and keratoderma blennorrhagica. axial spondyloarthritis (including ankylosing spondylitis) – this involves the spine, although an ra-like symmetrical small-joint polyarthritis may occur in the context of this condition. hepatitis c – ra-like symmetrical small-joint polyarthritis may occur in the context of this condition. hepatitis c may also induce rheumatoid factor auto-antibodies. rarer causes which usually behave differently but may cause joint pains: sarcoidosis, amyloidosis, and whipple's disease can also resemble ra. hemochromatosis may cause hand joint arthritis. acute rheumatic fever can be differentiated by a migratory pattern of joint involvement and evidence of antecedent streptococcal infection. bacterial arthritis (such as by streptococcus) is usually asymmetric, while ra usually involves both sides of the body symmetrically. gonococcal arthritis (a bacterial arthritis) is also initially migratory and can involve tendons around the wrists and ankles. sometimes arthritis is in an undifferentiated stage (i.e. none of the above criteria is positive), even if synovitis is witnessed and assessed with ultrasound imaging. difficult-to-treat rheumatoid arthritis (d2t ra) is a specific classification ra by the european league against rheumatism (eular). signs of illness: persistence of signs and symptoms drug resistance does not respond on two or more biological treatments does not respond on anti-rheumatic drugs with different mechanism of action factors contributing to difficult-to-treat disease: genetic risk factors environmental factors (diet, smoking, physical activity) overweight and obese genetic factors genetic factors such as hla-dr1b1, traf1, psors1c1 and microrna 146a are associated with difficult to treat rheumatoid arthritis, other gene polymorphisms seem to be correlated with response to biologic modifying anti-rheumatic drugs (bdmards). next one is foxo3a gene region been reported as associated with worst disorder. the minor allele at foxo3a summon a differential response of monocytes in ra patients. foxo3a can provide an increase of pro-inflammatory cytokines, including tnfα. possible gene polymorphism: stat4, ptpn2, psors1c1 and traf3ip2 genes had been correlated with response to tnf inhibitors. hla-dr1 and hla-drb1 gene the hla-drb1 gene is part of a family of genes called the human leukocyte antigen (hla) complex. the hla complex is the human version of the major histocompatibility complex (mhc). currently, have been identified at least 2479 different versions of the hla-drb1 gene. the presence of hla-drb1 alleles seems to predict radiographic damage, which may be partially mediated by acpa development, and also elevated sera inflammatory levels and high swollen joint count. hla-dr1 is encoded by the most risk allele hla-drb1 which share a conserved 5-aminoacid sequence that is correlated with the development of anti-citrullinated protein antibodies. hla-drb1 gene have more strong correlation with disease development. susceptibility to and outcome for rheumatoid arthritis (ra) may associate with particular hla-dr alleles, but these alleles vary among ethnic groups and geographic areas. micrornas micrornas are a factor in the development of that type of disease. micrornas usually operate as a negative regulator of the expression of target proteins and their increased concentration after biologic treatment (bdmards) or after anti-rheumatic drugs. level of mirna before and after anti-tnfa/dmrads combination therapy are potential novel biomarkers for predicting and monitoring outcome. for instance, some of them were found significantly upregulated by anti-tnfa/dmrads combination therapy. for example, mirna-16-5p, mirna-23-3p, mirna125b-5p, mirna-126-3p, mirna-146a-5p, mirna-223-3p. curious fact is that only responder patients showed an increase in those mirnas after therapy, and paralleled the reduction of tnfα, interleukin (il)-6, il-17, rheumatoid factor (rf), and c-reactive protein (crp). monitoring progression many tools can be used to monitor remission in rheumatoid arthritis. das28: disease activity score of 28 joints (das28) is widely used as an indicator of ra disease activity and response to treatment. joints included are (bilaterally): proximal interphalangeal joints (10 joints), metacarpophalangeal joints (10), wrists (2), elbows (2), shoulders (2) and knees (2). when looking at these joints, both the number of joints with tenderness upon touching (ten28) and swelling (sw28) are counted. the erythrocyte sedimentation rate (esr) is measured and the affected person makes a subjective assessment (sa) of disease activity during the preceding 7 days on a scale between 0 and 100, where 0 is "no activity" and 100 is "highest activity possible". with these parameters, das28 is calculated as: d a s 28 = 0.56 × t e n 28 + 0.28 × s w 28 + 0.70 × ln ⁡ ( e s r ) + 0.014 × s a +0.28\times +0.70\times \ln(esr)+0.014\times sa} from this, the disease activity of the affected person can be classified as follows: current das28das28 decrease from initial value > 1.2> 0.6 but ≤ 1.2≤ 0.6 ≤ 3.2inactivegood improvementmoderate improvementno improvement > 3.2 but ≤ 5.1moderatemoderate improvementmoderate improvementno improvement > 5.1very activemoderate improvementno improvementno improvement it is not always a reliable indicator of treatment effect. one major limitation is that low-grade synovitis may be missed. other: other tools to monitor remission in rheumatoid arthritis are: acr-eular provisional definition of remission of rheumatoid arthritis, simplified disease activity index and clinical disease activity index. some scores do not require input from a healthcare professional and allow self-monitoring by the person, like haq-di. prevention there is no known prevention for the condition other than the reduction of risk factors. supplementation evidence suggests that increasing vitamin d levels to the range of 40–60 ng/ml could reduce the risk of rheumatoid arthritis. management there is no cure for ra, but treatments can improve symptoms and slow the progress of the disease. disease-modifying treatment has the best results when it is started early and aggressively. the results of a recent systematic review found that combination therapy with tumor necrosis factor (tnf) and non-tnf biologics plus methotrexate (mtx) resulted in improved disease control, disease activity score (das)-defined remission, and functional capacity compared with a single treatment of either methotrexate or a biologic alone. the goals of treatment are to minimize symptoms such as pain and swelling, to prevent bone deformity (for example, bone erosions visible in x-rays), and to maintain day-to-day functioning. this is primarily addressed with disease-modifying antirheumatic drugs (dmards); dosed physical activity; analgesics and physical therapy may be used to help manage pain. ra should generally be treated with at least one specific anti-rheumatic medication. the use of benzodiazepines (such as diazepam) to treat the pain is not recommended as it does not appear to help and is associated with risks. lifestyle regular exercise is recommended as both safe and useful to maintain muscle strength and overall physical function. physical activity is beneficial for people with rheumatoid arthritis who experience fatigue, although there was little to no evidence to suggest that exercise may have an impact on physical function in the long term, a study found that carefully dosed exercise has shown significant improvements in patients with ra. moderate effects have been found for aerobic exercises and resistance training on cardiovascular fitness and muscle strength in ra. furthermore, physical activity had no detrimental side effects like increased disease activity in any exercise dimension. it is uncertain if eating or avoiding specific foods or other specific dietary measures help improve symptoms. occupational therapy has a positive role to play in improving functional ability in people with rheumatoid arthritis. weak evidence supports the use of wax baths (thermotherapy) to treat arthritis in the hands. educational approaches that inform people about tools and strategies available to help them cope with rheumatoid arthritis may improve a person's psychological status and level of depression in the shorter-term. the use of extra-depth shoes and molded insoles may reduce pain during weight-bearing activities such as walking. insoles may also prevent the progression of bunions. disease-modifying agents disease-modifying antirheumatic drugs (dmards) are the primary treatment for ra. they are a diverse collection of drugs, grouped by use and convention. they have been found to improve symptoms, decrease joint damage, and improve overall functional abilities. dmards should be started early in the disease as they result in disease remission in approximately half of people and improved outcomes overall. the following drugs are considered dmards: methotrexate, sulfasalazine, leflunomide, hydroxychloroquine, tnf inhibitors (certolizumab, adalimumab, infliximab and etanercept), abatacept, anakinra, and auranofin. additionally, rituximab and tocilizumab are monoclonal antibodies and are also dmards. use of tocilizumab is associated with a risk of increased cholesterol levels. the most commonly used agent is methotrexate with other frequently used agents including sulfasalazine and leflunomide. leflunomide is effective when used from 6–12 months, with similar effectiveness to methotrexate when used for 2 years. sulfasalazine also appears to be most effective in the short-term treatment of rheumatoid arthritis. hydroxychloroquine, in addition to its low toxicity profile, is considered effective for treatment of moderate ra treatment. agents may be used in combination, however, people may experience greater side effects. methotrexate is the most important and useful dmard and is usually the first treatment. a combined approach with methotrexate and biologics improves acr50, haq scores and ra remission rates. triple therapy consisting of methotrexate, sulfasalazine and hydroxychloroquine may also effectively control disease activity. adverse effects should be monitored regularly with toxicity including gastrointestinal, hematologic, pulmonary, and hepatic. side effects such as nausea, vomiting or abdominal pain can be reduced by taking folic acid. a 2015 cochrane review found rituximab with methotrexate to be effective in improving symptoms compared to methotrexate alone. rituximab works by decreasing levels of b-cells (immune cell that is involved in inflammation). people taking rituximab had improved pain, function, reduced disease activity and reduced joint damage based on x-ray images. after 6 months, 21% more people had improvement in their symptoms using rituximab and methotrexate. biological agents should generally be used only if methotrexate and other conventional agents are not effective after a trial of three months. they are associated with a higher rate of serious infections as compared to other dmards. biological dmard agents used to treat rheumatoid arthritis include: tumor necrosis factor alpha inhibitors (tnf inhibitors) such as infliximab; interleukin 1 blockers such as anakinra, monoclonal antibodies against b cells such as rituximab, interleukin 6 blockers such as tocilizumab, and t cell co-stimulation blockers such as abatacept. they are often used in combination with either methotrexate or leflunomide. biologic monotherapy or tofacitinib with methotrexate may improve acr50, ra remission rates and function. abatacept should not be used at the same time as other biologics. in those who are well controlled (low disease activity) on tnf inhibitors, decreasing the dose does not appear to affect overall function. discontinuation of tnf inhibitors (as opposed to gradually lowering the dose) by people with low disease activity may lead to increased disease activity and may affect remission, damage that is visible on an x-ray, and a person's function. people should be screened for latent tuberculosis before starting any tnf inhibitor therapy to avoid reactivation of tuberculosis. tnf inhibitors and methotrexate appear to have similar effectiveness when used alone and better results are obtained when used together. golimumab is effective when used with methotraxate. tnf inhibitors may have equivalent effectiveness with etanercept appearing to be the safest. injecting etanercept, in addition to methotrexate twice a week may improve acr50 and decrease radiographic progression for up to 3 years. abatacept appears effective for ra with 20% more people improving with treatment than without but long term safety studies are yet unavailable. adalimumab slows the time for the radiographic progression when used for 52 weeks. however, there is a lack of evidence to distinguish between the biologics available for ra. issues with the biologics include their high cost and association with infections including tuberculosis. use of biological agents may reduce fatigue. the mechanism of how biologics reduce fatigue is unclear. gold and cyclosporin sodium aurothiomalate, auranofin, and cyclosporin are less commonly used due to more common adverse effects. however, cyclosporin was found to be effective in the progressive ra when used up to one year. anti-inflammatory and analgesic agents glucocorticoids can be used in the short term and at the lowest dose possible for flare-ups and while waiting for slow-onset drugs to take effect. combination of glucocorticoids and conventional therapy has shown a decrease in rate of erosion of bones. steroids may be injected into affected joints during the initial period of ra, prior to the use of dmards or oral steroids. non-nsaid drugs to relieve pain, like paracetamol may be used to help relieve the pain symptoms; they do not change the underlying disease. the use of paracetamol may be associated with the risk of developing ulcers. nsaids reduce both pain and stiffness in those with ra but do