Initial combination therapy versus step-up therapy in treatment to the target of remission in daily clinical practice in early rheumatoid arthritis patients: results from the DREAM registry.

BACKGROUND: Treat to target (T2T) is widely accepted as the standard of care for patients with rheumatoid arthritis (RA) and has been shown to be more effective than traditional routine care. The objective of this study was to compare the effectiveness of two T2T strategies in patients with early RA: a step-up approach starting with methotrexate (MTX) monotherapy (cohort I) versus an initial disease-modifying antirheumatic drug combination approach (cohort II). METHODS: A total of 128 patients from cohort II were case-control-matched with 128 patients from cohort I on gender, age, and baseline disease activity. Twelve-month follow-up data were available for 121 patients in both cohorts. The primary outcome was the proportion of patients having reached at least one 28-joint Disease Activity Score (DAS28) score <2.6 (remission) during 12 months of follow-up. Secondary outcomes were time until remission was achieved and mean DAS28 scores at 6- and 12-month follow-up. RESULTS: After 12 months of follow-up, remission was reached at least once in 77.3 % of the patients in cohort II versus 71.9 % in cohort I (P = 0.31). Median time until first remission was 17 weeks in cohort II versus 27 weeks in cohort I (P = 0.04). A significant time by strategy interaction was found in mean DAS28 scores. Post hoc analysis revealed a significant difference in mean DAS28 scores between both cohorts at 6 months (P = 0.04), but not at 12 months (P = 0.36). CONCLUSIONS: The initial combination strategy resulted in a comparable remission rate after 1 year but a significantly shorter time until remission. At 6 months, mean DAS28 scores were lower in patients with initial combination treatment than in those with step-up therapy. At 12 months, no significant differences remained in mean DAS28 scores or the proportion of patients in remission.

Prediction of cardiovascular risk in rheumatoid arthritis: performance of original and adapted SCORE algorithms.

OBJECTIVES: Predictive performance of cardiovascular disease (CVD) risk calculators appears suboptimal in rheumatoid arthritis (RA). A disease-specific CVD risk algorithm may improve CVD risk prediction in RA. The objectives of this study are to adapt the Systematic COronary Risk Evaluation (SCORE) algorithm with determinants of CVD risk in RA and to assess the accuracy of CVD risk prediction calculated with the adapted SCORE algorithm. METHODS: Data from the Nijmegen early RA inception cohort were used. The primary outcome was first CVD events. The SCORE algorithm was recalibrated by reweighing included traditional CVD risk factors and adapted by adding other potential predictors of CVD. Predictive performance of the recalibrated and adapted SCORE algorithms was assessed and the adapted SCORE was externally validated. RESULTS: Of the 1016 included patients with RA, 103 patients experienced a CVD event. Discriminatory ability was comparable across the original, recalibrated and adapted SCORE algorithms. The Hosmer-Lemeshow test results indicated that all three algorithms provided poor model fit (p<0.05) for the Nijmegen and external validation cohort. The adapted SCORE algorithm mainly improves CVD risk estimation in non-event cases and does not show a clear advantage in reclassifying patients with RA who develop CVD (event cases) into more appropriate risk groups. CONCLUSIONS: This study demonstrates for the first time that adaptations of the SCORE algorithm do not provide sufficient improvement in risk prediction of future CVD in RA to serve as an appropriate alternative to the original SCORE. Risk assessment using the original SCORE algorithm may underestimate CVD risk in patients with RA.

Effect of Aerobic Exercise Training on Fatigue in Rheumatoid Arthritis: A Meta-Analysis.

OBJECTIVE: Rheumatoid arthritis (RA) fatigue is not being well-managed currently, and evidence of effective interventions is limited. Aerobic exercise may provide benefit to treat fatigue in RA. Therefore, the purpose of this meta-analysis is to analyze the effect of aerobic land-based exercise on fatigue in RA. METHODS: A literature search was conducted using PubMed, Cochrane Library, Embase, and trial registers to identify randomized controlled trials (RCTs) with a supervised land-based aerobic exercise program performed with an intensity between 50% and 90% of maximal heart rate, of at least 15 minutes' duration, performed at least 2 times a week, and lasting for a time period of at least 4 consecutive weeks. Risk of bias was assessed using the Cochrane tool. A meta-analysis of fatigue outcomes was performed by calculating the standardized mean difference (SMD) using a random-effects model. RESULTS: Five RCTs were included. None of the trials selected patients with RA for having fatigue. Risk of bias was low in 3 RCTs and unclear in 2. Land-based aerobic exercise programs had a positive effect on fatigue in RA compared to no exercise at 12 weeks, SMD -0.31 (95% confidence interval [95% CI] -0.55, -0.06). At 24 weeks, the effect of aerobic land-based exercise was smaller and not statistically significant: SMD -0.15 (95% CI -0.33, 0.02). CONCLUSION: There is evidence with low risk of bias that an aerobic exercise program is effective in reducing fatigue among patients with RA, especially in the short term; however, effects are small. To substantiate the evidence, RCTs should be performed in patients with RA selected for having fatigue.

An increased risk of non-melanoma skin cancer during TNF-inhibitor treatment in psoriasis patients compared to rheumatoid arthritis patients probably relates to disease-related factors.

BACKGROUND: Concerns exist about a risk of non-melanoma skin cancer (NMSC) in psoriasis patients and rheumatoid arthritis (RA) patients treated with TNF-inhibitors. However, current data also show that in some psoriasis patients, NMSC is diagnosed relatively short after the start of TNF-inhibitors, which suggests that these NMSC can be explained by previous therapies instead of by TNF-inhibitor therapy. OBJECTIVE: To investigate whether there was a difference in time until first NMSC and the rate of NMSC between psoriasis and RA patients on TNF-inhibitors. METHODS: Time until first NMSC and the rate of NMSC were compared between psoriasis and RA patients from the same region treated with TNF-inhibitors and followed up for at least one year in prospective cohort studies, by using Cox regression and Poisson regression. Both analyses were corrected for confounders (age, gender, disease duration, prior NMSC, duration of anti-TNF and other systemic therapies). RESULTS: The NMSC risk was significantly higher in the psoriasis group [fully adjusted HR 6.0 (1.6-22.4 95%CI)] with a shorter time until first NMSC in psoriasis compared to RA. By Poisson regression, psoriasis patients had a 5.5 (2.2-13.4 95%CI) higher rate of NMSC. CONCLUSION: The time until first NMSC was significantly shorter and the rate of NMSC was significantly higher in psoriasis compared with RA. This indicates that disease-related factors like phototherapy may be important contributing factors to NMSC diagnosed in psoriasis patients treated with TNF-inhibitors.

The development of the disease activity score (DAS) and the disease activity score using 28 joint counts (DAS28).

In rheumatoid arthritis, disease activity cannot be measured using a single variable. The Disease Activity Score (DAS) has been developed as a quantitative index to be able to measure, study and manage disease activity in RA in daily clinical practice, clinical trials, and long term observational studies. The DAS is a continuous measure of RA disease activity that combines information from swollen joints, tender joints, acute phase response and patient self-report of general health. Cut points were developed to classify patients in remission, as well as low, moderate, and severe disease activity in the 1990s. DAS-based EULAR response criteria were primarily developed to be used in clinical trials to classify individual patients as non-, moderate, or good responders, depending on the magnitude of change and absolute level of disease activity at the conclusion of the test.

The psychophysiological stress response in psoriasis and rheumatoid arthritis.

BACKGROUND: Psychosocial stress can be a risk factor for the maintenance and exacerbation of chronic inflammatory diseases, such as psoriasis and rheumatoid arthritis (RA). OBJECTIVES: To gain insight into the specificity of the psychophysiological stress response during chronic inflammation, we assessed autonomic and neuroendocrine responses to stress in different chronic inflammatory diseases. METHODS: Thirty patients with psoriasis (nine women, mean age 58·5 years ± 12·4), 34 patients with RA (16 women, mean age 60·8 years ± 9·2) and 25 healthy controls (16 women, mean age 55·6 years ± 8·7) underwent a standardized psychosocial stress task (Trier Social Stress Test). Salivary levels of α-amylase and cortisol and self-reported tension levels were measured before and after the stress test. RESULTS: The cortisol response to stress was heightened in patients with psoriasis compared with patients with RA and healthy controls, whereas there were no differences in the autonomic and self-reported measures. CONCLUSIONS: The altered neuroendocrine stress response in patients with psoriasis suggests that stressful events might have different physiological consequences for specific patient groups with chronic inflammatory conditions, possibly adversely affecting disease status.

Additive value for ultrasonographic signal in a screening algorithm for patients presenting with acute mono-/oligoarthritis in whom gout is suspected.

Crystal arthritides such as gout can be detected by ultrasonography (US). This study reveals the performance of joint US (double contour sign (DCS), tophus (T), hyperechoic spots cq. "snow storm" (SS)) for diagnosing gout and calcium pyrophosphate dihydrate crystal deposition disease (CPPD) in patients with acute mono- or oligoarthritis (MOA). The gold standard is the presence of monosodium urate (MSU)/CPPD crystals. Fifty-four Dutch patients had an acute MOA. US was performed on the following six joints maximum: the arthritic joint, the contra lateral side, metatarsophalangeal (MTP)-1, and knees bilaterally in case of arthritis in one of these joints. In case of wrist/PIP/MCP-arthritis, the knees and MTP-1 were scanned. These were examined for DCS, T, SS, and intercartilage rim (CPPD). Synovial fluid was aspirated from the affected joint for MSU proof. Twenty-six of the 54 (48 %) patients with MOA had MSU-proven gout. Sensitivity of DCS and any US abnormality (DCS, T, SS) was 77 and 96 %, respectively. The positive likelihood ratio (LR+) for DCS and any ultrasonographic abnormality (USabn) was 3.08 and 2.99, respectively, and the LR- was 0.31 and 0.06, respectively. In MSU-proven gout patients where the affected joint is not MTP-1, MTP-1 still showed USabn in 42 % of the patients. None of the CPPD patients had an intercartilage rim. In dedicated hands, ultrasonography deserves a place early in a screening algorithm of MOA patients, particularly if specificity is high enough to make punctures abundant or when microscopy is not available. In 86 % of the MSU-proven gout patients, the DCS is not present in another joint other than the affected or MTP-1 joint.

Relationship between objectively assessed physical activity and fatigue in patients with rheumatoid arthritis: inverse correlation of activity and fatigue.

OBJECTIVE: Fatigue is generally associated with low physical activity in patients with various chronic medical conditions. However, such an association has not been reported among patients with rheumatoid arthritis (RA). The objectives of this study were to investigate whether daily activity level is associated with fatigue in patients with RA, and whether pain, disability, coping, and/or cognition are associated with the level of daily activity. METHODS: Patients with RA who visited our outpatient clinic were recruited consecutively. Fatigue severity was measured using the Checklist Individual Strength (CIS20). Physical activity was measured for 14 consecutive days using an ankle-worn actometer. The daily activity level of each patient was calculated, and each patient was classified as having a low or high activity level with respect to the group average. Data were analyzed by linear regression. RESULTS: A total of 167 patients were included in the analysis; 25% had a low activity level and 75% had a high activity level. A regression analysis revealed that higher activity levels were associated with reduced fatigue (P = 0.008). The mean ± SD CIS fatigue score was 30.9 ± 12.3 among the patients with a high activity level and 35.7 ± 12.8 among the patients with a low activity level (P = 0.03). Pain, disability, coping, and cognition were not associated significantly with daily activity level. CONCLUSION: Among patients with RA, a higher level of daily physical activity was associated with reduced levels of fatigue. This relationship was not explained by differences in sex, age, disease duration, pain, disability, or other fatigue-related factors.

Association between fatigue and pain in rheumatoid arthritis: does pain precede fatigue or does fatigue precede pain?

OBJECTIVE: Fatigue and pain are important symptoms for patients with rheumatoid arthritis (RA), but their temporal association is unknown. Therefore, the objective of this study was to investigate the longitudinal relationship between fatigue and pain in patients with RA using time-lag models. METHODS: Consecutive RA outpatients (n = 228) were enrolled for this 1-year study. Fatigue was assessed monthly with the Checklist Individual Strength (CIS; range 8-56) and pain was assessed monthly with the bodily pain subscale (inverted, range 0-100) of the Short Form 36. The association between monthly changes in fatigue and pain was analyzed using longitudinal regression (mixed models), using the same months and with a 1-month time lag. RESULTS: A total of 198 patients were included in the analyses. At baseline, the mean ± SD pain score was 35.23 ± 19.82 and the mean ± SD CIS fatigue score was 31.0 ± 12.4. Severe fatigue at baseline (CIS score ≥35) was present in 42% of the patients. The mean ± SD patient-averaged CIS fatigue score over 1 year was 30.9 ± 6.0 and the mean ± SD patient-averaged pain score over 1 year was 36.4 ± 18.3. The longitudinal regression analysis showed a significant positive relationship between fatigue and pain during the same month (ß = 2.04; 95% confidence interval 1.82, 2.27). The models using a time lag showed no significant association between changes in pain and changes in fatigue. CONCLUSION: In established RA, pain and fatigue show monthly fluctuations that are synchronous rather than showing a temporal relationship with a time lag; within this timeframe, the results do not indicate that one precedes the other.

Sustained beneficial effects of a protocolized treat-to-target strategy in very early rheumatoid arthritis: three-year results of the Dutch Rheumatoid Arthritis Monitoring remission induction cohort.

OBJECTIVE: Treat-to-target (T2T) leads to improved clinical outcomes in early rheumatoid arthritis (RA). The question is whether these results sustain in the long term. Our objective was to investigate the 3-year results of a protocolized T2T strategy in daily clinical practice. METHODS: In the Dutch Rheumatoid Arthritis Monitoring remission induction cohort, patients newly diagnosed with RA were treated according to a T2T strategy aimed at remission (Disease Activity Score in 28 joints [DAS28] <2.6). Patients were treated with methotrexate, followed by the addition of sulfasalazine, and exchange of sulfasalazine with anti-tumor necrosis factor α agents in case of failure. Primary outcomes were disease activity, Health Assessment Questionnaire (HAQ) score, Short Form 36 physical component summary (PCS) and mental component summary (MCS) scores, and the Sharp/van der Heijde score (SHS) after 3 years. Secondary outcomes were sustained DAS28 remission (≥6 months) and remission according to the provisional American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) definition. RESULTS: After 3 years (n = 342), 61.7% of patients were in DAS28 remission and 25.3% met the provisional ACR/EULAR definition of remission. Sustained remission was experienced by 70.5%, which in the majority was achieved with conventional disease-modifying antirheumatic drugs only. The median scores were 0.4 (interquartile range [IQR] 0.0-1.0) for the HAQ, 45.0 (IQR 38.4-53.2) for the PCS, 53.1 (IQR 43.2-60.8) for the MCS, and 6.0 (IQR 3.0-13.0) for the total SHS. CONCLUSION: In very early RA, T2T leads to high (sustained) remission rates, improved physical function and health-related quality of life, and limited radiographic damage after 3 years in daily clinical practice.

Long-term follow-up of the cervical spine with conventional radiographs in patients with rheumatoid arthritis.

OBJECTIVES: To investigate the prevalence of cervical spine damage due to rheumatoid arthritis (RA) in the long term and to investigate which disease-specific factors are related to this damage. METHOD: Patients with early RA from the Nijmegen inception cohort with 6 to 12 years of follow-up were included. Conventional radiographs of the cervical spine were obtained at baseline, 3, 6, 9, and 12 years and scored for erosions of C1 and C2, anterior atlantoaxial subluxation (AAS) and atlantoaxial impaction (AAI). Disease-specific factors, such as disease activity, functionality, and peripheral joint damage, at baseline, 3, 6, and 9 years, were compared between patients with and without cervical spine damage at 9 years. RESULTS: A total of 196 patients were included, of whom 134 had radiographs at 9 years. Cervical spine damage was present in 16% (22/134) of the patients at 9 years. During the total 12 years of follow-up, AAS and erosions of C2 were observed most frequently. Erosions of C1 and AAI were very rare. Patients with cervical spine damage at 9 years had a higher number of erosions of the peripheral joints and failed more disease-modifying anti-rheumatic drugs (DMARDs) at 3, 6, and 9 years. Patients without peripheral erosive disease at 3 years were unlikely to develop cervical spine damage within 9 years of disease duration. CONCLUSIONS: The prevalence of cervical spine damage due to RA was 16% at 9 years. Patients without peripheral erosive disease at 3 years were unlikely to develop cervical spine damage at 9 years.

The effect of anti-TNF-α vs. DMARDs on fatigue in rheumatoid arthritis patients.

OBJECTIVES: Fatigue is experienced frequently by patients with rheumatoid arthritis (RA). Fatigue may be caused by high levels of pain and disease activity in RA but can remain present while disease activity is moderate to low. It is not clear whether RA patients receiving anti-tumour necrosis factor (TNF) treatment reach lower levels of acute fatigue than RA patients receiving disease-modifying anti-rheumatic drug (DMARD) treatment. The aim of our study was to analyse whether, in patients with RA, the effect of anti-TNF on fatigue is greater than the effect of DMARD treatment. METHOD: Sixty-seven RA patients receiving anti-TNF treatment and 104 RA patients receiving DMARDs were included. All patients were on stable treatment for at least 6 months prior to baseline measurement. Fatigue was measured monthly over 1 year with the fatigue severity subscale of the Checklist Individual Strength (CIS-fatigue). The association between persistent severe fatigue and medication group was analysed using multiple linear regression including confounders. RESULTS: In the anti-TNF group the mean (SD) level of persistent fatigue was significantly higher than in the DMARD group [32.2 (11.4) vs. 28.3 (10.9), p = 0.025] and more patients experienced persistent severe (CIS-fatigue score ≥ 35) fatigue (42% and 27% respectively, p = 0.043). However, when correcting for age, disease activity, haemoglobin, treatment duration, pain, physical disability, and clinical depression, medication type seemed to influence neither the mean level of persistent fatigue (p = 0.251) nor the percentage of patients with persistent severe fatigue (p = 0.745). CONCLUSIONS: When taking into account probable confounders including disease activity, medication type did not influence persistent fatigue in RA patients. It seems that, besides its anti-inflammatory effect, anti-TNF has no complementary effect on persistent fatigue.

Role of induced negative and positive emotions in sensitivity to itch and pain in women.

BACKGROUND: Itch and pain are common symptoms in skin disease. It has been suggested that negative emotions may play a role in itch and pain. To date, however, the role of emotions has only been studied for pain in experimental studies, not yet for itch. OBJECTIVES: To investigate the effects of negative and positive emotions on the sensitivity to itch and pain. METHODS: Film fragments were used to induce a negative or positive emotional state in healthy women. Itch and pain were induced using the following somatosensory stimuli: electrical stimulation, histamine iontophoresis and the cold pressor test. RESULTS: Results showed that the scores for itch and pain evoked by histamine and the cold pressor test, respectively, were significantly higher in the negative than in the positive emotion condition, whereas tolerance thresholds to electrical stimulation and the cold pressor test, and stimulus unpleasantness scores did not differ between the two conditions. CONCLUSIONS: These findings for the first time indicate in an experimental design that emotions play a role in sensitivity to somatosensory sensations of both itch and pain.

Prevalence and predictors of health care use in patients with early hip or knee osteoarthritis: two-year follow-up data from the CHECK cohort.

OBJECTIVE: To describe health care utilization (HCU) and predict analgesic use and health professional (HP) contact at baseline and 2 years in individuals with early symptomatic hip and/or knee osteoarthritis (OA). DESIGN: Baseline and two-year data on HCU of the 1002 participants from the multi-centre Cohort Hip & Cohort Knee study were used. Six forms of health care services were described: analgesic use, supplement use, contact with a General Practitioner (GP), contact with a HP, contact in secondary care, and alternative medicine use. Multivariable logistic regression was performed in order to identify predisposing, enabling and disease-related variables that predict analgesic use and HP contact at 2 years; treatment modalities of first choice in early OA. RESULTS: For the hip (n=170), the knee (n=414) and the hip and knee (n=418) group analgesic use (38%, 29% and 47%, respectively), contact with a GP (32%, 38% and 36%, respectively) and contact with a HP (26%, 18% and 20%, respectively), were reported most often at baseline. Contact with a GP significantly decreased, supplement use increased (to about one third), and other treatment modalities remained stable at 2 years. In all three groups, analgesic use at baseline was the strongest predictor for analgesic use at 2 years, whereas contact with a HP at baseline was the strongest predictor of contact with a HP after 2 years. Belonging to a first generation minority was a predisposing risk factor [Odds Ratio (95%-CI), 8.72 (1.55-48.97)] for analgesic use in the hip and knee group. CONCLUSIONS: In early OA, familiarity with HCU and other predisposing factors are, apart from disease-related factors strongly associated with HCU at 2 years. Further research is necessary to examine whether our findings reflect sub-optimal management of early OA in terms of efficacy and equity.

Abatacept modulates proinflammatory macrophage responses upon cytokine-activated T cell and Toll-like receptor ligand stimulation.

OBJECTIVES: We investigated whether Abatacept might reduce proinflammatory cytokine production by macrophages upon contact with cytokine activated T cells and/or stimulation with TLR ligands. METHODS: Macrophages and cytokine stimulated T cells (Tck) were added together in the presence of Abatacept or a control Ig, with or without TLR ligands. The production of cytokines was determined by luminex. RESULTS: Abatacept reduced Tck-induced production of TNFa by macrophages. Tck and TLR ligands synergistically induced the production of proinflammatory cytokines by macrophages, especially IL-12p70. The production of IL-12p70 coincided with the production of IFNg, which were both reduced in the presence of Abatacept. CONCLUSIONS: Tck induce the production of TNFa by macrophages and facilitate the highly increased production of proinflammatory cytokines in the presence of TLR ligands. Abatacept was shown to potently suppress these pathways suggesting that its role may extend beyond antigen specific T cell mediated effector function.

Tailored cognitive-behavioural therapy and exercise training improves the physical fitness of patients with fibromyalgia.

OBJECTIVES: Patients with fibromyalgia have diminished levels of physical fitness, which may lead to functional disability and exacerbating complaints. Multidisciplinary treatment comprising cognitive-behavioural therapy (CBT) and exercise training has been shown to be effective in improving physical fitness. However, due to the high drop-out rates and large variability in patients' functioning, it was proposed that a tailored treatment approach might yield more promising treatment outcomes. METHODS: High-risk fibromyalgia patients were randomly assigned to a waiting list control group (WLC) or a treatment condition (TC), with the treatment consisting of 16 twice-weekly sessions of CBT and exercise training tailored to the patient's cognitive-behavioural pattern. Physical fitness was assessed with two physical tests before and 3 months after treatment and at corresponding intervals in the WLC. Treatment effects were evaluated using linear mixed models. RESULTS: The level of physical fitness had improved significantly in the TC compared with the WLC. Attrition rates were low, effect sizes large and reliable change indices indicated a clinically relevant improvement among the TC. CONCLUSIONS: A tailored multidisciplinary treatment approach for fibromyalgia consisting of CBT and exercise training is well tolerated, yields clinically relevant changes, and appears a promising approach to improve patients' physical fitness. ClinicalTrials.gov ID NCT00268606.