Johanna M. W. Hazes

The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide.

OBJECTIVEnSince modern treatment of rheumatoid arthritis (RA) is shifting toward aggressive antirheumatic therapy in an early phase of the disease, diagnostic tests with high specificity are desirable. A new serologic test (anti-cyclic citrullinated peptide [anti-CCP] enzyme-linked immunosorbent assay [ELISA]) was developed to determine the presence of antibodies directed toward citrullinated peptides, using a synthetic peptide designed for this purpose.nnnMETHODSnA cyclic peptide variant that contains deiminated arginine (citrulline) was designed and used as antigenic substrate in ELISA. Test parameters and diagnostic characteristics of the test were studied in patients with and without RA, in patients with various infectious diseases, and in a group of patients from an early arthritis clinic (EAC).nnnRESULTSnUsing prevalent RA and non-RA sera, the anti-CCP ELISA proved to be extremely specific (98%), with a reasonable sensitivity (68%). Also, in the EAC study group, the anti-CCP ELISA appeared to be highly specific for RA (96%). In comparison with the IgM rheumatoid factor (IgM-RF) ELISA, the anti-CCP ELISA had a significantly higher specificity (96% for CCP versus 91% for IgM-RF; P = 0.016) at optimal cut-off values. The sensitivity of both tests for RA was moderate: 48% and 54% for the anti-CCP ELISA and the IgM-RF ELISA, respectively (P = 0.36). Combination of the anti-CCP and the IgM-RF ELISAs resulted in a significantly higher positive predictive value of 91% (P = 0.013) and a slightly lower negative predictive value of 78% (P = 0.35) as compared with the use of the IgM-RF ELISA alone. The ability of the 2 tests performed at the first visit to predict erosive disease at 2 years of followup in RA patients was comparable (positive predictive value 91%).nnnCONCLUSIONnThe anti-CCP ELISA might be very useful for diagnostic and therapeutic strategies in RA of recent onset.

Early versus delayed treatment in patients with recent-onset rheumatoid arthritis: comparison of two cohorts who received different treatment strategies

PURPOSEnTo compare the effect of delayed and early treatment strategies on disease outcome in patients with rheumatoid arthritis.nnnSUBJECTS AND METHODSnBetween 1993 and 1995, 109 patients diagnosed with probable or definite rheumatoid arthritis of recent onset were initially treated with analgesics; if they had persistent active disease, they were treated subsequently with the disease-modifying drugs chloroquine or salazopyrine (delayed treatment). Between 1996 and 1998, similar patients (n = 97) were promptly treated with either chloroquine or salazopyrine (early treatment).nnnRESULTSnThe median lag to the initiation of disease-modifying treatment was 15 days in the early treatment group and 123 days in the delayed treatment group. There was less radiologic joint damage after 2 years in the early treatment group (median Sharp score, 3.5; 95% confidence interval [CI]: 1 to 7) compared with the delayed treatment group (median Sharp score, 10; 95% CI: 5 to 15; P <0.05). The median area under the curve of the 2-year disease activity score was lower in the early treatment group (64 units; 95% CI: 59 to 69 units) compared with the delayed treatment group (73 units; 95% CI: 69 to 77 units; P = 0.002).nnnCONCLUSIONnIn this nonrandomized comparison, early introduction of disease-modifying antirheumatic drugs was associated with a better disease outcome after 2 years.

Long-term course and outcome of functional capacity in rheumatoid arthritis: the effect of disease activity and radiologic damage over time.

OBJECTIVEnTo investigate the evolution of functional capacity, disease activity, and joint destruction over time in a 12-year prospective cohort of rheumatoid arthritis (RA) patients, and to study the relative contribution of disease activity and joint destruction to the loss of functional capacity.nnnMETHODSnOne hundred thirty-two female patients with recent-onset RA were assessed at 0, 3, 6, and 12 years of followup for functional capacity (Health Assessment Questionnaire [HAQ] score), disease activity (Disease Activity Score [DAS]), and joint destruction (Sharp score of radiologic damage).nnnRESULTSnThe Sharp score deteriorated steadily over time, while the HAQ score and DAS showed a variable course. The DAS correlated strongly with the HAQ score throughout the disease course. The correlation between the Sharp score and the HAQ score was weak at study start, but became strong after 12 years. After 12 years of followup, disease activity was the main determinant of the HAQ score when entered in a multivariate analysis.nnnCONCLUSIONnFunctional capacity is strongly influenced by disease activity throughout the course of RA. Even in longstanding RA, disease activity proves to be the main determinant of the HAQ score for functional capacity.

Sarcoid arthritis: clinical characteristics, diagnostic aspects, and risk factors

Objectives: (a) To describe the clinical characteristics of acute sarcoid arthritis and the diagnostic value of its presenting clinical features; (b) to evaluate whether disease onset is seasonal; and (c) to evaluate whether smoking behaviour or the presence of HLA class II alleles is a risk factor for the disease. Methods: 579 consecutive patients with recent onset arthritis who had been newly referred to a rheumatology outpatient clinic were included in a prospective cohort study. The presenting clinical features, the smoking behaviour, and the results of HLA-DQ and HLA-DR DNA typing of 55 patients with sarcoid arthritis, 524 patients with other arthritides of recent onset, and samples of the normal population were compared. Results: In all cases the disease showed a self limiting arthritis and overall good prognosis. The diagnostic ability of a combination of four clinical features—symmetrical ankle arthritis, symptoms of less than two months, age below 40 years, and erythema nodosum—was exceptionally high. When test positivity is defined as the presence of at least three of four criteria the set rendered a sensitivity of 93%, a specificity of 99%, a positive predictive value of 75%, and a negative predictive value of 99.7%. The disease clustered in the months March–July. The disease was negatively associated with smoking (odds ratio (OR) 0.09; 95% confidence interval (95% CI) 0.02 to 0.37) and positively associated with the presence of the DQ2 (DQB1*0201)-DR3 (DRB1*0301) haplotype (OR 12.33; 95% CI 5.97 to 25.48). Conclusion: The disease entity acute sarcoid arthritis has highly diagnostic clinical features. The seasonal clustering, the protective effect of smoking, and the association with specific HLA class II antigens support the hypothesis that it results from exposure of susceptible hosts to environmental agents through the lungs.

Limited efficacy of conventional DMARDs after initial methotrexate failure in patients with recent-onset rheumatoid arthritis treated according to the Disease Activity Score

Objectives: To determine the efficacy of subsequent disease modifying antirheumatic drug (DMARD) therapies after initial methotrexate (MTX) failure in patients with recent onset rheumatoid arthritis (RA), treated according to the DAS for 2 years. Methods: In groups 1 and 2 of the BeSt study, 244 RA patients were initially treated with MTX 15–25 mg/week. Patients who discontinued MTX because of insufficient clinical response (disease activity score, DAS >2.4) or toxicity were classified as “MTX failures.” In group 1, these patients switched to sulfasalazine (SSA), then leflunomide and finally to MTX + infliximab (IFX). In group 2, “MTX failures” added SSA to MTX, then hydroxychloroquine (HCQ), then prednisone, and eventually switched to MTX + IFX. “MTX successes” were patients who achieved a DAS ⩽2.4 after 2 years while still on MTX monotherapy. Total Sharp/van der Heijde score (TSS) progression from 0–2 years was assessed in “MTX failures” versus “MTX successes.” Results: After 2 years, 162/244 patients (66%) had discontinued MTX because of insufficient response or toxicity. Of these, 78% also failed on SSA (adding or switching), 87% subsequently failed on leflunomide (in group 1), and 64% on MTX + SSA + HCQ (in group 2). 34 of 48 patients (71%) in groups 1 and 2 were successfully treated with MTX + IFX. After 2 years, regardless of the “success” on subsequent DMARDs, “ MTX failures” had a median TSS progression of 3 units (mean 9) versus 1 unit (mean 3) in “MTX successes” (pu200a=u200a0.007). Conclusion: After failure on initial MTX, treatment with subsequent conventional DMARDs is unlikely to result in a DAS ⩽2.4 and allows progression of joint damage.

Efficacy of multidisciplinary team care programs in rheumatoid arthritis

OBJECTIVEnTo assess the efficacy of multidisciplinary team care programs in rheumatoid arthritis (RA).nnnMETHODSnData were obtained by a Medline and a manual search of the literature through January 1997. Both the design and analysis aspects of controlled trials were evaluated.nnnRESULTSnForty-two papers reporting on 35 clinical trials of multidisciplinary team care were initially identified. Fifteen trials had a controlled design, nine of which were randomized. Patient characteristics, interventions, end point measures, and presentation of the data varied widely among the controlled studies. In 12 trials, inpatient (n = 6) or outpatient (n = 6) multidisciplinary programs were compared with regular outpatient care. Inpatient programs (average duration, 10 to 28 days) had a direct favorable effect on disease activity, lasting up to 1 year. The effect of outpatient programs (average duration, 1 to 2 years) was less marked, with greater improvement of functional status at the end of the treatment program shown in one study. In three trials, inpatient multidisciplinary programs were compared with similar outpatient programs. One study showed that inpatient care was more effective, whereas in two studies similar results were obtained in both groups.nnnCONCLUSIONnFavorable effects on disease activity were seen in most trials comparing short inpatient team care with regular outpatient care. Proof of efficacy of prolonged outpatient team care is scanty. Results of trials comparing inpatient with outpatient team care remain inconclusive.

TNF blockade requires 1,25(OH)2D3 to control human Th17-mediated synovial inflammation

Objectives T helper 17 (Th17) cells from patients with early rheumatoid arthritis (RA) induce a proinflammatory feedback loop upon RA synovial fibroblast (RASF) interaction, including autocrine interleukin (IL)-17A production. A major challenge in medicine is how to control the pathogenic Th17 cell activity in human inflammatory autoimmune diseases. The objective of this study was to examine whether tumour necrosis factor (TNF) blockade and/or 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) controls Th17-mediated synovial inflammation. Methods Peripheral CD4+CD45RO+CCR6+ Th17 cells of patients with early RA, Th17–RASF cocultures and synovial biopsy specimens were cultured with or without 1,25(OH)2D3 and/or TNFα blockade. Intracellular cytokine expression was detected by flow cytometry. Cytokine and matrix metalloprotease (MMP) production was determined by ELISA. Results The authors show that the 1,25(OH)2D3, but not TNFα blockade, significantly suppressed autocrine IL-17A production in Th17–RASF and synovial biopsy cultures. Combining 1,25(OH)2D3 and TNFα blockade had a significant additive effect compared with single treatment in controlling synovial inflammation, indicated by a further reduction in IL-6, IL-8, MMP-1 and MMP-3 in Th17–RASF cocultures and IL-6 and IL-8 expression in cultures of RA synovial tissue. Conclusions These data show that TNF blockade does not suppress IL-17A and IL-22, which can be overcome by 1,25(OH)2D3. The combination of neutralising TNF activity and 1,25(OH)2D3 controls human Th17 activity and additively inhibits synovial inflammation. This indicates more valuable therapeutic potential of activation of Vitamin D receptorsignalling over current TNF neutralisation strategies in patients with RA and potentially other Th17-mediated inflammatory diseases.

Measurement of Morning Stiffness in Rheumatoid Arthritis Clinical Trials

OBJECTIVEnMorning stiffness (MS) is a common problem for patients with rheumatoid arthritis (RA). However the clinical evaluation of the symptom has proved to be difficult. The aim of the study was to determine the responsiveness of two methods for measuring MS.nnnMETHODSnData from an uncontrolled (n = 63) and a controlled study (n = 80) of inpatient multidisciplinary team care for RA were analyzed. MS was measured by its duration to maximum improvement and by its severity on a visual analog scale (VAS). The responsiveness of both assessment methods was computed by calculating effect sizes and t-statistics, and by receiver operating characteristic (ROC) curves with clinical improvement according to the definition of the American College of Rheumatology as an external criterion.nnnRESULTSnWith respect to the ability to detect a clinical improvement between admission and discharge in the uncontrolled study, and a difference in improvement between the treatment and the control group in the controlled study, the effect sizes and t-values of the VAS for severity of MS were consistently higher than those of the duration of MS. In contrast to the duration, the responsiveness of the VAS for MS compared favorably with the responsiveness of other endpoint measures. The ROC surface area of the VAS was higher than that of the duration.nnnCONCLUSIONnFor the evaluation of MS in RA clinical trials, the assessment of MS by a severity score is more responsive than one based on duration and compares favorably with the performance of other endpoint measures.

A comparison of three radiologic scoring systems for the long‐term assessment of rheumatoid arthritis: Findings of an ongoing prospective inception cohort study of 132 women followed up for a median of twelve years

OBJECTIVEnTo compare the sensitivity and efficiency of 3 different radiologic scoring systems in measuring radiologic progression of rheumatoid arthritis (RA) over a 12-year period.nnnMETHODSnRadiographs of the hands and feet of 112 RA patients were assessed at 0, 3, 6, and 12 years of disease duration using the Sharp score as modified by van der Heijde (SHS), the Sharp score with increased maximum scores (Sharp Max), and the Kellgren score. The sensitivity to change was tested using the standardized response mean (SRM); the efficiency was determined by calculating the number of patients needed to detect 50% difference in progression between 2 patient groups.nnnRESULTSnRadiologic abnormalities were steadily progressive irrespective of the scoring method used. In early disease, the SRM was significantly larger for the SHS and Kellgren scores compared with the Sharp Max score. In late disease, the Kellgren score was slightly more sensitive to change compared with the SHS and Sharp Max scores; the difference, however, did not reach significance. In erosive disease, the SRM was significantly larger for the Kellgren compared with the SHS and Sharp Max scores. The numbers of patients needed to detect a 50% difference during the 0-3-year followup period were 129, 138, and 124 for the SHS, the Sharp Max, and the Kellgren, respectively. The numbers of patients needed to detect a 50% difference during the 6-12-year followup period were 117, 121, and 104, respectively. The numbers of patients needed to detect a 50% difference during the 6-12-year followup in patients with erosive disease were 74, 78, and 68, respectively, for the 3 scores. The Kellgren required 33 minutes to score 10 sets of radiographs of the hands and feet; the SHS score took 55 minutes.nnnCONCLUSIONnThe Kellgren scoring system is the most efficient method for monitoring the radiologic progression of RA. The Kellgren and the SHS are equally sensitive to change early in the disease, whereas the Kellgren score becomes more sensitive to change late in the disease in patients with erosions.

Facilitators and Barriers to Adherence in the Initiation Phase of Disease-modifying Antirheumatic Drug (DMARD) Use in Patients with Arthritis Who Recently Started Their First DMARD Treatment

Objective. To explore themes associated with adherence in the initiation phase for first-time use of disease-modifying antirheumatic drugs (DMARD) in patients with inflammatory arthritis using focus groups and individual interviews. Methods. Thirty-three patients were interviewed in focus groups and individual interviews. Interviews were transcribed verbatim and imported into ATLAS.ti software (Scientific Software Development GmbH). Responses that included reasons for adherence or nonadherence in the initiation phase were extracted and coded by 2 coders separately. The 2 coders conferred until consensus on the codes was achieved. Codes were classified into overarching themes. Results. Five themes emerged: (1) symptom severity, (2) experiences with medication, (3) perceptions about medication and the illness, (4) information about medication, and (5) communication style and trust in the rheumatologist. Conclusion. Perceptions about medication and the communication style with, and trust in, the rheumatologist were mentioned the most in relation to starting DMARD. The rheumatologist plays a crucial role in influencing adherence behavior by addressing perceptions about medication, providing information, and establishing trust in the treatment plan.