Саркоидоз: проявления, диагностика и поражение сердца.

Sarcoidosis may resolve without any treatment within a few years. In cases where the condition causes significant health problems, steroids such as prednisone are indicated. The risk of death is 1–7%. The chance of the disease returning in someone who has had it previously is less than 5%. It is most common in Scandinavians, but occurs in all parts of the world. It usually begins between the ages of 20 and 50. Sarcoidosis was first described in 1877 by the English doctor Jonathan Hutchinson as a non painful skin disease.

Histologically, 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 heart cavities and thinning of heart muscles. As the situation progresses, it leads to aneurysm of 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 are 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 occurs 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 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 Development of scleral nodule associated with sarcoidosis has been observed.

Any of the components 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, but in sarcoidosis patients, hydroxylation of vitamin D can occur outside the kidneys, namely inside the immune cells found in the granulomas the condition produces. 1,25 dihydroxy vitamin D is the main cause for 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. Testicular involvement has been reported in about 5% of people at autopsy. 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. 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 and 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. About 5–15% of cases affect the bones, joints, or muscles.

The exact cause of sarcoidosis is not known. Some cases may be caused by treatment with tumor necrosis factor (TNF) inhibitors like etanercept.

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.

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.

Association of autoimmune disorders has been frequently observed. The exact mechanism of this relation is not known, but some evidence supports the hypothesis that this is a consequence of Th1 lymphokine prevalence. Tests of delayed cutaneous hypersensitivity have been used to measure progression.

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 paradoxic 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.

Sarcoidosis may be divided into the following types: 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, 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.

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, although 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 a number of 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, although 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 has 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 treatment of sarcoidosis fatigue. Treatments for symptomatic neuropathic pain in sarcoidosis patients is similar to that for other causes, and include antidepressants, anticonvulsants and prolonged release opioids, however, only 30 to 60% of patients experience limited pain relief. 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. 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 also has 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 four fold (to 86 cases per 100,000). Later in 1892 lupus pernio's histology was defined.

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.

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. 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.

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 it is worth noting that 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.