ObjectiveTo investigate whether antidrug antibodies and/or drug non‐trough levels predict the long‐term treatment response in a large cohort of patients with rheumatoid arthritis (RA) treated with adalimumab or etanercept and to identify factors influencing antidrug antibody and drug levels to optimize future treatment decisions.MethodsA total of 331 patients from an observational prospective cohort were selected (160 patients treated with adalimumab and 171 treated with etanercept). Antidrug antibody levels were measured by radioimmunoassay, and drug levels were measured by enzyme‐linked immunosorbent assay in 835 serial serum samples obtained 3, 6, and 12 months after initiation of therapy. The association between antidrug antibodies and drug non‐trough levels and the treatment response (change in the Disease Activity Score in 28 joints) was evaluated.ResultsAmong patients who completed 12 months of followup, antidrug antibodies were detected in 24.8% of those receiving adalimumab (31 of 125) and in none of those receiving etanercept. At 3 months, antidrug antibody formation and low adalimumab levels were significant predictors of no response according to the European League Against Rheumatism (EULAR) criteria at 12 months (area under the receiver operating characteristic curve 0.71 [95% confidence interval (95% CI) 0.57, 0.85]). Antidrug antibody–positive patients received lower median dosages of methotrexate compared with antidrug antibody–negative patients (15 mg/week versus 20 mg/week; P = 0.01) and had a longer disease duration (14.0 versus 7.7 years; P = 0.03). The adalimumab level was the best predictor of change in the DAS28 at 12 months, after adjustment for confounders (regression coefficient 0.060 [95% CI 0.015, 0.10], P = 0.009). Etanercept levels were associated with the EULAR response at 12 months (regression coefficient 0.088 [95% CI 0.019, 0.16], P = 0.012); however, this difference was not significant after adjustment. A body mass index of ≥30 kg/m2 and poor adherence were associated with lower drug levels.ConclusionPharmacologic testing in anti–tumor necrosis factor–treated patients is clinically useful even in the absence of trough levels. At 3 months, antidrug antibodies and low adalimumab levels are significant predictors of no response according to the EULAR criteria at 12 months.
Objective. Rheumatoid arthritis (RA) has an estimated genetic contribution of 30-50%, approximately one-third of which arises from the major histocompatibility complex on 6p21.3. Many studies have implicated alleles of DRB1 that encode a shared epitope. However, several recent studies have suggested that additional telomeric genetic influences may exist. In this study, we sought to investigate whether a separate non-DRB1 effect could be detected and to determine its likely location.Methods. We typed 13 single-nucleotide polymorphisms, located mainly in the telomeric class III region of the major histocompatibility complex, in 164 British Caucasian families with RA that had at least 1 affected offspring and used unconditioned and DRB1-conditioned transmission disequilibrium tests (TDTs).Results. Unconditioned TDTs revealed overtransmission of shared epitope alleles (P ؍ 2.12 ؋ 10 ؊5 ) and an allele of the HLA-B-associated transcript 1 (BAT1) gene in the telomeric class III region (P ؍ 0.009). Using a DRB1-conditioned TDT to assess whether an independent effect existed, we detected unequal transmission of alleles of lymphocyte-specific transcript 1 (P ؍ 0.004), BAT1 (P ؍ 0.003), and PG8 (P ؍ 0.003). Conclusion.At least 1 additional non-DRB1 susceptibility locus for RA exists in an interval that encompasses the junction of the class III and I regions. This is a genomic segment of high linkage disequilibrium containing a large number of poorly characterized immunomodulatory genes.
Objective. To assess the inter-rater reliability of the BILAG2004-Pregnancy index for assessment of SLE disease activity in pregnancy.Methods. Pregnant SLE patients were recruited from four centres and assessed separately by two raters/physicians in routine clinical practice. Disease activity was determined using the BILAG2004-Pregnancy index. Reliability was assessed using level of agreement, κ-statistics and analysis of disagreement. Major disagreement was defined as a score difference of A and C/D/E or B and D/E between the two raters, and minor disagreement was a score difference of A and B or B and C between raters.Results. A total of 30 patients (63.3% Caucasian, 13.3% Afro-Caribbean, 16.7% South Asian) were recruited. The majority of patients had low-level disease activity according to the local rater’s assessment, and there was no grade A activity, with grade B activity present in the following systems: mucocutaneous (nine patients), musculoskeletal (two patients), cardiorespiratory (one patient) and renal (one patient). The distribution of disease activity was similar to the external rater’s assessment. Good levels of agreement (>70%) were achieved in all systems. κ-statistics were not appropriate for use in the gastrointestinal, ophthalmic, constitutional and neuropsychiatric systems, as there was minimal variation between patients but good levels of agreement otherwise. There were three major disagreements (0.1 per patient, all differences between B and D/E) and five minor disagreements (0.17 per patient).Conclusion. The BILAG2004-Pregnancy index is reliable for assessment of disease activity in pregnant SLE patients.
The telomeric class III region of the major histocompatibility complex is gene dense, but apart from the three tumour necrosis factor (TNF) superfamily members (TNF, lymphotoxin alpha and lymphotoxin beta) little is known of the expression and function of the majority of the genes. Recent genetic studies in autoimmune diseases, particularly rheumatoid arthritis (RA), have suggested a human leukocyte antigen (HLA)-DR-independent disease effect in this region. To gain further insights into these associations, we used lipopolysaccharide-stimulated human macrophages to examine inducible mRNA expression and genotype-phenotype relationships for genes in this region. Following stimulation in addition to the expected induction of TNF mRNA, a 14-fold increase of ATP6V1G2 at 18 h (Po0.001) was seen, whereas B-associated transcript (BAT)2 (Po0.001) and leucocyte-specific transcript (LST)1 (Po0.001) were both downregulated. By genotyping single-nucleotide polymorphisms spanning a 70 kb interval centred on the TNF locus, we constructed haplotypes and determined associated expression profiles for 10 genes in the cluster using quantitative real-time polymerase chain reaction. Overexpression of BAT1 mRNA was associated with carriers of a haplotype containing the LST1 marker transmitted to RA cases in a family study and also DRB1*15 associated with susceptibility to nephritis in systemic lupus erythematosus. The implications of our findings for the understanding of genetic associations with disease susceptibility in this region are discussed.
Objectives This study was to determine if the BILAG2004-Pregnancy Index (BILAG2004-P) has construct/criterion validity and is sensitive to change. Methods This was an observational multi-centre study which recruited pregnant SLE patients. Data was collected on disease activity (using BILAG2004-P and physician’s global assessment, PGA), investigations and therapy at each assessment. Overall BILAG2004-P score as determined by the highest score achieved by any system was used in the analysis. Cross sectional analysis was used for construct and criterion validity. The comparison was with C3, C4 and anti-dsDNA for construct validity whilst it was with change in therapy and PGA in criterion validity. Sensitivity to change was assessed by determining the relationship between change in BILAG2004-P and change in therapy between 2 consecutive visits. Results 97 patients with 112 pregnancies were recruited. There were 610 assessments available for construct/criterion validity analysis (98.2% pregnancies had more than 1 assessment) and 497 observations for sensitivity to change analysis. Increasing BILAG2004-P scores were associated with low C3. Active BILAG2004-P score (Grade A or B) was associated with increase in therapy and PGA of active disease. There was increasing likelihood of higher overall scores with increase in therapy and PGA of active disease. In the sensitivity to change analysis, increase in BILAG2004-P score was associated with increase in therapy and inversely associated with decrease in therapy. Decrease in BILAG2004-P score was associated with decrease in therapy and inversely associated with increase in therapy. Conclusion The BILAG2004-Pregnancy index has criterion validity and is sensitive to change. Lay Summary What does this mean for patients? Lupus is a chronic autoimmune disease that mainly affects women of child-bearing age. Thanks to improvements in lupus management, more women with lupus are able to become pregnant. However, changes during pregnancy can mimic some features of active lupus, which makes it more difficult to assess disease activity. Therefore, we have to adjust the way we assess lupus in pregnant patients. The BILAG2004-Pregnancy Index is a modified version of the BILAG-2004 index. While the BILAG-2004 Index is used to assess non-pregnant patients, the modified version should allow us to assess lupus activity in pregnant patients. This large study involved several medical centres and compared the BILAG2004-Pregnancy Index to other markers and an external standard reference. We found that the BILAG2004-Pregnancy Index appropriately measures lupus activity and is therefore a valid way to assess disease activity in pregnant patients. This finding will enable further research into lupus disease activity during pregnancy.
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