All biologic agents approved for the treatment of rheumatoid arthritis (RA) have been tested versus methotrexate (MTX) for efficacy on damage progression in several randomized clinical trials (RCTs), but direct head-to-head comparisons have never been conducted. The purpose of this investigation is to analyse data coming from main RA RCTs and to perform an indirect comparison.
A systematic review of literature from 1988 to 2011 was conducted. Only randomized, double-blind, controlled, comparative trials, with evaluation of radiographic progression were included. The radiographic score was standardized and mean difference in the percentage of the annual radiographic progression rate was used as the effect measure. Heterogeneity between studies was estimated by I2 test. For each trial, the effect was plotted according to its standard error in a funnel plot.
Of 44 potentially relevant trials, 12 RCTs were included in the study. In order to optimize RCTs comparison, studies were stratified in early and late RA group. Main population characteristics were similar in both early and late RA groups, whereas the standardized baseline radiographic score value significantly differs among trials in both early (range 2.7–21.9) and late (range 23.46–75) RA groups. The standardized annual estimated progression is similar across the late RA group. Strong evidence of heterogeneity (I2 = 97%, p = 0.00001) but no asymmetry of the funnel plot was observed in the early RA group. Total mean difference was −16.28 (95% confidence interval [CI] −24.42 to −8.14). For the late RA group a random model was used (I2 = 99%, p = 0.00001) and a total mean difference of −39.25 (95% CI −53.77 to −24.73) was found.
All biologic agents provide a favourable effect on disease progression both in early and late RA. The significant heterogeneity among various RCTs did not allow an effective comparison of the performance of biologic agents in each study.
Rheumatoid arthritis; biologic therapy; radiographic progression; metaanalysis
Severity of rheumatoid arthritis and progression of radiographic joint damage have decreased over the last decades.
To examine whether this trend is attributable to an underlying trend towards milder disease or to improved treatment.
The study used an inception cohort of patients with early rheumatoid arthritis seen at the Wichita Arthritis Center, Wichita, Kansas, USA, since 1973 and monitored prospectively since their first clinic visit through clinical, radiographic, laboratory, demographic and self‐reported data. The radiographic disease progression in patients with disease onset in the 1970s, 1980s and 1990s was compared using a multivariate regression model for longitudinal data. The analysis was adjusted for differences in baseline predictors, type of disease‐modifying antirheumatic drugs (DMARDs) and steroid use.
418 patients with rheumatoid arthritis with radiographic follow‐up were included. Patients in earlier decades used fewer DMARDs, had longer disease durations and higher tender joint counts at their first visit. Other important predictors of disease progression did not differ significantly between decades of disease onset. The unadjusted rates of radiographic progression differed between decades (analysis of variance, p = 0.01), with a significant trend towards less radiographic progression in more recent times (trend, p<0.001). However, after adjusting for DMARD use, steroid use and baseline predictors, differences between decades vanished (analysis of variance, p = 0.40) and the trend towards less radiographic progression disappeared (trend, p = 0.45).
These results suggest that the observed trend towards milder disease in rheumatoid arthritis is attributable to more effective antirheumatic treatment and not to a secular trend.
Etanercept (ETN) is the first anti-tumor necrosis factor (TNF) agent to be approved for the treatment of rheumatoid arthritis (RA). Over the last 8 years, several clinical trials have shown its efficacy and safety in established and early RA, as well as a monotherapy or in combination with methotrexate. ETN not only reduces the signs and symptoms of RA, but also retards the progression of radiographic damage and improves the quality of life and function of patients. Its safety profile has been predictable since the first clinical trials with no new major safety concerns. Beyond its efficacy in RA, ETN is also indicated for the treatment of psoriatic arthritis. This current report reviews the evidence and the data in RA and psoriatic arthritis (PsA).
etanercept; tumor necrosis factor-α; rheumatoid arthritis; psoriatic arthritis
Radiographic progression in clinical trials is assessed by interpreting changes in total radiographic joint score, and the reliability of those scores depends on an evaluation of sum scores. It is not known how consistently changes in individual joints are identified by independent readers and in independent readings.
Patients and Methods:
7255 single joints from 178 patients who participated in the Trial of Etanercept and Methothrexate with Radiographic Patient Outcomes (TEMPO) trial were evaluated. Every image was independently scored twice according to the Sharp–van der Heijde method by two independent readers, so that four scores per joint were available. Absolute agreement and consistency of negative and positive erosion change scores across readers and readings were compared on a per-joint level, as well as on a per-patient level.
The number of joints showing a change for erosion was very low in this trial: 691/7255 analysed joints had at least one non-zero change score out of four readings. Absolute agreement between readings was remarkably poor: only 12 joints showed a consistently positive or negative change in all four readings. Change scores in opposite directions in the same joint across independent readings were rare (25 joints). Frequency of opposite joint scores in the same patient (mixed change patterns) was reader dependent.
Substantial intra and interreader disagreement in scoring change in individual joints is common. Opposite joint scores in the same patient, however, are rare and reader dependent. Notwithstanding these subtle inconsistencies on the individual joint level, the total Sharp score is a useful and discriminatory outcome measure.
Because an increasing number of clinical trials evaluating disease‐modifying antirheumatic drugs in rheumatoid arthritis (RA) emphasise radiographic outcomes as a primary outcome, using a reproducible radiographic measure should be placed at a premium.
To evaluate the reporting of radiographic methods in randomised trials assessing radiographic outcomes in RA.
Medline was searched for randomised controlled trials assessing radiographic outcomes published between January 1994 and December 2005 in general medical and specialty journals with a high impact factor. One reader extracted data (radiographic acquisition, assessment and reproducibility) using a standardised form.
A total of 46 reports were included in the analysis. The mean (SD) methodological quality scores on the Jadad scale (range 0–5) and the Delphi list (0–9) were 2.9 (1.2) and 6.4 (1.3), respectively. Use of a standardised procedure for the acquisition of the radiographs was reported in 2 (4.3%) articles. 2 (4.3%) reports indicated that the quality of the radiographs was evaluated. In 65.2% of the reports, ⩾2 radiographic scores were used. Reporting of radiographic assessment was well detailed for number of readers (91.3%), information on readers (71.7%), blinding (91.4%) and how films were viewed (74.0%). The reproducibility of the reading was reported in 39.1% of the articles.
The reporting of results of randomised controlled trials of radiographic outcomes in RA shows great variability in radiographic scores used. Reporting of radiographic methods could be improved upon, especially the acquisition procedure and the reproducibility of the reading.
Because an increasing number of clinical trials evaluating disease modifying anti-rheumatic drugs in rheumatoid arthritis (RA) emphasize radiographic outcomes as a primary outcome, using a reproducible radiographic measure should be placed at a premium. We aimed to evaluate the reporting of radiographic methods in randomized trials assessing radiographic outcomes in RA.
We searched MEDLINE for randomized controlled trials assessing radiographic outcomes published between January 1994 and December 2005 in general medical and specialty journals with a high impact factor. One reader extracted data (radiographic acquisition, assessment and reproducibility) using a standardized form.
A total of 46 reports were included in the analysis. The mean (SD) methodological quality scores on the Jadad scale (range 0–5) and the Delphi list (0–9) were 2.9 (1.2) and 6.4 (1.3), respectively. Use of a standardized procedure for the acquisition of the radiographs was reported in 2 articles (4.3%). Two reports (4.3%) indicated that the quality of the radiographs was evaluated. In 65.2% of the reports, 2 or more radiographic scores were used. Reporting of radiographic assessment was well detailed for number of readers (91.3%), information on readers (71.7%), blinding (91.4%) and how films were viewed (74.0%). The reproducibility of the reading was reported in 39.1% of the articles.
Our results highlight that the reporting of results of randomized controlled trials of radiographic outcomes in RA shows great variability in radiographic scores used and that reporting of radiographic methods could be improved upon, especially the acquisition procedure and the reproducibility of the reading.
Arthritis, Rheumatoid; drug therapy; radiography; Arthrography; methods; Clinical Competence; Foot Joints; radiography; Hand Joints; radiography; Humans; Periodicals; Randomized Controlled Trials; standards; Reproducibility of Results; Research Design; Treatment Outcome; rheumatoid arthritis, randomized controlled trials, reproducibility; radiographic acquisition; radiographic assessment
We studied rheumatoid arthritis (RA) patients with foot complaints to address the associations between clinical signs and symptoms, radiographic changes, and function in connection with disease duration. Secondly, we describe the contribution of several foot segments to the clinical presentation and function. In 30 RA patients with complaints of their feet, attributed to either signs of arthritis and/or radiographic damage, we compared radiographic, ultrasound, clinical, and functional parameters of the feet and ankle. Pain and swelling of the ankle were correlated weakly but statistically significantly with limitation and disability (0.273 to 0.293) as measured on the 5-Foot Function Index (FFI). The clinical signs of the forefoot joints did not influence any of the functional outcome measures. Radiographic scores for both forefeet (SvdH) and hindfeet (Larsen) were correlated with the total Health Assessment Questionnaire Disability Index (HAQ DI) and the 5-FFI limitation subscale. Pain and disease duration, more than radiographic damage, influence the total HAQ DI significantly. With the progression of time, structural damage and function of the rheumatic foot worsen in RA patients. Pain and swelling of the ankle contribute more to disability than radiographic damage of the foot and ankle.
Ankle; 5-FFI; Foot; Function; HAQ; Radiographic damage; Rheumatoid arthritis
In this study, we compare the health-related quality of life (HRQoL) of patients with moderate-to-severe rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS), and study the effect of treatment with infliximab on the HRQoL of patients with these diseases. Short Form Health Survey-36 (SF-36) data from the placebo-controlled phases of 4 studies of infliximab in patients with inflammatory rheumatic diseases (n = 1990) were evaluated. Data came from the Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) (n = 428), the Safety Trial for Rheumatoid Arthritis with REMICADE Therapy (START) (n = 1083), the Ankylosing Spondylitis Study for the Evaluation of Recombinant Infliximab Therapy (ASSERT) (n = 279), and the Infliximab Multinational Psoriatic Arthritis Clinical Trial II (IMPACT II) (n = 200). SF-36 assessments were made at weeks 0, 10, 30, and 54 in ATTRACT, weeks 0, 6, and 22 in START, weeks 0, 12, and 24 in ASSERT, and weeks 0 and 14 in IMPACT II. All patient populations had significantly impaired physical aspects of HRQoL at baseline relative to the general population of the United States, and the magnitude of impairment was similar across the diseases. Mean baseline physical component summary scores were 29 in the RA cohort, 32 in the PsA cohort, and 29 in the AS cohort. In all 3 diseases, patients who received infliximab showed significant improvement in physical component summary scores compared with those who received placebo. The magnitude of the difference of improvement (effect size, 95%CI) between infliximab and placebo groups was similar in the AS (10.1, 9.2–11.0), PsA (8.6, 7.8–9.4), and RA (10.1, 9.2–11.0) cohorts. Patients with RA and those with PsA treated with infliximab also showed greater improvement in the mental component summary score than those in the placebo group with an effect size of 4.6 (4.2–5.1) in RA and 2.7 (2.4–3.1) in PsA. Patients in large randomized controlled studies of infliximab in RA, PsA, and AS had similar impairment in physical aspects of HRQoL at baseline and showed significantly greater improvement in HRQoL after treatment with infliximab.
Several health authorities have recently revised the indication of infliximab (IFX) to include the treatment of early rheumatoid arthritis (RA). The aim of this systematic review of the literature was to appraise the efficacy, safety, and cost-effectiveness of early therapy with IFX.
We identified published clinical trials from 1966 to May 2006. We included randomized clinical trials (RCTs) in RA with disease duration of less than 3 years comparing the treatment of methotrexate-IFX (MTX-IFX) with methotrexate-placebo (MTX-placebo).
A total of 8 studies met inclusion criteria. Three studies reported redundant data regarding the vdH Sharp Score. Out of the 5 remaining studies, 4 analyzed structural joint destruction (vdH Sharp Score) and demonstrated a significant reduction in radiographic damage progression in favor of the combination of MTX-IFX compared with MTX-placebo (−4.1 vdH Sharp Score units (95% CI: 3.5; 4.6). Three studies also displayed a benefit of MTX-IFX on functional outcomes of RA (HAQ score) and disease activity measures (DAS, ACR response criteria), although less markedly.
Although data might be skewed because of only 2 existing large studies with concordant data, results from RCTs demonstrate improved efficacy of the combination MTX-IFX compared with MTX-placebo in early RA. However, many early RA patients probably do not require the addition of IFX to achieve a satisfying clinical and radiological course. So far, no evidence has established the superiority of MTX-IFX over MTX-prednisone or other combinations of traditional disease-modifying anti-rheumatic agents.
rheumatoid arthritis; antirheumatic agents; infliximab
Observational studies have suggested that patients with rheumatoid arthritis (RA) who experience inadequate response to anti-tumour necrosis factor (anti-TNF) agents respond more favourably to rituximab (RTX) than to an alternative anti-TNF agent. However, the relative effectiveness of these agents on long-term outcomes, particularly in radiographic damage, remains unclear.
To compare the effectiveness of RTX against anti-TNF agents in preventing joint damage in patients with RA who have experienced inadequate response to at least one prior anti-TNF agent.
This is a prospective cohort study within the Swiss registry of patients with RA who discontinued at least one anti-TNF agent and subsequently received either RTX or an alternative anti-TNF agent. The primary outcome, progression of radiographic joint erosions (Ratingen erosion score)over time, and the secondary outcome, functional disability (Health Assessment Questionnaire Disability Index), were analysed using regression models for longitudinal data and adjusted for potential confounders.
Of the 371 patients included, 104 received RTX and 267 received an alternative anti-TNF agent. During the 2.6-year median follow-up period, the rates of Ratingen erosion score progression were similar between patients taking RTX and patients taking an alternative anti-TNF agent (p=0.67). The evolution of the Health Assessment Questionnaire score was statistically significantly better in the RTX group (p=0.016), but the magnitude of the effect was probably not clinically relevant.
This observational study suggests that RTX is as effective as an alternative anti-TNF agent in preventing erosions in patients with RA who have previously experienced inadequate response to anti-TNF agents.
Recent evidence has highlighted a major genetic contribution to radiographic damage in rheumatoid arthritis (RA). The objective of this study was to determine whether genetic variants in the loci for interleukin-1 (IL-1), IL-6, IL-10, protein tyrosine phosphatase N22 (PTPN22), and selenoprotein S are associated with radiographic damage.
Modified Larsen scores of radiographic damage were determined in a cross-sectional population of patients with RA (n = 964). Rheumatoid factor (RF) and anti–cyclic citrullinated peptide (anti-CCP) were also assayed. The Kruskal-Wallis nonparametric test was used to compare median radiographic damage scores across genotype groups, followed by the Cuzick nonparametric test for trend to assess gene-dose effects.
An allele-dose association of IL-6 −174G with increasing radiographic damage was present (P = 0.005), but only in patients who were RF positive (P = 0.004) or anti-CCP positive (P = 0.01). Patients with the IL-10 −592CC genotype had more extensive radiographic damage than did those with the AC or AA genotype (P = 0.006), but this was observed only among patients who were RF negative (P = 0.002) or anti-CCP negative (P = 0.002). However, RF status and anti-CCP status were not associated with the IL-6 or IL-10 genotype. No other genetic associations were detected, apart from a marginal association of PTPN22 +1858T with increased radiographic damage.
The reported associations of IL-6 −174G with high IL-6 production and IL-10 −592 with low IL-10 production and our own results support a role of genetically determined dysregulated cytokine production in disease severity. The lack of association of these genotypes with RF and anti-CCP antibody status suggests that they act downstream of autoantibody production. We conclude that IL-6 and IL-10 genotypes may be useful in predicting disease severity in autoantibody-positive and autoantibody-negative patients, respectively.
Objective: To identify variables that can predict a progressive outcome after one year of follow up in patients presenting with undifferentiated polyarthritis (UPA) at an early arthritis clinic.
Methods: New patients with arthritis in two or more joints of less than three years' duration were categorised at entry as UPA or as rheumatoid arthritis (RA) based on the clinical diagnosis of the rheumatologist. Outcome variables after one year were radiographic damage (Sharp/van der Heijde score) and functional status (Health Assessment Questionnaire: HAQ score). A progressive disease at one year was defined as radiographic progression ≥4, or one year radiographic damage ≥10, or HAQ score ≥1. The baseline variables of patients with UPA with a progressive or mild outcome were compared.
Results: 280 patients (70% women; median age 56 years (range 18–90), median duration of symptoms 3.5 months) were included. 203 (72%) patients were clinically diagnosed as having RA and 77 (27%) as having UPA. The group of patients with progressive UPA (n=32 (42%)) had a significantly higher mean age, prevalence of arthritis of the hands, and disease activity (DAS28) at the first visit compared with the patients of the mild UPA group (n=45 (58%)). The RA group had significantly more frequent serum IgM-RF positivity, higher mean disease activity (DAS28) and mean C reactive protein concentration, more frequent symmetric arthritis, and arthritis in more than three joint groups than the progressive UPA group. Six (19%) of the progressive UPA group versus eight (4%) of the RA group did not receive disease modifying antirheumatic drugs during the first year.
Conclusions: After one year of follow up, 32 (42%) of the patients with UPA had a progressive disease. A progressive outcome was associated with older age, higher disease activity, and arthritis of the hands at baseline. To avoid undertreatment of patients with UPA, treatment should be based on severity rather than on diagnosis.
The main aim of the study was to investigate the relationship between persistent disease activity and radiographic progression of joint damage in early rheumatoid arthritis (ERA).
Forty-eight patients with active ERA was assessed every 3 months for disease activity for 3 years. Radiographic damage was measured by the Sharp/van der Heijde method (SHS). The cumulative inflammatory burden was estimated by the time-integrated values (area under the curve-AUC) of Disease Activity Score 28 joint based on C-reactive protein (DAS28-CRP) in rapid progressors versus non-progressors. Bland and Altman's 95% limits of agreement method were used to estimate the smallest detectable difference (SDD) of radiographic progression. The relationship between clinical and laboratory predictors of radiographic progression and their interactions with time was analysed by logistic regression model.
After 3-years of follow-up, radiographic progression was observed in 54.2% (95%CI: 39.8% to 67.5%) of patients and SDD was 9.5 for total SHS. The percentage of patients with erosive disease increased from 33.3% at baseline to 76% at 36 months. The total SHS of the progressors worsened from a median (interquartile range) of 18.5 (15-20) at baseline to 38.5 (34-42) after 3 years (p < 0.0001) whereas non-progressors worsened from a median of 14.5 (13-20) at baseline to 22.5 (20-30) after 3 years (p < 0.001). In the regression model, time-integrated values of DAS28-CRP and anti-CCP positivity have the highest positive predictive value for progression (both at level of p < 0.0001). Radiographic progression was also predicted by a positive IgM-RF (p0.0009), and a high baseline joint damage (p = 0.0044).
These data indicate that the level of disease activity, as measured by time-integrated DAS28-CRP, anti-CCP and IgM-RF positivity and a high baseline joint damage, affects subsequent progression of radiographic damage in ERA.
There have been substantial advances in the treatment of rheumatoid arthritis in recent years. Traditional disease-modifying antirheumatic drugs (DMARDs) have been shown to have small effects on the progression of radiographic damage. This quantitative overview summarizes the evidence for biologic DMARDs and radiographic damage either alone or in combination with methotrexate. Two outcomes were used (standardized mean difference and odds of progression). A total of 21 trials were identified of which 18 had useable data. For biologic monotherapy, tocilizumab, adalimumab, and etanercept were significantly better than methotrexate, with tocilizumab ranking first in both outcomes while golimumab was ineffective in both outcomes. For a biologic in combination with methotrexate compared with methotrexate alone, most therapies studied (etanercept, adalimumab, infliximab, certolizumab, tocilizumab, and rituximab) were effective at slowing X-ray progression using either outcome, with infliximab ranking first in both outcomes. The exceptions to this were golimumab (no effect on standardized mean difference) and abatacept (no effect on odds of progression). This effect was additional to methotrexate; thus, the overall benefit is moderate to large in magnitude, which is clearly of major clinical significance for sufferers of rheumatoid arthritis and supports the use of biologic DMARDs in those with a poor disease prognosis.
rheumatoid; trials; meta-analysis; radiographs; biologic; disease-modifying antirheumatic drugs; DMARDs
Biologic agents used in the treatment of rheumatoid arthritis (RA) are able to reduce both disease activity and radiographic progression of joint disease. These drugs are directed against several proinflammatory cytokines (TNFα, IL-6, and IL-1) which are involved both in the pathogenesis of chronic inflammation and progression of joint structural damage and in systemic and local bone loss typically observed in RA. However, the role of biologic drugs in preventing bone loss in clinical practice has not yet clearly assessed. Many clinical studies showed a trend to a positive effect of biologic agents in preventing systemic bone loss observed in RA. Although the suppression of inflammation is the main goal in the treatment of RA and the anti-inflammatory effects of biologic drugs exert a positive effect on bone metabolism, the exact relationship between the prevention of bone loss and control of inflammation has not been clearly established, and if the available biologic drugs against TNFα, IL-1, and IL-6 can exert their effect on systemic and local bone loss also through a direct mechanism on bone cell metabolism is still to be clearly defined.
Markers of collagen type I (CTX‐1) and type II (CTX‐II) degradation, reflecting bone and cartilage breakdown, appear to predict long term radiographic progression in chronic persistent arthritis.
To analyse longitudinally whether changes in arthritis severity are linked to immediate changes in the level of CTX‐I and CTX‐II degradation.
CTX‐I and CTX‐II were measured in urine samples from 105 patients with early rheumatoid arthritis who had participated in the COBRA trial at baseline and at 3, 6, 9, and 12 months after the start of treatment. The course of the biomarkers over time was compared with the course of ESR, swollen and tender joint counts, and 28 joint disease activity score (DAS28), measured at the same time points, with adjustment for rheumatoid factor, treatment, and baseline radiographic damage, by generalised estimating equations (GEE) with first order autoregression.
GEE showed that CTX‐I was longitudinally associated with DAS28, but not with ESR, swollen joint count, or tender joint count. CTX‐II, however, was longitudinally associated with ESR, swollen joint count and DAS28, but not with tender joint count. The longitudinal association implies that an increase in the extent of arthritis is immediately followed by an increase in collagen type II degradation, and to a lesser extent collagen type I degradation.
Cartilage degradation as measured by CTX‐II and to a lesser extent bone degradation as measured by CTX‐I closely follows indices of arthritis. Clinically perceptible arthritis is responsible for immediate damage, which will become visible on plain x rays only much later.
rheumatoid arthritis; collagen type II; collagen type I; biomarkers
Whereas many patients respond quickly to treatment with tumour necrosis factor (TNF) inhibitors, some patients may experience significant but delayed responses.
To evaluate the clinical response between 12 and 24 weeks in subjects with rheumatoid arthritis from the Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes.
Clinical response was assessed at 24 weeks in 12-week non-responders, according to American College of Rheumatology (ACR) response criteria. The proportion of subjects who successfully maintained response to 52 weeks was analysed, as were radiographic outcomes.
Data from 682 subjects were included in the analysis. Non and partial responders in all three groups (etanercept, methotrexate and etanercept plus methotrexate) at week 12 showed an improvement in responses at week 24. Over 80% of the week 24 ACR20/50/70 responders in the etanercept plus methotrexate arm sustained their response to 52 weeks. In the etanercept arms, a delayed clinical response was not associated with increased radiographic progression at week 52.
A significant proportion of non and partial responders to etanercept with or without methotrexate therapy at week 12 achieved a good clinical response or improved their overall clinical response at week 24. Discontinuing TNF inhibitor therapy at 12 weeks may be premature in some rheumatoid arthritis patients.
To describe radiographic changes in African-Americans with rheumatoid arthritis (RA) from the CLEAR (Consortium for the Longitudinal Evaluation of African-Americans with Early Rheumatoid Arthritis) Registry, a multicenter observational study.
Self-declared African-American patients, were enrolled in CLEAR I, a longitudinal cohort of early RA (disease duration <2 years) from 2000 to 2005; or in CLEAR II, a cross-sectional cohort (any disease duration), from 2006 to the present. Demographic and clinical data were obtained, and sets of hand/wrist and foot radiographs were scored using the modified Sharp/van der Heijde scoring system.
A total of 357 and 418 patients, respectively, have been enrolled into CLEAR I and CLEAR II. We report here an interim analysis of radiographic severity in these patients. For the CLEAR I cohort, 294 patients had a mean radiographic score of 2.89 at the baseline visit; 32.0% showed either erosions (25.9%) or joint space narrowing (JSN) (19.4%). At the 36-month visit the mean score was 5.65; 44.2% had erosions, 41.5% JSN and 55.4% had either. Among those patients without radiographic damage at baseline, 18.9% had progressed at the 36-month visit, compared to 57.1% of those with baseline damage (p<0.0001). For the CLEAR II cohort, 167 patients with RA of any duration, 65.3% exhibited joint erosions, 65.3% JSN and 74.8% exhibited either. The mean radiographic score was 33.42.
This is the largest radiographic study of African American RA patients. Damage occurs early in the disease and is associated with radiographic progression at 3 years of disease duration. The CLEAR Registry will provide a valuable resource for future analyses of genetic, clinical, and environmental factors associated with radiographic severity of RA in African-Americans.
A review of literature revealed that, although the involvement of temporomandibular joint (TMJ) in rheumatoid arthritis (RA) patients is not uncommon, variation in presentation persist. Comparative studies of bony changes in the right and left TMJ with the right and left peripheral hand (Metacarpophalangeal-MCP)/wrist joints have not been done, to the best of our knowledge.
Materials and Methods:
In this cross-sectional study, the temporomandibular and hand (MCP) and wrist joints of fifteen rheumatoid arthritis patients were evaluated with questionnaires, clinical and lab assessment and radiographically using conventional radiographs and computed tomography. Students t-test was applied for the statistical analysis of the data obtained and a P value of 0.05 was considered as statistically significant.
Comparisons between the right TMJ with right MCP/wrist joint and left TMJ with left MCP/wrist joint did not reveal statistically significant results. Radiographically, flattening and erosions were the common manifestations. MCP joints were more affected than the wrist, but whenever the wrist was involved, it was more likely to be bilaterally affected.
Although the TMJ showed osseous changes of a higher grade than the hand (MCP) and wrist joints radiographically, it was observed that patients were more aware of the peripheral joint discomfort. There were no significant differences between TMJ and peripheral joints on both right and left sides.
Diagnostic imaging; hand joints; rheumatoid arthritis; temporomandibular joint
OBJECTIVE--To determine whether a polymorphism within the tumour necrosis factor alpha (TNF alpha) gene is associated with susceptibility to, or severity of, rheumatoid arthritis (RA). METHODS--Consecutive patients with recent onset RA were enrolled in a prospective trial. DNA was collected, disease activity was measured at presentation, and radiographic progression at three years was assessed. Typing of TNF alpha was by polymerase chain reaction and single stranded conformation polymorphism analysis. RESULTS--No association of TNF alpha alleles and susceptibility to, or severity of, RA was demonstrated. CONCLUSIONS--These results indicate that this TNF alpha polymorphism does not play a part in the genetic background of RA.
Neovascularization is observed in a spectrum of diseases such as solid tumors, diabetic retinopathy, and rheumatoid arthritis. It is also evident in rat collage-induced arthritis (CIA), an animal model with histologic, clinical, and radiographic manifestations resembling rheumatoid arthritis. To evaluate the effects of angioinhibition in CIA, Louvain rats were immunized with type II collagen to induce arthritis and then administered an angiogenesis inhibitor, AGM-1470, in an attempt to either prevent arthritis or suppress established disease. Using clinical and radiographic criteria, AGM-1470 prevented CIA and significantly suppressed established disease without evidence of immunosuppression. Histologic sections from control ankle joints manifested pannus and neovascularization, which were absent in experimental animals. This is the first study to investigate this novel agent in an autoimmune disease, and additional evaluation of this promising compound in other diseases that are potentially angiogenesis dependent, such as rheumatoid arthritis, might be warranted.
Given the inconsistency of remission definitions in rheumatoid arthritis (RA) trials, the goal of this American College of Rheumatology/European League Against Rheumatism committee was to define remission.
The committee instructed a working group that a new remission definition, among other requirements, needed to allow for little, if any, active clinical disease and to be defined using the core set of outcome measures for RA trials and that those in remission at one time needed to have a low risk of later worsening function or radiograph progression. Remission was to be defined using trial data for use in trials but needed to anticipate use in a practice setting.
The working group started by evaluating the thresholds for core set measures compatible with remission and determined that patient-reported outcomes contributed importantly to the ability of outcome assessment to distinguish more from less effective treatments. The group created a candidate group of remission definitions to test, including Boolean versions and widely used indexes. Testing how well these candidate definitions predicted later good outcomes, the group found that Disease Activity Score 28 thresholds for remission performed worse than Simplified Disease Activity Index/Clinical Disease Activity Index or Boolean versions. Also, persons with low Disease Activity Score 28 occasionally had high joint counts, which were incompatible with remission. The parent committee chose two definitions: one Boolean (patient had to have all of the following: tender joint count, swollen joint count ≤1, C reactive protein ≤1 mg/dl) and patient global assessment ≤1 (on a 0–10 scale) and one Simplified Disease Activity Index ≤3.3.
The American College of Rheumatology/European League Against Rheumatism has promulgated two new similar definitions of remission for RA trials.
Non-steroidal anti-inflammatory agents (NSAIDs) remain the mainstay of treatment for ankylosing spondylitis (AS) though one recent trial suggests that continuous as opposed to on-demand use may be superior in preventing progression of structural damage. One particular NSAID, which is a highly selective cyclo-oxygenase 2 inhibitor, etoricoxib, may be superior to standard NSAIDs for AS. Second-line agents typically used for rheumatoid arthritis appear to lack efficacy. Salazopyrin is only moderately effective in the subgroup of AS patients with concomitant peripheral arthritis and not in those with purely axial disease. A recent trial showed that there is no greater efficacy in patients presenting early in their disease course. Three anti-tumor necrosis factor alpha agents, infliximab, etanercept, and adalimumab, are now available for the treatment of AS, the latest being adalimumab. All possess similar clinical efficacy in phase III trials with response rates of about 60%. Imaging studies using magnetic resonance show substantial amelioration of inflammatory lesions in the spine and sacroiliac joints. There is as yet no evidence that any of these agents prevent progression of structural damage. One study that evaluated etanercept demonstrated no impact on damage progression. Increasing evidence points to the superiority of the two monoclonal antibodies, infliximab and adalimumab, over etanercept for the treatment of extra-articular manifestations typically seen in AS such as acute anterior uveitis and inflammatory bowel disease. All three agents can be used as monotherapy and concomitant methotrexate appears to offer no advantages although insufficient doses have been used to date. Future studies should target patients earlier in their disease course as well as those with adverse prognostic factors such as elevated serum metalloproteinase 3 levels and radiographic evidence of spinal ankylosis.
infliximab; etanercept; adalimumab; ankylosing spondylitis; NSAIDs
To incorporate a new trial design to examine clinical response, cytokine expression and joint imaging in patients with rheumatoid arthritis (RA) switching from etanercept to infliximab treatment.
A randomised, open‐label, clinical trial of 28 patients with an inadequate response to etanercept was conducted. Eligible patients received background methotrexate and were randomised 1:1 to discontinue etanercept and receive infliximab 3 mg/kg at weeks 0, 2, 6, 14 and 22, or to continue etanercept 25 mg twice weekly. Data were analysed for clinical response, serum biomarker levels, radiographic progression, MRI and adverse events.
At week 16, 62% of infliximab‐treated patients achieved American College of Rheumatology 20% criteria for improvement in RA (ACR20) responses compared with 29% of etanercept‐treated patients. A 30.8% decrease from baseline in Disease Activity Score 28 was observed in patients receiving infliximab, compared with a 16.0% decrease in patients receiving etanercept. ACR20 and American College of Rheumatology 50% criteria for improvement in RA responses correlated at least minimally with intracellular adhesion molecule‐1 and interleukin 8 in patients receiving infliximab. 38% of patients who were switched to infliximab showed reductions in Health Assessment Questionnaire scores (>0.4), compared with 0% of patients receiving etanercept. MRI analyses were inconclusive. Both drugs were well tolerated; 54% of infliximab‐treated patients and 50% of etanercept‐treated patients reported adverse events.
In this exploratory, open‐label trial (with single‐blind evaluator), patients were randomised to continue with etanercept or switch to infliximab. The small sample size of this hypothesis‐generating study was underpowered to show statistical differences between groups. There was a numerical trend favouring patients who switched to infliximab, therefore warranting further study with a more rigorous design.
To investigate the predictive value of the distribution of inflamed joints at first presentation for the severity of the disease course in rheumatoid arthritis (RA).
Of the 1009 consecutive patients included in the Leiden Early Arthritis Clinic (Leiden, The Netherlands), 285 patients fulfilled the American College of Rheumatology criteria for RA within 1 year of follow‐up. Of these, 28 patients achieved remission. Radiographs of hands and feet were scored according to the Sharp–van der Heijde method, and the 28 patients with the most destructive disease were selected. The distribution of inflamed joints of the patients with the extreme disease courses was compared. The association between the distribution of inflamed joints and the level of destruction of the joints of hands and feet in the whole group of patients with RA was assessed using regression analysis.
Comparison of patients with extreme disease courses using univariate and logistic regression analyses showed that arthritis of the large joints—in particular, the knee—was associated with severe RA. In the whole group of patients with RA, the total number of swollen joints and the presence of knee arthritis were associated independently with the level of destruction of the small joints. Patients with RA with knee arthritis had higher C reactive protein (CRP) levels than patients without knee arthritis, and investigating the distribution of inflamed joints together with other variables yielded the number of swollen joints, CRP, presence of anti‐cyclic citrullinated peptide antibodies and symptom duration as predictors for severity of RA.
Arthritis of large joints—in particular, the knee—at first presentation is associated with a destructive course of RA.