyes (anterior uveitis)
  • Paralysis (palsy) of the facial nerve which is an inability to move the muscles that control smiling, blinking and other facial movements
• Pulmonary and respiratory problems – 50% of cases
  • Shortness of breath during exercise or other physical activities (dyspnea on exertion)
  • Cough
  • Chest pain
  • Nose blood (hemoptysis)
  • Wheezing sound
  • Collapse of a portion of the lung or failure to expand completely (atelectasis)
  • Inflammation of the membrane that surrounds the lungs (pleura) known as pleuritis
  • Accumulation of fluid on one side of the chest cavity (pleural effusion)
  • Scarring of the lungs with replacement of normal lung tissue with fibrous tissue (fibrosis)
  • Nasal congestion
  • Abnormal, high-pitched sounds heard upon inhalation (stridor)
  • Pulmonary hypertension, a serious complication that develops when the blood pressure in the lungs is higher than normal
• Skin problems
  • Erythema nodosum (as explained above)
  • Lupus pernio (the most specific associated skin lesion) characterized by skin sores that usually affect the face, especially the nose, cheeks, lips and ears and that usually last a long time
  • Rash of purple color on the cheeks or nose (common)
  • Inflammation in old scars and/or tattoos that may produce reddish-violet lesions that eventually fade to a brownish color (scarring from erythema nodosum or earlier biopsies and/or sites used for inoculation or skin testing are also susceptible to this inflammatory involvement)
• Eye or vision problems which may lead to blindness if untreated
• Tips of the fingers that are abnormally enlarged and fleshy (clubbed) with skin that appears chafed or rough
  • Clubbing of the fingertips is often associated with chronic fibrosis of the lungs

Other possible signs and symptoms may include:^1,2

• Bone problems
  • Bone cysts, particularly in the small bones of the hands and feet
• Heart problems
  • Heart palpitations or an irregular heartbeat
  • Heart failure from enlargement of the heart (cardiomyopathy) which is rare
  • Heart block and sudden death
  • Irregularities of the electrical impulses (signals) that coordinate the heart’s muscular contractions (electrocardiographic conduction defects)
  • Inflammation of the membrane (pericardium) surrounding the heart (pericarditis)
  • Abnormalities of the valve(s) of the heart and/or reduced function of the left lower chamber of the heart (ventricle)
  • Inability of the heart to pump blood effectively throughout the body (congestive heart failure) which may cause breathlessness, lightheadedness, fainting spells upon exertion, fatigue, fever, chest pain and/or other associated symptoms and findings
• Nervous system problems
  • Dizziness
  • Seizures
  • Abnormal emotional, behavioral and/or mental changes (psychiatric abnormalities) such as:
    • Mood swings
    • Hallucinations
    • Delusions
  • Nerve pain
  • Cranial nerve palsies (the most common finding in such cases is involvement of the seventh cranial nerve (facial nerve) resulting in sudden, usually temporary, one-sided (unilateral) facial paralysis (palsy)
  • Problems with the gland in the brain known as hypothalamus that controls the hormone (endocrine) system
  • Mild inflammation of the membranes (meninges) surrounding the brain and spinal cord (meningitis) which may result in symptoms such as headache, fever, nausea and/or stiffness of the neck
  • Hydrocephalus, a condition characterized by inhibition of the normal flow of cerebrospinal fluid (CSF) and abnormal widening (dilatation) of the cerebral spaces of the brain (ventricles) causing accumulation of CSF in the skull and potentially increased pressure on the brain which may result in:
    • Headache
    • Swelling of the optic disk (papilledema), the portion of the optic nerve that enters the eye and joins with the retina
    • Impaired muscle coordination
  • Impaired transmission of certain nerve impulses due to disturbances of nerves outside the brain and spinal cord (peripheral neuropathy) which may affect motor or sensory nerve fibers
    • Motor nerve involvement may be characterized by progressive muscle thinning and weakness
    • Sensory nerve involvement may cause tingling, numbness and abnormal sensations of pain or cold
  • Muscle problems
    • Muscle weakness
    • Muscle inflammation (polymyositis)
  • Joint pain and swelling of the joints (arthralgia)
    • May affect several joints (polyarthralgia) especially the large joints
    • Usually occurring in association with erythema nodosum and may be severe but is often of short duration
    • Chronic polyarthralgia may develop along with a thickening of the fluid that lubricates the joints (synovial fluid)
    • Joint pain may recur and is often accompanied by additional skin and bone changes
  • Larger than normal liver (hepatomegaly) or spleen (splenomegaly)
  • Gastric problems
    • Abdominal pain
    • Nausea
    • Vomiting
    • Lack of appetite (anorexia)
    • Liver problems that may result in jaundice and can make eyes or skin yellow
  • Swollen salivary glands
  • Enlarged lymph nodes (in many people) in the chest cavity (intrathoracic) but also other parts of the body such as in the neck (cervical), armpits (axillary) and/or groin (inguinal).
    • Lymph gland enlargement usually does not present problems except when excessively swollen nodes intrude upon other body organs or blood vessels
  • Bone marrow (the part inside the bones where blood cells are formed) involvement which may result in:
    • Lower than normal amount of red blood cells or hemoglobin (anemia)
    • Abnormally low levels of circulating blood platelets (thrombocytopenia)
    • Decreased numbers of certain white blood cells (neutropenia)
    • Increased number of white blood cells called eosinophils (eosinophilia)
  • Granulomas in the spleen which may result in:
    • Decreased number of white blood cell count (leukopenia)
    • Thrombocytopenia, possibly resulting in small hemorrhages within skin (dermal) layers or layers below the mucous membranes (submucosal)
    • Increased susceptibility to bruising (thrombocytopenic purpura)

Other symptoms may include.⁸

• Excessive amount of calcium in the blood (hypercalcemia) and in the urine (hypercalcuria) which may result from the granulomas associated with sarcoidosis producing 1,25-dihydroxyvitamin D, a hormone that increases intestinal absorption of calcium and that may result in the following symptoms:
• Nausea
• Lack of appetite (anorexia)
• Fatigue
• Abdominal pain
• Muscle pain
• Weakness
• Confusion
• Kidney stones (nephrolithiasis) in cases of mild, chronic hypercalcemia and hypercalcuria which may cause:
  • Intense pain that comes and goes in waves (fluctuates) or less severe, more constant pain, depending upon the exact location of the stones
  • Chills
  • Fever
  • Nausea
  • Vomiting
  • Traces of blood in the urine (hematuria)
  • Inability to urinate (anuria)
  • Swelling (distention) of the abdomen
• Calcium deposits in the tissues of the kidneys (nephrocalcinosis) which may result in:
  • Blood in the urine (hematuria)
  • Infection
  • Decreased or insufficient kidney function

When granulomas develop in some glands that produce internal secretions (endocrine glands) this may result in:

• Diabetes insipidus, an irregularity of metabolism characterized by excessive urination (polyuria) and excessive thirst (polydipsia)

In addition, several other organs can be affected with sarcoid granulomas and sometimes there are no serious symptoms and may not be noticed.

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Causes

The exact cause of sarcoidosis is not known. Possible infectious, environmental, genetic and immunological factors are being studied as potential causes of sarcoidosis, but no single cause has been identified to date.^1,3,9

Genetic factors: Sarcoidosis tends to occur in families, and it is more common in certain races or ethnic groups. In addition, some studies suggest that genetic factors are important in establishing the risk of having the disease and for the outcome of sarcoidosis. There are 11 sarcoidosis risk loci (BTNL2, HLA-B, HLA-DPB1, ANXA11, IL23R, SH2B3/ATXN2, IL12B, NFKB1/MANBA, FAM177B, chromosome 11q13.1, and RAB23) that have been identified to date.⁹ Genetic risk loci are specific locations on the genome that are associated with an increased risk of developing a particular disease or condition. These loci can be identified through genome-wide association studies (GWAS), a genetic test that analyze the genetic variations across the entire genome to identify common genetic variants that are more frequent in people affected with the disease compared to those without the disease. The identified risk loci are often located near or within genes that are involved in biological pathways relevant to the disease.^9,10

In addition, genome wide association studies have demonstrated that several HLA and non-HLA genes are associated with the development of this disease. HLA-DRB1*0301/ DQB1*0201, transforming growth factor β (TGF-β), tumor necrosis factor α (TNF-α) and Toll-like receptor 4 (TLR-4) are all considered indicators for the risk of developing sarcoidosis.

The human major histocompatibility (HLA) complex or human leukocyte antigen system is comprised of over 200 genes, encoding several different molecules involved in immune defense.⁹ An HLA disease association is defined as an increased frequency of an HLA gene variant in people with specific disease compared to the frequency in people without the disease.

Environmental factors: Exposure to wood stoves, soil, tree pollen, inorganic particulates, insecticides and nanoparticles seem to increase the risk for developing sarcoidosis. In addition to these factors, some workers, such as those involved in hardware, gardening materials, building supplies and metal work as well as ship servicemen in the navy, fire workers and educators, are prone to sarcoidosis. It has been suggested that silica exposure also triggers the risk of sarcoidosis. Researchers think that the environment is an important risk factor for the development of sarcoidosis, which has been further strengthened by reports that U.S. World Trade Center workers exposed to the crash debris (in particular firefighters) all experienced an increased risk for developing sarcoidosis or “sarcoid-like” disease.⁹

Infectious diseases: Infectious agents such as mycobacteria may be associated with the development of sarcoidosis because the body produces granulomas as an immune defense response against these agents. Studies have identified many of these infectious agents that can start an immune response in sarcoidosis including Leptospira species, Mycoplasma species, herpes virus, retrovirus, Chlamydia pneumoniae, Borrelia burgdorferi, Pneumocystis jirovecii, Mycobacterium and Propionibacterium species. Also, a few studies have suggested that hepatitis C infection on its own could increase the risk of developing sarcoidosis.⁹

Autoimmunity: The term autoimmunity refers to a failure of the body’s immune system to recognize its own cells and tissues as “self”. In people affected with sarcoidosis, the immune system, which is responsible for defending the body against foreign agents (such as toxins and microorganisms including bacteria and viruses), may respond inappropriately to the presence of certain agents (antigens). Due to inappropriate immune responses, there is an abnormal proliferation of certain white blood cells (macrophages) that serve to surround and destroy microorganisms, cellular debris and foreign particles (phagocytosis). The abnormal proliferation of macrophages in affected tissue(s) results in the formation of the inflammatory masses or nodules (epithelioid granulomas) associated with sarcoidosis.⁹

Researchers suspect that enhanced immune responses occurring in sarcoidosis do not damage affected organs but rather, the granulomas that are formed replace the normal organ tissue (parenchyma).¹¹

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Affected populations

The estimated prevalence of sarcoidosis is about 60 per 100,000. Previous studies reported higher incidence of sarcoidosis in the Midwest and Northeast compared to the Southwest United States. The total number of cases in the United States is estimated to be between 150,000 and 200,000 people. In the United States, the disease has been found to be more common among African Americans than among white individuals and more common in females than males.^14,15

Erythema nodosum (EN) in Europeans, chronic uveitis in U. S. blacks and lupus pernio in Puerto Ricans are the extra-thoracic symptoms in specific populations.⁹ Sarcoidosis is also more frequent in Scandinavia.

It is important to note that estimates about the numbers of individuals with sarcoidosis may not reflect the true frequency of the disorder in the general population. This may be due to the extreme variability in symptom range and severity, the lack of apparent symptoms in some individuals and the fact that some people may remain undiagnosed. In addition, a high incidence of reported cases in certain regions or countries may be a result of more frequent testing, as may be suggested by the relatively high number of affected school children with sarcoidosis of the heart in Japan, where routine chest X-ray screening is performed.⁶

Additionally, researchers have described familial cases of the disorder among individuals within several hundred families (kindreds). Sarcoidosis has also been reported among husbands and wives and in other unrelated individuals who live or work in close proximity. Such observations give credence to the theory that genetic predisposition and/or environmental factors may play a role in some cases of sarcoidosis.⁶

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Disorders with Similar Symptoms

Sarcoidosis is the most common noninfectious cause of granulomatous inflammation, but a diagnosis is made after ruling out other similar disorders.

The first step that the doctors need to take is to obtain a complete medical history to find out if the person had exposure to known risk factors (such as infectious, occupational and environmental agents) and exposure to drugs taken for therapeutic or recreational purposes. The clinical history, physical examination and chest computed tomography indicate which other diseases should be considered (such as microbiological investigations, lymphocyte proliferation tests with metals, autoantibody assays and genetic tests).¹²

The goal is to rule out all diagnoses other than sarcoidosis that are consistent with the signs and symptoms that the person has.

Doctors should investigate any mycobacterial and endemic fungal infections, especially in people who do not meet all the diagnosis criteria for sarcoidosis and in people who have symptoms of extrapulmonary disease.

Some specific features such as the presence of poor immunity (including AIDS), a history of exposure to potential occupational or environmental agents (such as beryllium, aluminum, titanium. zirconium, organic dusts), or the use of illicit substances (by inhalation or injection) may increase the likelihood of the diagnosis being other granulomatous conditions and not sarcoidosis.¹³

When a person who is been investigated for sarcoidosis has very severe systemic symptoms (such as fever, night sweats, weight loss and/or fatigue) this may indicate that the person may have an infection or malignancy (although sometimes serious systemic symptoms can present in sarcoidosis). In these people, a lymph node biopsy showing non-necrotizing granulomas needs to be carefully examined to rule out the presence of malignant cells in the lesions.

Symptoms of the following disorders may be similar to those of sarcoidosis. Comparisons may be useful for a differential diagnosis:^4,6,12,13

• Infections (especially tuberculosis, nontuberculous mycobacterial infections and fungal infections such as histoplasmosis)
  • Tuberculosis (TB) is an acute or chronic bacterial infection most found in the lungs, although the kidneys, bones, lymph nodes and/or membranes surrounding the brain (meninges) may also be affected. Tuberculosis rarely resembles sarcoidosis but must be ruled out, especially in regions with high number of tuberculosis cases (endemic tuberculosis). Similarly, in high-income countries, tuberculosis is far more common in migrants from low-income countries than in locals. All biopsy specimens of people with suspected sarcoidosis should be examined with special stains for mycobacteria and cultures should be obtained whenever possible
  • Leprosy is a progressive chronic infectious disease caused by the bacteria Mycobacterium leprae. This disease is rare in the United States but not in third world countries and affects the nerves that are located outside the central nervous system (peripheral nerves), the skin and/or other tissues of the body.
  • Histoplasmosis, a fungal infection caused by the inhalation or ingestion of spores of the fungus Histoplasma capsulatum is seen worldwide but is most prevalent in the midwestern United States. Affected people may experience fever, generalized discomfort and fatigue (malaise), cough and/or swollen lymph glands (lymphadenopathy). Additional symptoms may include erythema nodosum and/or pain and swelling in the joints (arthralgia or polyarthralgia). Biopsy samples in those with suspected sarcoidosis should be routinely examined with special stains for fungus. People from endemic areas should also do serologic testing.
  • Other infections that may have some similarities with sarcoidosis include other fungal infections such as aspergillosis, blastomycosis, coccidioidomycosis and cryptococcosis and other infections such as brucellosis and cat-scratch disease.
• Pneumoconiosis, especially chronic beryllium disease (CBD), can mimic sarcoidosis radiographically and the ways it affects the body (pathology). CBD results from inhalation of the dust or fumes of beryllium or its compounds, a metallic element often found in alloys and fluorescent powders which is often used in occupational settings, specifically in the aerospace and nuclear power industries. Inhalation of or, in some cases, exposure to beryllium through the skin may result in the formation of granulomas in the lungs and/or throughout the body). The diagnosis of chronic beryllium disease is based on a careful occupational history and, when needed, a blood and/or BAL beryllium lymphocyte proliferation test.
• Hypersensitivity pneumonitis (HP; also called extrinsic allergic alveolitis) can be misdiagnosed as sarcoidosis if the history of exposures to potential antigens is missed or characteristic radiologic and pathologic features are not well evaluated. HP granulomas are different from sarcoidosis granulomas and, compared with sarcoidosis granulomas, HP granulomas are smaller, less well-formed and associated with greater chronic interstitial inflammation.
• Foreign body granulomatosis can be caused by aspiration or intravenous injection of foreign materials. Of these, granulomatous talcosis, a type of pneumoconiosis that can be more frequent in intravenous drug users, can resemble sarcoidosis. Talc (magnesium silicate) used in the preparation of oral tablets as a filler can be smashed and then dissolved and injected in the vein for illicit use. The talc accumulates in the pulmonary circulation and causes pulmonary problems that may resemble sarcoidosis findings.
• Drug-induced granulomatosis (notably due to TNF-a antagonists, immune checkpoint inhibitors, targeted therapies and interferons). Specific agents described in case reports include etanercept, infliximab, adalimumab, azacytidine, oxaliplatin, amoxicillin, sirolimus, fluoxetine, immune checkpoint inhibitors, antiretroviral agents and interferons.
• Immune deficiencies, which may cause a sarcoid-like disorder, called granulomatous and lymphocytic interstitial lung disease (GLILD) can present with granulomatous disease in the liver and lungs of people affected with common variable immunodeficiency (CVID). Therefore, people with apparent sarcoidosis who are immune deficient and have recurrent infections and/or autoimmune diseases should be evaluated for CVID.
• Blau syndrome, a genetic disorder, which very rarely involves the lungs, is usually diagnosed at a younger age compared to pediatric sarcoidosis. Onset before the 3–4 years of age; no lung involvement; familial history in 40%.
• Intestinal sarcoidosis can mimic Crohn disease, an inflammatory bowel disease characterized by severe, chronic inflammation of the intestinal wall. Therefore, it is important to evaluate alternative diagnoses in people diagnosed with sarcoidosis who present with atypical symptoms or do not respond to conventional therapy.
• Diseases associated with vascular inflammation including granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), and pulmonary lymphomatoid granulomatosis can be differentiated from sarcoidosis by their specific “angiocentric pattern” and by the presence of vasculitis. The “granulomas” seen in vasculitis are not compact structures seen in sarcoidosis. Measurement of blood antineutrophil cytoplasmic antibody (ANCA) test may be helpful in identifying systemic vasculitis.
• Malignancy-associated granulomatosis, such as lymphoma, an abnormal growth of lymphoid tissue, frequently malignant, that often first appears as an enlarged lymph node(s) in the neck, groin, armpit and/or other areas. Initial symptoms may include generalized weakness, fever, weight loss and/or decreased levels of the oxygen-carrying portion (hemoglobin) of red blood cells (anemia). There are many different types of lymphomas, each with its own name and unique characteristics.

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Diagnosis

The diagnosis of sarcoidosis is based on three main criteria: signs and symptoms compatible with sarcoidosis, the presence of the non-caseating granulomas on tissue specimens examined under a microscope (histological examination) and ruling out any other diseases that have similar symptoms. However, even when all these criteria are met, the diagnosis of sarcoidosis varies from “definite” to only “possible” depending upon the presence of characteristics, on radiologic-clinical and histopathological findings and on the person’s ethnic group (as sarcoidosis is most frequent in certain populations).^2,6

Imaging studies for sarcoidosis are as follows:^1,4

• Chest radiography which is essential to evaluation
• Routine chest computed tomography (CT) which in most people adds little information to radiography
• High-resolution CT (HRCT) scanning of the chest, a type of computed tomography (CT) with specific techniques to enhance image resolution, which may be helpful because it identifies an inflammation in the small air sacs of the lungs (alveolitis)
• Gallium scan, a study that uses radioactive gallium to create nuclear medicine images (not used frequently but may be helpful when there are doubts about the diagnosis)

Other exams may include:⁴

• Pulmonary function tests
• Carbon monoxide diffusion capacity test of the lungs for carbon monoxide (DLCO) which measures how well the lungs exchange gases, as the major function of the lungs is to allow oxygen to diffuse or pass into the blood from the lungs and to allow carbon dioxide to diffuse from the blood into the lungs
• Cardiopulmonary exercise testing is an adequate test to determine the lung and heart involvement
• Neurological tests such as electromyography, evoked potentials, spinal taps or nerve conduction tests
• Eye exams that look for eye damage which can occur without symptoms in a person with sarcoidosis
• Heart exams that help to monitor the heart function and how well the heart is working (sarcoidosis only rarely affects the heart, but cardiac sarcoidosis may be life threatening). Tests may include:
  • Electrocardiography (ECG or EKG) annually and a Holter monitor, a small, wearable device that records the heart’s rhythm, usually for 1 to 2 days when there are heart palpitations
  • Echocardiography (all people affected with sarcoidosis should have an annual electrocardiogram) and a Holter monitor if they have heart palpitations
  • Heart MRI

Doctors use stages to describe the severity of the disease in sarcoidosis based on the lung or lymph nodes of the chest. The stages are based on where the lumps or granulomas are found and whether there is scarring on imaging tests.¹ Staging of sarcoidosis is as follows:⁴

• Stage 0: Normal chest radiographic findings
• Stage I: Bilateral hilar lymphadenopathy
• Stage II: Bilateral hilar lymphadenopathy and infiltrates
• Stage III: Infiltrates alone
• Stage IV: Fibrosis (permanent scarring in the lungs)

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Standard Therapies

Treatment

Not everyone affected by sarcoidosis needs treatment (in about 30% of people the disease may resolve by itself without treatment). Treatment will depend on the specific symptoms and on which organs are affected. Medicines can help treat inflammation or lower the body’s immune response. Many people recover with few or no long-term problems, but sometimes the disease causes permanent scarring (fibrosis) in the lungs or other organs and can lead to life-threatening heart or lung problems.^1,2,4,9,16

Certain disease manifestations (anterior uveitis, skin disease other than lupus pernio) may be treated only locally.^4,9

Treatment is necessary when there is danger of permanent debilitating organ damage or dysfunction with associated illness and/or a decreased quality of life. Thus, the goal of treatment is to prevent the change of an active granulomatous inflammation to fibrosis.^4,9,16

Treatment of sarcoidosis requires the coordinated efforts of a team of specialists who need to work together to plan an affected individual’s treatment systematically and comprehensively. Such specialists may include internists, physicians who diagnose and treat disorders of the lungs (pulmonologists), dermatologists, eye specialists (ophthalmologists), physicians who diagnose and treat inflammatory disorders of the joints, muscles, and related structures (rheumatologists), neurologists, physicians who diagnose and treat abnormalities of the heart (cardiologists) and/or other health care professionals.

The first option of treatment of sarcoidosis is corticosteroids, such as prednisone.  These medications have been proven to improve overall disease control, symptoms, quality of life and pulmonary radiology and/or delay disease deterioration.^9,16

Corticosteroids can be taken as pills or be injected, inhaled, or taken as eye drops or other topical medicines. Corticosteroid ointments or drops are sometimes effective in treating eye inflammation that may develop in the forward portion of the eye, whereas deep-seated inflammatory activity may require oral medication. In addition, in people with symptoms that are mainly limited to skin, oral treatment is not indicated and topical application of steroid ointment or cream may be better.^9,17

However, corticosteroids can have serious side effects with long-term use, especially if taken in high doses.¹

Other drugs may include:^3,8,16,17,18

• Medicines such as methotrexate (also given in combination with corticosteroids), leflunomide and azathioprine are used as a second option instead of corticosteroids.
• Monoclonal antibodies, also called immunotherapy, which include rituximab, infliximab, golimumab and adalimumab, usually taken as injections or through a vein. Side effects are rare but can include a life-threatening immune reaction, heart problems, low blood counts, or a higher risk of certain cancers.
  • infliximab and thalidomide have also been used for cases of sarcoidosis that do not improve, especially for cutaneous disease (sarcoidosis affecting the skin) and long-term treatment with infliximab can be effective for extrapulmonary sarcoidosis
• Mycophenolate mofetil
• Medicines used to treat malaria include hydroxychloroquine or chloroquine and are given to people withs sarcoidosis with increased calcium levels, neurological sarcoidosis and bone lesions (chloroquine has also been shown to be effective for the treatment and maintenance of chronic pulmonary sarcoidosis)
• Corticotropin (a hormone medicine) is given as a shot. It may be used when corticoids do not work or have serious side effects. Side effects of this medicine may include high blood pressure, controlling blood sugar, increased appetite, or mood changes.
• Cyclophosphamide instead of corticoids, in people who do not improve
• Chlorambucil which may be beneficial in patients with progressive disease who do not improve with corticosteroids
• Cyclosporine for skin sarcoidosis or in progressive sarcoidosis resistant to conventional treatment
• Pentoxifylline, taken as a pill and normally prescribed to improve blood flow. Side effects may include nausea

If untreated, or if the treatment does not work, sarcoidosis can cause serious health problems. If symptoms recur after the course of medication is completed, another course of medication may be indicated.¹

Medicines to treat other symptoms that may occur in sarcoidosis may include:

• Antibiotics that can be used to treat sarcoidosis of the skin (such as minocycline, tetracycline and doxycycline) or for any other infections that can occur in people with sarcoidosis
• Colchicine to treat joint pain from sarcoidosis
• Inhaled corticosteroids or oxygen therapy to help with breathing problems
• Vasodilator treatment for pulmonary hypertension
• Pulmonary rehabilitation
• Implantable cardioverter defibrillator (ICD) for people with heart problems to prevent cardiac arrest
• High blood pressure medicines such as ACE inhibitors and beta blockers to lower blood pressure
• Hormone replacement treatment to treat some types of sarcoidosis
• Anti-seizure medicines for seizures
• Pain medicines for nerve or muscle pain
• Physical therapy to improve muscle strength
• Surgery to remove brain tumors
• Transplant surgery if sarcoidosis causes life-threatening lung, heart, or liver damage.

Other treatment is symptomatic and supportive and is directed toward those symptoms that may most impact on the activities and general well-being of each individual.

Lifestyle changes, such as avoiding too much sunlight, drinking plenty of fluids and eating fewer foods with calcium, may be needed if having too much calcium in the blood or urine.¹

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact: www.centerwatch.com

For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/

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References

1. What is sarcoidosis? National Heart, Lung and Blood Institute. March 24, 2022. https://www.nhlbi.nih.gov/health/sarcoidosis Accessed Nov 13, 2024.

2. Sarcoidosis, what is it? Foundation for Sarcoidosis Research. https://www.stopsarcoidosis.org/what-is-sarcoidosis/ Accessed Nov 13, 2024.

3. Sreeja C, Priyadarshini A, Premika, Nachiammai N. Sarcoidosis – A review article. J Oral Maxillofac Pathol. 2022 Apr-Jun;26(2):242-253.

4. Kamangar N. Sarcoidosis. Medscape. July 21, 2024. https://emedicine.medscape.com/article/301914-overview Accessed Nov 13, 2024.

5. Susceptibility to sarcoidosis 1 clinical synopsis. Online Mendelian Inheritance in Men (OMIM). 01/06/2018. https://www.omim.org/clinicalSynopsis/181000 Accessed Nov 13, 2024.

6. Sève P, Pacheco Y, Durupt F, Jamilloux Y, Gerfaud-Valentin M, Isaac S, Boussel L, Calender A, Androdias G, Valeyre D, El Jammal T. Sarcoidosis: a clinical overview from symptoms to diagnosis. Cells. 2021 Mar 31;10(4):766. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066110/

7. Baughman RP, Culver DA, Judson MA. A concise review of pulmonary sarcoidosis. Am J Respir Crit Care Med. 2011 Mar 1;183(5):573-81. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3081278/

8. Burke RR, Rybicki BA, Rao DS. Calcium and vitamin D in sarcoidosis: how to assess and manage. Semin Respir Crit Care Med. 2010 Aug;31(4):474-84. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4876288/

9. Jain R, Yadav D, Puranik N, Guleria R, Jin JO. Sarcoidosis: causes, diagnosis, clinical features, and treatments. J Clin Med. 2020 Apr 10;9(4):1081. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230978/

10. What is genetic risk loci. Scispace. https://typeset.io/questions/what-is-genetic-risk-loci-1xnhx3ycvr Accessed Nov 13, 2024.

11. Saidha S, Sotirchos ES, Eckstein C. Etiology of sarcoidosis: does infection play a role? Yale J Biol Med. 2012 Mar;85(1):133-41. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3313528/

12. Valeyre D, Brauner M, Bernaudin JF, Carbonnelle E, Duchemann B, Rotenberg C, Berger I, Martin A, Nunes H, Naccache JM, Jeny F. Differential diagnosis of pulmonary sarcoidosis: a review. Front Med (Lausanne). 2023 May 12;10:1150751. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10213276/

13. King, Jr TE & Culver DA. Clinical manifestations and diagnosis of sarcoidosis. UpToDate. Apr 29, 2024. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-sarcoidosis Accessed Nov 13, 2024.

14. Nam HH, Washington A, Butt M, Maczuga S, Guck D, Yanosky JD, Helm MF. The prevalence and geographic distribution of sarcoidosis in the United States. JAAD Int. 2022 Aug 5;9:30-32. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9449733/

15. Baughman RP, Field S, Costabel U, Crystal RG, Culver DA, Drent M, Judson MA, Wolff G. Sarcoidosis in America. Analysis based on health care use. Ann Am Thorac Soc. 2016 Aug;13(8):1244-52. https://www.atsjournals.org/doi/pdf/10.1513/AnnalsATS.201511-760OC

16. Papanikolaou IC, Antonakis E, Pandi A. State-of-the-art treatments for sarcoidosis. Methodist Debakey Cardiovasc J. 2022 Mar 14;18(2):94-105. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9237819/

17. Nara M, Sasamori K, Shimura S, Ogawa H, Ishigaki-Suzuki S, Nagaoka M, Tamada T, Ichinose M, Tamura G, Hattori T. Long-term use of corticosteroid eye drops delays the spontaneous remission of pulmonary sarcoidosis. https://www.jstage.jst.go.jp/article/tjem/202/4/202_4_275/_article

18. Matsou A, Tsaousis KT. Management of chronic ocular sarcoidosis: challenges and solutions. Clin Ophthalmol. 2018 Mar 19;12:519-532. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5863717/

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Programs & Resources

• Assistance Programs
• Patient Organizations
• More Information

RareCare^® Assistance Programs

NORD strives to open new assistance programs as funding allows. If we don’t have a program for you now, please continue to check back with us.

Additional Assistance Programs

MedicAlert Assistance Program

NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.

Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/

Rare Disease Educational Support Program

Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.

Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/

Rare Caregiver Respite Program

This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.

Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/

Learn more about Patient Assistance Programs >

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