to monitor potentially toxic effects. corticosteroids, most commonly prednisone or prednisolone, have been the standard treatment for many years. 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. 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. 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. 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. due to these safety concerns it is often recommended that methotrexate is combined with folic acid in order to prevent toxicity. azathioprine treatment can also lead to liver damage. however, the risk of infection appears to be about 40% lower in those treated with methotrexate instead of azathioprine. leflunomide is being used as a replacement for methotrexate, possibly due to its purportedly lower rate of pulmonary toxicity. mycophenolic acid has been used successfully in uveal sarcoidosis, 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, although there was evidence of increased toxicity from the addition of cyclosporine to the steroid treatment including infections, malignancies (cancers), hypertension, and kidney dysfunction. 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. infliximab has been used successfully to treat pulmonary sarcoidosis in clinical trials in a number of cases. etanercept, on the other hand, has failed to demonstrate any significant efficacy in people with uveal sarcoidosis in a couple of clinical trials. likewise golimumab has failed to show any benefit in those with pulmonary sarcoidosis. 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. specific organ treatments ursodeoxycholic acid has been used successfully as a treatment for cases with liver involvement. 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. cutaneous disease may be successfully managed with antimalarials (such as chloroquine and hydroxychloroquine) and the tetracycline antibiotic, minocycline. antimalarials have also demonstrated efficacy in treating sarcoidosis-induced hypercalcemia and neurosarcoidosis. long-term use of antimalarials is limited, however, by their potential to cause irreversible blindness and hence the need for regular ophthalmologic screening. this toxicity is usually less of a problem with hydroxychloroquine than with chloroquine, although hydroxychloroquine can disturb the glucose homeostasis. 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. pentoxifylline has been used successfully to treat acute disease although its use is greatly limited by its gastrointestinal toxicity (mostly nausea, vomiting, and diarrhea). 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. 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. symptoms people with sarcoidosis may have a range of symptoms that do not correspond with objective physical evidence of disease but that still decrease quality of life. physical therapy, rehabilitation, and counseling can help avoid deconditioning,: 733 and improve social participation, psychological well-being, and activity levels. key aspects are avoiding exercise intolerance and muscle weakness.: 734 low or moderate-intensity physical training has been shown to improve fatigue, psychological health, and physical functioning in people sarcoidosis without adverse effects. 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.: 734 neurostimulants such as methylphenidate and modafinil have shown some effectiveness as an adjunct for treatment of sarcoidosis fatigue.: 733 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.: 733 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 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. some cases, however, may persist several decades. two-thirds of people with the condition achieve a remission within 10 years of the diagnosis. 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. in a swedish population-based analysis, the majority of cases who did not have severe disease at diagnosis had comparable mortality to the general population. 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. serious infections, sometimes multiple during the course of disease, and heart failure might contribute to the higher risk of early death in some patients with sarcoidosis. 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. 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. 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. 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. 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. 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 people, ophthalmologic and cardiac involvement are more common than in other races. it is more common in certain occupations, namely firefighters, educators, military personnel, those who work in industries where pesticides are used, law enforcement, and healthcare personnel. in the year after the september 11 attacks, the rate of sarcoidosis incidence went up four-fold (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. in 1889 the term lupus pernio was coined by dr. ernest besnier, another dermatologist. later in 1892 lupus pernio's histology was defined. in 1902 bone involvement was first described by a group of three doctors. between 1909 and 1910 uveitis in sarcoidosis was first described, and later in 1915 it was emphasised, by dr. jörgen nielsen schaumann, that it was a systemic condition. this same year lung involvement was also described. in 1937 uveoparotid fever was first described and likewise in 1941 löfgren syndrome was first described. in 1958 the first international conference on sarcoidosis was called in london, likewise the first usa sarcoidosis conference occurred in washington, d.c., in the year 1961. it has also been called besnier–boeck disease or besnier–boeck–schaumann disease. etymology the word "sarcoidosis" comes from greek sarco- meaning "flesh", the suffix -(e)ido (from the greek εἶδος -eidos ) 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