The trajectory of clinical responses in patients with early rheumatoid arthritis who achieve sustained remission in response to abatacept: subanalysis of AVERT-2, a randomized phase IIIb study.

BACKGROUND: AVERT-2 (a phase IIIb, two-stage study) evaluated abatacept + methotrexate versus methotrexate alone, in methotrexate-naive, anti-citrullinated protein antibody-positive patients with early (≤ 6 months), active RA. This subanalysis investigated whether individual patients who achieved the week 24 Simplified Disease Activity Index (SDAI) remission primary endpoint could sustain remission to 1 year and then maintain it following changes in therapy. METHODS: During the 56-week induction period (IP), patients were randomized to weekly subcutaneous abatacept 125 mg + methotrexate or abatacept placebo + methotrexate. Patients completing the IP who achieved SDAI remission (≤ 3.3) at weeks 40 and 52 entered a 48-week de-escalation (DE) period. Patients treated with abatacept + methotrexate were re-randomized to continue weekly abatacept + methotrexate, or de-escalate and then withdraw abatacept (after 24 weeks), or receive abatacept monotherapy. Proportions of patients achieving sustained SDAI and Boolean remission, and Disease Activity Score in 28 joints using C-reactive protein (DAS28 [CRP]) < 2.6, were assessed. For patients achieving early sustained SDAI remission at weeks 24/40/52, flow between disease activity categories and individual trajectories was evaluated; flow was also evaluated for later remitters (weeks 40/52 but not week 24). RESULTS: Among patients treated with abatacept + methotrexate (n/N = 451/752) at IP week 24, 22% achieved SDAI remission, 17% achieved Boolean remission, and 42% achieved DAS28 (CRP) < 2.6; of these, 56%, 58%, and 74%, respectively, sustained a response throughout IP weeks 40/52. Among patients with a sustained response at IP weeks 24/40/52, 82% (14/17) on weekly abatacept + methotrexate, 81% (13/16) on abatacept monotherapy, 63% (12/19) who de-escalated/withdrew abatacept, and 65% (11/17) on abatacept placebo + methotrexate were in SDAI remission at end of the DE period; rates were higher than for later remitters in all arms except abatacept placebo + methotrexate. CONCLUSIONS: A high proportion of individual patients achieving clinical endpoints at IP week 24 with abatacept + methotrexate sustained their responses through week 52. Of patients achieving early and sustained SDAI remission through 52 weeks, numerically more maintained remission during the DE period if weekly abatacept treatment continued. TRIAL REGISTRATION: NCT02504268 (ClinicalTrials.gov), registered July 21, 2015.

Sustained Remission and Outcomes with Abatacept plus Methotrexate Following Stepwise Dose De-escalation in Patients with Early Rheumatoid Arthritis.

INTRODUCTION: One target of rheumatoid arthritis (RA) treatment is to achieve early sustained remission; over the long term, patients in sustained remission have less structural joint damage and physical disability. We evaluated Simplified Disease Activity Index (SDAI) remission with abatacept + methotrexate versus abatacept placebo + methotrexate and impact of de-escalation (DE) in anti-citrullinated protein antibody (ACPA)-positive patients with early RA. METHODS: The phase IIIb, randomized, AVERT-2 two-stage study (NCT02504268) evaluated weekly abatacept + methotrexate versus abatacept placebo + methotrexate. PRIMARY ENDPOINT: SDAI remission (≤ 3.3) at week 24. Pre-planned exploratory endpoint: maintenance of remission in patients with sustained remission (weeks 40 and 52) who, from week 56 for 48 weeks (DE period), (1) continued combination abatacept + methotrexate, (2) tapered abatacept to every other week (EOW) + methotrexate for 24 weeks with subsequent abatacept withdrawal (abatacept placebo + methotrexate), or (3) withdrew methotrexate (abatacept monotherapy). RESULTS: Primary study endpoint was not met: 21.3% (48/225) of patients in the combination and 16.0% (24/150) in the abatacept placebo + methotrexate arm achieved SDAI remission at week 24 (p = 0.2359). There were numerical differences favoring combination therapy in clinical assessments, patient-reported outcomes (PROs) and week 52 radiographic non-progression. After week 56, 147 patients in sustained remission with abatacept + methotrexate were randomized (combination, n = 50; DE/withdrawal, n = 50; abatacept monotherapy, n = 47) and entered DE. At DE week 48, SDAI remission (74%) and PRO improvements were mostly maintained with continued combination therapy; lower remission rates were observed with abatacept placebo + methotrexate (48.0%) and with abatacept monotherapy (57.4%). Before withdrawal, de-escalating to abatacept EOW + methotrexate preserved remission. CONCLUSIONS: The stringent primary endpoint was not met. However, in patients achieving sustained SDAI remission, numerically more maintained remission with continued abatacept + methotrexate versus abatacept monotherapy or withdrawal. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02504268. Video abstract (MP4 62241 KB).

Patients with rheumatoid arthritis (RA) experience inflamed and damaged joints. RA is an autoimmune disease in which proteins called autoantibodies, particularly anti-citrullinated protein autoantibodies, target the patient's own joint tissue and organs by mistake, leading to symptomatic inflammation. Successful treatment can decrease the disease's activity to a state known as remission. Patients in remission may experience little or no symptoms and it may be possible for some to then be able to decrease their treatment. Here, we report the results of a large, international study that looked at two treatments, abatacept and methotrexate, in patients with RA and anti-citrullinated protein autoantibodies. The study had two parts. Firstly, to see how many patients had success (remission) with weekly abatacept and/or methotrexate treatment, and secondly, to see if remission was maintained when treatment was either continued or decreased and stopped. The study showed that the number of patients in remission 6 months after treatment started was not greatly different between patients treated with both abatacept and methotrexate and those treated with just methotrexate. Those taking abatacept and methotrexate together had better remission rates 1 year later. More patients also stayed in remission when they continued to receive both abatacept and methotrexate compared with those who were just treated with abatacept or when their abatacept treatment was decreased and stopped. More patients stayed in remission when abatacept was decreased than when it was stopped. The results from this study may help determine possible future treatment reduction and/or withdrawal plans for some patients with RA.

The Role of Genetics in Clinically Suspect Arthralgia and Rheumatoid Arthritis Development: A Large Cross-Sectional Study.

OBJECTIVE: To investigate whether established genetic predictors for rheumatoid arthritis (RA) differentiate healthy controls, patients with clinically suspect arthralgia (CSA), and RA patients. METHODS: Using analyses of variance, chi-square tests, and mean risk difference analyses, we investigated the association of an RA polygenic risk score (PRS) and HLA shared epitope (HLA-SE) with all participant groups, both unstratified and stratified for anti-citrullinated protein antibody (ACPA) status. We used 3 separate data sets sampled from the same Dutch population (1,015 healthy controls, 479 CSA patients, and 1,146 early classified RA patients). CSA patients were assessed for conversion to inflammatory arthritis over a period of 2 years, after which they were classified as either CSA converters (n = 84) or CSA nonconverters (n = 395). RESULTS: The PRS was increased in RA patients (mean ± SD PRS 1.31 ± 0.96) compared to the complete CSA group (1.07 ± 0.94) and compared to CSA converters (1.12 ± 0.94). In ACPA- strata, PRS distributions differed strongly when comparing the complete CSA group (mean ± SD PRS 1.05 ± 0.94) and CSA converters (0.97 ± 0.87) to RA patients (1.20 ± 0.94), while in the ACPA+ strata, the complete CSA group (1.25 ± 0.99) differed clearly from healthy controls (1.05 ± 0.94) and RA patients (1.41 ± 0.96). HLA-SE was more prevalent in the RA group (prevalence 0.64) than the complete CSA group (0.45), with small differences between RA patients and CSA converters (0.64 versus 0.60) and larger differences between CSA converters and CSA nonconverters (0.60 versus 0.42). HLA-SE prevalence differed more strongly within the ACPA+ strata as follows: healthy controls (prevalence 0.43), CSA nonconverters (0.48), complete CSA group (0.59), CSA converters (0.66), and RA patients (0.79). CONCLUSION: We observed that genetic predisposition increased across pre-RA participant groups. The RA PRS differed in early classified RA and inflammatory pre-disease stages, regardless of ACPA stratification. HLA-SE prevalence differed between arthritis patients, particularly ACPA+ patients, and healthy controls. Genetics seem to fulfill different etiologic roles.

Glycobiology of rheumatic diseases.

Glycosylation has a profound influence on protein activity and cell biology through a variety of mechanisms, such as protein stability, receptor interactions and signal transduction. In many rheumatic diseases, a shift in protein glycosylation occurs, and is associated with inflammatory processes and disease progression. For example, the Fc-glycan composition on (auto)antibodies is associated with disease activity, and the presence of additional glycans in the antigen-binding domains of some autoreactive B cell receptors can affect B cell activation. In addition, changes in synovial fibroblast cell-surface glycosylation can alter the synovial microenvironment and are associated with an altered inflammatory state and disease activity in rheumatoid arthritis. The development of our understanding of the role of glycosylation of plasma proteins (particularly (auto)antibodies), cells and tissues in rheumatic pathological conditions suggests that glycosylation-based interventions could be used in the treatment of these diseases.

Health-related quality of life in patients with mixed connective tissue disease: a comparison with matched systemic sclerosis patients.

OBJECTIVES: Health-Related Quality of Life (HRQoL) in adult patients with mixed connective tissue disease (MCTD) has not been described so far. Therefore, we performed an explorative study to evaluate HRQoL in MCTD patients. METHODS: MCTD patients fulfilling the Kahn criteria and participating in the prospective follow-up cohort for MCTD of the Leiden University Medical Center were included; and matched to systemic sclerosis (SSc) patients based on age, sex and disease duration. Data on disease characteristics and HRQoL (SF36 and EQ-5D) were collected annually. HRQoL was compared between MCTD and SSc patients at baseline. Factors associated with HRQoL in MCTD were identified using linear regression and change in HRQoL over 3 years using linear mixed models. RESULTS: Thirty-four MCTD patients (121 visits) and 102 SSc patients (424 visits) were included. At baseline, MCTD patients presented with interstitial lung disease, cardiac involvement, synovitis and myositis more frequently compared to SSc patients, while use of immunosuppressive medication was less frequent. In both groups, mean SF36 scores were lower than in the general Dutch population. The SF36 subscore "general health perception" was impacted most in both groups (MCTD: 38.5 [SD:7.0], SSc: 39.9 [SD:8.9]). During follow-up, SF36 scores improved in MCTD patients, while EQ5DNL remained stable. No specific characteristics were identified that associated with baseline HRQoL or change in HRQol over time. CONCLUSIONS: Like in SSc, HRQoL in MCTD is significantly impaired, especially the general health perception of patients. Evaluation in larger prospective cohorts is needed to identify characteristics that impact HRQol most.

Prediction of flare following remission and treatment withdrawal in early rheumatoid arthritis: post hoc analysis of a phase IIIb trial with abatacept.

BACKGROUND: Drug-free remission is a desirable goal in rheumatoid arthritis (RA) for both patients and clinicians. The aim of this post hoc analysis was to investigate whether clinical and magnetic resonance imaging (MRI) variables in patients with early RA who achieved remission with methotrexate and/or abatacept at 12 months could predict disease flare following treatment withdrawal. METHODS: In the AVERT study of abatacept in early RA, patients with low disease activity at month 12 entered a 12-month period with all treatment discontinued (withdrawal, WD). This post hoc analysis assessed predictors of disease flare at WD+6months (mo) and WD+12mo of patients with Disease Activity Score in 28 joints (DAS28)-defined remission (DAS28[C-reactive protein (CRP)] <2.6) at withdrawal using univariate and multivariable regression models. Predictors investigated included the Health Assessment Questionnaire-Disability Index (HAQ-DI), pain, Patient Global Assessment; MRI synovitis, erosion, bone edema, and combined (synovitis + bone edema) inflammation scores. RESULTS: Remission was achieved by 172 patients; 100 (58%) and 113 (66%) patients had experienced a flare at WD+6mo and WD+12mo, respectively. In univariate analyses, higher HAQ-DI and MRI synovitis, erosion, bone edema, and combined inflammation scores at WD were identified as potential predictors of flare (P ≤ 0.01). In multivariable analysis, high scores at WD for HAQ-DI and MRI erosion were confirmed as independent predictors of flare at WD+6mo and WD+12mo (P < 0.01). CONCLUSION: In patients with early RA achieving clinical remission, patient function (HAQ-DI), and MRI measures of bone damage (erosion) predicted disease flare 6 and 12 months after treatment withdrawal. These variables may help identify patients with early RA in clinical remission as candidates for successful treatment withdrawal. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01142726 (date of registration: June 11, 2010).

A framework for employing longitudinally collected multicenter electronic health records to stratify heterogeneous patient populations on disease history.

OBJECTIVE: To facilitate patient disease subset and risk factor identification by constructing a pipeline which is generalizable, provides easily interpretable results, and allows replication by overcoming electronic health records (EHRs) batch effects. MATERIAL AND METHODS: We used 1872 billing codes in EHRs of 102 880 patients from 12 healthcare systems. Using tools borrowed from single-cell omics, we mitigated center-specific batch effects and performed clustering to identify patients with highly similar medical history patterns across the various centers. Our visualization method (PheSpec) depicts the phenotypic profile of clusters, applies a novel filtering of noninformative codes (Ranked Scope Pervasion), and indicates the most distinguishing features. RESULTS: We observed 114 clinically meaningful profiles, for example, linking prostate hyperplasia with cancer and diabetes with cardiovascular problems and grouping pediatric developmental disorders. Our framework identified disease subsets, exemplified by 6 "other headache" clusters, where phenotypic profiles suggested different underlying mechanisms: migraine, convulsion, injury, eye problems, joint pain, and pituitary gland disorders. Phenotypic patterns replicated well, with high correlations of ≥0.75 to an average of 6 (2-8) of the 12 different cohorts, demonstrating the consistency with which our method discovers disease history profiles. DISCUSSION: Costly clinical research ventures should be based on solid hypotheses. We repurpose methods from single-cell omics to build these hypotheses from observational EHR data, distilling useful information from complex data. CONCLUSION: We establish a generalizable pipeline for the identification and replication of clinically meaningful (sub)phenotypes from widely available high-dimensional billing codes. This approach overcomes datatype problems and produces comprehensive visualizations of validation-ready phenotypes.

Left Ventricular Systolic Function in Patients with Systemic Lupus Erythematosus and Its Association with Cardiovascular Events.

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder with potential cardiovascular involvement. The aim of this study was to assess left ventricular (LV) systolic function in a large cohort of patients with SLE using standard echocardiographic measurements and global longitudinal strain (GLS) by two-dimensional speckle-tracking analysis. Furthermore, the association between echocardiographic parameters and the occurrence of cardiovascular events was assessed. METHODS: A total of 102 patients with SLE (88% women; mean age, 43 ± 14 years) undergoing a dedicated multidisciplinary assessment were analyzed, including echocardiography, at the time of their first visit. A control group consisted of 50 age- and sex-matched healthy subjects. RESULTS: Compared with control subjects, patients with SLE showed impaired LV systolic function on the basis of LV ejection fraction (51 ± 6% vs 62 ± 6%, P < .001) and by LV GLS (-15 ± 3% vs -19 ± 2%, P < .001). During a median follow-up period of 2 years (interquartile range, 1-6 years), 38 patients (37%) developed cardiovascular events. Kaplan-Meier survival curves showed that patients with SLE with more impaired LV GLS (on the basis of the median value of -15%) experienced higher cumulative rates of cardiovascular events compared with those with less impaired LV GLS (χ2 = 8.292, log-rank P = .004). On multivariate Cox regression analysis, LV GLS demonstrated an independent association with cardiovascular events (hazard ratio, 2.171; 95% CI, 1.015-4.642; P = .046), whereas LV ejection fraction was not significantly associated with the outcome. CONCLUSIONS: In patients with SLE, LV systolic function as measured by LV GLS is significantly impaired and associated with cardiovascular events, potentially representing a new tool to improve risk stratification in these patients.

Arthritis prevention in the pre-clinical phase of RA with abatacept (the APIPPRA study): a multi-centre, randomised, double-blind, parallel-group, placebo-controlled clinical trial protocol.

TRIAL DESIGN: We present a study protocol for a multi-centre, randomised, double-blind, parallel-group, placebo-controlled trial that seeks to test the feasibility, acceptability and effectiveness of a 52-week period of treatment with the first-in-class co-stimulatory blocker abatacept for preventing or delaying the onset of inflammatory arthritis. METHODS: The study aimed to recruit 206 male or female subjects from the secondary care hospital setting across the UK and the Netherlands. Participants who were at least 18 years old, who reported inflammatory sounding joint pain (clinically suspicious arthralgia) and who were found to be positive for serum autoantibodies associated with rheumatoid arthritis (RA) were eligible for enrolment. All study subjects were randomly assigned to receive weekly injections of investigational medicinal product, either abatacept or placebo treatment over the course of a 52-week period. Participants were followed up for a further 52 weeks. The primary endpoint was defined as the time to development of at least three swollen joints or to the fulfilment of the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for RA using swollen but not tender joints, whichever endpoint was met first. In either case, swollen joints were confirmed by ultrasonography. Participants, care givers, and those assessing the outcomes were all blinded to group assignment. Clinical assessors and ultrasonographers were also blinded to each other's assessments for the duration of the study. CONCLUSIONS: There is limited experience of the design and implementation of trials for the prevention of inflammatory joint diseases. We discuss the rationale behind choice and duration of treatment and the challenges associated with defining the "at risk" state and offer pragmatic solutions in the protocol to enrolling subjects at risk of RA. TRIAL REGISTRATION: Current Controlled Trials, ID: ISRCTN46017566 . Registered on 4 July 2014.

Comment on "Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis".

The link between rheumatoid arthritis and exposure to a bacterial toxin was not found in a population of rheumatoid arthritis patients from Netherlands.

A multi-biomarker score measures rheumatoid arthritis disease activity in the BeSt study.

OBJECTIVE: To evaluate a multi-biomarker disease activity (MBDA) score, a novel index based on 12 serum proteins, as a tool to guide management of RA patients. METHODS: A total of 125 patients with RA from the Behandel Strategieën study were studied. Clinical data and serum samples were available from 179 visits, 91 at baseline and 88 at year 1. In each serum sample, 12 biomarkers were measured by quantitative multiplex immunoassays and the concentrations were used as input to a pre-specified algorithm to calculate MBDA scores. RESULTS: MBDA scores had significant correlation with DAS28-ESR (Spearman's ρ = 0.66, P < 0.0001) and also correlated with simplified disease activity index, clinical disease activity index and HAQ Disability Index (all P < 0.0001). Changes in MBDA between baseline and year 1 were also correlated with changes in DAS28-ESR (ρ = 0.55, P < 0.0001). Groups stratified by European League Against Rheumatism disease activity (DAS28-ESR ≤ 3.2, 3.2-5.1 and > 5.1) had significantly different MBDA scores (P < 0.0001) and MBDA score could discriminate ACR/EULAR Boolean remission with an area under the receiver operating characteristic curve of 0.83 (P < 0.0001). CONCLUSION: The MBDA score reflects current clinical disease activity and can track changes in disease activity over time.

Application of the 2010 ACR/EULAR classification criteria in patients with very early inflammatory arthritis: analysis of sensitivity, specificity and predictive values in the SAVE study cohort.

OBJECTIVE: Performance of the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) rheumatoid arthritis (RA) criteria was analysed in an internationally recruited early arthritis cohort (≤16 weeks symptom duration) enrolled in the 'Stop-Arthritis-Very-Early' trial. This sample includes patients with a variety of diseases diagnosed during follow-up. METHODS: Two endpoints were defined: Investigators' diagnosis and disease-modifying antirheumatic drug (DMARD) treatment start during the 12-month follow-up. The 2010 criteria were applied to score Patients' baseline data. Sensitivity, specificity, predictive values and areas under the receiver operating curves of this scoring with respect to both endpoints were calculated and compared to the 1987 criteria. The optimum level of agreement between the endpoints and the 2010 classification score ways estimated by Cohen's Ï° coefficients. RESULTS: 303 patients had 12-months follow-up. Positive predictive values of the 2010 criteria were 0.68 and 0.71 for RA-diagnosis and DMARD-start, respectively. Sensitivity for RA-diagnosis was 0.85, for DMARD-start 0.8, whereas the 1987 criteria's sensitivities were 0.65 and 0.55. The areas under the receiver operating curves of the 2010 criteria for RA-diagnosis and DMARD-start were 0.83 and 0.78. Analysis of inter-rater-agreement using Cohen's Ï° demonstrated the highest Ï° values (0.5 for RA-diagnosis and 0.43 for DMARD-start) for the score of 6. CONCLUSIONS: In this international very early arthritis cohort predictive and discriminative abilities of the 2010 ACR/EULAR classification criteria were satisfactory and substantially superior to the 'old' 1987 classification criteria. This easier classification of RA in early stages will allow targeting truly early disease stages with appropriate therapy.

The Stop Arthritis Very Early (SAVE) trial, an international multicentre, randomised, double-blind, placebo-controlled trial on glucocorticoids in very early arthritis.

BACKGROUND: Glucocorticoids (GCs) are often used as early arthritis treatment and it has been suggested that they induce remission or at least delay the development of rheumatoid arthritis (RA) and the need to start disease-modifying antirheumatic drugs (DMARDs). OBJECTIVE: To test the effect of GCs on patients with very early arthritis (symptom duration of <16 weeks) in a randomised controlled trial. METHODS: Patients received a single intramuscular injection of 120 mg methylprednisolone or placebo (PL) and were followed up for 52 weeks. Primary end point was drug-free clinical remission, both at weeks 12 and 52. Among secondary outcomes were fulfillment of remission criteria at weeks 2, 12 or 52, time course of 'core set variables' and proportion of patients starting DMARDs. RESULTS: 17.0% of all analysed subjects (65/383) achieved persistent remission: 17.8% (33/185) of the PL group, 16.2% (32/198) of the patients receiving methylprednisolone (OR=1.13, 95% CI 0.66 to 1.92, p=0.6847). Analyses of secondary end points showed significant clinical benefits of the GC only at week 2. These differences subsequently disappeared. DMARDs were started in 162 patients: 50.3% methylprednisolone and 56.7% PL patients had to start DMARD treatment (OR=0.78, 95% CI 0.49 to 1.22, p=0.30). Significantly more patients with polyarthritis than with oligoarthritis received DMARDs (OR=2.84, 95% CI 1.75 to 4.60, p<0.0001). CONCLUSIONS: Neither remission nor development of RA is delayed by GC treatment. Remission is rare in the first year of very early arthritis, occurring in <20% of the patients. Also, the need to start DMARDs was not influenced by GC treatment.

The prognostic value of baseline erosions in undifferentiated arthritis.

INTRODUCTION: Undifferentiated arthritis (UA) has a variable disease course; 40 to 50% of UA patients remit spontaneously, while 30% develop rheumatoid arthritis (RA). Identifying the UA patients who will develop RA is essential to initiate early disease-modifying anti-rheumatic drug (DMARD) therapy. Although the presence of bone erosions at baseline is predictive for a severe destructive disease course in RA, the prognostic importance of erosive joints for disease outcome in UA is unknown. This study evaluates the predictive value of erosive joints for the disease outcome in UA as measured by RA development and disease persistency. METHODS: Baseline hands and feet radiographs of 518 UA patients were evaluated for erosions using a clinical definition as well as the Sharp/van der Heijde method. After 1 year follow-up, patients were re-assessed for the fulfillment of the 1987 ACR classification criteria for RA. Disease persistency was defined as the absence of sustained remission during all available follow-up (mean 8 +/- 3 years). RESULTS: At baseline, 28.6% of UA patients had erosive joints. Presence of > or = 2 erosive joints showed a positive predictive value for RA development of 53% and for persistent disease of 68%. Patients with erosions that did not develop RA were less often anticyclic citrullinated peptide antibody (ACPA)+ve, rheumatoid factor (RF)+ve and had lower C-reactive protein (CRP), erythrocytic sedimentation rate (ESR) and number of swollen joints compared to those who developed RA. Feet erosions are equally predictive compared to erosions at hands. CONCLUSIONS: Presence of > or = 2 erosive joints at baseline in UA patients gives a risk for RA development of 53% and for persistent disease of 68%, indicating that erosions in UA are not always predictive for unfavorable disease outcomes.

Enhanced concentrations of interleukin 16 are associated with joint destruction in patients with rheumatoid arthritis.

OBJECTIVE: To investigate the role of interleukin 16 (IL-16) in the development of rheumatoid arthritis (RA) and joint destruction. METHODS: We measured systemic IL-16 levels longitudinally in 39 patients with recent-onset RA, in 13 patients with initially undifferentiated arthritis who will develop RA over time, in 15 patients with undifferentiated arthritis, and in 12 healthy controls, and correlated the levels with joint damage and disease activity. Systemic IL-16 levels were measured by ELISA. Joint destruction was measured according to the Sharp method and the disease activity variables included C-reactive protein (CRP) and Disease Activity Score (DAS) measured at disease onset, and after one and 2 years of followup. RESULTS: A significantly increased IL-16 level in RA patients at disease onset [median (25th-75th percentile) 45.2 (37.7-82.4) pg/ml] was observed compared to both controls [30.4 (24.4-37.0) pg/ml, p = 0.0008], and to patients with undifferentiated arthritis [29.0 (21.5-52.4) pg/ml; p = 0.005]. The IL-16 levels of the patients who presented with undifferentiated arthritis but who developed RA over time were also increased [47.9 (34.5-108.2) pg/ml] compared to the controls (p = 0.004) and to the patients who over time remained diagnosed with undifferentiated arthritis (p = 0.01). We found that high IL-16 levels correlated positively with joint destruction during the 2-year followup (p = 0.02) and not with the disease activity variables. CONCLUSION: Our results suggest that the cytokine IL-16 plays a role in the disease process underlying RA and joint destruction.