Sarcoidosis

Sarcoidosis is a systemic inflammatory disease that can affect any organ, although it can be asymptomatic and is discovered by accident in about 5% of cases. Common symptoms, which tend to be vague, include fatigue (unrelieved by sleep; occurs in up to 85% of cases), lack of energy, weight loss, joint aches and pains (which occur in about 70% of cases), Less commonly, people may cough up blood. The cutaneous symptoms vary, and range from rashes and noduli (small bumps) to erythema nodosum, granuloma annulare, or lupus pernio. Sarcoidosis and cancer may mimic one another, making the distinction difficult. The combination of erythema nodosum, bilateral hilar lymphadenopathy, and joint pain is called Löfgren syndrome, which has a relatively good prognosis. At least 90% of those affected experience lung involvement. In acute and subacute cases, physical examination usually reveals dry crackles. The upper respiratory tract (including the larynx, pharynx, and sinuses) may be affected, which occurs in between 5 and 10% of cases. • Stage I: bilateral hilar lymphadenopathy (BHL) alone • Stage II: BHL with pulmonary infiltrates • Stage III: pulmonary infiltrates without BHL • Stage IV: fibrosis Use of the Scadding scale provides general information regarding the prognosis of the pulmonary disease over time. Caution is recommended, as it only shows a general relation with physiological markers of the disease, and the variation is such that it has limited applicability in individual assessments, including treatment decisions. Treatment is not required, since the lesions usually resolve spontaneously in 2–4 weeks. Although it may be disfiguring, cutaneous sarcoidosis rarely causes major problems. Sarcoidosis of the scalp presents with diffuse or patchy hair loss. Bone, joints, and muscles Sarcoidosis can involve the joints, bones, and muscles. This causes a wide variety of musculoskeletal complaints that act through different mechanisms. About 5–15% of cases affect the bones, joints, or muscles. Heart Histologically, cardiac sarcoidosis (sarcoidosis of the heart) is an active granulomatous inflammation surrounded by reactive oedema. The distribution of affected areas is patchy with localised enlargement of heart muscles. This causes scarring and remodelling of the heart, which leads to dilatation of the heart cavities and thinning of the heart muscle. As the situation progresses, it leads to aneurysm of the heart chambers. When the distribution is diffuse, there would be dilatation of both ventricles of the heart, causing heart failure and arrhythmia. When the conduction system in the intraventricular septum is affected, it would lead to heart block, ventricular tachycardia and ventricular arrhythmia, causing sudden death. Nevertheless, the involvement of pericardium and heart valves is uncommon. The frequency of cardiac involvement varies and is significantly influenced by race; in Japan, more than 25% of those with sarcoidosis have symptomatic cardiac involvement, whereas in the US and Europe, only about 5% of cases present with cardiac involvement. Conduction abnormalities are the most common cardiac manifestations of sarcoidosis in humans and can include complete heart block. Second to conduction abnormalities, in frequency, are ventricular arrhythmias, which occur in about 23% of cases with cardiac involvement. Cardiac sarcoidosis can cause fibrosis, granuloma formation, or the accumulation of fluid in the interstitium of the heart, or a combination of the former two. Cardiac sarcoidosis may also cause congestive heart failure when granulomas cause myocardial fibrosis and scarring. Congestive heart failure affects 25-75% of those with cardiac sarcoidosis. Diabetes mellitus and sarcoidosis-related arrhythmias are believed to be strong risk factors of heart failure in sarcoidosis. A small (20-40%) increased risk of acute myocardial infarction has also been described. Pulmonary arterial hypertension occurs by two mechanisms in cardiac sarcoidosis: reduced left heart function due to granulomas weakening the heart muscle or from impaired blood flow. Eye Eye involvement occurs in about 10–90% of cases. The most common ophthalmologic manifestation of sarcoidosis is uveitis. The combination of anterior uveitis, parotitis, VII cranial nerve paralysis and fever is called uveoparotid fever or Heerfordt syndrome (). Scleral nodules associated with sarcoidosis have been observed. Nervous system Any part of the nervous system can be involved. Sarcoidosis affecting the nervous system is known as neurosarcoidosis. Other common manifestations of neurosarcoidosis include optic nerve dysfunction, papilledema, palate dysfunction, neuroendocrine changes, hearing abnormalities, hypothalamic and pituitary abnormalities, chronic meningitis, and peripheral neuropathy. Neuroendocrine sarcoidosis accounts for about 5–10% of neurosarcoidosis cases and can lead to diabetes insipidus, changes in menstrual cycle and hypothalamic dysfunction. The latter can lead to changes in body temperature, mood, and prolactin (see the endocrine and exocrine section for details). this frequently leads to amenorrhea, galactorrhea, or nonpuerperal mastitis in women. It also frequently causes an increase in 1,25-dihydroxy vitamin D, the active metabolite of vitamin D, which is usually hydroxylated within the kidney. In sarcoidosis patients, vitamin D hydroxylation can occur outside the kidneys, namely inside immune cells found in the granulomas that the condition produces. 1,25-dihydroxy vitamin D is the main cause of hypercalcemia in sarcoidosis and is overproduced by sarcoid granulomata. Gamma-interferon produced by activated lymphocytes and macrophages plays a major role in the synthesis of 1 alpha, 25(OH)2D3. Hypercalciuria (excessive secretion of calcium in one's urine) and hypercalcemia (an excessively high amount of calcium in the blood) are seen in <10% of individuals and likely results from the increased 1,25-dihydroxy vitamin D production. Thyroid dysfunction is seen in 4.2–4.6% of cases. Parotid enlargement occurs in about 5–10% of cases. Studies at autopsy have revealed GI involvement in less than 10% of people. Usually, these changes reflect a cholestatic pattern and include raised levels of alkaline phosphatase (which is the most common liver function test anomaly seen in those with sarcoidosis), while bilirubin and aminotransferases are only mildly elevated. Jaundice is rare. Testicular involvement has been reported in about 5% of people at autopsy. Other nonspecific findings include monocytosis, occurring in the majority of sarcoidosis cases, increased hepatic enzymes or alkaline phosphatase. People with sarcoidosis often have immunologic anomalies like allergies to test antigens such as Candida or purified protein derivative. Lymphadenopathy (swollen glands) is common in sarcoidosis; it occurs in 15% of cases. Approximately 75% of cases show microscopic involvement of the spleen, although only in about 5–10% of cases does splenomegaly appear. ==Cause==

The exact cause of sarcoidosis is not known. Some cases may be caused by treatment with tumor necrosis factor (TNF) inhibitors like etanercept. Genetics The heritability of sarcoidosis varies according to ethnicity. About 20% of African Americans with sarcoidosis have a family member with the condition, whereas the same figure for European Americans is about 5%. Additionally, in African Americans, who seem to experience more severe and chronic disease, siblings and parents of sarcoidosis cases have about a 2.5-fold increased risk for developing the disease. In Swedish individuals heritability was found to be 39%. In this group, if a first-degree family member was affected, a person has a four-fold greater risk of being affected. In persistent sarcoidosis, the HLA haplotype HLA-B7-DR15 is either cooperating in disease or another gene between these two loci is associated. In nonpersistent disease, a strong genetic association exists with HLA DR3-DQ2. Cardiac sarcoid has been connected to tumor necrosis factor alpha (TNFA) variants. Infectious agents Several infectious agents appear to be significantly associated with sarcoidosis, but none of the known associations is specific enough to suggest a direct causative role. The major implicated infectious agents include: mycobacteria, fungi, borrelia, and rickettsia. Mycobacterium tuberculosis catalase-peroxidase has been identified as a possible antigen catalyst of sarcoidosis. The disease has also been reported by transmission via organ transplants. A large epidemiological study found little evidence that infectious diseases spanning years before sarcoidosis diagnosis could confer measurable risks for sarcoidosis diagnosis in the future. Autoimmune An association with autoimmune disorders has been frequently observed. The exact mechanism of this relation is not known, but some evidence supports the hypothesis that it is a consequence of Th1 lymphokine prevalence. Tests of delayed cutaneous hypersensitivity have been used to measure progression. ==Pathophysiology==

Granulomatous inflammation is characterized primarily by the accumulation of macrophages and activated T-lymphocytes, with increased production of key inflammatory mediators, tumor necrosis factor alpha (TNF), interferon gamma, interleukin 2 (IL-2), IL-8, IL-10, IL-12, IL-18, IL-23 and transforming growth factor beta (TGF-β), indicative of a T helper cell-mediated immune response. Sarcoidosis has paradoxical effects on inflammatory processes; it is characterized by increased macrophage and CD4 helper T-cell activation, resulting in accelerated inflammation, but immune response to antigen challenges such as tuberculin is suppressed. This paradoxical state of simultaneous hyper- and hypoactivity is suggestive of a state of anergy. The anergy may also be responsible for the increased risk of infections and cancer. The regulatory T-lymphocytes in the periphery of sarcoid granulomas appear to suppress IL-2 secretion, which is hypothesized to cause the state of anergy by preventing antigen-specific memory responses. While TNF is widely believed to play an important role in the formation of granulomas (this is further supported by the finding that in animal models of mycobacterial granuloma formation inhibition of either TNF or IFN-γ production inhibits granuloma formation), sarcoidosis can and does still develop in those being treated with TNF antagonists like etanercept. B cells also likely play a role in the pathophysiology of sarcoidosis. Giant cells, specifically Langhans giant cells, are often seen in sarcoidosis. Schaumann bodies seen in sarcoidosis are calcium and protein inclusions inside of giant cells as part of a granuloma. Hamazaki–Wesenberg bodies can be seen in lymph nodes and more rarely in lung biopsies with sarcoidosis and are inclusion bodies of lysosomes with protein, glycoprotein and iron. Image:Sarcoidosis_(1)_lymph_node_biopsy.jpg|Sarcoidosis in a lymph node Image:Asteroid body intermed mag.jpg|Pulmonary sarcoidosis with granulomas with Langhans giant cells and asteroid bodies Image:Sarcoidosis - Schaumann body 2.jpg|Schaumann body in sarcoidosis Image:Sarcoidosis - Asteroid body (6152059052).jpg|Asteroid body in sarcoidosis Image:Sarcoidosis - Hamazaki-Wesenberg (H-W) bodies- Lymph node (6134890353).jpg|Hamazaki–Wesenberg bodies in sarcoidosis in lymph node ==Diagnosis==

of the chest showing lymphadenopathy (arrows) in the mediastinum due to sarcoidosis Diagnosis of sarcoidosis is a diagnosis of exclusion, as there is no specific test for the condition other than the Kveim-Siltzbach test. To exclude sarcoidosis in a case presenting with pulmonary symptoms might involve a chest radiograph, CT scan of chest, PET scan, CT-guided biopsy, mediastinoscopy, open lung biopsy, bronchoscopy with biopsy, endobronchial ultrasound, and endoscopic ultrasound with fine-needle aspiration of mediastinal lymph nodes (EBUS FNA). Tissue from biopsy of lymph nodes is subjected to both flow cytometry to rule out cancer and special stains (acid fast bacilli stain and Gömöri methenamine silver stain) to rule out microorganisms and fungi. Serum markers of sarcoidosis include: serum amyloid A, soluble interleukin-2 receptor, lysozyme, angiotensin converting enzyme, and the glycoprotein KL-6. A bronchoalveolar lavage can show an elevated (of at least 3.5) CD4/CD8 T cell ratio, which is indicative (but not proof) of pulmonary sarcoidosis. Sarcoidosis is confused most commonly with neoplastic diseases, such as lymphoma, or with disorders characterized also by a mononuclear cell granulomatous inflammatory process, such as the mycobacterial and fungal disorders. • bihilar lymphadenopathy • bihilar lymphadenopathy and reticulonodular infiltrates • bilateral pulmonary infiltrates • fibrocystic sarcoidosis, typically with upward hilar retraction, cystic and bullous changes Although people with stage 1 radiographs tend to have the acute or subacute, reversible form of the disease, those with stages 2 and 3 often have the chronic, progressive disease; these patterns do not represent consecutive "stages" of sarcoidosis. Thus, except for epidemiologic purposes, this categorization is mostly of historic interest. Cardiac magnetic resonance imaging (CMR) is one modality for diagnosing cardiac sarcoidosis. It has 78% specificity in diagnosing cardiac sarcoidosis. PET scan can quantify disease activity, which cannot be performed by CMR. File:HilarAdenopathy.png|Hilar adenopathy, especially on the person's left (AP CXR) File:HilarAdenopathyLt.png|Hilar adenopathy, especially on the person's left (lateral CXR) File:HilarAdenopathyCCor.png|Hilar adenopathy, especially on the person's left (coronal CT) File:HilarAdenopathyCT.png|Hilar adenopathy, especially on the person's left (transverse CT) Classification Sarcoidosis may be divided into the following types: • Annular sarcoidosis • Erythrodermic sarcoidosis • Ichthyosiform sarcoidosis • Hypopigmented sarcoidosis • Löfgren syndrome • Lupus pernio • Morpheaform sarcoidosis • Mucosal sarcoidosis • Neurosarcoidosis • Papular sarcoid • Scar sarcoid • Subcutaneous sarcoidosis • Systemic sarcoidosis • Ulcerative sarcoidosis ==Treatment==

Treatments for sarcoidosis vary greatly depending on the patient. At least half of patients require no systemic therapy. Most people (>75%) only require symptomatic treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen or aspirin. For those presenting with lung symptoms, unless the respiratory impairment is devastating, active pulmonary sarcoidosis is observed usually without therapy for two to three months; if the inflammation does not subside spontaneously, therapy is instituted. Antimetabolites Antimetabolites, also categorized as steroid-sparing agents, such as azathioprine, methotrexate, mycophenolic acid, and leflunomide are often used as alternatives to corticosteroids. Of these, methotrexate is most widely used and studied. Methotrexate is considered a first-line treatment in neurosarcoidosis, often in conjunction with corticosteroids. Leflunomide is being used as a replacement for methotrexate, possibly due to its purportedly lower rate of pulmonary toxicity. neurosarcoidosis (especially CNS sarcoidosis; minimally effective in sarcoidosis myopathy), and pulmonary sarcoidosis. Immunosuppressants As the granulomas are caused by collections of immune system cells, particularly T cells, there has been some success using immunosuppressants (like cyclophosphamide, cladribine, chlorambucil, and cyclosporine), immunomodulatory (pentoxifylline and thalidomide), and anti-tumor necrosis factor treatment (such as infliximab, etanercept, golimumab, and adalimumab). In a clinical trial, cyclosporine added to prednisone treatment failed to demonstrate any significant benefit over prednisone alone in people with pulmonary sarcoidosis. There was evidence of increased toxicity from the addition of cyclosporine to the steroid treatment, including infections, malignancies (cancers), hypertension, and kidney dysfunction. Infliximab has been used successfully to treat pulmonary sarcoidosis in clinical trials in several cases. Thalidomide has also been tried successfully as a treatment for treatment-resistant lupus pernio in a clinical trial, which may stem from its anti-TNF activity. It failed to exhibit any efficacy in a pulmonary sarcoidosis clinical trial. Pentoxifylline has been used successfully to treat acute disease although its use is greatly limited by its gastrointestinal toxicity (mostly nausea, vomiting, and diarrhea). ACE inhibitors have been reported to cause remission in cutaneous sarcoidosis and improvement in pulmonary sarcoidosis, including improvement in pulmonary function, remodeling of lung parenchyma and prevention of pulmonary fibrosis in separate case series'. Nicotine patches have been found to possess anti-inflammatory effects in sarcoidosis patients, although whether they had disease-modifying effects requires further investigation. Antimycobacterial treatment (drugs that kill off mycobacteria, the causative agents behind tuberculosis and leprosy) has also proven itself effective in treating chronic cutaneous (that is, it affects the skin) sarcoidosis in one clinical trial. Quercetin has also been tried as a treatment for pulmonary sarcoidosis with some early success in one small trial. Because of its uncommon nature, the treatment of male reproductive tract sarcoidosis is controversial. Since the differential diagnosis includes testicular cancer, some recommend orchiectomy, even if evidence of sarcoidosis in other organs is present. In the newer approach, testicular, epididymal biopsy, and resection of the largest lesion have been proposed. Physical therapy, rehabilitation, and counseling can help avoid deconditioning, Inspiratory muscle training has also decreased severe fatigue perception in subjects with early stages of sarcoidosis, as well as improving functional and maximal exercise capacity and respiratory muscle strength. The duration, frequency, and physical intensity of exercise needs to accommodate impairments such as joint pain, muscle pain, and fatigue. Neurostimulants such as methylphenidate and modafinil have shown some effectiveness as an adjunct for the treatment of sarcoidosis fatigue. Treatments for symptomatic neuropathic pain in sarcoidosis patients are similar to those for other causes, and include antidepressants, anticonvulsants, and prolonged-release opioids; however, only 30 to 60% of patients experience limited pain relief. ==Prognosis==

The disease can remit spontaneously or become chronic, with exacerbations and remissions. In some cases, it can progress to pulmonary fibrosis and death. In benign cases, remission can occur in 24 to 36 months without treatment, but regular follow-ups are required. In some cases, however, the condition may persist for several decades. When the heart is involved, the prognosis is generally less favourable, though corticosteroids appear effective in improving AV conduction. The prognosis tends to be less favourable in African Americans than in white Americans. The risk for premature death was markedly (2.3-fold) increased compared to the general population for a smaller group of cases with severe disease at diagnosis. Some 1990s studies indicated that people with sarcoidosis appear to be at significantly increased risk for cancer, in particular lung cancer, lymphomas, and cancer in other organs known to be affected in sarcoidosis. In sarcoidosis-lymphoma syndrome, sarcoidosis is followed by the development of a lymphoproliferative disorder such as non-Hodgkin lymphoma. This may be attributed to the underlying immunological abnormalities that occur during the sarcoidosis disease process. Sarcoidosis can also follow cancer or occur concurrently with cancer. There have been reports of hairy cell leukemia, acute myeloid leukemia, and acute myeloblastic leukemia associated with sarcoidosis. Sometimes, sarcoidosis, even untreated, can be complicated by opportunistic infections although these are rare. ==Epidemiology==

Sarcoidosis most commonly affects young adults of both sexes, although studies have reported more cases in females. Incidence is highest for individuals younger than 40 and peaks in the age group from 20 to 29 years; a second peak is observed for women over 50. In the United States, sarcoidosis is more common in people of African descent than Caucasians, with annual incidence reported as 35.5 and 10.9 per 100,000, respectively. Sarcoidosis is less commonly reported in South America, Spain, India, Canada, and the Philippines. There may be a higher susceptibility to sarcoidosis in those with celiac disease. An association between the two disorders has been suggested. There has also been a seasonal clustering observed in sarcoidosis-affected individuals. In Greece about 70% of diagnoses occur between March and May every year, in Spain about 50% of diagnoses occur between April and June, and in Japan it is mostly diagnosed during June and July. In the year after the September 11 attacks, the rate of sarcoidosis incidence went up fourfold (to 86 cases per 100,000). ==History==

It was first described in 1877 by Dr. Jonathan Hutchinson, a dermatologist, as a condition causing red, raised rashes on the face, arms, and hands. Later in 1892 lupus pernio's histology was defined. Etymology The word "sarcoidosis" comes from Greek [σάρκο-] sarco- meaning "flesh", the suffix -(e)ido (from the Greek εἶδος -eidos [usually omitting the initial e in English as the diphthong epsilon-iota in Classic Greek stands for a long "i" = English ee]) meaning "type", " resembles" or "like", and -sis, a common suffix in Greek meaning "condition". Thus, the whole word means "a condition that resembles crude flesh". The first cases of sarcoïdosis, which were recognised as a new pathological entity in Scandinavia at the end of the 19th century, exhibited skin nodules resembling cutaneous sarcomas, hence the name initially given. ==Society and culture==

The World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) is an organisation of physicians involved in the diagnosis and treatment of sarcoidosis and related conditions. WASOG publishes the journal Sarcoidosis, Vasculitis and Diffuse Lung Diseases. Additionally, the Foundation for Sarcoidosis Research (FSR) is devoted to supporting research into sarcoidosis and its possible treatments. There have been concerns that World Trade Center rescue workers are at a heightened risk for sarcoidosis. Comedian and actor Bernie Mac had sarcoidosis. In 2005, he mentioned that the disease was in remission. His death on August 9, 2008, was caused by complications from pneumonia, though Mac's agent states the sarcoidosis was not related to his fatal pneumonia. Karen "Duff" Duffy, MTV personality and actress, was diagnosed with neurosarcoidosis in 1995. American football player Reggie White died in 2004, with pulmonary and cardiac sarcoidosis being contributing factors to his fatal heart arrhythmia. Singer Sean Levert died in 2008 of sarcoidosis complications. Manning Marable, a professor of public policy at Columbia University, died of pneumonia in 2011, less than a year after undergoing a double lung transplant following a diagnosis of sarcoidosis. In 2012, he was posthumously awarded a Pulitzer Prize in history for his biography "Malcolm X: A Life of Reinvention." Joseph Rago, Pulitzer Prize-winning writer known for his work at The Wall Street Journal, died of sarcoidosis complications in 2017. The late American chess grandmaster Daniel Naroditsky had systemic sarcoidosis, and it was reported that the disease was the underlying cause of the cardiac arrhythmia that led to his death in 2025. Several historical figures are suspected of having sarcoidosis. In a 2014 letter to the British medical journal The Lancet, it was suggested that the French Revolution leader Maximilien Robespierre may have had sarcoidosis, causing him impairment during his time as head of the Reign of Terror. The symptoms associated with Ludwig van Beethoven's 1827 death have been described as possibly consistent with sarcoidosis. Author Robert Louis Stevenson (1850–1894) had a history of chronic coughs and chest complaints, and sarcoidosis has been suggested as a diagnosis. ==Pregnancy==

Sarcoidosis generally does not prevent successful pregnancy and delivery; the increase in estrogen levels during pregnancy may even have a slightly beneficial immunomodulatory effect. In most cases, the course of the disease is unaffected by pregnancy, with improvement in a few cases and worsening of symptoms in very few cases, although a number of the immunosuppressants (such as methotrexate, cyclophosphamide) used in corticosteroid-refractory sarcoidosis are known teratogens. Increased risks associated with sarcoidosis, ranging from 30 to 70%, have been reported for preeclampsia/eclampsia, cesarian or preterm delivery, as well as (non-cardiac) birth defects in first singleton pregnancies. In absolute numbers, birth defects and other complications such as maternal death, cardiac arrest, placental abruption or venous thromboembolism are extremely rare in sarcoidosis pregnancies. == References ==