risk alleles within the hla (particularly hla-drb1) genes harbor more risk than other loci. the hla encodes proteins that control recognition of self- versus non-self molecules. other risk loci include genes affecting co-stimulatory immune pathways—for example cd28 and cd40, cytokine signaling, lymphocyte receptor activation threshold (e.g., ptpn22), and innate immune activation—appear to have less influence than hla mutations. environmental there are established epigenetic and environmental risk factors for ra. smoking is an established risk factor for ra in caucasian populations, increasing the risk three times compared to non-smokers, particularly in men, heavy smokers, and those who are rheumatoid factor positive. modest alcohol consumption may be protective. silica exposure has been linked to ra. vitamin d deficiency epidemiological studies show that patients with vitamin d levels 8-10 ng/ml lower than healthy controls are at risk for rheumatoid arthritis. negative findings no infectious agent has been consistently linked with ra and there is no evidence of disease clustering to indicate its infectious cause, but periodontal disease has been consistently associated with ra. the many negative findings suggest that either the trigger varies, or that it might, in fact, be a chance event inherent with the immune response. pathophysiology ra primarily starts as a state of persistent cellular activation leading to autoimmunity and immune complexes in joints and other organs where it manifests. the clinical manifestations of disease are primarily inflammation of the synovial membrane and joint damage, and the fibroblast-like synoviocytes play a key role in these pathogenic processes. three phases of progression of ra are an initiation phase (due to non-specific inflammation), an amplification phase (due to t cell activation), and chronic inflammatory phase, with tissue injury resulting from the cytokines, il–1, tnf-alpha, and il–6. non-specific inflammation factors allowing an abnormal immune response, once initiated, become permanent and chronic. these factors are genetic disorders which change regulation of the adaptive immune response. genetic factors interact with environmental risk factors for ra, with cigarette smoking as the most clearly defined risk factor. other environmental and hormonal factors may explain higher risks for women, including onset after childbirth and hormonal medications. a possibility for increased susceptibility is that negative feedback mechanisms – which normally maintain tolerance – are overtaken by positive feedback mechanisms for certain antigens, such as igg fc bound by rheumatoid factor and citrullinated fibrinogen bound by antibodies to citrullinated peptides (acpa – anti–citrullinated protein antibody). a debate on the relative roles of b-cell produced immune complexes and t cell products in inflammation in ra has continued for 30 years, but neither cell is necessary at the site of inflammation, only autoantibodies to iggfc, known as rheumatoid factors and acpa, with acpa having an 80% specificity for diagnosing ra. as with other autoimmune diseases, people with ra have abnormally glycosylated antibodies, which are believed to promote joint inflammation. amplification in the synovium once the generalized abnormal immune response has become established – which may take several years before any symptoms occur – plasma cells derived from b lymphocytes produce rheumatoid factors and acpa of the igg and igm classes in large quantities. these activate macrophages through fc receptor and complement binding, which is part of the intense inflammation in ra. binding of an autoreactive antibody to the fc receptors is mediated through the antibody's n-glycans, which are altered to promote inflammation in people with ra. this contributes to local inflammation in a joint, specifically the synovium with edema, vasodilation and entry of activated t-cells, mainly cd4 in microscopically nodular aggregates and cd8 in microscopically diffuse infiltrates. synovial macrophages and dendritic cells function as antigen-presenting cells by expressing mhc class ii molecules, which establishes the immune reaction in the tissue. chronic inflammation x-ray of the wrist of a woman with rheumatoid arthritis, showing unaffected carpal bones in the left image, and ankylosing fusion of the carpal bones 8 years later in the right image. the disease progresses by forming granulation tissue at the edges of the synovial lining, pannus with extensive angiogenesis and enzymes causing tissue damage. the fibroblast-like synoviocytes have a prominent role in these pathogenic processes. the synovium thickens, cartilage and underlying bone disintegrate, and the joint deteriorates, with raised calprotectin levels serving as a biomarker of these events. importantly inflammatory events are not limited to synovium but it appear to be systemic, evidence suggest that alterations in t helper profile favoring inflammation such as inflammatory il-17a producing t helper cells and pathogenic th17 cells are come from both memory and effector compartment in ra patients peripheral blood. cytokines and chemokines attract and accumulate immune cells, i.e. activated t- and b cells, monocytes and macrophages from activated fibroblast-like synoviocytes, in the joint space. by signalling through rankl and rank, they eventually trigger osteoclast production, which degrades bone tissue. the fibroblast-like synoviocytes that are present in the synovium during rheumatoid arthritis display altered phenotype compared to the cells present in normal tissues. the aggressive phenotype of fibroblast-like synoviocytes in rheumatoid arthritis and the effect these cells have on the microenvironment of the joint can be summarized into hallmarks that distinguish them from healthy fibroblast-like synoviocytes. these hallmark features of fibroblast-like synoviocytes in rheumatoid arthritis are divided into 7 cell-intrinsic hallmarks and 4 cell-extrinsic hallmarks. the cell-intrinsic hallmarks are: reduced apoptosis, impaired contact inhibition, increased migratory invasive potential, changed epigenetic landscape, temporal and spatial heterogeneity, genomic instability and mutations, and reprogrammed cellular metabolism. the cell-extrinsic hallmarks of fls in ra are: promotes osteoclastogenesis and bone erosion, contributes to cartilage degradation, induces synovial angiogenesis, and recruits and stimulates immune cells. diagnosis imaging x-ray of the hand in rheumatoid arthritis. appearance of synovial fluid from a joint with inflammatory arthritis. closeup of bone erosions in rheumatoid arthritis. x-rays of the hands and feet are generally performed when many joints affected. in ra, there may be no changes in the early stages of the disease or the x-ray may show osteopenia near the joint, soft tissue swelling, and a smaller than normal joint space. as the disease advances, there may be bony erosions and subluxation. other medical imaging techniques such as magnetic resonance imaging (mri) and ultrasound are also used in ra. technical advances in ultrasonography like high-frequency transducers (10 mhz or higher) have improved the spatial resolution of ultrasound images depicting 20% more erosions than conventional radiography. color doppler and power doppler ultrasound are useful in assessing the degree of synovial inflammation as they can show vascular signals of active synovitis. this is important, since in the early stages of ra, the synovium is primarily affected, and synovitis seems to be the best predictive marker of future joint damage. blood tests when ra is clinically suspected, a physician may test for rheumatoid factor (rf) and anti-citrullinated protein antibodies (acpas measured as anti-ccp antibodies). the test is positive approximately two thirds of the time, but a negative rf or ccp antibody does not rule out ra, rather, the arthritis is called seronegative, which occurs in approximately a third of people with ra. during the first year of illness, rheumatoid factor is more likely to be negative with some individuals becoming seropositive over time. rf is a non-specific antibody and seen in about 10% of healthy people, in many other chronic infections like hepatitis c, and chronic autoimmune diseases such as sjögren's syndrome and systemic lupus erythematosus. therefore, the test is not specific for ra. hence, new serological tests check for anti-citrullinated protein antibodies acpas. these tests are again positive in 61–75% of all ra cases, but with a specificity of around 95%. as with rf, acpas are many times present before symptoms have started. the by far most common clinical test for acpas is the anti-cyclic citrullinated peptide (anti ccp) elisa. in 2008 a serological point-of-care test for the early detection of ra combined the detection of rf and anti-mcv with a sensitivity of 72% and specificity of 99.7%. to improve the diagnostic capture rate in the early detection of patients with ra and to risk stratify these individuals, the rheumatology field continues to seek complementary markers to both rf and anti-ccp. 14-3-3η (ywhah) is one such marker that complements rf and anti-ccp, along with other serological measures like c-reactive protein. in a systematic review, 14-3-3η has been described as a welcome addition to the rheumatology field. the authors indicate that the serum based 14-3-η marker is additive to the armamentarium of existing tools available to clinicians, and that there is adequate clinical evidence to support its clinical benefits. other blood tests are usually done to differentiate from other causes of arthritis, like the erythrocyte sedimentation rate (esr), c-reactive protein, full blood count, kidney function, liver enzymes and other immunological tests (e.g., antinuclear antibody/ana) are all performed at this stage. elevated ferritin levels can reveal hemochromatosis, a mimic of ra, or be a sign of still's disease, a seronegative, usually juvenile, variant of rheumatoid arthritis. classification criteria in 2010, the 2010 acr / eular rheumatoid arthritis classification criteria were introduced. the new criteria are not diagnostic criteria, but are classification criteria to identify disease with a high likelihood of developing a chronic form. however a score of 6 or greater unequivocally classifies a person with a diagnosis of rheumatoid arthritis. these new classification criteria overruled the "old" acr criteria of 1987 and are adapted for early ra diagnosis. the "new" classification criteria, jointly published by the american college of rheumatology (acr) and the european league against rheumatism (eular) establish a point value between 0 and 10. four areas are covered in the diagnosis: joint involvement, designating the metacarpophalangeal joints, proximal interphalangeal joints, the interphalangeal joint of the thumb, second through fifth metatarsophalangeal joint and wrist as small joints, and shoulders, elbows, hip joints, knees, and ankles as large joints: involvement of 1 large joint gives 0 points involvement of 2–10 large joints gives 1 point involvement of 1–3 small joints (with or without involvement of large joints) gives 2 points involvement of 4–10 small joints (with or without involvement of large joints) gives 3 points involvement of more than 10 joints (with involvement of at least 1 small joint) gives 5 points serological parameters – including the rheumatoid factor as well as acpa – "acpa" stands for "anti-citrullinated protein antibody": negative rf and negative acpa gives 0 points low-positive rf or low-positive acpa gives 2 points high-positive rf or high-positive acpa gives 3 points acute phase reactants: 1 point for elevated erythrocyte sedimentation rate, esr, or elevated crp value (c-reactive protein) duration of arthritis: 1 point for symptoms lasting six weeks or longer the new criteria accommodate to the growing understanding of ra and the improvements in diagnosing ra and disease treatment. in the "new" criteria, serology and autoimmune diagnostics carries major weight, as acpa detection is appropriate to diagnose the disease in an early state, before joints destructions occur. destruction of the joints viewed in radiological images was a significant point of the acr criteria from 1987. this criterion no longer is regarded to be relevant, as this is just the type of damage that treatment is meant to avoid. differential diagnoses synovial fluid examination typewbc (per mm3) % neutrophilsviscosityappearance normal<2000hightransparent osteoarthritis<5000<25highclear yellow trauma<10,000<50variablebloody inflammatory2,000–50,00050–80lowcloudy yellow septic arthritis>50,000>75lowcloudy yellow gonorrhea~10,00060lowcloudy yellow tuberculosis~20,00070lowcloudy yellow inflammatory: gout, rheumatoid arthritis, rheumatic fever several other medical conditions can resemble ra, and need to be distinguished from it at the time of diagnosis: crystal induced arthritis (gout, and pseudogout) – usually involves particular joints (knee, mtp1, heels) and can be distinguished with an aspiration of joint fluid if in doubt. redness, asymmetric distribution of affected joints, pain occurs at night and the starting pain is less than an hour with gout. osteoarthritis – distinguished with x-rays of the affected joints and blood tests, older age, starting pain less than an hour, asymmetric distribution of affected joints and pain worsens when using joint for longer periods. systemic lupus erythematosus (sle) – distinguished by specific clinical symptoms and blood tests (antibodies against double-stranded dna) one of the several types of psoriatic arthritis resembles ra – nail changes and skin symptoms distinguish between them lyme disease causes erosive arthritis and may closely resemble ra – it may be distinguished by blood test in endemic areas reactive arthritis – asymmetrically involves heel, sacroiliac joints and large joints of the leg. it is usually associated with urethritis, conjunctivitis, iritis, painless buccal ulcers,