PMC:3845430 / 7020-11964 JSONTXT

{"project":"2_test","denotations":[{"id":"24324289-9195506-25763411","span":{"begin":268,"end":270},"obj":"9195506"},{"id":"24324289-22798565-25763412","span":{"begin":272,"end":274},"obj":"22798565"},{"id":"24324289-17548411-25763413","span":{"begin":361,"end":363},"obj":"17548411"},{"id":"24324289-15878904-25763414","span":{"begin":365,"end":367},"obj":"15878904"},{"id":"24324289-4599390-25763415","span":{"begin":559,"end":561},"obj":"4599390"},{"id":"24324289-12408052-25763416","span":{"begin":615,"end":617},"obj":"12408052"},{"id":"24324289-15103252-25763417","span":{"begin":664,"end":665},"obj":"15103252"},{"id":"24324289-12215644-25763418","span":{"begin":1102,"end":1104},"obj":"12215644"},{"id":"24324289-3264319-25763418","span":{"begin":1102,"end":1104},"obj":"3264319"},{"id":"24324289-20176268-25763419","span":{"begin":1335,"end":1337},"obj":"20176268"},{"id":"24324289-9833253-25763420","span":{"begin":1764,"end":1766},"obj":"9833253"},{"id":"24324289-9536830-25763421","span":{"begin":1768,"end":1770},"obj":"9536830"},{"id":"24324289-20597112-25763422","span":{"begin":1831,"end":1833},"obj":"20597112"},{"id":"24324289-23515604-25763423","span":{"begin":2058,"end":2060},"obj":"23515604"},{"id":"24324289-3358796-25763424","span":{"begin":2154,"end":2156},"obj":"3358796"},{"id":"24324289-20872595-25763425","span":{"begin":2304,"end":2306},"obj":"20872595"},{"id":"24324289-17548411-25763426","span":{"begin":2496,"end":2498},"obj":"17548411"},{"id":"24324289-12709545-25763427","span":{"begin":2655,"end":2657},"obj":"12709545"},{"id":"24324289-14558078-25763428","span":{"begin":2703,"end":2705},"obj":"14558078"},{"id":"24324289-17548411-25763429","span":{"begin":2854,"end":2856},"obj":"17548411"},{"id":"24324289-23480744-25763430","span":{"begin":3006,"end":3008},"obj":"23480744"},{"id":"24324289-23205355-25763430","span":{"begin":3006,"end":3008},"obj":"23205355"},{"id":"24324289-23965485-25763430","span":{"begin":3006,"end":3008},"obj":"23965485"},{"id":"24324289-23686569-25763430","span":{"begin":3006,"end":3008},"obj":"23686569"},{"id":"24324289-17548411-25763431","span":{"begin":3268,"end":3270},"obj":"17548411"},{"id":"24324289-23126558-25763432","span":{"begin":3272,"end":3274},"obj":"23126558"},{"id":"24324289-19365265-25763433","span":{"begin":3435,"end":3437},"obj":"19365265"},{"id":"24324289-20597112-25763434","span":{"begin":3575,"end":3577},"obj":"20597112"},{"id":"24324289-20510231-25763435","span":{"begin":3579,"end":3581},"obj":"20510231"},{"id":"24324289-23378461-25763436","span":{"begin":3917,"end":3919},"obj":"23378461"},{"id":"24324289-15593224-25763437","span":{"begin":4106,"end":4108},"obj":"15593224"},{"id":"24324289-15142273-25763438","span":{"begin":4149,"end":4151},"obj":"15142273"},{"id":"24324289-15166003-25763438","span":{"begin":4149,"end":4151},"obj":"15166003"},{"id":"24324289-15726373-25763438","span":{"begin":4149,"end":4151},"obj":"15726373"},{"id":"24324289-15975966-25763439","span":{"begin":4169,"end":4171},"obj":"15975966"},{"id":"24324289-12905467-25763440","span":{"begin":4202,"end":4204},"obj":"12905467"},{"id":"24324289-16947627-25763441","span":{"begin":4206,"end":4208},"obj":"16947627"},{"id":"24324289-23290690-25763442","span":{"begin":4241,"end":4243},"obj":"23290690"},{"id":"24324289-22441966-25763443","span":{"begin":4245,"end":4247},"obj":"22441966"},{"id":"24324289-16705046-25763444","span":{"begin":4489,"end":4491},"obj":"16705046"},{"id":"24324289-18785316-25763444","span":{"begin":4489,"end":4491},"obj":"18785316"},{"id":"24324289-21454308-25763445","span":{"begin":4561,"end":4563},"obj":"21454308"},{"id":"24324289-18375541-25763446","span":{"begin":4565,"end":4567},"obj":"18375541"},{"id":"24324289-17785317-25763447","span":{"begin":4712,"end":4714},"obj":"17785317"},{"id":"24324289-15201414-25763448","span":{"begin":4936,"end":4938},"obj":"15201414"},{"id":"24324289-19789202-25763448","span":{"begin":4936,"end":4938},"obj":"19789202"},{"id":"24324289-22689315-25763448","span":{"begin":4936,"end":4938},"obj":"22689315"}],"text":"6. RFs and Rheumatoid Arthritis\nAlthough RFs can be detected in patients with other connective tissue diseases, RF isotypes are helpful in the management of RA patients from the time of diagnosis until deciding on the choice of therapeutic strategy (Figures 1 and 2) [44, 45]. RF testing in RA patients has a sensitivity of 60% to 90% and a specificity of 85% [46, 47].\nA number of hypotheses have been postulated in order to explain the possible key role of RFs in RA, including their capacity to increase the elimination of immune complexes by macrophages [48], the improved cytotoxicity of antiviral antibodies [49], and the increased elimination of parasites [1]. It has also been suggested that RFs potentiate the presentation of antigens to T cells by means of the dendritic cell uptake of immune complexes with exogenous antigens and by means of RF B cells, which seem to be more efficient APCs than other B cells [50] (Figure 3). Finally, it is possible that the rapid secretion of large amounts of low-affinity RFs prevents the activation of higher-affinity RF B cells and additional B cells [51–53].\nDefining RFs as anti-IgG or anti-gamma-globulins is inaccurate because it restricts RF reactivity to the IgG Fc fragment. IgM RFs are the most frequently detected isotype, but IgG, IgA, IgE, and IgD RFs can also be observed [54].\nIt has been shown that three RF isotypes (IgM, IgA, and IgG) are detected in up to 52% of RA patients but in fewer than 5% of patients with other connective tissue diseases. Moreover, the presence of IgA and IgG RF isotypes in absence of IgM-RF is more prevalent in patients with connective tissue diseases than in RA patients, whereas an increase in both IgM and IgA RFs is almost exclusively observed in patients with RA [55, 56]. IgM-RF specificity increases considerably at high titres [57].\n\n6.1. The Role of RFs in the Diagnosis of Rheumatoid Arthritis\nIt has long been recognised that RFs play a pivotal role in the differential diagnosis of polyarthritis because they make it possible to identify RA patients [58]. For this reason, RF testing has been one of the classification criteria for RA since 1987 [59] and, although many years have passed since their identification, their crucial role in classifying RA has been confirmed by the updated criteria [60].\nHowever, in order to increase the specificity of the latest RA classification criteria, anti-cyclic citrullinated protein/peptide antibody (ACPA) testing has been added. A meta-analysis [46] has shown that the pooled sensitivities of ACPA and RF are similar, but ACPA positivity is more specific for RA than IgM RF, IgG RF, or IgA RF positivity [61] and more specific for early RA than IgM RF [62]. On the other hand, sensitivity is reduced because positivity for both ACPA and RF is a more stringent criterion than positivity for either alone [46]; combining ACPA and RF positivity is more permissive in terms of sensitivity because the antibodies complement each other, especially for early RA [63–66]. \nFurthermore, although the cut-off value of each commercial kit is slightly different, it has been suggested that the best ACPA cut-off value should be ≥40 U/mL, which leads to a positive likelihood ratio of 5.49 and a negative likelihood ratio of 0.50 [46, 67].\nIt has also been shown that RFs are useful in predicting the development of RA, as the detection of IgM, IgA, and IgG RFs may predate its onset by years [38, 68], and it has been reported that their appearance in serum is sequential before diagnosis: first IgM RF, then IgA RF, and finally IgG RF [57, 69].\n\n6.2. Prognostic and Therapeutic Relevance in Rheumatoid Arthritis\nThe detection of IgM RFs is also helpful as a prognostic index, and some studies have shown that immunosuppressive treatment can decrease serum RF levels. However, the clinical usefulness of RFs in monitoring disease activity [70] and treatment response is limited [71]. \nIt has been shown that a progressive decrease in the RF levels parallels the decrease of clinical activity in patients treated with traditional disease modifying antirheumatic drugs [72] or biologic agents such as infliximab [73–75], etanercept [76], adalimumab [77], rituximab [78, 79], and abatacept or tocilizumab [80, 81].\nThere are conflicting published data concerning the potential role of RFs in predicting responses to antitumor necrosis factor alpha (TNF-α): some studies have found that RF positivity before therapy is insufficient to predict a response [82–85], whereas others have found that it predicts a negative response [86, 87]. In particular, it has been reported that high pretreatment levels of IgA RF are associated with a poor clinical response to TNF-α inhibitors [88].\nHigh serum levels of RF are predictors of more severe disease forms and B cell-depleting therapy can have a beneficial effect: RF-positive RA patients have a better response to rituximab than those who are RF negative [89–92].\n"}