M. van Krugten

TNF-308A and HLA–DR3 alleles contribute independently to susceptibility to systemic lupus erythematosus

OBJECTIVE To evaluate the respective contributions of tumor necrosis factor (TNF) promoter polymorphisms and HLA-DR alleles to susceptibility to systemic lupus erythematosus (SLE). METHODS TNF-238G/A and 308G/A promoter polymorphisms and HLA-DRB1 alleles were determined in 99 consecutive Caucasian SLE patients and 177 Caucasian controls. Standard and Mantel-Haenszel odds ratios were calculated to assess the magnitude of the susceptibility factors. The presence or absence of the SLE classification criteria was determined and correlated with the TNF promoter and HLA-DRB1 genotypes. RESULTS The frequency of the TNF-308A/A and 308G/A genotypes was significantly higher in SLE patients (odds ratio 5.0). Conversely, TNF-238G/A and 238A/A genotypes were equally prevalent in SLE patients and controls. The HLA-DR3 specificity (DRBI*0301 allele) was significantly more prevalent in the SLE population (odds ratio 4.4). Stratification to correct for interdependence of the 2 loci confirmed the association of both TNF-308A and HLA-DR3 with SLE (Mantel-Haenszel odds ratio 3.2 and 2.4, respectively). No correlation was found between TNF promoter and HLA-DRB1 genotypes and any SLE classification criterion or disease manifestation. CONCLUSION TNF-308A and HLA-DR3 alleles are independent susceptibility factors for SLE.

Allele-specific quantification of tumor necrosis factor alpha (TNF) transcription and the role of promoter polymorphisms in rheumatoid arthritis patients and healthy individuals.

Interindividual variation in the expression of tumor necrosis factor α (TNF) suggests the existence of functionally distinct TNF alleles that could play a role in susceptibility to TNF associated diseases such as rheumatoid arthritis (RA). To determine whether differential expression of TNF alleles exists, the relative contribution of TNF alleles in total TNF RNA production in peripheral blood mononuclear cells (PBMC) of healthy individuals and synovial tissue of RA patients was analyzed. By using a Tai I restriction fragment length polymorphism (RFLP) located at position +489 in the first intron of the gene, the relative contribution of each allele in precursor transcript production in heterozygous individuals could be measured. By means of this method we studied whether differences exist between TNF alleles in TNF pre-mRNA production. The relative contribution of TNF alleles to the non-spliced RNA pool was measured in PBMC of healthy individuals which were stimulated with LPS, PMA and anti-CD3 and anti-CD28 monoclonal antibodies for different time periods. Moreover, synovial biopsy material of RA patients was analyzed. The results of this study do not reveal a difference in the contribution of distinct TNF alleles in TNF pre-mRNA production upon in vitro and physiological stimulation conditions in healthy individuals and RA patients. Since some of the individuals whose PBMC were tested were also heterozygous for either −308, −1031, −863, −857 TNF promoter/enhancer single nucleotide polymorphisms (SNPs), the data argue against functional relevance of these TNF promoter/enhancer SNPs in the regulation of transcription. In conclusion, the data do not provide evidence for the existence of transcriptionally distinct TNF alleles to explain interindividual variation in TNF expression.

Randomised comparison of initial triple DMARD therapy with methotrexate monotherapy in combination with low-dose glucocorticoid bridging therapy; 1-year data of the tREACH trial

Objectives To compare 1-year clinical efficacy of (1) initial triple disease-modifying antirheumatic drug therapy (iTDT) with initial methotrexate (MTX) monotherapy (iMM) and (2) different glucocorticoid (GC) bridging therapies: oral versus a single intramuscular injection in early rheumatoid arthritis. Methods In a single-blinded randomised clinical trial patients were randomised into three arms: (A) iTDT (methotrexate+sulfasalazine+hydroxychloroquine) with GCs intramuscularly; (B) iTDT with an oral GC tapering scheme and (C) MTX with oral GCs similar to B. Primary outcomes were (1) area under the curve (AUC) of Health Assessment Questionnaire (HAQ) and Disease Activity Score (DAS) and (2) the proportion of patients with radiographic progression. Results 281 patients were randomly assigned to arms A (n=91), B (n=93) or C (n=97). The AUC DAS and HAQ were respectively −2.39 (95% CI −4.77 to −0.00) and −1.67 (95% CI −3.35 to 0.02) lower in patients receiving iTDT than in those receiving iMM. After 3 months, treatment failure occurred less often in the iTDT group, resulting in 40% fewer treatment intensifications. The difference in treatment intensifications between the arms required to maintain the predefined treatment goal remained over time. No differences were seen between the two GC bridging therapies. Respectively 21%, 24% and 23% of patients in arms A, B and C had radiographic progression after 1 year. Patients receiving iTDT had more adjustments of their medication owing to adverse events than those receiving iMM. Conclusions Treatment goals are attained more quickly and maintained with fewer treatment intensifications with iTDT than with iMM. However, no difference in radiographic progression is seen. Both GC bridging therapies are equally effective and, therefore, both can be used. Trial registration number ISRCTN26791028.

Association of the TNF +489 polymorphism with susceptibility and radiographic damage in rheumatoid arthritis

Multiple genetic factors contribute to susceptibility to rheumatoid arthritis (RA). The extent of variability in disease presentation in RA may be related to genetic heterogeneity. In this study we investigated the association of the TNF gene polymorphism at position +489 with susceptibility to and severity of RA. Analysis of the frequency of the +489 A and G alleles in a group of 293 consecutive RA patients and 138 healthy controls revealed a significant decrease of the A allele. The +489 GA patients had a 3.9 times decreased chance of having erosive disease than +489 GG patients. These results were confirmed in a prospective study using a cohort of 112 patients who were followed for 12 years. The progression rate of the erosion score over 12 years expressed as Sharp score for X-rays of hands and feet was 3.4 per year for the GA-genotyped patients and 12.1 for the GG-genotyped patients. These associations were independent of rheumatoid factor and HLA-shared epitope positivity. In conclusion, these data suggest that the intron TNF +489 polymorphism is associated with susceptibility to and disease severity of RA independently of HLA-shared epitope-positive alleles.

Treatment with TNF-α inhibitor infliximab might reduce hand osteoarthritis in patients with rheumatoid arthritis

OBJECTIVES To investigate the association between systemic and local inflammation and incident and progressive radiographic secondary osteoarthritis (OA) in interphalangeal joints (IPJs) over 3 years in rheumatoid arthritis (RA) patients and the effect of tumor necrosis factor alpha (TNF-α) inhibitor infliximab on secondary OA in IPJs. METHODS In the present observational longitudinal study baseline and 3-year hand X-rays of 416 recent-onset RA patients were scored for osteophytes and erosions in IPJs, blinded for time, using Osteoarthritis Research Society International atlas and Sharp-van der Heijde score. The associations between inflammatory factors and incident and progressive secondary OA in distal IPJs (DIPJs) and proximal IPJs (PIPJs) and the effect of infliximab compared to disease-modifying anti-rheumatic drug treatment on secondary OA were analyzed by multivariable regression and generalised estimating equations analyses. RESULTS Sixty-seven percent of the patients were female with, at baseline, a mean age of 54 years and OA present in DIPJs and PIPJs in 37% and 13%. Three years later, new secondary OA in DIPJs and PIPJs was seen in 11% and 10%, and progressive secondary OA in 36% and 35%. High erythrocyte sedimentation rate over 3 years and progressive erosive damage were risk factors for incident secondary OA in DIPJs, but not in PIPJs. At joint level, progression of erosions was associated with both incident and progressive secondary OA, only in DIPJs. Infliximab treatment was associated with lower incident secondary OA in PIPJs [relative risk 0.5 (95% confidence interval 0.2, 1.0)], independent of decrease in inflammation. CONCLUSION Incident and progressive secondary OA in DIPJs over 3 years was associated with high inflammatory activity in RA. Infliximab treatment reduced incident secondary OA in PIPJs independent of decrease in inflammation, suggesting that anti-TNF-α therapy might be effective against secondary hand OA via other pathways than suppression of inflammation. Further studies in populations of primary hand OA are necessary to determine the role of anti-TNF-α in treatment of primary hand OA.

Probability of continued low disease activity in patients with recent onset rheumatoid arthritis treated according to the disease activity score

Objective: To assess the duration and the probability of maintaining low disease activity once a low disease activity score (DAS) is achieved in recent onset rheumatoid arthritis (RA) patients. Methods: The BeSt study is a randomised trial comparing four different treatment strategies in patients with recent onset, active RA. Treatment adjustments were mandatory as long as the DAS was >2.4. If the DAS was ⩽2.4, treatment was continued and after 6 months, tapered to maintenance dose. We analysed thrice-monthly DAS calculations in order to assess the duration and the probability of maintaining a DAS ⩽2.4. Results: Patients treated with initial combination therapy achieved a DAS ⩽2.4 significantly earlier than patients treated with initial monotherapy. Independent of treatment strategy and without treatment adjustments, the probability of a next DAS ⩽2.4 3 months after a first DAS ⩽2.4 was 74%. The probability increased to 85% after two preceding DAS ⩽2.4 and to 88–97% after one to two preceding DAS<1.6. The median duration of a DAS ⩽2.4 was 12 months. Conclusion: Once recent onset RA patients achieve a low DAS, the probability of maintaining a low DAS without treatment adjustments is high. This may have implications for the monitoring of patients in daily practice.

Insights in the relationship of joint space narrowing versus erosive joint damage and physical functioning of patients with RA

Objective To evaluate the contribution of joint space narrowing (JSN) and erosions in general and in four different joint groups in relation to physical disability in rheumatoid arthritis (RA). Methods 5-year follow-up data from the Behandel Strategieën (BeSt) trial were used, where 508 patients with recent onset RA were treated aiming at a disease activity score ≤2.4. Joint damage was assessed annually and scored according to the Sharp-van der Heijde method. Physical disability was measured 3-monthly with the Health Assessment Questionnaire (HAQ). Generalised Estimating Equations analyses were performed to assess the relationship between the HAQ and JSN scores and erosions scores, separately and in joint groups. Results Overall, damage scores were low, and neither total JSN nor erosions showed a significant effect on HAQ (β=0.001 95% CI −0.003 to 0.004 and β=0.002 95% CI −0.001 to 0.006, respectively). Of the total damage scores per joint group, damage in the wrist shows a trend for association with physical disability displaying the largest effect size (β=0.005 95% CI 0.000 to 0.011). Also in the analysis with erosions per joint group, the wrist was most strongly related with physical functioning (β=0.016 95% CI 0.003 to 0.029); in the analysis with JSN per joint group no joint group was significantly related to the HAQ. Analysis of all erosion and narrowing scores per joint group in one model reveals only erosions in the wrist to be independently associated with impaired physical functioning (β=0.017 95% CI 0.003 to 0.030). Conclusions Joint damage in the wrist, erosions more than JSN, is associated with impaired physical functioning even in patients with early RA with limited overall damage after 5 years tightly controlled treatment.

Tapering conventional synthetic DMARDs in patients with early arthritis in sustained remission: 2-year follow-up of the tREACH trial

Objectives With early and intensive treatment many patients with early RA attain remission. Aims were to investigate (1) the frequency and time to sustained remission and subsequent tapering in patients initially treated with conventional synthetic disease modifying anti-rheumatic drug ((cs)DMARD) strategies and (2) the frequency and time to flare and regained remission in patients tapering csDMARDs and biological (b)DMARDs during 2 years of follow-up. Methods Two-year follow-up data from the treatment in the Rotterdam Early Arthritis Cohort (tREACH) cohort were used. Patients were randomised to initial treatment with triple DMARD therapy (iTDT) with glucocorticoid (GC) bridging or methotrexate monotherapy (iMM) with GC bridging. Patients were evaluated every 3 months. In case Disease Activity Score (DAS) was >2.4 treatment was switched to a TNF-blocker. In case DAS<1.6 at 2 consecutive time points, tapering was initiated according to protocol. Outcomes were rates of sustained remission (DAS<1.6 at 2 consecutive time points), flare (medication increase after tapering) and remission after flare (DAS<1.6). Data were analysed using Kaplan-Meier analyses. Results During 2 years of follow-up, sustained remission was achieved at least once by 159 (57%) of patients, of whom 118 and 23 patients initiated tapering of csDMARDs and bDMARDs, respectively. Thirty-four patients achieved drug-free remission. Flare rates were 41% and 37% and within 1 year, respectively. After flare, 65% of patients tapering csDMARDs re-achieved remission within 6 months after treatment intensification. Conclusions Regardless of initial treatment strategy, 57% of patients achieved sustained remission during 2 years of follow-up. Flare rates were 41% and 37% within 12 months in patients tapering csDMARDs and bDMARDs, respectively. Trial registration number ISRCTN26791028; Post-results.

OP0154 Clinical and radiological outcomes of four disease activity driven treatment strategies: 8-year results of the best study:

Objectives To compare clinical and radiological outcomes of 8 years targeted treatment with four treatment strategies in recent onset rheumatoid arthritis (RA) patients. Methods Patients (n=508) with recent onset RA were randomized to 4 treatment strategies: 1. sequential monotherapy, 2. step-up combination therapy, 3. initial combination with prednisone, 4. initial combination with infliximab. Treatment was DAS≤2.4 steered, with measurements every three months: DAS >2.4: next treatment step; DAS ≤2.4 during ≥6 months: taper to maintenance dose, next if DAS <1.6 during ≥6 months: stop anti-rheumatic treatment. Functional ability, measured with the Health Assessment Questionnaire (HAQ), was analyzed with a linear mixed model with time, treatment and time*treatment as independent variables. Radiographs of baseline and years 1-8 were scored with the Sharp/vd Heijde Score (SHS), blinded for patient identity and in random order, to asses radiological damage progression. Results After 8 years, 347 patients were still in follow-up. A DAS ≤2.4 was achieved in 79% of these and 52% were in remission (DAS <1.6), without differences between the treatment groups (table). 18, 19, 17 and 15% of the patients in groups 1-4 were in drug-free remission with a median (mean) duration of 45 (39) months. Six patients lost and 12 patients achieved drug-free remission in year 8, while 8 patients with prolonged drug-free remission dropped out. After initial differences in years 1 and 2 between the 4 groups, yearly radiological damage progression rates were low and similar between all groups, reflecting the efficacy of DAS-steered therapy. Median (mean) total damage progression after 8 years was 3 (11) points SHS (n.s. between groups). Patients in sustained drug-free remission had a mean SHS progression of 0.1 (median (IQR) 0 (0-0.03)) per personyear drug-free. The initial improvement of function, which occurred earlier in groups 3 and 4 than in groups 1 and 2, was maintained without deterioration over 8 years in all groups. No differences were found for functional ability over time, with the exception of better functional ability in group 4, compared to group 2: mean HAQ: 0.57 and 0.71. Toxicity was comparable between the groups. Table 1. 8-year results Group 1 Group 2 Group 3 Group 4 p-value n=126 n=121 n=133 n=128 DAS ≤2.4, (%)† 79 76 84 76 0.5 DAS <1.6, (%)† 49 56 57 47 0.5 DAS <1.6 drug free, %† 18 19 17 15 0.9 Still on initial treatment step, %† 29 22 45 66 <0.001 Mean HAQ over 8 years‡ 0.69 0.71 0.63 0.57 <0.05* IFX current use, (%)† 21 10 13 24 0.06 Lost to follow-up, n (%)‡ 41 (33) 43 (36) 47 (35) 30 (23) 0.1 Missing data, no. 8 12 9 4 SHS progression, median (mean)† year 0-8 3.0 (14.6) 4.3 (13.9) 2.0 (8.5) 2.0 (8.3) 0.6 †Completers analysis, ‡intention to treat. *LMM: group 2 vs 4, p<0.05, group 1 vs 4, p=0.055, all other, p>0.05. Conclusions After 8 years DAS≤2.4 targeted treatment, radiological damage is still very low and following initial improvement (earlier with initial combination therapy than with initial monotherapy), functional ability was maintained in all groups without deterioration over time. A stabilization of the percentages of patients in clinical remission and in drug-free remission was observed. Disclosure of Interest M. van den Broek Grant/Research support from: Dutch College of Health Insurances, Centocor inc and MSD (formerly Schering Plough), L. Dirven: None Declared, N. Klarenbeek: None Declared, M. van Krugten: None Declared, H. Ronday: None Declared, P. Kerstens: None Declared, T. Huizinga: None Declared, W. Lems: None Declared, C. Allaart: None Declared

FRI0087 Predictors for Attaining Remission at Two Consecutive Visits in Newly Diagnosed Early RA Patients

Background Early and intensive treatment with DMARDs are essential for remission induction in newly diagnosed RA patients. However, demographic, psychosocial and disease related factors may play a role as well. Objectives To investigate which demographic, psychosocial and disease related factors are associated with attaining remission at two consecutive visits in early RA patients treated in a treat-to-target manner Methods We used 12 months follow-up data from patients participating in the tREACH trial1,2 in which induction therapy strategies were compared: (A) combination high dose conventional therapy ((MTX + sulfasalazine + hydroxychloroquine or (B) MTX. Both groups had glucocorticoid (GCs) bridging. Disease activity (DAS) was assessed every 3 months. Remission was defined as DAS<1.6 at 2 consecutive visits (3 months). Univariate and multivariate logistic and Cox regression analyses were performed including demographic, disease related and psychosocial factors evaluated at baseline as predictors for attaining remission during 12 months of follow-up. Results 281 patients (68% female; mean DAS 3.4, median HAQ 1.00) were included. During 1 year of follow-up, 129 of 281 (46%) patients (group A: 90 (49%), group B: 39 (40%)) attained remission at 2 consecutive visits. 76/281 (27)% achieved remission within 6 months. Univariate analyses revealed that female sex was associated with a lower chance of attaining remission (demographic factors). Similar relations were observed for higher DAS, HAQ and worse physical functioning (disease factors) and higher levels of anxiety, depression, fatigue and passive coping with pain and lower levels of mental functioning and internal locus of control (psychosocial factors). In multivariate analyses, female sex, treatment and higher levels of fatigue were associated with a lower chance to attain remission within 6 months, whereas older age, female sex and higher levels of depression were associated with increased time to remission within 12 months. Conclusions In the tREACH trial, 46% of early RA patients attained remission within 1 year of follow-up. Female sex, higher baseline DAS, HAQ, and several psychosocial factors were predictors for attaining remission, but in the final models age, sex, baseline DAS, fatigue and depression remained. Results suggest that high levels of fatigue and depressive symptoms may prevent patients from attaining remission despite treatment according to a tight control and treat-to-target strategy. References Claessen et al. BMC Musculoskelet Disord 2009:71. De Jong et al. Ann Rheum Dis. 2013 Jan;72. Disclosure of Interest None declared