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Biomedical subjects

F C Breedveld

Publications and source records attributed to F C Breedveld.

At least 55 records · Page 3Linked to original sources
PubMed2004

Long term high intensity exercise and damage of small joints in rheumatoid arthritis.

OBJECTIVE: To investigate the effect of long term high intensity weightbearing exercises on radiological damage of the joints of the hands and feet in patients with rheumatoid arthritis (RA). METHODS: Data of the 281 completers of a 2 year randomised controlled trial comparing the effects of usual care physical therapy (UC) with high intensity weightbearing exercises were analysed for the rate of radiological joint damage (Larsen score) of the hands and feet. Potential determinants of outcome were defined: disease activity, use of drugs, change in physical capacity and in bone mineral density, and attendance rate at exercise sessions. RESULTS: After 2 years, the 136 participants in high intensity weightbearing exercises developed significantly less radiological damage than the 145 participants in UC. The mean (SD) increase in damage was 3.5 (7.9) in the exercise group and 5.7 (10.2) in the UC group, p = 0.045. Separate analysis of the damage to the hands and feet suggests that this difference in rate of increase of damage is more pronounced in the joints of the feet than in the hands. The rate of damage was independently associated with less disease activity, less frequent use of glucocorticoids, and with an improvement in aerobic fitness. CONCLUSION: The progression of radiological joint damage of the hands and feet in patients with RA is not increased by long term high intensity weightbearing exercises. These exercises may have a protective effect on the joints of the feet.

Adult↗
PubMed2003

Validation of a novel satisfaction questionnaire for patients with rheumatoid arthritis receiving outpatient clinical nurse specialist care, inpatient care, or day patient team care.

OBJECTIVES: To develop and validate a questionnaire for measuring satisfaction with different forms of complex multidisciplinary care in patients with rheumatoid arthritis (RA). METHODS: The satisfaction questionnaire (score range 0-100) comprised 28 items covering 11 domains. Together with a visual analog scale (VAS, range 0-100) on overall satisfaction, the questionnaire was applied in 210 RA patients who participated in a randomized trial comparing 3 types of multidisciplinary care. RESULTS: The questionnaire was returned by 174 patients (83%). The questionnaire and VAS scores in the total group were 75 (SD 12) and 83 (SD 20), respectively. Reliability analysis showed Cronbach's alpha of the questionnaire was 0.91. Spearman's correlation coefficient between the satisfaction questionnaire score and VAS score was 0.58 (P < 0.01). Mean total satisfaction questionnaire scores were 72 (SD 9), 76 (SD 14), and 78 (SD 11), in the nurse specialist, inpatient and day patient groups, respectively (nurse specialist versus day patient, P = 0.004). Significant differences between nurse specialist and day patients were seen in the following domains: waiting time during the treatment, autonomy, coordination, non-financial access, and quality of general information (all P < 0.05). CONCLUSION: Overall, patients were highly satisfied with the multidisciplinary care they received. Major differences regarding the organization of care were reflected in the results of the questionnaire scores. The satisfaction questionnaire appears to be a useful instrument for measuring satisfaction with complex multidisciplinary care in RA patients.

Adult↗
PubMed2003

Association of the -2849 interleukin-10 promoter polymorphism with autoantibody production and joint destruction in rheumatoid arthritis.

OBJECTIVE: To analyze the -2849 A/G interleukin-10 (IL-10) promoter polymorphism, which is associated with high (AG/GG) and low (AA) IL-10 production, in a cohort of rheumatoid arthritis (RA) patients and controls in order to gain a better understanding of its role in the incidence and progression of RA. METHODS: Allele frequencies of the promoter polymorphism -2849 A/G and carriage rates were compared in 283 RA patients, 413 patients with other rheumatic diseases, and 1,220 healthy controls. The rate of joint damage and baseline levels of IgG and IgM rheumatoid factors and anti-citrullinated peptide antibodies were measured and were correlated with the IL-10 gene polymorphism. Furthermore, the correlation between the invasiveness of fibroblast-like synoviocytes (FLS) and the -2849 IL-10 genotype was tested. RESULTS: The IL-10 genotype was not associated with the incidence of RA, but instead, correlated with disease progression, as determined by the extent of joint destruction. A higher rate of joint destruction was observed in patients with the genotype associated with high IL-10 production. Since FLS are thought to be involved in joint destruction, we analyzed IL-10 genotypes in conjunction with FLS invasiveness. Although adenoviral gene transfer of IL-10 to FLS inhibited their invasiveness, no differences were observed in vitro in the FLS from RA patients who were -2849 non-G carriers compared with those who were G carriers. Instead, patients with the -2849 AG/GG genotype, which is associated with high IL-10 production, had higher autoantibody titers at baseline. CONCLUSION: The -2849 IL-10 promoter polymorphism is associated with autoantibody production and subsequent joint damage in RA.

Adult↗
PubMed2003

Discovery of distinctive gene expression profiles in rheumatoid synovium using cDNA microarray technology: evidence for the existence of multiple pathways of tissue destruction and repair.

Rheumatoid arthritis (RA) is a heterogeneous disease. We used cDNA microarray technology to subclassify RA patients and disclose disease pathways in rheumatoid synovium. Hierarchical clustering of gene expression data identified two main groups of tissues (RA-I and RA-II). A total of 121 genes were significantly higher expressed in the RA-I tissues, whereas 39 genes were overexpressed in the RA-II tissues. Among the 121 genes overexpressed in RA-I tissues, a relative majority of nine genes are located on chromosome 6p21.3. An interpretation of biological processes that take place revealed that the gene expression profile in RA-I tissues is indicative for an adaptive immune response. The RA-II group showed expression of genes suggestive for fibroblast dedifferentiation. Within the RA-I group, two subgroups could be distinguished; the RA-Ia group showed predominantly immune-related gene activity, while the RA-Ib group showed an additional higher activity of genes indicative for the classical pathway of complement activation. All tissues except the RA-Ia subgroup showed elevated expression of genes involved in tissue remodeling. These results confirm the heterogeneous nature of RA and suggest the existence of distinct pathogenic mechanisms that contribute to RA. The differences in expression profiles provide opportunities to stratify patients based on molecular criteria.

Arthritis, Rheumatoid↗
PubMed2003

Cartilage degradation and invasion by rheumatoid synovial fibroblasts is inhibited by gene transfer of TIMP-1 and TIMP-3.

Matrix metalloproteinases (MMPs) are believed to be pivotal enzymes in the invasion of articular cartilage by synovial tissue in rheumatoid arthritis (RA). Here, we investigated the effects of gene transfer of tissue inhibitors of metalloproteinases (TIMPs) on the invasiveness of RA synovial fibroblasts (RASF) in vitro and in vivo. Adenoviral vectors (Ad) were used for gene transfer. The effects of AdTIMP-1 and AdTIMP-3 gene transfer on matrix invasion were investigated in vitro in a transwell system. Cartilage invasion in vivo was studied in the SCID mouse co-implantation model for 60 days. In addition, the effects of AdTIMP-1 and AdTIMP-3 on cell proliferation were investigated. A significant reduction in invasiveness was demonstrated in vitro as well as in vivo in both the AdTIMP-1- and AdTIMP-3-transduced RASF compared with untransduced SF or SF that were transduced with control vectors. in vitro, the number of invading cells was reduced to 25% (P<0.001) in the AdTIMP-1-transduced cells and to 13% (P<0.0001) in the AdTIMP-3-transduced cells (% of untransduced cells). Cell proliferation was significantly inhibited by AdTIMP-3 and, less, by AdTIMP-1. In conclusion, overexpression of TIMP-1 and TIMP-3 by Ad gene transfer results in a marked reduction of the invasiveness of RASF in vitro and in the SCID mouse model. Apart from the inhibition of MMPs, a reduction in proliferation rate may contribute to this effect. These results suggest that overexpression of TIMPs, particularly TIMP-3 at the invasive front of pannus tissue, may provide a novel therapeutic strategy for inhibiting joint destruction in RA.

Adenoviridae↗
PubMed2003

Human IgG Fc-binding phage antibodies constructed from synovial fluid CD38+ B cells of patients with rheumatoid arthritis show the imprints of an antigen-dependent process of somatic hypermutation and clonal selection.

The persistent presence of rheumatoid factors (RFs) in the circulation is a characteristic phenomenon in patients with rheumatoid arthritis (RA). Recent data indicate that RFs associated with seropositive RA are derived from terminally differentiated CD20-, CD38+ plasma cells (PCs) present in synovial fluids of the inflamed joints. These cells were shown to secrete RFs actively and are thought to originate from germinal centre (GC)-like structures present in the inflamed synovium. To obtain a representative image of the structural properties of IgM and IgG RFs associated with RA, phage antibody display libraries were constructed from CD38+ PCs isolated from the inflamed joints of RF-seropositive patients with RA. Subsequently, human IgG Fc-binding monoclonal phage antibodies were selected and analysed. The data suggest that RA-associated RFs are encoded by a diverse set of VL and a more restricted set of VH regions. VH gene family usage of PC-derived IgM- and IgG-RFs was found to be restricted to the VH1 and 3 gene families, with a preference for VH3, and many different VL genes were shown to contribute to RF specificity. Clonally related VH as well as VL sequences were identified, based on the presence of identical CDR3 regions and shared somatic mutations. In this B cell selection process base-pair substitutions as well as deletions of triplets in CDR regions, leaving the transcripts in frame, were involved. Together, these data provide further evidence for an Ag-driven immune response in the terminal differentiation into RF-producing PCs in patients with RA, including expansion of clonally related B cells, selection and isotype switching, all hallmarks of a GC reaction.

ADP-ribosyl Cyclase↗
PubMed2003

A simplified disease activity index for rheumatoid arthritis for use in clinical practice.

OBJECTIVE: The objective of this study was to verify the usefulness of a simple disease activity index (SDAI) for rheumatoid arthritis (RA). METHODS: The SDAI is the numerical sum of five outcome parameters: tender and swollen joint count (based on a 28-joint assessment), patient and physician global assessment of disease activity [visual analogue scale (VAS) 0-10 cm] and level of C-reactive protein (mg/dl, normal <1 mg/dl). Analysis initially focused on MN301, one of the three phase III clinical trials of leflunomide, in order to assess possible correlations between the SDAI and the Health Assessment Questionnaire (HAQ) and Disease Activity Score 28 (DAS 28). Results were then compared with the other two trials, MN302 and US301. A total of 1839 patients were evaluated. At baseline, 6 and 12 months, the SDAI, DAS 28, American College of Rheumatology (ACR) response criteria and mean HAQ scores were determined for each patient and compared by linear regression for significant correlation. The SDAI was compared qualitatively to the ACR 20% at 3, 6 and 12 months. The index was further validated by comparing the SDAI with survey results obtained from rheumatologists' evaluations of disease activity in test cases. The survey results included defining categorical changes in the SDAI indicating major, minor or no improvement in disease activity in response to treatment. Changes in total Sharp score at 6 and 12 months of treatment were determined for each of these categories of the SDAI and for comparable categories of the DAS 28. RESULTS: The mean SDAI calculated for patients at baseline in study MN301 was 50.06 (range 25.10-96.10) and was, respectively, 50.55 (range 22.10-98.10) and 43.20 (range 12.90-78.20) in studies MN302 and US301. In all three trials, the SDAI was correlated with a high level of statistical significance to the DAS 28 and HAQ scores at baseline, endpoint and change at endpoint. Patients achieving the ACR 20, 50, 70 or 90% response showed proportionate changes in the SDAI. Analysis of surveyed physician responses showed a significant association between the perception of disease activity and the SDAI, as well as changes in the SDAI. Qualitative analysis of radiographic progression at 6 and 12 months for patients showing either major, minor or no improvement of the SDAI showed correspondingly larger increases of the total Sharp score at 12 months. CONCLUSION: The SDAI is a valid and sensitive assessment of disease activity and treatment response that is comparable with the DAS 28 and ACR response criteria; it is easy to calculate and therefore a viable tool for day-to-day clinical assessment of RA treatment. Overall results indicate that the SDAI has content, criterion and construct validity.

Aged↗
PubMed2003

Efficacy and safety of the fully human anti-tumour necrosis factor alpha monoclonal antibody adalimumab (D2E7) in DMARD refractory patients with rheumatoid arthritis: a 12 week, phase II study.

OBJECTIVES: To evaluate efficacy, dose response, safety, and tolerability of adalimumab (D2E7) in disease modifying antirheumatic drug (DMARD) refractory patients with longstanding, active rheumatoid arthritis (RA). METHODS: During a 12 week, double blind, placebo controlled study, 284 patients were randomly allocated to receive weekly subcutaneous injections of adalimumab 20 mg (n = 72), 40 mg (n = 70), or 80 mg (n = 72) or placebo (n = 70) without concomitant DMARDs. RESULTS: Adalimumab significantly improved the signs and symptoms of RA for all efficacy measures. ACR20 responses with adalimumab were significant at each assessment versus placebo (p</=0.01). Additionally, ACR responses with adalimumab were achieved more rapidly than with placebo, with 82/115 (71%) of the ultimate ACR20 response rate to adalimumab treatment achieved at week 2. At week 12, for adalimumab 20, 40, and 80 mg, ACR20 response rates were 50.7%, 57.1%, and 54.2%, respectively, versus 10.0% for placebo (p</=0.001 for all comparisons); ACR50 rates were 23.9%, 27.1%, and 19.4%, respectively, versus 1.4% for placebo (p</=0.001 for all comparisons); and ACR70 rates were 11.3%, 10.0%, and 8.3%, respectively, versus 0.0% for placebo (p</=0.05 for all comparisons). All adalimumab doses significantly improved all ACR core criteria at all assessments. The 40 mg and 80 mg doses provided similar benefit. Adalimumab at all doses was generally well tolerated, with only mild or moderate adverse events. Completion rates were 87% for adalimumab and 67% for placebo. CONCLUSIONS: Adalimumab given as monotreatment to patients with longstanding, severe RA refractory to traditional DMARDs produced a rapid, sustained response and was safe and well tolerated, with no dose limiting side effects.

Adalimumab↗
PubMed2003

Comparison of the responsiveness of the Harris Hip Score with generic measures for hip function in osteoarthritis of the hip.

OBJECTIVE: To compare responsiveness of the Harris Hip Score with generic measures (that is, the Short Form-36 (SF-36), and a test of walking speed and pain during walking) in patients with osteoarthritis (OA) of the hip. METHOD: The first 75 cases within the population of a randomised clinical trial on manual therapy and exercise therapy were selected for secondary analysis. Experienced (self reported) recovery by the patients after treatment (five weeks) was used as an external criterion for clinically relevant improvement. Responsiveness was evaluated by comparing responsiveness ratios and receiver operating characteristic curves. RESULTS: The responsiveness ratio for the Harris Hip Score was high (1.70) compared with walking speed (0.45), pain during walking (0.66), and the subscales of the SF-36-"bodily pain" (0.42) and "physical functioning" (0.36). The area under the curve also was highest for the Harris Hip Score (0.92) compared with walking speed (0.71), pain during walking (0.73), and the SF-36 subscales-bodily pain and physical functioning (both 0.66). CONCLUSION: The Harris Hip Score is more responsive than the test of walking speed, pain, and subscales for function of the SF-36 in patients with OA of the hip. The Harris Hip Score seems to be a suitable instrument to evaluate change in hip function in patients with OA of the hip.

Aged↗
PubMed2003

Matrix metalloproteinases-3, -8, -9 as markers of disease activity and joint damage progression in early rheumatoid arthritis.

OBJECTIVE: To analyse the relation between systemic levels of pro-MMP-3, -8, and -9 matrix metalloproteinase (MMP) activity in alpha(2) macroglobulin (alpha(2)M)/MMP complexes and the progression of joint destruction in patients with recent onset rheumatoid arthritis (RA). METHODS: 109 patients with RA of recent onset were entered into this longitudinal study. Patients were followed up for two years; clinical data, blood samples, and radiographs were obtained at baseline and at 1 and 2 years. Serum levels of MMPs were measured by sandwich ELISA and MMP activity assays. RESULTS: During the two years joint damage progressed from 0 to 10 (median Sharp score, p<0.001). Stable levels of pro-MMP-3 and a significant decrease in the levels of pro-MMP-8 and -9 and alpha(2)M/MMP complexes were seen throughout the two years. Regression analysis showed that serum pro-MMP-3 levels at disease onset were independently associated with the progression of joint damage (B=0.7, 95% CI 0.3 to 1.1, p=0.001). Based on the rate of joint destruction, patients were divided into two subgroups: patients with mild and severe joint damage progression. The pro-MMP-3 levels were significantly higher in the group with severe compared with mild disease at all times. Levels of pro-MMP-8 and -9 were decreased in both groups, whereas alpha(2)M/MMP complex levels decreased in the group with mild disease only. CONCLUSION: Serum levels of the MMPs studied are associated with disease activity, but serum pro-MMP-3 levels at the onset of disease are also predictive of joint damage progression.

Adult↗
PubMed2003

Cost effectiveness and cost utility analysis of multidisciplinary care in patients with rheumatoid arthritis: a randomised comparison of clinical nurse specialist care, inpatient team care, and day patient team care.

OBJECTIVE: To assess the relative cost effectiveness of clinical nurse specialist care, inpatient team care, and day patient team care. METHODS: Incremental cost effectiveness analysis and cost utility analysis, alongside a prospective randomised controlled trial with two year follow up. Included were patients with rheumatoid arthritis (RA) with increasing difficulty in performing activities of daily living over the previous six weeks. Quality of life and utility were assessed by the Rheumatoid Arthritis Quality of Life questionnaire, the Short Form-6D, a transformed rating scale, and the time tradeoff. A cost-price analysis was conducted to estimate the costs of inpatient and day patient hospitalisations. Other healthcare and non-healthcare costs were estimated from cost questionnaires. RESULTS: 210 patients with RA (75% female, median age 59 years) were included. Aggregated over the two year follow up period, no significant differences were found on the quality of life and utility instruments. The costs of the initial treatment were estimated at euro 200 for clinical nurse specialist care, euro 5000 for inpatient team care, and euro 4100 for day patient team care. Other healthcare costs and non-healthcare costs were not significantly different. The total societal costs did not differ significantly between inpatients and day patients, but were significantly lower for the clinical nurse specialist patients by at least euro 5400. CONCLUSIONS: Compared with inpatient and day patient team care, clinical nurse specialist care was shown to provide equivalent quality of life and utility, at lower costs. Therefore, for patients with health conditions that allow for any of the three types of care, the preferred treatment from a health-economic perspective is the care provided by the clinical nurse specialist.

Activities of Daily Living↗
PubMed2003

Diagnostic strategy for the assessment of rheumatoid vasculitis.

OBJECTIVE: To determine the clinical features associated with histologically proven rheumatoid vasculitis (HRV) and the additional diagnostic value of serological markers in an inception cohort of 81 patients with rheumatoid arthritis (RA) suspected of RV. METHODS: The presence and number of recently developed extra-articular manifestations (EAMs) and a weighted EAM score, as well as the levels of serological markers, were compared between 31 patients with RA with histologically proven vasculitis and 50 patients with RA in whom vasculitis could not be documented histologically. The following markers were evaluated: circulating immune complexes, complement components C3 and C4, class-specific rheumatoid factors (IgM RF, IgG RF, IgA RF), antineutrophil cytoplasmic antibodies, antinuclear antibodies, antiendothelial antibodies, circulating intercellular adhesion molecule-1 and -3, circulating vascular cell adhesion molecule and E-selectin, cellular fibronectin, von Willebrand factor antigen, and C reactive protein. The diagnostic value of these markers, in addition to the clinical features, was evaluated with logistic regression analysis. RESULTS: Peripheral neuropathy or purpura/petechiae, or both, were the most important clinical features to discriminate patients with RA with and without histologically proven RV. The presence of a high number of EAMs and a higher weighted EAM score in patients with RA suspected of vasculitis were also associated with an increased probability of histologically proven RV. After adjustment for EAMs, only the combination of an increased serum IgA RF level and a decreased serum C3 level appeared to make an additional contribution to the diagnosis histologically proven RV. Evidence of systemic vasculitis was found in a muscle biopsy of the rectus femoris in 9/14 (64%) patients with vasculitis with neuropathy and in 3/11 (27%) patients with purpura/petechiae and vasculitis of the skin. CONCLUSIONS: In the diagnostic process of RV the presence of peripheral neuropathy and/or purpura/petechiae or a high weighted EAM score will increase the probability of histologically proven RV. Of the circulating factors previously suggested to be markers for RV only IgA RF and C3 further increase the probability of histologically proven RV and may be useful to guide diagnostic decisions.

Aged↗
PubMed2003

Analysis of the cell infiltrate and expression of proinflammatory cytokines and matrix metalloproteinases in arthroscopic synovial biopsies: comparison with synovial samples from patients with end stage, destructive rheumatoid arthritis.

BACKGROUND: Synovial tissue (ST) from end stage destructive rheumatoid arthritis (RA) and arthroscopic biopsies obtained during active inflammation might exhibit different characteristics. OBJECTIVE: To define the cell infiltrate and the expression of proinflammatory cytokines, angiogenic factors, and matrix metalloproteinases (MMPs) in ST selected at arthroscopy compared with that from end stage RA. METHODS: Synovial biopsy specimens were obtained from the actively inflamed knee joints of 13 patients with chronic RA by arthroscopy and compared with ST from 10 patients with end stage, destructive RA. Immunohistological analysis was performed to detect T cells, plasma cells, macrophages, fibroblast-like synoviocytes (FLS), and the expression of interleukin (IL)1beta, IL6, tumour necrosis factor alpha (TNFalpha), MMP-1, MMP-3, MMP-13, TIMP-1, and VEGF. RESULTS: The expression of CD68+ macrophages was significantly higher in ST selected at arthroscopy than in samples obtained at surgery, both in the intimal lining layer and in the synovial sublining. The expression of CD3+ T cells also tended to be higher in arthroscopic samples. The expression of TNFalpha, IL6, MMP-1, MMP-3, MMP-13, TIMP-1, and VEGF was on average higher in ST obtained at arthroscopy. In contrast, the expression of IL1beta was on average higher in surgical samples. CONCLUSION: Active arthritis activity is associated with increased cell infiltration, expression of proinflammatory cytokines, MMPs, and angiogenic growth factors in synovial biopsy samples selected at arthroscopy. Increased expression of IL1beta in the synovium of patients with destructive RA requiring joint replacement may well reflect the important role of IL1beta in cartilage and bone destruction.

Adult↗
PubMed2003

TNF-alpha blockade and tuberculosis: better look before you leap.

According to several reports, the risk of active tuberculosis in patients who are latently infected with Mycobacterium tuberculosis is increased after treatment with tumour necrosis factor alpha (TNF)-blocking agents. These drugs have demonstrated effectiveness and are increasingly being used for treatment of several inflammatory diseases, including rheumatoid arthritis and Crohn's disease. Specialists prescribing TNF-blocking agents should be aware of the risk of tuberculosis and other infections, the unusual and severe clinical presentations and the available preventive measures. In this review, we will weigh currently available data on the risk of infection with intracellular pathogens and in particular tuberculosis in patients treated with TNF-blocking agents, discuss the role of TNF in the pathogenesis of tuberculosis and describe the risk profile of this complication. Awaiting further consensus protocols, a provisional flow chart is presented that is based on dinical parameters to provide a logical framework to reduce and minimise the risk of tuberculosis during TNF blockade.

Antibodies, Monoclonal↗
PubMed2002

Early and aggressive treatment of rheumatoid arthritis patients affects the association of HLA class II antigens with progression of joint damage.

OBJECTIVE: The presence of certain HLA class II antigens is strongly associated with the progression of joint destruction in rheumatoid arthritis (RA). Such antigens may be more effective than other class II antigens in inducing the formation of autoreactive T cells after presentation of (auto)antigens. We investigated whether early and aggressive treatment with disease-modifying antirheumatic drugs could modify this relationship. METHODS: We analyzed data from 2 studies of patients with early RA treated according to different strategies. The first study consisted of 2 cohorts, one (n = 109; median disease duration before treatment 4 months) was treated according to the pyramid strategy (initial nonsteroidal antiinflammatory drugs, followed by chloroquine [CQ] or sulfasalazine [SSZ] when necessary), and the other (n = 97; median disease duration before treatment 2 weeks) was immediately treated with CQ or SSZ. The second study comprised 155 patients (median disease duration 4 months) from the Combinatietherapie Bij Reumatoide Artritis (COBRA) trial, in which patients were randomly assigned to combination treatment with step-down prednisolone, methotrexate (MTX), and SSZ (n = 76) or with SSZ alone (n = 79). Prednisolone and MTX dosages were tapered and stopped after 28 and 40 weeks, respectively. The extent of joint damage was measured by the modified Sharp method. RESULTS: In the pyramid treatment cohort, the median increase in Sharp score after 2 years was 12 in patients positive for the shared epitope (SE) and 1 in SE- patients. In the immediate treatment cohort, the median increase was 3 in SE+ patients and 2 in SE- patients. In the SSZ group of the COBRA study, the median increase in Sharp score after 1 year was 11 in DR4+ patients and 3 in DR4- patients. In the combination treatment group, the median increase was 4 in DR4+ patients and 2 in DR4- patients. Significance was confirmed by multiple regression using log-transformed scores. CONCLUSION: Early and aggressive antirheumatic drug treatment affects the association of HLA class II alleles with progression of joint damage in RA.

Adult↗