Sarcoidosis

Sarcoidosis

Chest X-ray showing the typical nodularity of sarcoidosis in the base of the lungs.
Classification and external resources
ICD-10 D86
ICD-9 135
OMIM 181000
DiseasesDB 11797
MedlinePlus 000076
eMedicine med/2063
Patient UK Sarcoidosis
MeSH D012507

Sarcoidosis, also called sarcoid, is a disease involving abnormal collections of inflammatory cells (granulomas) that can form as nodules in multiple organs.[1] The granulomas are most often located in the lungs or its associated lymph nodes, but any organ can be affected.[2] Sarcoidosis seems to be caused by an immune reaction to an infection or some other trigger (called an antigen, which may be from one's environment) that continues even after the initial infection or other antigen is cleared from the body.[3] In most cases it clears up by itself without any medical intervention, but some cases go on to affect the person long-term or become life-threatening and require medical intervention, most often with medications.[2] 1 alpha, 25(OH)2 Vitamin D3 is the main cause for high blood calcium 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)2 Vitamin D3.

Treatment is usually designed to help relieve the symptoms and thus does not directly alter the course of the disease.[4] This treatment usually consists of drugs like ibuprofen or aspirin.[4] In cases where the condition develops to the point that it has a progressive and/or life-threatening course, the treatment is most often steroid treatment with prednisone or prednisolone.[4] Alternatively, drugs that are most commonly used to treat cancer and suppress the immune system, such as methotrexate, azathioprine and leflunomide, may be used.[4][5][6] The average mortality rate is less than 5% in untreated cases.[7]

In the United States it most commonly affects people of Northern European (especially Scandinavian or Icelandic) or African/African American ancestry between the ages of 20 and 29, although any race or age group can be affected.[7] Japan has a lower rate of sarcoidosis than the United States, although in these people the disease is usually more aggressive in its course with the heart often affected.[7] Japanese individuals also have a different peak age for sarcoidosis, 25–40 years of age.[8] It occurs about twice as often in women, where it usually takes a more aggressive course.[7] In developing countries, it often goes misdiagnosed as tuberculosis (TB) as its symptoms often resemble those of TB.[7]

Sarcoidosis was first described in 1877 by an English doctor named Dr. Jonathan Hutchinson as a skin disease causing red, raised lesions on the arms, face, and hands.[9]

Etymology

The word "sarcoidosis" comes from Greek [σάρκο-] sarcο- 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".

Signs and symptoms

Signs and symptoms of sarcoidosis.[10]
Multiple reddish-brownish papules and plaques on the left mandibular region of an adult face
Systemic 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.[11] Common symptoms, which tend to be vague, include fatigue (unrelieved by sleep; occurs in 66% of cases), lack of energy, weight loss, joint aches and pains (which occur in about 70% of cases),[5] arthritis (14–38% of persons), dry eyes, swelling of the knees, blurry vision, shortness of breath, a dry, hacking cough, or skin lesions.[1][12][13][14] Less commonly, people may cough up blood.[1] 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.[15]

The combination of erythema nodosum, bilateral hilar lymphadenopathy, and joint pain is called Löfgren syndrome which has a relatively good prognosis.[1] This form of the disease occurs significantly more commonly in Scandinavian patients, than in those of non-Scandinavian origin.[7]

Respiratory tract

Localization to the lungs is by far the most common manifestation of sarcoidosis.[16] At least 90% of affected persons experience lung involvement.[2] Overall, about 50% develop permanent pulmonary abnormalities, and 5 to 15% have progressive fibrosis of the lung parenchyma. Sarcoidosis of the lung is primarily an interstitial lung disease in which the inflammatory process involves the alveoli, small bronchi and small blood vessels.[17] In acute and subacute cases, physical examination usually reveals dry rales.[2] At least 5% of persons will suffer pulmonary arterial hypertension.[2][18] Less commonly, the upper respiratory tract (including the larynx, pharynx, and sinuses) may be affected, which occurs in between 5 and 10% of cases.[19]

Sarcoidosis of the lungs can be divided into four stages. Stage 0 — No intrathoracic involvement. Stage I — Bilateral hilar adenopathy. Stage II — Pulmonary parenchyma involved. Stage III — Pulmonary infiltrates with fibrosis.[2] Stage 4 is end-stage lung disease with pulmonary fibrosis and honeycombing.[20]

Skin

Sarcoidosis involves the skin in between 9 and 37% of persons and is more common in African Americans than in their white counterparts.[2] The skin is the second most commonly affected organ, after the lungs.[21] The most common lesions are erythema nodosum, plaques, maculopapular eruptions, subcutaneous nodules, and lupus pernio.[21] Treatment is not required, since the lesions usually resolve spontaneously in two to four weeks. Although it may be disfiguring, cutaneous sarcoidosis rarely causes major problems.[2][22][23] Sarcoidosis of the scalp presents with diffuse or patchy hair loss.[24][25]

Heart

The frequency of cardiac involvement varies and is significantly influenced by race; in Japan over 25% of persons with sarcoidosis experience symptomatic cardiac involvement, whereas in the US and Europe only about 5% of cases present with cardiac involvement.[2] Autopsy studies in the US have revealed a frequency of cardiac involvement of about 20–30%, whereas autopsy studies in Japan have shown a frequency of 60%.[13] The presentation of cardiac sarcoidosis can range from asymptomatic conduction abnormalities to fatal ventricular arrhythmia.[26] Conduction abnormalities are the most common cardiac manifestations of sarcoidosis among persons and can include complete heart block.[27] Second to conduction abnormalities, in frequency, are ventricular arrhythmias and occurs in about 23% of persons with cardiac involvement.[27] Sudden cardiac death, either due to ventricular arrhythmias or complete heart block is a rare complication of cardiac sarcoidosis.[28][29] 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.[30]

Eye

Eye involvement occurs in about 10–90% of cases.[13] Manifestations in the eye include uveitis, uveoparotitis, and retinal inflammation, which may result in loss of visual acuity or blindness.[31] The most common ophthalmologic manifestation of sarcoidosis is uveitis.[13][32] The combination of anterior uveitis, parotitis, VII cranial nerve paralysis and fever is called uveoparotid fever or Heerfordt syndrome (D86.8). Development of scleral nodule associated with sarcoidosis have been observed.[33]

Nervous system

Main article: Neurosarcoidosis

Any of the components of the nervous system can be involved.[34] Sarcoidosis affecting the nervous system is known as neurosarcoidosis.[34] Cranial nerves are most commonly affected, accounting for about 5–30% of neurosarcoidosis cases, and peripheral facial nerve palsy, often bilateral, is the most common neurological manifestation of sarcoidosis.[34][35][36] It occurs suddenly and is usually transient. The central nervous system involvement is present in 10–25% of sarcoidosis cases.[19] Other common manifestations of neurosarcoid include optic nerve dysfunction, papilledema, palate dysfunction, neuroendocrine changes, hearing abnormalities, hypothalamic and pituitary abnormalities, chronic meningitis, and peripheral neuropathy.[2] Myelopathy, that is spinal cord involvement, occurs in about 16–43% of neurosarcoidosis cases and is often associated with the poorest prognosis of the neurosarcoidosis subtypes.[34] Whereas facial nerve palsies and acute meningitis due to sarcoidosis tends to have the most favourable prognosis.[34] Another common finding in sarcoidosis with neurological involvement is autonomic or sensory small fiber neuropathy.[37][38] Neuroendocrine sarcoidosis accounts for about 5–10% of neurosarcoidosis cases and can lead to diabetes insipidus, changes in menstrual cycle and hypothalamic dysfunction.[34][36] The latter can lead to changes in body temperature, mood and prolactin (see the endocrine and exocrine section for details).[34]

Endocrine and exocrine

Prolactin is frequently increased in sarcoidosis, between 3% and 32% of cases have hyperprolactinemia[39] 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 hydrolysed 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 alpha, 25(OH)2D3 is the main cause for hypercalcemia in sarcoidosis and 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. [40] 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.[41] Thyroid dysfunction is seen in 4.2–4.6% of cases.[42][43]

Parotid enlargement occurs in about 5–10% of persons.[5] Bilateral involvement is the rule. The gland is usually not tender, but firm and smooth. Dry mouth can occur; other exocrine glands are affected only rarely.[2] The eyes, their glands, or the parotid glands are affected in 20%-50% of cases.[44]

Gastrointestinal and genitourinary

Symptomatic GI involvement occurs in less than 1% of persons (note that this is if one excludes the liver), and most commonly the stomach is affected, although the small or large intestine may also be affected in a small portion of cases.[5] Studies at autopsy have revealed GI involvement in less than 10% of people.[36] These cases would likely mimic Crohn's disease, which is a more commonly intestine-affecting granulomatous disease.[5] About 1–3% of people have evidence of pancreatic involvement at autopsy.[36] Symptomatic kidney involvement occurs in just 0.7% of cases, although evidence of kidney involvement at autopsy has been reported in up to 22% of people and occurs exclusively in cases of chronic disease.[5][13][36] Symptomatic kidney involvement is usually nephrocalcinosis, although granulomatous interstitial nephritis that presents with reduced creatinine clearance and little proteinuria is a close second.[5][36] Less commonly, the epididymis, testicles, prostate, ovaries, fallopian tubes, uterus, or the vulva may be affected, the latter may cause vulva itchiness.[13][45][46] Testicular involvement has been reported in about 5% of people at autopsy.[36][46] In males, sarcoidosis may lead to infertility.[47]

Around 70% of people have granulomas in their livers, although only in about 20–30% of cases liver function test anomalies reflecting this fact are seen.[1][2] About 5–15% of persons exhibit hepatomegaly, that is an enlarged liver.[13] Only 5–30% of cases of liver involvement are symptomatic.[48] 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 persons with sarcoidosis), while bilirubin and aminotransferases are only mildly elevated. Jaundice is rare.[2][5]

Hematologic and immunologic

Abnormal clinical blood tests are frequent, accounting for over 50% of cases, but is not diagnostic.[2][19] Lymphopenia is the most common hematologic anomaly in sarcoidosis.[2] Anemia occurs in about 20% of people with sarcoidosis.[2] Leukopenia is less common and occurs in even fewer persons but is rarely severe.[2] Thrombocytopenia and hemolytic anemia are fairly rare.[5] In the absence of splenomegaly, leukopenia may reflect bone marrow involvement, but the most common mechanism is a redistribution of blood T cells to sites of disease.[49] Other nonspecific findings include monocytosis, occurring in the majority of sarcoidosis cases,[50] 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 (PPD).[44] Polyclonal hypergammaglobulinemia is also a fairly common immunologic anomaly seen in sarcoidosis.[44]

Lymphadenopathy (swollen glands) is common in sarcoidosis and occurs in 15% of cases.[14] Intrathoracic nodes are enlarged in 75 to 90% of all people; usually this involves the hilar nodes, but the paratracheal nodes are commonly involved. Peripheral lymphadenopathy is very common, particularly involving the cervical (the most common head and neck manifestation of the disease), axillary, epitrochlear, and inguinal nodes.[51] Approximately 75% of cases show microscopic involvement of the spleen, although only in about 5–10% of cases does splenomegaly appear.[5][44]

Bone, joints, and muscles

Bone involvement in sarcoidosis has been reported in 1–13% of cases.[36] About 5–15% of cases affect the bones, joints, or muscles.[19]

Causes

The exact cause of sarcoidosis is not known. The current working hypothesis is, in genetically susceptible individuals, sarcoidosis is caused through alteration to the immune response after exposure to an environmental, occupational, or infectious agent.[52] Some cases may be caused by treatment with TNF inhibitors like etanercept.[53]

Genetics

The heritability of sarcoidosis varies according to race, about 20% of African Americans with sarcoidosis have a family member with the condition, whereas the same figure for whites is about 5%.[7] Investigations of genetic susceptibility yielded many candidate genes, but only few were confirmed by further investigations and no reliable genetic markers are known. Currently, the most interesting candidate gene is BTNL2; several HLA-DR risk alleles are also being investigated.[54][55] In persistent sarcoidosis, the HLA haplotype HLA-B7-DR15 are either cooperating in disease or another gene between these two loci is associated. In nonpersistent disease, there is a strong genetic association with HLA DR3-DQ2.[56][57]

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.[58] The major implicated infectious agents include: mycobacteria, fungi, borrelia, and rickettsia.[59] A recent meta-analysis investigating the role of mycobacteria in sarcoidosis found it was present in 26.4% of cases, but the meta-analysis also detected a possible publication bias, so the results need further confirmation.[60][61] Mycobacterium tuberculosis catalase-peroxidase has been identified as a possible antigen catalyst of sarcoidosis.[62] The disease has also been reported by transmission via organ transplants.[63]

Autoimmune

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.[42][64] Tests of delayed cutaneous hypersensitivity have been used to measure progression.[65]

Pathophysiology

Granulomatous inflammation is characterized primarily by accumulation of monocytes, macrophages, and activated T-lymphocytes, with increased production of key inflammatory mediators, TNF, IFN-γ, IL-2, IL-8, IL-10, IL-12, IL-18, IL-23 and TGF-β, indicative of a Th1-mediated immune response.[59][66] 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.[67] Schaumann bodies seen in sarcoidosis are calcium and protein inclusions inside of Langhans giant cells as part of a granuloma.

While TNF is widely believed to play an important role in the formation of granulomas (which 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 do still develop in persons being treated with TNF antagonists like etanercept.[68] B cells also likely play a role in the pathophysiology of sarcoidosis.[7] Serum levels of soluble HLA class I antigens and ACE are higher in persons with sarcoidosis.[7] Likewise the ratio of CD4/CD8 T cells in bronchoalveolar lavage is usually higher in persons with pulmonary sarcoidosis (usually >3.5), although it can be normal or even abnormally low in some cases.[7] Serum ACE levels have been found to usually correlate with total granuloma load.[59]

Cases of sarcoidosis have also been reported as part of the immune reconstitution syndrome of HIV, that is, when people receive treatment for HIV their immune system rebounds and the result is that it starts to attack the antigens of opportunistic infections caught prior to said rebound and the resulting immune response starts to damage healthy tissue.[66]

Diagnosis

Diagnosis of sarcoidosis is a matter of exclusion, as there is no specific test for the condition. To exclude sarcoidosis in a case presenting with pulmonary symptoms might involve chest X-ray, CT scan of chest, PET scan, CT-guided biopsy, mediastinoscopy, open lung biopsy, bronchoscopy with biopsy, endobronchial ultrasound, and endoscopic ultrasound with FNA 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.[69][70][71][72]

Serum markers of sarcoidosis, include: serum amyloid A, soluble interleukin 2 receptor, lysozyme, angiotensin converting enzyme, and the glycoprotein KL-6.[73] Angiotensin-converting enzyme blood levels are used in the monitoring of sarcoidosis.[73] 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.[7] In at least one study the induced sputum ratio of CD4/CD8 and level of TNF was correlated to those in the lavage fluid.[73]

Differential diagnosis includes metastatic disease, lymphoma, septic emboli, rheumatoid nodules, granulomatosis with polyangiitis, varicella infection, tuberculosis, and atypical infections, such as Mycobacterium avium complex, cytomegalovirus, and cryptococcus.[74] 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.[2]

CT scan of the chest showing lymphadenopathy (arrows) in the mediastinum due to sarcoidosis

Chest X-ray changes are divided into four stages:[75]

Although people with stage 1 X-rays 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 X-ray categorization is mostly of historic interest.[2]

In sarcoidosis presenting in the Caucasian population, hilar adenopathy and erythema nodosum are the most common initial symptoms. In this population, a biopsy of the gastrocnemius muscle is a useful tool in correctly diagnosing the person. The presence of a noncaseating epithelioid granuloma in a gastrocnemius specimen is definitive evidence of sarcoidosis, as other tuberculoid and fungal diseases extremely rarely present histologically in this muscle.[76]

Classification

Sarcoidosis may be divided into the following types:[24]

  • 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

Most persons (>75%) only require symptomatic treatment with non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen or aspirin.[4] For persons 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.[2] Corticosteroids, most commonly prednisone or prednisolone, have been the standard treatment for many years.[5] In some people, this treatment can slow or reverse the course of the disease, but other people do not respond to steroid therapy. The use of corticosteroids in mild disease is controversial because in many cases the disease remits spontaneously.[77] Despite their widespread use, the evidence supporting corticosteroid use is weak at best.[78]

Severe symptoms are generally treated with corticosteroids although steroid-sparing agents such as azathioprine, methotrexate, mycophenolic acid, and leflunomide[79][80] are often used as alternatives.[5][6] Of these, methotrexate is most widely used and studied.[6][81] Methotrexate is considered a first-line treatment in neurosarcoidosis, often in conjunction with corticosteroids.[6][34] Long-term treatment with methotrexate is associated with liver damage in about 10% of people and hence may be a significant concern in people with liver involvement and requires regular liver function test monitoring.[5] Methotrexate can also lead to pulmonary toxicity (lung damage), although this is fairly uncommon and more commonly it can confound the leukopenia caused by sarcoidosis.[5] Due to these safety concerns it is often recommended that methotrexate is combined with folic acid in order to prevent toxicity.[5] Azathioprine treatment can also lead to liver damage.[81] Leflunomide is being used as a replacement for methotrexate, possibly due to its purportedly lower rate of pulmonary toxicity.[81] Mycophenolic acid has been used successfully in uveal sarcoidosis,[82] neurosarcoidosis (especially CNS sarcoidosis; minimally effective in sarcoidosis myopathy),[83] and pulmonary sarcoidosis.[84][85]

As the granulomas are caused by collections of immune system cells, particularly T cells, there has been some success using immunosuppressants (like cyclophosphamide, cladribine,[86] chlorambucil, and cyclosporine), immunomodulatory (pentoxifylline and thalidomide), and anti-tumor necrosis factor treatment[87][88] (such as infliximab, etanercept, golimumab, and adalimumab).[4][89][90]

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.[81] Likewise chlorambucil and cyclophosphamide are seldom used in the treatment of sarcoidosis due to their high degree of toxicity, especially their potential for causing malignancies.[91] Infliximab has been used successfully to treat pulmonary sarcoidosis in clinical trials in a number of persons.[81] Etanercept, on the other hand, has failed to demonstrate any significant efficacy in people with uveal sarcoidosis in a couple of clinical trials.[81] Likewise golimumab has failed to show any benefit in persons with pulmonary sarcoidosis.[81] One clinical trial of adalimumab found treatment response in about half of subjects, which is similar to that seen with infliximab, but as adalimumab has better tolerability profile it may be preferred over infliximab.[81]

Ursodeoxycholic acid has been used successfully as a treatment for cases with liver involvement.[92] 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.[66][89] Cutaneous disease may be successfully managed with antimalarials (such as chloroquine and hydroxychloroquine) and the tetracycline antibiotic, minocycline.[2][89] Antimalarials have also demonstrated efficacy in treating sarcoidosis-induced hypercalcemia and neurosarcoidosis.[5] Long-term use of antimalarials is limited, however, by their potential to cause irreversible blindness and hence the need for regular ophthalmologic screening.[91] This toxicity is usually less of a problem with hydroxychloroquine than with chloroquine, although hydroxychloroquine can disturb the glucose homeostasis.[91]

Recently selective phosphodiesterase 4 (PDE4) inhibitors like apremilast (a thalidomide derivative), roflumilast, and the less subtype-selective PDE4 inhibitor, pentoxifylline, have been tried as a treatment for sarcoidosis, with successful results being obtained with apremilast in cutaneous sarcoidosis in a small open-label study.[93][94] Pentoxifylline has been used successfully to treat acute disease although its use is greatly limited by its gastrointestinal toxicity (mostly nausea, vomiting, and diarrhea).[80][81][91] Case reports have supported the efficacy of rituximab, an anti-CD20 monoclonal antibody and a clinical trial investigating atorvastatin as a treatment for sarcoidosis is under-way.[95][96] 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'. [97] [98] [99] Nicotine patches have been found to possess anti-inflammatory effects in sarcoidosis patients, although whether they had disease-modifying effects requires further investigation.[100] 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.[101] Quercetin has also been tried as a treatment for pulmonary sarcoidosis with some early success in one small trial.[102]

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.[47]

Prognosis

Gross pathology image showing sarcoidosis with honeycombing: Prominent honeycombing is present in the lower lobes accompanied by fibrosis and some honeycombing in the upper lungs. Honeycombing consists of cystically dilated airways separated by scar tissue resembling the honeycomb of bees. It is a nonspecific end stage of many types of interstitial lung disease.

The disease can remit spontaneously or become chronic, with exacerbations and remissions. In some persons, it can progress to pulmonary fibrosis and death. About half of cases resolve without treatment or can be cured within 12–36 months, and most within five years. Some cases, however, may persist several decades.[5] Two-thirds of people with the condition achieve a remission within 10 years of the diagnosis.[103] When the heart is involved, the prognosis is generally less favourable, although, corticosteroids appear effective in improving AV conduction.[104][105] The prognosis tends to be less favourable in African Americans, compared to white Americans.[7] Persons with sarcoidosis appear to be at significantly increased risk for cancer, in particular lung cancer, lymphomas,[106] and cancer in other organs known to be affected in sarcoidosis.[107][108] In sarcoidosis-lymphoma syndrome, sarcoidosis is followed by the development of a lymphoproliferative disorder such as non-Hodgkin lymphoma.[109] This may be attributed to the underlying immunological abnormalities that occur during the sarcoidosis disease process.[110] Sarcoidosis can also follow cancer[111] or occur concurrently with cancer.[112][113] There have been reports of hairy cell leukemia,[114] acute myeloid leukemia,[115] and acute myeloblastic leukemia[116] associated with sarcoidosis.

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.[5][104]

Sarcoidosis occurs throughout the world in all races with an average incidence of 16.5 per 100,000 in men and 19 per 100,000 in women. The disease is most common in Northern European countries and the highest annual incidence of 60 per 100,000 is found in Sweden and Iceland. In the United Kingdom the prevalence is 16 in 100,000.[117] 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.[118] 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.[119]

There also has been a seasonal clustering observed in sarcoidosis-affected individuals.[120] 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.[120]

The differing incidence across the world may be at least partially attributable to the lack of screening programs in certain regions of the world, and the overshadowing presence of other granulomatous diseases, such as tuberculosis, that may interfere with the diagnosis of sarcoidosis where they are prevalent.[104] There may also be differences in the severity of the disease between people of different ethnicities. Several studies suggest the presentation in people of African origin may be more severe and disseminated than for Caucasians, who are more likely to have asymptomatic disease.[49] Manifestation appears to be slightly different according to race and sex. Erythema nodosum is far more common in men than in women and in Caucasians than in other races. In Japanese persons, ophthalmologic and cardiac involvement are more common than in other races.[5]

It is more common in certain occupations, namely firefighters, educators, military personnel, persons who work in industries where pesticides are used, law enforcement, and healthcare personnel.[121] In the year after the September 11 attacks, the rate of sarcoidosis incidence went up four-fold (to 86 cases per 100,000).[19][121]

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.[9] In 1888 the term Lupus pernio was coined by Dr. Ernest Besnier, another dermatologist.[122] Later in 1892 lupus pernio's histology was defined.[122] In 1902 bone involvement was first described by a group of three doctors.[122] Between 1909 and 1910 uveitis in sarcoidosis was first described, and later in 1915 it was emphasised, by Dr. Schaumann, that it was a systemic condition.[122] This same year lung involvement was also described.[122] In 1937 uveoparotid fever was first described and likewise in 1941 Löfgren syndrome was first described.[122] In 1958 the first international conference on sarcoidosis was called in London, likewise the first USA sarcoidosis conference occurred in Washington, DC in the year 1961.[122] It has also been called Besnier-Boeck disease or Besnier-Boeck-Schaumann disease.[123]

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.[124] 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.[125]

There have been concerns that World Trade Center rescue workers are at a heightened risk for sarcoidosis.[126][127]

In 2014, in a letter to the British medical journal The Lancet, it was suggested that the French Revolution leader Maximilien Robespierre suffered from sarcoidosis, and suggested that the condition caused him a notable impairment during his time as the head of the Reign of Terror.[128]

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 it is worth noting that a number of the immunosuppressants (such as methotrexate, cyclophosphamide, and azathioprine) used in corticosteroid-refractory sarcoidosis are known teratogens.[129]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 King, TE, Jr. (March 2008). "Sarcoidosis: Interstitial Lung Diseases: Merck Manual Home Edition". The Merck Manual Home Edition. Merck Sharp & Dohme Corp. Retrieved 19 February 2014.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 2.19 2.20 Fauci, A.; Kasper, D.; Hauser, S.; Jameson, J.; Loscalzo, J. (2011). Harrison's Principles of Internal Medicine (18 ed.). New York: McGraw-Hill Professional. ISBN 978-0-07174889-6.
  3. ↑ Baughman RP, Culver DA, Judson MA; Culver; Judson (March 2011). "A concise review of pulmonary sarcoidosis". American Journal of Respiratory and Critical Care Medicine 183 (5): 573–81. doi:10.1164/rccm.201006-0865CI. PMC 3081278. PMID 21037016.
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External Links

official site for the Foundation for Sarcoidosis Research