occurs in about 20% of people with sarcoidosis. leukopenia is less common and occurs in even fewer cases but is rarely severe. thrombocytopenia and hemolytic anemia are fairly rare. 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. 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. polyclonal hypergammaglobulinemia is also a fairly common immunologic anomaly seen in sarcoidosis. lymphadenopathy (swollen glands) is common in sarcoidosis and occurs in 15% of cases. 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. approximately 75% of cases show microscopic involvement of the spleen, although only in about 5–10% of cases does splenomegaly appear. bone, joints, and muscles sarcoidosis can be involved with 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. arthritic syndromes can be categorized as acute or chronic. sarcoidosis patients with acute arthritis often also have bilateral hilar lymphadenopathy and erythema nodosum. these three associated syndromes often occur together in löfgren syndrome. the arthritis symptoms of löfgren syndrome occur most frequently in the ankles, followed by the knees, wrists, elbows, and metacarpophalangeal joints. usually, true arthritis is not present, but instead, periarthritis appears as a swelling in the soft tissue around the joints that can be seen by ultrasonographic methods. these joint symptoms tend to precede or occur at the same time as erythema nodosum develops. even when erythema nodosum is absent, it is believed that the combination of hilar lymphadenopathy and ankle periarthritis can be considered as a variant of löfgren syndrome. enthesitis also occurs in about one-third of patients with acute sarcoid arthritis, mainly affecting the achilles tendon and heels. soft-tissue swelling of the ankles can be prominent, and biopsy of this soft tissue reveals no granulomas, but does show panniculitis similar to erythema nodosum. chronic sarcoid arthritis usually occurs in the setting of more diffuse organ involvement. the ankles, knees, wrists, elbows, and hands may all be affected in the chronic form and often this presents itself in a polyarticular pattern. dactylitis similar to that seen in psoriatic arthritis, that is associated with pain, swelling, overlying skin erythema, and underlying bony changes may also occur. development of jaccoud arthropathy (a nonerosive deformity) is very rarely seen. bone involvement in sarcoidosis has been reported in 1–13% of cases. the most frequent sites of involvement are the hands and feet, whereas the spine is less commonly affected. half of the patients with bony lesions experience pain and stiffness, whereas the other half remain asymptomatic. periostitis is rarely seen in sarcoidosis and has been found to present itself at the femoral bone. cause 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. 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. 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. 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. a meta-analysis investigating the role of mycobacteria in sarcoidosis found it was present in 26.4% of cases, but they also detected a possible publication bias, so the results need further confirmation. 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 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. 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 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. serum levels of soluble human leukocyte antigen (hla) class i antigens and angiotensin converting enzyme (ace) are higher in people with sarcoidosis. likewise the ratio of cd4/cd8 t cells in bronchoalveolar lavage is usually higher in people with pulmonary sarcoidosis (usually >3.5), although it can be normal or even abnormally low in some cases. serum ace levels have been found to usually correlate with total granuloma load. 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. histopathology sarcoidosis is characterized by the formation of non-necrotizing ("non-caseating") granulomas in various organs and tissues. 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. asteroid bodies can be seen in sarcoidosis. 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 in a lymph node pulmonary sarcoidosis with granulomas with langhans giant cells and asteroid bodies schaumann body in sarcoidosis asteroid body in sarcoidosis hamazaki–wesenberg bodies in sarcoidosis in lymph node diagnosis ct scan of the chest showing lymphadenopathy (arrows) in the mediastinum due to sarcoidosis 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 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. angiotensin-converting enzyme blood levels are used in the monitoring of sarcoidosis. 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. in at least one study the induced sputum ratio of cd4/cd8 and level of tnf was correlated to those in the lavage fluid. a sarcoidosis-like lung disease called granulomatous–lymphocytic interstitial lung disease can be seen in patients with common variable immunodeficiency (cvid) and therefore serum antibody levels should be measured to exclude cvid. 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. 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. chest radiograph changes are divided into four stages: 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. 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. cardiac magnetic resonance imaging (cmr) is one modality for diagnosing cardiac sarcoidosis. it has 78% specificity in diagnosing cardiac sarcoidosis. its t2-weighted imaging can detect acute inflammation. meanwhile, late gadolinium contrast (lge) can detect fibrosis or scar. lesions at the subpericardium and midwall enhancement of basal septum or inferolateral wall is strongly suggestive of sarcoidosis. mri can also follow up on the treatment efficacy of corticosteroids and prognosis of cardiac sarcoidosis. pet scan is able to quantify disease activity which cannot be performed by cmr. hilar adenopathy especially on the person's left (ap cxr) hilar adenopathy especially on the person's left (lateral cxr) hilar adenopathy especially on the person's left (coronal ct) 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. major categories of drug interventions include glucocorticoids, antimetabolites, biologic agents especially monoclonal anti-tumor necrosis factor antibodies. investigational treatments include specific antibiotic combinations and mesenchymal stem cells. if drug intervention is indicated, a step-wise approach is often used to explore alternatives in order of increasing side effects and