Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that primarily affects the lining of the synovial joints and is associated with progressive disability, premature death, and socioeconomic burdens. A better understanding of how the pathological mechanisms drive the deterioration of RA progress in individuals is urgently required in order to develop therapies that will effectively treat patients at each stage of the disease progress. Here we dissect the etiology and pathology at specific stages: (i) triggering, (ii) maturation, (iii) targeting, and (iv) fulminant stage, concomitant with hyperplastic synovium, cartilage damage, bone erosion, and systemic consequences. Modern pharmacologic therapies (including conventional, biological, and novel potential small molecule disease-modifying anti-rheumatic drugs) remain the mainstay of RA treatment and there has been significant progress toward achieving disease remission without joint deformity. Despite this, a significant proportion of RA patients do not effectively respond to the current therapies and thus new drugs are urgently required. This review discusses recent advances of our  understanding of RA pathogenesis, disease modifying drugs, and provides perspectives on next generation therapeutics for RA

The Symptoms in Persons At Risk of Rheumatoid Arthritis (SPARRA) questionnaire: predicting clinical arthritis development

Objective: There is a need to better define symptom characteristics associated with arthritis development in individuals at risk of rheumatoid arthritis (RA). We investigated whether reported symptoms in at-risk individuals could predict arthritis development and whether predictive symptoms differed between seropositive and seronegative at-risk individuals. Method: At-risk individuals from four cohorts (Netherlands, UK, Sweden, and Switzerland) completed the Symptoms in Persons At Risk of Rheumatoid Arthritis (SPARRA) questionnaire. Participants had either (i) anti-citrullinated protein antibodies and/or rheumatoid factor, or (ii) relevant symptoms with or without RA antibodies. Follow up was ≥ 24 months or until clinical arthritis development. Stepwise forward selection created SPARRA prediction models for the combined group and for a seropositive subgroup. Results: Of 214 participants, the mean age was 50 years, 67% were female, and 27% (n = 58) developed clinical arthritis after a median time of 7 months. Four symptoms predicted arthritis development: self-reported joint swelling, joint pain moving from side to side (combined group only), feeling pins and needles in the joints, and often feeling fatigued (predicting non-arthritis). Conclusion: Specific symptoms can provide useful information to estimate a person’s RA risk. Differences in predictive symptoms between seropositive and seronegative at-risk individuals need to be further investigated. Future research is needed to determine whether changes in symptoms over time improve prediction and to determine the value of SPARRA in optimizing the selection of individuals who need to consult a rheumatologist

The Symptoms in Persons At Risk of Rheumatoid Arthritis (SPARRA) questionnaire: predicting clinical arthritis development

Objective: There is a need to better define symptom characteristics associated with arthritis development in individuals at risk of rheumatoid arthritis (RA). We investigated whether reported symptoms in at-risk individuals could predict arthritis development and whether predictive symptoms differed between seropositive and seronegative at-risk individuals. Method: At-risk individuals from four cohorts (Netherlands, UK, Sweden, and Switzerland) completed the Symptoms in Persons At Risk of Rheumatoid Arthritis (SPARRA) questionnaire. Participants had either (i) anti-citrullinated protein antibodies and/or rheumatoid factor, or (ii) relevant symptoms with or without RA antibodies. Follow up was ≥ 24 months or until clinical arthritis development. Stepwise forward selection created SPARRA prediction models for the combined group and for a seropositive subgroup. Results: Of 214 participants, the mean age was 50 years, 67% were female, and 27% (n = 58) developed clinical arthritis after a median time of 7 months. Four symptoms predicted arthritis development: self-reported joint swelling, joint pain moving from side to side (combined group only), feeling pins and needles in the joints, and often feeling fatigued (predicting non-arthritis). Conclusion: Specific symptoms can provide useful information to estimate a person's RA risk. Differences in predictive symptoms between seropositive and seronegative at-risk individuals need to be further investigated. Future research is needed to determine whether changes in symptoms over time improve prediction and to determine the value of SPARRA in optimizing the selection of individuals who need to consult a rheumatologist.</p

Additional file 1: Table S1. of IgG Fc galactosylation predicts response to methotrexate in early rheumatoid arthritis

Demographic characteristics of the nationwide EIRA cohort. Table S2. Characterized complement pathway proteins and IgG-isotype proteins. Table S3. Individual IgG-Fc glycan distribution values in IgG1 and in IgG2 in control subjects, as well as in patients with RA prior to and following MTX treatment. Table S4. Significant differences for the 19 characterized glycan species when comparing healthy versus all, good, moderate, and nonresponding patients prior to and following MTX treatment. Table S5. IgG1 and IgG2 Fc glycan distributions grouped according to structural features, comparing healthy control subjects and patients with RA prior to and following MTX treatment. Table S6. Intra- and interindividual differences in the patients with RA, comparing individual glycan species prior to and following MTX treatment. Table S7. Complete list, ranking, and correlation (with response versus no response to MTX) of the features used in the OPLS-DA model shown in Fig. 3b. Figure S1. Extracted ion chromatograms of IgG1 and IgG2 Fc glycans quantified in a control subject and a patient with RA. Figure S2. Intraindividual changes in galactosylation status on IgG1 and on IgG2 for good and moderate responders and for nonresponders. Figure S3. Intraindividual correlation between the aGal/Gal status of glycans with different types of structural features and of IgG1 and IgG2 substituted glycans. Figure S4. Significant differences between control subjects and patients with early RA at baseline in the classical pathway initiating complements C1 and C9. Figure S5. Intraindividual correlation between the classical and lectin pathway inhibitor C4bBPα versus FA2/(FA2G1 + FA2G2). (DOCX 1180 kb