Joint destruction is a measure for RA severity that is accurate, sensitive and reflective of the cumulative disease burden. Risk factors for this outcome measure may be used to arrive at... Show moreJoint destruction is a measure for RA severity that is accurate, sensitive and reflective of the cumulative disease burden. Risk factors for this outcome measure may be used to arrive at individualized treatment strategies. Currently, relatively few risk factors for joint destruction are known. New risk factors, genetic risk factors in particular, may have relatively small effects on the rate of joint destruction. A sensitive determination of joint damage is then crucial in order to identify these risk factors and will reduce the risk on type 2 errors. The present article addresses the question how the rate of joint destruction is ideally measured. Different methods are discussed and suggestions for corrections of factors that affect the natural course of joint destruction, such as applied treatment strategies, are made. It is concluded that a precise estimation of the rate of radiological joint destruction is obtained by using quantitative and validated scoring methods as well as repetitive measurements over time in order to reduce within patient variation. Show less
Helm-van Mil, A.H.M. van der; Knevel, R.; Heijde, D. van der; Huizinga, T.W.J. 2010
Joint destruction is a measure for RA severity that is accurate, sensitive and reflective of the cumulative disease burden. Risk factors for this outcome measure may be used to arrive at... Show moreJoint destruction is a measure for RA severity that is accurate, sensitive and reflective of the cumulative disease burden. Risk factors for this outcome measure may be used to arrive at individualized treatment strategies. Currently, relatively few risk factors for joint destruction are known. New risk factors, genetic risk factors in particular, may have relatively small effects on the rate of joint destruction. A sensitive determination of joint damage is then crucial in order to identify these risk factors and will reduce the risk on type 2 errors. The present article addresses the question how the rate of joint destruction is ideally measured. Different methods are discussed and suggestions for corrections of factors that affect the natural course of joint destruction, such as applied treatment strategies, are made. It is concluded that a precise estimation of the rate of radiological joint destruction is obtained by using quantitative and validated scoring methods as well as repetitive measurements over time in order to reduce within patient variation. Show less
Cui, J.; Saevarsdottir, S.; Thomson, B.; Padyukov, L.; Helm-van Mil, A.H.M. van der; Nititham, J.; ... ; Ge 2010
Objective. Anti-tumor necrosis factor alpha (anti-TNF) therapy is a mainstay of treatment in rheumatoid arthritis (RA). The aim of the present study was to test established RA genetic risk factors... Show moreObjective. Anti-tumor necrosis factor alpha (anti-TNF) therapy is a mainstay of treatment in rheumatoid arthritis (RA). The aim of the present study was to test established RA genetic risk factors to determine whether the same alleles also influence the response to anti-TNF therapy. Methods. A total of 1,283 RA patients receiving etanercept, infliximab, or adalimumab therapy were studied from among an international collaborative consortium of 9 different RA cohorts. The primary end point compared RA patients with a good treatment response according to the European League Against Rheumatism (EULAR) response criteria (n = 505) with RA patients considered to be nonresponders (n = 316). The secondary end point was the change from baseline in the level of disease activity according to the Disease Activity Score in 28 joints (Delta DAS28). Clinical factors such as age, sex, and concomitant medications were tested as possible correlates of treatment response. Thirty-one single-nucleotide polymorphisms (SNPs) associated with the risk of RA were genotyped and tested for any association with treatment response, using univariate and multivariate logistic regression models. Results. Of the 31 RA-associated risk alleles, a SNP at the PTPRC (also known as CD45) gene locus (rs10919563) was associated with the primary end point, a EULAR good response versus no response (odds ratio [OR] 0.55, P = 0.0001 in the multivariate model). Similar results were obtained using the secondary end point, the Delta DAS28 (P = 0.0002). There was suggestive evidence of a stronger association in autoantibody-positive patients with RA (OR 0.55, 95% confidence interval [95% CI] 0.39-0.76) as compared with autoantibody-negative patients (OR 0.90, 95% CI 0.41-1.99). Conclusion. Statistically significant associations were observed between the response to anti-TNF therapy and an RA risk allele at the PTPRC gene locus. Additional studies will be required to replicate this finding in additional patient collections. Show less
Purpose of review The incidence of acute rheumatic fever (ARF) in the United States and Western Europe is decreasing and postStreptococcal reactive arthritis (PSRA) is more prevalent. It is not... Show morePurpose of review The incidence of acute rheumatic fever (ARF) in the United States and Western Europe is decreasing and postStreptococcal reactive arthritis (PSRA) is more prevalent. It is not clear whether PSRA is a forme fruste of ARF or a separate disease entity. Therefore, this review explores similarities and dissimilarities in initial symptoms and signs, disease course and underlying pathophysiologic mechanisms. Recent findings ARF and PSRA present differently. PSRA patients are generally older, have a longer interval between group A streptococcus infection and symptom onset, and respond less dramatically to salicylates than ARF patients. The course of ARF may be complicated by carditis and valvular heart disease. Echocardiographic studies in Caucasian adults with PSRA have revealed no increase in valvular heart disease. The course of PSRA is characterized by arthritis that, in contrast to ARF, is additive, nonmigratory and is frequently chronic. Factors of the host, the Streptococcus and the immune response involved in the development of PSRA are scarcely explored, hampering comparisons with ARF. Summary On the basis of the differences in clinical presentation and disease course, ARF and PSRA are separate disease entities. Development of validated diagnostic criteria for PSRA is mandatory to proceed with studies on pathophysiological mechanisms and treatment in PSRA. Show less
Woude, D. van der; Syversen, S.W.; Voort, E.I.H. van der; Verpoort, K.N.; Goll, G.L.; Linden, M.P.M. van der; ... ; Toes, R.E.M. 2010
Background The presence of anti-citrullinated protein antibodies (ACPA) is a powerful predictive factor for the development and progression of rheumatoid arthritis (RA). The ACPA response has been... Show moreBackground The presence of anti-citrullinated protein antibodies (ACPA) is a powerful predictive factor for the development and progression of rheumatoid arthritis (RA). The ACPA response has been shown to consist of various isotypes, but the consequences of differences in isotype distribution have not been extensively investigated. Objective To investigate the relationship between ACPA isotypes, disease progression and radiological outcome. Methods ACPA isotypes were determined in sera of anti-cyclic citrullinated peptide 2-positive patients by enzyme-linked immunosorbent assay (ELISA). To investigate whether the ACPA response continues to evolve during disease development, the ACPA isotype profile during progression of undifferentiated arthritis (UA) to RA was studied. The association of disease progression with ACPA isotype use was assessed using long-term radiographic follow-up data from patients with RA in two independent cohorts. Results The ACPA isotype distribution did not expand during disease progression from UA to RA, but was relatively stable over time. In both RA cohorts, the baseline ACPA isotype profile was a significant predictor of disease severity, with more isotypes indicating a higher risk of radiographic damage (odds ratio for every additional isotype: 1.4 (95% CI 1.1 to 1.9) p < 0.001). ACPA isotypes supplied additional prognostic information to ACPA status alone, even after correction for other predictive factors. Conclusions The magnitude of the ACPA isotype profile at baseline reflects the risk of future radiographic damage. These results indicate that the presence and the constitution of the ACPA response are relevant to the disease course of RA. Show less
To identify new genetic risk factors for rheumatoid arthritis, we conducted a genome-wide association study meta-analysis of 5,539 autoantibody-positive individuals with rheumatoid arthritis (cases... Show moreTo identify new genetic risk factors for rheumatoid arthritis, we conducted a genome-wide association study meta-analysis of 5,539 autoantibody-positive individuals with rheumatoid arthritis (cases) and 20,169 controls of European descent, followed by replication in an independent set of 6,768 rheumatoid arthritis cases and 8,806 controls. Of 34 SNPs selected for replication, 7 new rheumatoid arthritis risk alleles were identified at genome-wide significance (P < 5 x 10(-8)) in an analysis of all 41,282 samples. The associated SNPs are near genes of known immune function, including IL6ST, SPRED2, RBPJ, CCR6, IRF5 and PXK. We also refined associations at two established rheumatoid arthritis risk loci (IL2RA and CCL21) and confirmed the association at AFF3. These new associations bring the total number of confirmed rheumatoid arthritis risk loci to 31 among individuals of European ancestry. An additional 11 SNPs replicated at P < 0.05, many of which are validated autoimmune risk alleles, suggesting that most represent genuine rheumatoid arthritis risk alleles. Show less
Damjanovska, L.; Thabet, M.M.; Levarth, E.W.N.; Stoeken-Rijsbergen, G.; Voort, E.I. van der; Toes, R.E.M.; ... ; Helm-van Mil, A.H.M. van der 2010
Objectives To evaluates the diagnostic performance of the anti-CCP2, anti-CCP3 and anti-mutated citrullinated vimentin (anti-MCV) tests in differentiating rheumatoid arthritis (RA) from other forms... Show moreObjectives To evaluates the diagnostic performance of the anti-CCP2, anti-CCP3 and anti-mutated citrullinated vimentin (anti-MCV) tests in differentiating rheumatoid arthritis (RA) from other forms of arthritis in a clinical setting of early arthritis. Methods In 917 patients with recent-onset arthritis (566 RA, 351 other diseases) and in 99 healthy controls the anti-MCV, anti-CCP2 and anti-CCP3.1 tests were performed and the test characteristics compared. Results Comparison of the tests for differentiating RA from other causes of arthritis showed a lower specificity for anti-MCV (82.9%) than for anti-CCP2 (93.4%) and anti-CCP3.1 (90.0%). Similarly, the positive likelihood ratio for anti-MCV was also lower (3.6, compared with 8.7, 5.8 for anti-CCP2 and anti-CCP3.1). The anti-MCV test had a higher sensitivity (62% vs 56.9% and 58.1%, respectively). In psoriatic arthritis, spondyloarthropathy and other arthritis anti-MCV antibodies had a prevalence of 15.2%, 13.9% and 19.4%. Conclusion The diagnostic performance of the antitest in the differential diagnosis of early arthritis is lower than that of the anti-CCP tests. Show less
Linden, M.P.M. van der; Boja, R.; Klarenbeek, N.B.; Huizinga, T.W.J.; Heijde, D.M. van der; Helm-van Mil, A.H.M. van der 2010
Background Joint destruction in rheumatoid arthritis (RA) was until recently seen as an irreversible state. Lately, it was found that repair of bone erosions occurs; however, little is known about... Show moreBackground Joint destruction in rheumatoid arthritis (RA) was until recently seen as an irreversible state. Lately, it was found that repair of bone erosions occurs; however, little is known about its prevalence. Objective To investigate the frequency of repair and patients' characteristics associated with repair in an inception cohort. Patients and methods 250 patients with RA, included in the Leiden Early Arthritis Clinic between 1993 and 2000 and treated with conventional disease-modifying antirheumatic drugs, were studied (mean follow-up 10.1 years). Radiographs obtained annually were scored using the Sharp-van der Heijde method, initially aware of the chronology. Patients with a negative change in erosion scores on subsequent radiographs were selected and their series of radiographs were rescored with concealed time sequence by three readers. Repair was defined as agreement between two readers of a negative change in erosion scores that persisted for at least 2 years. Results Repair was identified in 32 joints in 18 patients (7.2%). Patients with repair had a greater prevalence of autoantibodies (rheumatoid arthritis, anti-citrullinated protein antibody) and a higher level of joint destruction. In the joints with repair, arthritis was absent in the 2 years preceding repair. Conclusions Repair occurred in 7.2% of the patients with RA, particularly in clinically inactive joints in patients with severe destructive disease. Show less
This thesis investigated the association between several genetic factors and autoantibodies and the development of undifferentiated arthritis (UA) and rheumatoid arthritits (RA). Second, this... Show moreThis thesis investigated the association between several genetic factors and autoantibodies and the development of undifferentiated arthritis (UA) and rheumatoid arthritits (RA). Second, this thesis described a prediction model that estimates the chance to progress from UA to RA. The most important genetic risk factor for RA are the HLA-Class II alleles that encode for a common amino acid sequence, called the ‘Shared Epitope’. Investigating the progression to RA from UA revealed that the HLA-Shared Epitope alleles are not primarily a risk factor for RA but for the presence of anti-CCP antibodies, that are known to be specific for RA. Smoking in the presence of HLA-Shared Epitope alleles particularly increased the risk on anti-CCP-positive RA.. The HLA-DR3 alleles were associated with anti-CCP-negative RA. The presence of HLA-alleles encoding for D70ERAA correlated with a lower risk on RA and a less severe disease course. The presence of the PTPTN22 T-allele conferred an increased risk for both UA and RA. The knowledge on risk factors for RA-development was translated in a model that estimates the chance to progress to RA in patients that present with UA by using 9 clinical variables. The discriminative ability was high and this model allows individualized treatment decisions in UA. Show less
