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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 DASRESULTS: 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.

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.

Objective To optimize use of the Disease Activity Score in 28 joints (DAS28) in early rheumatoid arthritis (RA) by adding the “squeeze test” of forefeet. Methods The squeeze test is used to examine bilateral compression pain (BCP) across the metatarsophalangeal (MTP) joints. For this study, data for patients participating in the Treatment in the Rotterdam Early Arthritis Cohort study, an ongoing clinical trial that evaluates different induction therapies in patients with early RA, were randomly divided into 2 subsets. In subset 1 (149 patients and 819 disease activity assessments), the mathematical function of the DAS28-squeeze was constructed using a linear regression model with the DAS as the dependent variable and the DAS28 and squeeze test as the independent variables. A DAS28-BCP disease state was also constructed, in which DAS28 disease state categorizations were upgraded one state if the result of the squeeze test was positive. In subset 2 (153 patients and 754 assessments), concordance in disease states between the DAS28, DAS28-squeeze, and DAS28-BCP disease states was compared, using both the DAS and Boolean-defined remission criteria as reference. Results Agreement between the DAS and the DAS28-squeeze (82%) was significantly higher than agreement between the DAS and the DAS28 (76%). When we assessed the group of patients who had arthritis of the forefeet only (22 patients and 46 assessments), overall agreement between the DAS and the DAS28 was 40%, while agreement between the DAS and the DAS28-squeeze was 59% and that between the DAS and the DAS28-BCP disease state was 65%. Furthermore, the specificities of the DAS28-squeeze and the DAS28-BCP (80% and 81%, respectively) were higher than that of the DAS28 (76%), while the sensitivities of the DAS28, DAS28-squeeze, and DAS28-BCP to identify true remission according to the Boolean criteria were 88%, 87%, and 81%, respectively. Conclusion Adding the squeeze test of forefeet to the DAS28 has value for dependably classifying the disease state in patients with early RA.

Objective To evaluate three disease activity score (DAS) alternatives without the Ritchie articular index (RAI). To compare the use of patient global assessment (PGA) of disease activity versus global assessment of health (GH) in DAS, DAS alternatives and DAS28. Methods Data from the BeSt study were used, a treatment strategy trial in early rheumatoid arthritis patients aiming at a DAS ≤2.4. DAS alternatives were DAS 0–1, with the RAI (0–3) reduced to a no–yes (0–1) score, DAS tender joint count 53 (DAS TJC53), with a 0–1 TJC in 53 separate joints and DAS TJC44 in 44 joints. Correlation patterns, mean difference from original DAS, classification differences in disease activity level and patient percentages with radiological damage progression per level were determined for all scores. Results In the majority of patients the scores were equal and correlation was high. Mean difference with the DAS at year 1 was −0.03 for DAS 0–1, 0.18 for DAS TJC53 and 0.11 for DAS TJC44. Classification agreement between scores was high (κ year 1 0.76–0.98). Patient percentages with joint damage progression were similar for all scores. DAS, DAS alternative and DAS28 perform similarly using either PGA or GH. Conclusion DAS without the RAI perform comparably to the original DAS and may be chosen as alternatives. PGA can replace GH in the DAS, the alternatives and DAS28.

Objective To evaluate the efficacy of infliximab plus methotrexate (MTX) as induction therapy in patients with early rheumatoid arthritis (RA). Methods Disease-modifying antirheumatic drug (DMARD)–naive patients with active, early RA who were included as group 4 of the BeSt study were initially treated with infliximab (3 mg/kg) in combination with MTX (25 mg/week). The Disease Activity Score (DAS) was measured every 3 months. In patients with persistent low disease activity (DAS ≤2.4) for at least 6 months, the infliximab dosage was tapered and finally discontinued; the MTX dosage then was tapered to 10 mg/week. In patients with a DAS of >2.4, the infliximab dosage was increased (maximum 10 mg/kg), and they were subsequently switched to another DMARD. Except for intraarticular administration, corticosteroids were not permitted. Functional ability and the modified Sharp/van der Heijde score were determined after 2 years of therapy. Results Of the 120 patients, 67 responders (56%) had persistent low disease activity and discontinued infliximab after a median of 9.9 months, with a median MTX dosage of 10 mg/week after 2 years. Ten other patients experienced a disease flare after discontinuation and resumed infliximab after a median of 3.7 months. Thirteen patients did not achieve persistent low disease activity and received infliximab at various dosages. Treatment was unsuccessful in 30 patients. In the 67 responders, the progression of joint damage was lower than in the 30 patients in whom treatment failed. Conclusion Fifty-six percent of patients with active early RA, initially treated with infliximab plus MTX, could discontinue infliximab after achieving a DAS of ≤2.4. Low disease activity was maintained in these patients while the MTX dosage was tapered to 10 mg/week.

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 (DRB1*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.

ObjectiveTo 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).Methods5-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.ResultsOverall, 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).ConclusionsJoint 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.

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 trial 1,2 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 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

The reactivity of islet cell cytoplasmic antibodies (ICA)-positive and ICA-negative sera of recent onset type 1 diabetic patients was studied in human fetal pancreata of 12–18 weeks' gestation and compared with the reactivity of these sera in adult human control pancreata. The aims of the study were: (1) to observe the presence of ICA staining in human fetal islet cells; (2) to compare endpoint titres (in Juvenile Diabetes Foundation units) of ICA-positive patient sera in fetal pancreata and adult human control pancreata. Ten ICA-positive sera and eight ICA-negative sera from newly diagnosed diabetic patients and four sera from healthy controls were tested on three human adult and eight human fetal pancreata. As in the adult control pancreata. ICA-positive sera reacted to insulin-, glucagon-, and somatostatin-positive cells of fetal pancreata of all gestational ages. This was observed both in single cells and in cells in islet-like cell clusters. Dilution of a reference serum gave similar results in both adult and fetal pancreata. In contrast, the ICA-positive patient sera yielded a striking heterogeneity in fetal as well as in adult pancreata. However, end-point titres between adult and fetal pancreata did not differ significantly (P>0.05). In conclusion, ICA-positive sera from recent onset diabetic patients show that the expression of molecules to which ICA react is present in all islet cells and starts before week 12 of gestation.

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-alpha) 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-alpha 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-alpha in treatment of primary hand OA. (C) 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

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.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 was2.4. If the DAS wasor=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 DASor=2.4.Patients treated with initial combination therapy achieved a DASor=2.4 significantly earlier than patients treated with initial monotherapy. Independent of treatment strategy and without treatment adjustments, the probability of a next DASor=2.4 3 months after a first DASor=2.4 was 74%. The probability increased to 85% after two preceding DASor=2.4 and to 88-97% after one to two preceding DAS1.6. The median duration of a DASor=2.4 was 12 months.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.

OBJECTIVE: Several treatment strategies have proven value in the amelioration of rheumatoid arthritis (RA), but the optimal strategy for preventing long-term joint damage and functional decline is unclear. We undertook this study to compare clinical and radiographic outcomes of 4 different treatment strategies, with intense monitoring in all patients. METHODS: In a multicenter, randomized clinical trial, 508 patients were allocated to 1 of 4 treatment strategies: sequential disease-modifying antirheumatic drug monotherapy (group 1), step-up combination therapy (group 2), initial combination therapy with tapered high-dose prednisone (group 3), and initial combination therapy with the tumor necrosis factor antagonist infliximab (group 4). Treatment adjustments were made every 3 months in an effort to obtain low disease activity (a Disease Activity Score in 44 joints of < or =2.4). RESULTS: Initial combination therapy including either prednisone (group 3) or infliximab (group 4) resulted in earlier functional improvement than did sequential monotherapy (group 1) and step-up combination therapy (group 2), with mean scores at 3 months on the Dutch version of the Health Assessment Questionnaire (D-HAQ) of 1.0 in groups 1 and 2 and 0.6 in groups 3 and 4 (P < 0.001). After 1 year, mean D-HAQ scores were 0.7 in groups 1 and 2 and 0.5 in groups 3 and 4 (P = 0.009). The median increases in total Sharp/Van der Heijde radiographic joint score were 2.0, 2.5, 1.0, and 0.5 in groups 1-4, respectively (P < 0.001). There were no significant differences in the number of adverse events and withdrawals between the groups. CONCLUSION: In patients with early RA, initial combination therapy including either prednisone or infliximab resulted in earlier functional improvement and less radiographic damage after 1 year than did sequential monotherapy or step-up combination therapy

Objectives Objective of this study was to investigate whether the initial treatment strategy that included triple DMARD therapy or methotrexate monotherapy differed at 24 months in the tREACH trial in their: (i) DAS, HAQ and X-ray progression (ii) Prevalence of flares (iii) Prevalence of attaining DAS 44 (iv) Prevalence of drug free remission at 24 months of follow-up Methods Data were used from patients with recent-onset arthritis participating in a single-blinded clinical trial (treatment in the Rotterdam Early Arthritis CoHort (tREACH)) [1,2] in which induction therapy strategies were compared: (A) combination therapy (methotrexate (MTX) + sulfasalazine + hydroxychloroquine) with glucocorticoid (GCs) bridging or (B) MTX with bridging GCs. Disease activity scores (original DAS) were assessed every 3 months. Functional ability was assessed using the Health assessment questionnaire (HAQ). Actual medication use was obtained from medical charts and from patient diaries. DMARDs (synthetic (s) and/or biologic (b)) were tapered stepwise by protocol if DAS was Results 281 rheumatoid arthritis patients (68% female; mean DAS 3.4, median HAQ 1.00) were initially randomized. After two years the difference in HAQ between group A and B was significantly different, irrespective of the DAS. Radiographic progression was minimal and similar for both groups, irrespective of tapering. Data on DMARD use at 2 years were available from 248 patients (88%). Over time 139 of 281 (49%) patients (group A: 93 (51%), group B: 46 (47%)) attained DAS Conclusions Half of patients in the tREACH trial was able to taper down medication after reaching sustained remission between 6 and 24 months of follow-up. Drug free remission was achieved by 11% of patients. Prevalence, time of initiation, radiographic progression and success of tapering were not different among the initial treatment groups. HAQ scores were significantly higher in the MTX monotherapy group compared to the triple DMARD therapy group. References Claessen et al. BMC Musculoskelet Disord 2009;10:71. De Jong et al. Ann Rheum Dis. 2013 Jan;72(1):72-8. Disclosure of Interest None declared

Background Fewer patients on biologicals and better functional ability two years after induction therapy with combination DMARD therapy versus methotrexate monotherapy Objectives To assess differences in frequency of biological therapy use in early RA patients two years after starting induction therapy according to three different treatment regimens Methods Data were used from patients with recent-onset arthritis participating in a single-blinded clinical trial (Treatment in the Rotterdam Early Arthritis CoHort (tREACH)) [1,2] in which three induction therapy strategies were compared: (A) combination therapy (methotrexate (MTX) + sulfasalazine + hydroxychloroquine) with glucocorticoids (GCs) intramuscularly; (B) combination therapy with an oral GC tapering scheme and (C) MTX with oral GCs similar to B. Disease activity scores (original DAS) were assessed every 3 months. Functional ability was assessed using the Health assessment questionnaire (HAQ). Actual medication use was obtained from medical charts and from patient diaries. Data were analysed using simple descriptive statistical techniques. Results 281 patients (91 men, 190 women; mean baseline DAS 3.4, median baseline HAQ 0.75) were initially randomized. Data on medication use at 2 years were available from 166 patients (59%). Mean DAS was 1.72 (95%CI 1.59-1.86) at 24 months with similar results for the initial treatment groups A-C. DAS remission (DAS Conventional DMARDs only were used in 58% of patients (A. 60%, B. 75% and C. 43%). Biological DMARDs only were used in 5% of patients (A. 8%, B. 2% and C 7.%). Thirteen percent of patients did not use any DMARD at all (A. 14%, B. 9% and C. 16%). Patients in group C used biological DMARDs more often compared to B (p=0.004), but no statistical difference was observed between groups A and B (p=0.241). Conclusions We observed lower use of biological therapy and better functional ability in induction triple therapy compared to induction monotherapy MTX with GC bridging at 2 years of follow-up in the treat-to-target tREACH study. No differences were found for disease activity scores. References Claessen et al. Use of risk stratification to target therapies in patients with recent onset arthritis; design of a prospective randomized multicenter controlled trial. BMC Musculoskelet Disord 2009;10:71. De Jong et al. Induction therapy with a combination of DMARDs is better than methotrexate monotherapy: first results of the tREACH trial. Ann Rheum Dis. 2013 Jan;72(1):72-8. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5357

Interindividual variation in the expression of tumor necrosis factor alpha (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.

To evaluate the respective contributions of tumor necrosis factor (TNF) promoter polymorphisms and HLA-DR alleles to susceptibility to systemic lupus erythematosus (SLE).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.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.TNF-308A and HLA-DR3 alleles are independent susceptibility factors for SLE.

BACKGROUND: Functional heterogeneity in the tumor necrosis factor alpha (TNF-alpha) gene may be responsible for the TNF-alpha response in infectious and autoimmune diseases. Recently, the TNF-238 promoter polymorphism was observed as being associated with a more destructive disease in rheumatoid arthritis (RA). To determine the relation between TNF-238 and disease progression, the extent of joint destruction in a cohort of 101 RA patients followed for 12 years was analyzed. Furthermore, we have attempted to link this polymorphism to TNF-alpha gene transcription in monocytes and lymphocytes in vitro. PATIENTS, MATERIALS, AND METHODS: The extent of joint destruction determined on X-rays of hands and feet assessed after 0, 3, 6, and 12 years was compared with TNF-238 genotypes. Functional consequences of TNF-alpha gene polymorphisms using reporter gene constructs were analyzed in cells of the monocyte and lymphocyte lineage by means of transient transfection systems. RESULTS: The rate of joint damage in -238GA patients was lower than that in the -238GG patients, independent of HLA-DR4. Damage after 12 years was 76 +/- 30 for the -238GA versus 126 +/- 13 for the -238GG patients as determined by the van der Heijde's modification of Sharp's method. Furthermore, TNF-238A was found to be in linkage disequilibrium with an additional polymorphism at position -376. Functional assays revealed no significant differences in the level of inducible reporter gene expression between the TNF-238/-376 promoter constructs in the cell types tested. CONCLUSION: In a prospective study, we show that the TNF-238GG genotype contributes to progression of joint destruction in RA, independent of the presence of HLA-DR4. However, in vitro transfection assays indicate that TNF-238A by itself or in combination with TNF-376A is not likely to be of direct functional relevance for transcriptional activation. Therefore, these polymorphisms may serve as markers for additional polymorphisms in the TNF/LT locus or neighboring genes that may influence disease severity.

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 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 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