Review of Routine Laboratory Monitoring for Patients with Rheumatoid Arthritis Receiving Biologic or Nonbiologic DMARDs.

Safety concerns associated with many drugs indicated for the treatment of rheumatoid arthritis (RA) can be attenuated by the early identification of toxicity through routine laboratory monitoring; however, a comprehensive review of the recommended monitoring guidelines for the different available RA therapies is currently unavailable. The aim of this review is to summarize the current guidelines for laboratory monitoring in patients with RA and to provide an overview of the laboratory abnormality profiles associated with each drug indicated for RA. Recommendations for the frequency of laboratory monitoring of serum lipids, liver transaminases, serum creatinine, neutrophil counts, and platelet counts in patients with RA were compiled from a literature search for published recommendations and guidelines as well as the prescribing information for each drug. Laboratory abnormality profiles for each drug were compiled from the prescribing information for each drug and a literature search including meta-analyses and primary clinical trials data.

Relationship Between Baseline and Early Changes in C-Reactive Protein and Interleukin-6 Levels and Clinical Response to Tocilizumab in Rheumatoid Arthritis.

OBJECTIVE: To clarify the relevance of measuring interleukin-6 (IL-6) and C-reactive protein (CRP) levels in order to predict clinical response to tocilizumab (TCZ) in rheumatoid arthritis patients. METHODS: In a pooled, post hoc analysis of 5 pivotal trials of TCZ, we examined the distributions of baseline serum concentrations of IL-6 and CRP, stratified by randomized treatment group, and week 24 Disease Activity Score in 28 joints (DAS28) status (DAS28 <2.6 versus DAS28 ≥2.6). Relationships between early biomarker changes and later changes in DAS28 scores were evaluated using Spearman's correlations and scatterplots. Finally, percentage changes from baseline in IL-6 and CRP levels were evaluated. RESULTS: Distributions of baseline IL-6 and CRP levels were similar for patients who achieved DAS28 scores <2.6 within 6 months of TCZ initiation and those who did not. Correlations between early changes in these 2 biomarkers and change in DAS28 scores were low (rho < 0.3 for all). Mean percentage increases from baseline in IL-6 concentrations were observed in all treatment groups (highest in the 8 mg/kg dose group); mean percentage decreases in CRP concentrations were greater at week 2 and at all visits for the 8 mg/kg dose group. CONCLUSION: Baseline serum concentrations of IL-6 and CRP may not be predictive of clinical outcomes after TCZ treatment. Data demonstrate the efficacy of TCZ in patients across a broad range of baseline serum IL-6 and CRP concentrations. Similarly, changes in these biomarkers after TCZ dosing are expected and may or may not correspond to changes in other clinical signs and symptoms. These results complement previous reports describing the complex interactions among biomarker changes, other therapeutic mechanisms of action, and clinical outcomes.

Interpreting the multi-biomarker disease activity score in the context of tocilizumab treatment for patients with rheumatoid arthritis.

The multi-biomarker disease activity (MBDA) score measures 12 proteins involved in the pathophysiology of rheumatoid arthritis (RA) to assess disease activity (DA). Previous studies demonstrated correlations between MBDA and clinical DA scores with some RA therapies. In this analysis, the relationship between DA and MBDA scores and changes in MBDA component biomarkers were evaluated in tocilizumab (TCZ)-treated patients. Patients from the ACT-RAY study were included in this analysis if they had DA measures and serum collected at pre-specified time points with sufficient serum for MBDA testing at ≥1 visit. Descriptive statistics, associations between outcomes, and percentage agreement between DA categories were calculated. Seventy-eight patients were included and were similar to the ACT-RAY population. Correlations between MBDA score and DAS28-CRP were ρ = 0.50 at baseline and ρ = 0.26 at week 24. Agreement between low/moderate/high categories of MBDA score and DAS28-CRP was observed for 77.1 % of patients at baseline and 23.7 % at week 24. Mean changes from baseline to weeks 4, 12, and 24 were proportionately smaller for MBDA score than DAS28-CRP. Unlike some other MBDA biomarkers, interleukin-6 (IL-6) concentrations increased in most patients during TCZ treatment. Correlations and agreement between MBDA and DAS28-CRP or CDAI scores were lower at week 24 versus baseline. The proportionately smaller magnitude of response observed for MBDA score versus DAS28-CRP may be due to the influence of the increase in IL-6 concentrations on MBDA score. Thus, MBDA scores obtained during TCZ treatment should be interpreted cautiously and in the context of available clinical information.

Proteomic analysis of circulating immune complexes in juvenile idiopathic arthritis reveals disease-associated proteins.

Juvenile idiopathic arthritis reflects a group of clinically heterogeneous arthritides hallmarked by elevated concentrations of circulating immune complexes. In this study, the circulating immune complex proteome was examined to elucidate disease-associated proteins that are overexpressed in patients with an aggressive, and at times destructive, disease phenotype. To solve this proteome, circulating immune complexes were isolated from the sera of patients with chronic, erosive or early-onset, aggressive disease and from patients in medical remission or healthy controls subsequent to protein separation by 2-DE. Thirty-seven protein spots were overexpressed in the circulating immune complexes of the aggressive disease groups as compared to controls, 28 of which have been confidently identified to date. Proteolytic fragments of glyceraldehyde-3-phosphate dehydrogenase, serotransferrin, and α-1-antitrypsin have been identified among others. In total, these 28 putative disease-associated proteins most definitely contribute to immune complex formation and likely have a significant role in disease etiology and pathogenesis. Moreover, these proteins represent markers of aggressive disease, which could aid in diagnosis and management strategies, and potential therapeutic targets to prevent or control disease outcome. This is the first in-depth analysis of the circulating immune complex proteome in juvenile idiopathic arthritis.

Determination of anti-cyclic citrullinated peptide antibodies in the sera of patients with juvenile idiopathic arthritis.

OBJECTIVE: Anti-cyclic citrullinated peptide (anti-CCP) antibodies have been found in sera of 76% of patients with rheumatoid arthritis (RA), mainly in rheumatoid factor (RF) positive patients, with a specificity of 96%. We evaluated the presence of anti-CCP antibodies in patients with juvenile idiopathic arthritis (JIA) and assessed the possibility of synthetic citrullinated peptides as antigenic determinants in JIA. METHODS: The presence of anti-CCP antibodies was determined using 3 synthetic citrullinated peptide variants and 2 commercial kits (Inova Diagnostics and Axis-Shield Diagnostics) optimized for detecting JIA-specific antibodies in serum by an ELISA based assay. We evaluated 66 patients with JIA (16 RF positive polyarthritis, 18 RF negative polyarthritis, 19 oligoarthritis, and 13 systemic arthritis). We also tested 9 adult RA patients, 34 patients with systemic lupus erythematosus (SLE), and 25 healthy persons as controls. RESULTS: Significant concentrations of anti-CCP antibodies were detected in the majority of RF positive JIA patients with polyarthritis. Using the 2 synthetic linear peptides, 12/16 (75%) were positive; 9/12 (75%) were positive with the Inova kit and 9/10 (90%) were positive with the Axis-Shield kit. However, utilizing the synthetic linear peptides, significant concentrations of anti-CCP antibodies were detected in 51/66 (77%) JIA patients, including 15/18 (83%) RF negative polyarthritis, 16/19 (84%) oligoarthritis, and 8/13 (62%) systemic arthritis patients. No healthy control showed elevated antibody levels. In contrast, 4/9 (44%) patients with adult RA and 2/6 (33%) with SLE had elevated anti-CCP levels. The synthetic cyclic variant cfc-1-cyc yielded significant anti-CCP levels for 13/14 (93%) patients with RF negative polyarthritis, 6/10 (60%) with oligoarthritis, and 3/7 (43%) with systemic arthritis, and 8/9 (88%) RF positive patients. No healthy control had increased anti-CCP levels. However, 4/9 (44%) adult RA and 9/34 (26%) SLE patients were found to have elevated anti-CCP levels. Using the Inova and Axis-Shield kits, much smaller percentages were found in the RF negative patients, with only 4/16 (25%) in the oligoarthritis and RF negative polyarthritis patients with the Inova kits and 0/25 (0%) by the Axis-Shield kits. The Inova kit revealed elevated anti-CCP antibodies in 5/9 (56%) adult RA patients and in 8/34 (24%) SLE patients. No healthy control had elevated anti-CCP antibodies. However, the Axis-Shield kits did not detect anti-CCP antibodies in adult RA (0/9) or SLE (0/34) patients. Moreover, 0/25 (0%) healthy individuals exhibited anti-CCP levels. The presence of anti-CCP antibodies correlated more frequently with the presence of RF. CONCLUSION: This study confirms the presence of anti-CCP antibodies in patients with JIA, especially those with RF positive polyarthritis, by all ELISA based methods. Use of synthetic peptides also revealed anti-CCP antibodies in a percentage of RF negative patients with polyarthritis, oligoarthritis, and systemic arthritis; there was a loss in specificity, but an increase in sensitivity. These results suggest that antibodies to these antigenic peptides may be markers for JIA, and indicate a possible role of citrulline-containing epitopes in the pathogenesis of JIA.