Neither low social support nor low decision latitude at work is associated with disease remission among patients with rheumatoid arthritis: results from the Swedish EIRA study.

OBJECTIVES: To investigate the association between psychosocial vulnerability, defined as either low social support or low decision latitude at work, and disease remission at 3, 12, and 60 months in patients with rheumatoid arthritis (RA). METHODS: This cohort study included all patients enrolled in both the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) 1996-2015 and the Swedish Rheumatology Quality Register (SRQ, n = 2820). Information on social support and decision latitude at work at RA diagnosis were identified from the EIRA questionnaire. Indexes for levels of social support and decision latitude at work, respectively, were calculated based on the questionnaire. Low social support and low decision latitude at work, respectively, were identified by a score in the lowest quartile and compared with the three other quartiles (not low). Disease-activity parameters were retrieved from SRQ at 3, 12, and 60 months. The associations between social support or decision latitude at work, respectively, and Disease Activity Score 28 joint count with C-reactive protein (DAS28-CRP) remission were analysed using logistic regression models adjusted for age, sex, smoking habits, alcohol habits, symptom duration, and educational level. RESULTS: Having low social support (n = 591) was not associated with DAS28-CRP remission at 3 (OR 0.93, 95% CI 0.74-1.16), 12 (OR 0.96, 95%CI 0.75-1.23), or 60 (OR 0.89, 95%CI 0.72-1.10) months compared to not low social support (n = 2209). No association was observed for low (n = 212) versus not low (n = 635) decision latitude at work and DAS28-CRP remission at 3 (OR 0.84, 95%CI 0.54-1.31), 12 (OR 0.81, 95%CI 0.56-1.16), or 60 (OR 1.37, 95%CI 0.94-2.01) months. CONCLUSION: In a country with general access to healthcare, psychosocial vulnerability does not influence the likelihood of achieving remission in early RA.

International Consortium for Health Outcome Measurement Set of Outcomes That Matter to People Living With Inflammatory Arthritis: Consensus From an International Working Group.

OBJECTIVE: The implementation of value-based health care in inflammatory arthritis requires a standardized set of modifiable outcomes and risk-adjustment variables that is feasible to implement worldwide. METHODS: The International Consortium for Health Outcomes Measurement (ICHOM) assembled a multidisciplinary working group that consisted of 24 experts from 6 continents, including 6 patient representatives, to develop a standard set of outcomes for inflammatory arthritis. The process followed a structured approach, using a modified Delphi process to reach consensus on the following decision areas: conditions covered by the set, outcome domains, outcome measures, and risk-adjustment variables. Consensus in areas 2 to 4 were supported by systematic literature reviews and consultation of experts. RESULTS: The ICHOM Inflammatory Arthritis Standard Set covers patients with rheumatoid arthritis (RA), axial spondyloarthritis, psoriatic arthritis, and juvenile idiopathic arthritis (JIA). We recommend that outcomes regarding pain, fatigue, activity limitations, overall physical and mental health impact, work/school/housework ability and productivity, disease activity, and serious adverse events be collected at least annually. Validated measures for patient-reported outcomes were endorsed and linked to common reporting metrics. Age, sex at birth, education level, smoking status, comorbidities, time since diagnosis, and rheumatoid factor and anti-citrullinated protein antibody lab testing for RA and JIA should be collected as risk-adjustment variables. CONCLUSION: We present the ICHOM inflammatory arthritis Standard Set of outcomes, which enables health care providers to implement the value-based health care framework and compare outcomes that are important to patients with inflammatory arthritis.

A Multi-Biomarker Disease Activity Score and the Choice of Second-Line Therapy in Early Rheumatoid Arthritis After Methotrexate Failure.

OBJECTIVE: To investigate whether the Multi-Biomarker Disease Activity (MBDA) score predicts optimal add-on treatment in patients with early rheumatoid arthritis (RA) who were inadequate responders to MTX (MTX-IRs). METHODS: We analyzed data from 157 MTX-IRs (with a Disease Activity Score using the erythrocyte sedimentation rate [DAS28-ESR] >3.2) from the Swedish Pharmacotherapy (SWEFOT) trial who were randomized to receive triple therapy (MTX plus sulfasalazine plus hydroxychloroquine) versus MTX plus infliximab. The MBDA score as a predictor of the subsequent DAS28-based response to each second-line treatment was analyzed at randomization with the Breslow-Day test for 2 × 2 groups, using both validated categories (low [<30], moderate [30-44], and high [>44]) and dichotomized categories (lower [≤38] versus higher [>38]). RESULTS: Among the 157 patients, 12% had a low MBDA score, 32% moderate, and 56% high. Of those with a low MBDA score, 88% responded to subsequent triple therapy, and 18% responded to MTX plus infliximab (P = 0.006); for those with a high MBDA score, the response rates were 35% and 58%, respectively (P = 0.040). When using 38 as a cutoff for the MBDA score (29% patients with lower scores versus 71% with higher scores), the differential associations with response to triple therapy versus MTX plus infliximab were 79% versus 44% and 36% versus 58%, respectively (P = 0.001). Clinical and inflammatory markers had poorer predictive capacity for response to triple therapy or MTX plus infliximab. CONCLUSION: In patients with RA who had an inadequate response to MTX, the MBDA score categories were differentially associated with response to subsequent therapies. Thus, patients with post-MTX biochemical improvements (lower MBDA scores) were more likely to respond to triple therapy than to MTX plus infliximab. If confirmed, these results may help to improve treatment in RA.

Current smoking status is a strong predictor of radiographic progression in early rheumatoid arthritis: results from the SWEFOT trial.

OBJECTIVES: To study clinical predictors for radiographic progression after 1 year in an early rheumatoid arthritis (RA) trial. METHODS: In the SWEFOT trial population, disease modifying antirheumatic drug (DMARD) naïve RA patients started methotrexate; 3-month responders (DAS28 <3.2) continued (n=147), while non-responders were randomised to addition of sulfasalazine+hydroxychloroquine (n=130) or infliximab (n=128). X-rays were scored by the Sharp-van der Hejde score (SHS) method and radiographic progression was defined as a ≥5 increase after 1 year. Potential baseline predictors of radiographic progression were tested using multivariable logistic regression, adjusted for potential confounders. RESULTS: 79 of 311 patients with available radiographs at baseline and follow-up had radiographic progression. The following baseline parameters were independent predictors of radiographic progression at 1 year: baseline erosions (adjusted OR=2.29, 95% CI 1.24 to 4.24), erythrocyte sedimentation rate (adjusted OR per tertile increase=1.72, 95% CI 1.12 to 2.65) and C-reactive protein (adjusted OR per tertile increase=1.52, 95% CI 1.03 to 2.26). Current smoking was an independent predictor of radiographic progression (adjusted OR=2.17, 95% CI 1.06 to 4.45). These results remained after further adjustment for treatment strategy. Three-dimensional matrix including current smoking status, erosions and C-reactive protein tertiles showed a 12-63% risk gradient from patients carrying none compared with all predictors. Rheumatoid factor (RF)/anti-cyclic citrullinated peptide (anti-CCP) positivity did not significantly predict radiographic progression using SHS increase ≥5 as cut-off. In a secondary exploratory analysis using cut-off >1, both RF and anti-CCP positivity were significant predictors in the unadjusted, but not the adjusted analyses. The other parameters also remained significant using this lower cut-off. CONCLUSIONS: In addition to previously described predictors, we identified smoking as a strong independent risk factor for radiographic progression in early RA. TRIAL REGISTRATION NUMBER: NCT00764725.

Biological vs. conventional combination treatment and work loss in early rheumatoid arthritis: a randomized trial.

IMPORTANCE: The introduction of biological tumor necrosis factor inhibitors has improved the treatment of rheumatoid arthritis (RA) but at a substantial cost. These drugs have been shown to lead to superior radiological outcomes compared with a combination of conventional disease-modifying antirheumatic drugs over 2 years. OBJECTIVE: To investigate whether radiological superiority translates into better work loss outcomes. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, 2-arm, parallel, randomized, active-controlled, open-label trial. Patients with early RA (symptom duration <1 year) were recruited from 15 rheumatology clinics in Sweden from October 1, 2002, through December 31, 2005. The study population was restricted to working-age patients (aged <63 years). INTERVENTIONS: Patients who did not achieve low disease activity after 3 to 4 months of methotrexate therapy were randomized to receive additional biological treatment with infliximab or conventional combination treatment with sulfasalazine plus hydroxychloroquine. MAIN OUTCOMES AND MEASURES: Monthly sick leave and disability pension days 21 months after randomization retrieved from the nationwide Swedish Social Insurance Office register. Main analyses were by intention to treat, including all patients, and adjusted for baseline sick leave and disability pension. RESULTS: Of 204 eligible patients, 105 were randomized to biological and 99 to conventional treatment. Seven patients in the biological and 4 in the conventional treatment group never received the study drug, and 72 and 52 patients, respectively, followed the study per protocol for 21 months. The baseline mean (SD) work loss was 17 (13) d/mo (median, 16 d/mo) in both groups (mean difference, 0.6 d/mo; 95% CI, -3.0 to 3.9). The mean changes in work loss at 21 months were -4.9 d/mo in the biological and -6.2 d/mo in the conventional treatment group (adjusted mean difference, 1.6 d/mo; 95% CI, -1.2 to 4.4). Including only patients receiving at least 1 dose of assigned treatment, the adjusted mean difference was 1.5 d/mo (95% CI, -1.5 to 4.4), and in per-protocol analysis the adjusted mean difference was 0.3 d/mo (95% CI, -2.8 to 3.8). CONCLUSIONS AND RELEVANCE: The radiological superiority of biological compared with conventional combination therapy did not translate into better work loss outcomes in patients with early RA who had experienced an insufficient response to methotrexate. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00764725.

Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in early rheumatoid arthritis: 2-year quality-of-life results of the randomised, controlled, SWEFOT trial.

OBJECTIVE: To compare EuroQol 5-Dimensions (EQ-5D) utility and quality-adjusted life-years (QALYs) in patients with early, methotrexate (MTX) refractory rheumatoid arthritis (RA), randomised to addition of infliximab (IFX) or sulfasalazine and hydroxychloroquine (SSZ+HCQ). METHODS: RA-patients with symptoms <1 year were enrolled between 2002 and 2005 at 15 Swedish centres. After 3-4 months of MTX monotherapy, patients with a remaining DAS28>3.2 were randomised to addition of IFX or SSZ+HCQ and followed for 21 months. EQ-5D profiles were collected every 3 months. Between-group comparisons of utility change and accumulated QALYs were performed, using last observation carried forward (LOCF) following protocol breach. Missing data were imputed by linear interpolation or LOCF. Sensitivity analyses applying baseline observation carried forward (BOCF) or restricted to completers were conducted. RESULTS: Of 487 patients initially enrolled, 128 and 130 were randomised to IFX or SSZ+HCQ, respectively. Mean utility in the IFX and SSZ+HCQ groups increased from 0.52 (SD 0.27) and 0.55 (SD 0.27) at randomisation to 0.66 (SD 0.25) and 0.63 (SD 0.27) at 21 months (adjusted mean difference favouring IFX 0.04; 95% CI -0.01, 0.09; p=0.15). Average accumulated QALYs were 1.10 (SD 0.37) and 1.07 (SD 0.42) in the IFX and SSZ+HCQ groups, respectively (adjusted mean difference favouring IFX 0.07; 95%CI -0.01, 0.14; p=0.07). BOCF analysis showed similar results, while differences were reversed, though remained statistically non-significant among completers. Dropout rates in the IFX/SSZ+HCQ groups were 30%/43% (p=0.01). CONCLUSIONS: Comparing addition of IFX or SSZ+HCQ to MTX in active early RA, no statistically significant differences in utility or QALY gain could be detected over 21 months. TRIAL REGISTRATION: Registered in WHO database at the Karolinska University Hospital, number CT20080004.

Conventional combination treatment versus biological treatment in methotrexate-refractory early rheumatoid arthritis: 2 year follow-up of the randomised, non-blinded, parallel-group Swefot trial.

BACKGROUND: Analysis of the Swedish Farmacotherapy (Swefot) trial at 12 months showed that the addition of an anti-tumour-necrosis-factor agent gave an improved clinical outcome compared with the addition of conventional disease-modifying antirheumatic drugs in patients with methotrexate-refractory early rheumatoid arthritis. Here we report the 2 year follow-up assessment. METHODS: In this randomised, non-blinded, parallel-group trial, we enrolled adult patients older than 18 years with rheumatoid arthritis and a symptom duration of less than 1 year from 15 rheumatology units in Sweden between December, 2002 and December, 2006. All patients were started on methotrexate. After 3-4 months, those who failed treatment were randomly assigned (1:1) to group A (conventional treatment; additional sulfasalazine and hydroxychloroquine) or group B (biological treatment; additional infliximab). Randomisation was done with a computer-generated sequence. We analysed clinical outcomes at months 18 and 24 by the response criteria of the American College of Rheumatology and the European League Against Rheumatism, and radiographs of patients' hands and feet at months 12 and 24 using the Van der Heijde modification of the Sharp score. Analysis was by intention to treat. This trial is registered with www.ClinicalTrials.gov, number NCT00764725. FINDINGS: Of 493 screened individuals, we enrolled 487, of whom 258 were randomly allocated to treatment. The proportion of patients in group B who received a EULAR-defined good response was non-significantly greater than it was in group A at 18 months (49 of 128 [38%] vs 38 of 130 [29%]) and at 24 months (49 of 128 [38%] vs 40 of 130 [31%]; p=0·204). After 24 months, radiological disease progression was greater in patients in group A than it was in those in group B (mean 7·23 [SD 12·72] vs 4·00 [10·0]; p=0·009). We recorded three serious adverse events: an extended generalised illness in group A, an extended febrile episode in group B, and a generalised illness in group B. INTERPRETATION: Additional biological treatment is a valid option for patients who fail initial methotrexate treatment. However, improved clinical outcomes after 12 months and better radiographical results after 24 months should be weighed against the absence of a convincing clinical difference at 24 months and substantially higher costs. Therefore, for many patients who fail initial methotrexate treatment, add-on treatment with disease-modifying antirheumatic drugs is an appropriate treatment option. FUNDING: Swedish Rheumatism Association, Stockholm County, and Schering-Plough/Merck Sharp and Dohme.

Predictors of response to methotrexate in early DMARD naive rheumatoid arthritis: results from the initial open-label phase of the SWEFOT trial.

OBJECTIVE: To identify predictors of response to methotrexate (MTX) in early rheumatoid arthritis (RA). METHODS: In the SWEFOT trial, patients with RA with symptom duration <1 year started MTX monotherapy (20 mg/weekly) and 405/487 continued until the 3-4- month visit. The primary outcome measure was the DAS28-based European League against Rheumatism (EULAR) response criteria. Multivariate logistic regression was used to study the association between response and the following baseline characteristics: gender, age, symptom duration, cigarette smoking habits, autoantibody status, Health Assessment Questionnaire (HAQ) score, concurrent prednisolone and treatment with non-steroidal anti-inflammatory drugs. Secondary response and remission measures were the American College of Rheumatology and the Simple Disease Activity Index and Clinical Disease Activity Index (SDAI/CDAI)-derived criteria. RESULTS: After 3-4 months of MTX treatment, the frequency of EULAR good/moderate/no response was 34%/41%/25%, respectively. Parameters associated with a decreased likelihood of EULAR response were female gender (adjusted OR (adj OR) 0.50, 95% CI 0.31 to 0.81), symptom duration (adj OR per month increase 0.93, 95% CI 0.88 to 0.99), current smoking (adj OR 0.35, 95% CI 0.20 to 0.63) and higher HAQ (adj OR 0.56, 95% CI 0.40 to 0.80). Parameters associated with an increased likelihood of EULAR response were higher age (adj OR per 10-year increase 1.30, 95% CI 1.11 to 1.51) and prednisolone treatment (adj OR 2.84, 95% CI 1.43 to 5.63). The findings were similar when patients on prednisolone were excluded and other response criteria tested, although current smoking was the only significant predictor using all response criteria, while HAQ was the only significant predictor of all the remission criteria used. A matrix showed up to ninefold differences between subgroups stratified by the main predictors. CONCLUSION: Current smoking, female sex, longer symptom duration and younger age predict a worse response to MTX in patients with new-onset RA. TrialRegNo NCT00764725.

Systemic TNF blockade does not modulate synovial expression of the pro-inflammatory mediator HMGB1 in rheumatoid arthritis patients--a prospective clinical study.

INTRODUCTION: High-mobility group box chromosomal protein 1 (HMGB1) has recently been identified as an endogenous mediator of arthritis. TNF and IL-1beta, pivotal cytokines in arthritis pathogenesis, both have the ability to induce the release of HMGB1 from myeloid and dendritic cells. It was, therefore, decided to investigate whether treatment based on TNF blockade in rheumatoid arthritis (RA) affects the expression of synovial HMGB1. METHODS: Repeated arthroscopy-guided sampling of synovial tissue was performed in nine patients with RA before and nine weeks after initiation of anti-TNF mAb (infliximab) therapy. Synovial biopsy specimens were analysed for HMGB1 protein by immunohistochemical staining and for HMGB1 mRNA expression by real-time reverse transcriptase PCR (RT-PCR). Statistical evaluations were based on Wilcoxon's signed rank tests or Spearman rank sum tests. RESULTS: Aberrant, extranuclear HMGB1 and constitutive nuclear HMGB1 expression, with histological signs of inflammation, were evident in all biopsies obtained before infliximab therapy. Signs of inflammation were still evident in the second biopsies obtained nine weeks after initiation of infliximab therapy. The cytoplasmic and extracellular expression of HMGB1 decreased in five patients, remained unchanged in one patient and increased in three patients, making the overall change in HMGB1 protein expression not significant. No correlation between the clinical response, as measured by disease activity score calculated for 28 joints (DAS28) or the American College of Rheumatology response criteria (ACR 20, 50, and 70), and the direction of change of HMGB1 expression in individual patients could be discerned. In addition, infliximab therapy did not alter HMGB1 mRNA synthesis. CONCLUSION: Pro-inflammatory HMGB1 expression during rheumatoid synovitis was not consistently influenced by TNF-blocking therapy with infliximab. This suggests that TNF is not the main inducer of extranuclear HMGB1 during synovitis and that HMGB1 may represent a TNF-independent molecule that could be considered as a possible target for future therapeutic intervention in RA.

Increased DHEAS levels in patients with rheumatoid arthritis after treatment with tumor necrosis factor antagonists: evidence for improved adrenal function.

OBJECTIVE: To determine if major reduction of inflammation with longterm tumor necrosis factor (TNF) antagonist treatment has any influence on the adrenal and gonadal axes in patients with rheumatoid arthritis (RA). METHODS: Forty-eight patients with RA were treated with infliximab or etanercept for 2 years. Disease activity, clinical response, and physical function were evaluated and serum levels of high sensitivity C-reactive protein and interleukin 6 were analyzed before start of treatment and after 1 and 2 years. At the same timepoints adrenocorticotropic hormone (ACTH), cortisol, and dehydroepiandrosterone sulfate (DHEAS) were analyzed; luteinizing hormone (LH), estradiol, and testosterone were analyzed as well in 18 male patients. RESULTS: DHEAS increased (p

Fcgamma receptor type IIIA genotype and response to tumor necrosis factor alpha-blocking agents in patients with rheumatoid arthritis.

OBJECTIVE: To determine whether a functional single-nucleotide polymorphism in the gene encoding Fcgamma receptor type IIIA (FcgammaRIIIA) correlates with the response to treatment with tumor necrosis factor alpha inhibitors in rheumatoid arthritis (RA). METHODS: The study population comprised 282 Swedish patients with RA in whom the therapeutic efficacy of conventional disease-modifying antirheumatic drugs had been insufficient. Infliximab or etanercept treatment was initiated, and patients were evaluated after 3 months, using the American College of Rheumatology 20% improvement criteria (ACR20), the ACR50, and the ACR70 or the European League Against Rheumatism (EULAR) criteria. The chi-square test was used to compare response rates across FcgammaRIIIA genotypes. RESULTS: No differences in genotype distribution were observed among nonresponders compared with ACR20 responders (P = 0.80), ACR50 responders (P = 0.56), or ACR70 responders (P = 0.91). Similar results were observed when analyzing infliximab and etanercept separately or when using the EULAR response criteria. CONCLUSION: Unlike the findings of a previous study, the results of the current study suggest that the 158V/F polymorphism of FcgammaRIIIA is very unlikely to influence the clinical efficacy of infliximab or etanercept in patients with RA.

Synovial expression of IL-15 in rheumatoid arthritis is not influenced by blockade of tumour necrosis factor.

Blockade of tumour necrosis factor (TNF) is an effective treatment in rheumatoid arthritis (RA), but both non-responders and partial responders are quite frequent. This suggests that other pro-inflammatory cytokines may be of importance in the pathogenesis of RA and as possible targets for therapy. In this study we investigated the effect of TNF blockade (infliximab) on the synovial expression of IL-15 in RA in relation to different cell types and expression of other cytokines, to elucidate whether or not IL-15 is a possible target for therapy, independently of TNF blockade. Two arthroscopies with multiple biopsies were performed on nine patients with RA and knee-joint synovitis before and after three infusions of infliximab (3 mg/kg). Synovial biopsies were analysed with immunohistochemistry for expression of IL-15, TNF, IL-1alpha, IL-1ss and IFN-gamma, and for the cell surface markers CD3, CD68 and CD163. Stained synovial biopsy sections were evaluated by computerized image analysis. IL-15 expression was detected in all synovial biopsies taken at baseline. After infliximab therapy, the expression of IL-15 was increased in four patients and reduced in five. Synovial expression of IL-15 was not correlated with any CD marker or with the presence of any other cytokine. Synovial cellularity was decreased after 8 to 10 weeks of treatment with a significant reduction of the CD68-positive synovial cells, whereas no significant change was seen in the number of CD3-positive T cells and CD163-expressing macrophages. The number of TNF-producing cells in the synovial tissue at baseline was correlated with a good response to therapy. Thus, in this study the synovial expression of IL-15 in RA was not consistently influenced by TNF blockade, being apparently independent of TNF expression in the synovium. Consequently, we propose that IL-15 should remain as a therapeutic target in RA, regardless of the response to TNF blockade.

Anti-tumor necrosis factor therapy increases synovial osteoprotegerin expression in rheumatoid arthritis.

OBJECTIVE: Treatment of rheumatoid arthritis (RA) with tumor necrosis factor (TNF)-blocking agents, including etanercept and infliximab, has resulted in reductions in the radiographic progression of RA. However, the exact mechanism by which this protection occurs has not been determined. In order to add to such knowledge, we investigated the effect of anti-TNF therapy on the expression of osteoprotegerin (OPG) and receptor activator of NF-kappaB ligand (RANKL) in synovial tissue. METHODS: The expression of OPG and RANKL in synovial biopsy specimens was evaluated by immunohistochemistry. Serial synovial biopsy specimens were obtained from 18 patients with RA, before and after treatment with etanercept (9 patients) or infliximab (9 patients). Biopsy specimens were evaluated by double-blind semiquantitative analysis and image analysis. The in vitro effect of TNF antagonists on the RANKL/OPG expression in osteoblasts and endothelial cells was evaluated by Western blotting. Statistical analysis was performed using Wilcoxon's signed rank test, followed by the Bonferroni correction for multiple comparisons of paired samples. The results of in vitro experiments were evaluated by one-way analysis of variance, with Tukey's post hoc test. RESULTS: Treatment with both infliximab and etanercept increased the expression of OPG in synovial tissue. After 8 weeks of treatment, neither infliximab nor etanercept influenced RANKL expression. In both groups of patients, the RANKL:OPG ratio decreased following therapy. In vitro, both of the TNF antagonists mimicked the in vivo effect, inducing a decrease in the RANKL:OPG ratio in TNF-primed osteoblasts and endothelial cells. CONCLUSION: Therapy with TNF antagonists in RA modulates the OPG/RANKL system, a potential mechanism that could explain the retardation of radiographic damage observed following anti-TNF therapy.

Reduction of temporomandibular joint pain after treatment with a combination of methotrexate and infliximab is associated with changes in synovial fluid and plasma cytokines in rheumatoid arthritis.

The aims were to investigate the effect of intravenous infusions of the tumor necrosis factor-alpha (TNF-alpha) antibody infliximab on symptoms and signs of temporomandibular joint (TMJ) involvement in relation to effects on synovial fluid and plasma proinflammatory TNF-alpha, interleukin-1beta (IL-1beta) and interleukin-6 as well as antiinflam matory soluble TNF receptor II (TNF-sRII), interleukin-1 receptor antagonist (IL-1ra), soluble IL-1 receptor II (IL-1sRII) and interleukin-10 (IL-10) in patients with active rheumatoid arthritis (RA). Nineteen patients with TMJ involvement taking methotrexate were included in the study. TMJ and general joint pain intensity as well as pain on mandibular movements, tenderness to digital palpation, pressure pain threshold and maximum mouth-opening capacity were assessed in a clinical examination. The effect of infliximab was assessed after 2 and 14 or 22 weeks. TMJ synovial fluid and venous blood were collected for cytokine analysis at all occasions while determination of erythrocyte sedimentation rate and C-reactive protein were performed at baseline and at long-term follow-up only. Reduction of TMJ pain was associated with raised levels of synovial fluid TNF-sRII and IL-1sRII as well as raised plasma levels of IL-1ra and IL-10. Decreased erythrocyte sedimentation rate was associated with decreased tenderness to digital palpation. Reduced general joint pain intensity was associated with reduced plasma levels of IL-6 and C-reactive protein. In conclusion, systemic treatment with a combination of infliximab and methotrexate reduces TMJ pain in RA in association with an increase in anti-inflammatory cytokines and receptors in synovial fluid and plasma.

[TNF blockade in rheumatoid arthritis can cause severe fibrosing alveolitis. Six case reports]. / TNF-blockad vid reumatoid artrit kan ge svår fibrotiserande alveolit. Sex fallbeskrivningar.

TNF-blockade has been increasingly used in the treatment of rheumatoid arthritis (RA). However, the safety is unclear and an increased risk of both tuberculosis and other infections has been identified. Recently severe fibrosing alveolitis has also been reported in RA-patients treated with TNF-blockade. We report a further six RA patients, who during treatment with infliximab or etanercept developed fulminant lung fibrosis with alveolitis. For four of the patients, the fibrosing alveolitis was fatal. All patients were RF positive and above 60 years and five had mild fibrosis associated with RA before TNF-blockade treatment. Duration of TNF-blockade treatment was for three patients only two months and for the other three, 20-51 months. Age above 60 years and previous lung fibrosis appear to be risk factors for developing fibrosing alveolitis in RA patients treated with TNF-blockade.

Etanercept versus etanercept plus methotrexate: a registry-based study suggesting that the combination is clinically more efficacious.

Etanercept can be used both as monotherapy and in combination with methotrexate (MTX), but direct comparisons of these two options have not yet been reported. In order to compare the results seen in actual practice between these two options, clinical data on 97 patients followed in the Stockholm TNFalpha Follow-Up Registry were analysed. In 57 of these patients etanercept was added to previously started MTX while the others were treated with etanercept alone. The two groups had similar levels of disease activity at baseline. After 3 months, a significantly lower mean disease activity score (28-joint count-based disease activity score) was attained by the patients on etanercept plus MTX. In this group, the number of patients achieving European League Against Rheumatism-defined remission was also significantly greater. Other disease outcomes showed non-significant trends in the same direction. These data suggest that the combination of etanercept plus MTX is clinically more efficacious than etanercept alone.

Evidence for immunostimulatory effects of intramuscular gold in patients with rheumatoid arthritis: correlation with skin reactions.

OBJECTIVE: Intramuscular gold is a well documented treatment in rheumatoid arthritis (RA), but its mechanism of action is still poorly understood. From an observation that gold sodium thiomalate (GSTM) induces monocyte-derived interleukin 6 (IL-6) and IL-10 production in vitro, a hypothesis has been proposed that gold exerts its action mainly as a selective immunostimulator rather than as a general immunosuppressant. In this prospective study we investigated cytokine production in peripheral blood from patients with RA during treatment with GSTM. METHODS: A total of 20 patients with RA were treated with GSTM for at least 3 months. Disease activity was recorded at baseline, 12, 20, and 28 weeks. The ELISPOT method was used to measure spontaneous production of IL-6, IL-10, and interferon-g (IFN-g) from peripheral blood mononuclear cells (PBMC) at baseline and 4 and 12 weeks and production after incubation with GSTM in vitro, at different concentrations (0, 3, 12.5, 40 micro g/ml) at baseline. IL-6 and IL-10 concentrations in serum were measured with ELISA. RESULTS: The numbers of IL-10-producing cells were increased after 4 weeks' treatment with GSTM (p < 0.01). The numbers of cells spontaneously producing IL-6 were increased after 4 weeks (p < 0.01) and 12 weeks (p < 0.01). The numbers of IFN-g-producing cells were increased after 4 weeks (p < 0.01). Serum concentrations of IL-10 were increased after 4 weeks (p < 0.01). Serum concentrations of IL-6 were not changed at any timepoint. The in vitro effect of GSTM on IL-10 production from PBMC at baseline predicted development of skin reactions during GSTM treatment, with lack of skin reactions being associated with high gold induced IL-10 production (p < 0.05). There was no correlation between clinical response and cytokine production. CONCLUSION: This study indicates an immunostimulatory effect of GSTM treatment in patients with RA. The increase in IL-10 production during GSTM treatment may contribute to the positive effects of gold in RA.