Marije F. Bakker

Low-Dose Prednisone Inclusion in a Methotrexate-Based, Tight Control Strategy for Early Rheumatoid Arthritis: A Randomized Trial

BACKGROUND Treatment strategies for tight control of early rheumatoid arthritis (RA) are highly effective but can be improved. OBJECTIVE To investigate whether adding prednisone, 10 mg/d, at the start of a methotrexate (MTX)-based treatment strategy for tight control in early RA increases its effectiveness. DESIGN A 2-year, prospective, randomized, placebo-controlled, double-blind, multicenter trial (CAMERA-II [Computer Assisted Management in Early Rheumatoid Arthritis trial-II]). (International Standard Randomised Controlled Trial Number: ISRCTN 70365169) SETTING 7 hospitals in the Netherlands. PATIENTS 236 patients with early RA (duration <1 year). INTERVENTION Patients were randomly assigned to an MTX-based, tight control strategy starting with either MTX and prednisone or MTX and placebo. Methotrexate treatment was tailored to the individual patient at monthly visits on the basis of predefined response criteria aiming for remission. MEASUREMENTS The primary outcome was radiographic erosive joint damage after 2 years. Secondary outcomes included response criteria, remission, and the need to add cyclosporine or a biologic agent to the treatment. RESULTS Erosive joint damage after 2 years was limited and less in the group receiving MTX and prednisone (n = 117) than in the group receiving MTX and placebo (n = 119). The MTX and prednisone strategy was also more effective in reducing disease activity and physical disability, achieving sustained remission, and avoiding the addition of cyclosporine or biologic treatment. Adverse events were similar in both groups, but some occurred less in the MTX and prednisone group. LIMITATION A tight control strategy for RA implies monthly visits to an outpatient clinic, which is not always feasible. CONCLUSION Inclusion of low-dose prednisone in an MTX-based treatment strategy for tight control in early RA improves patient outcomes. PRIMARY FUNDING SOURCE Catharijne Foundation.

Tight control in the treatment of rheumatoid arthritis: efficacy and feasibility

Objective: To evaluate the available evidence on the efficacy and feasibility of the new concept of tight control in randomised trials in patients with rheumatoid arthritis (RA). Tight control is a treatment strategy tailored to the individual patient with RA, which aims to achieve a predefined level of low disease activity or remission within a certain period of time. Methods: The literature database PubMed was searched and yielded four trials: the FIN-RACo trial, the TICORA study, the BeSt study and the CAMERA study. Results: Tight control resulted in greater improvement and a higher percentage of patients meeting the preset aim of low disease activity or remission when compared to the control intervention. In the FIN-RACo trial, aimed at DAS28<2.6, 51% of patients in the tight control group achieved remission versus 16% in the contrast group (p<0.001). In the TICORA study, 65% of patients in the tight control group versus 16% of the contrast group achieved remission, based on DAS<1.6 (p<0.0001). In the CAMERA study, 50% of patients in the tight control group using a computer decision model achieved remission, versus 37% in the contrast group (p = 0.029). The BeSt study consisted of only tight control groups aimed at a DAS<1.6; remission was achieved in 38–46% of patients. This is higher than the range of remission in earlier trials of 13–36%. Conclusion: Tight control aiming for low disease activity or even better still, remission, seems a promising option in treating patients with RA in clinical trials and probably also in daily practice.

Mammographic Density Phenotypes and Risk of Breast Cancer: A Meta-analysis

BACKGROUND Fibroglandular breast tissue appears dense on mammogram, whereas fat appears nondense. It is unclear whether absolute or percentage dense area more strongly predicts breast cancer risk and whether absolute nondense area is independently associated with risk. METHODS We conducted a meta-analysis of 13 case-control studies providing results from logistic regressions for associations between one standard deviation (SD) increments in mammographic density phenotypes and breast cancer risk. We used random-effects models to calculate pooled odds ratios and 95% confidence intervals (CIs). All tests were two-sided with P less than .05 considered to be statistically significant. RESULTS Among premenopausal women (n = 1776 case patients; n = 2834 control subjects), summary odds ratios were 1.37 (95% CI = 1.29 to 1.47) for absolute dense area, 0.78 (95% CI = 0.71 to 0.86) for absolute nondense area, and 1.52 (95% CI = 1.39 to 1.66) for percentage dense area when pooling estimates adjusted for age, body mass index, and parity. Corresponding odds ratios among postmenopausal women (n = 6643 case patients; n = 11187 control subjects) were 1.38 (95% CI = 1.31 to 1.44), 0.79 (95% CI = 0.73 to 0.85), and 1.53 (95% CI = 1.44 to 1.64). After additional adjustment for absolute dense area, associations between absolute nondense area and breast cancer became attenuated or null in several studies and summary odds ratios became 0.82 (95% CI = 0.71 to 0.94; P heterogeneity = .02) for premenopausal and 0.85 (95% CI = 0.75 to 0.96; P heterogeneity < .01) for postmenopausal women. CONCLUSIONS The results suggest that percentage dense area is a stronger breast cancer risk factor than absolute dense area. Absolute nondense area was inversely associated with breast cancer risk, but it is unclear whether the association is independent of absolute dense area.

Dietary fiber intake and risk of hormonal receptor–defined breast cancer in the European Prospective Investigation into Cancer and Nutrition study

BACKGROUND Limited scientific evidence has characterized the association between dietary fiber intake and risk of breast cancer (BC) by menopausal status and hormone receptor expression in tumors. OBJECTIVE We investigated the relation between total dietary fiber and its main food sources (vegetables, fruit, cereals, and legumes) and BC risk by using data from the European Prospective Investigation into Cancer and Nutrition (EPIC). DESIGN A total of 11,576 invasive BC cases in 334,849 EPIC women mostly aged 35-70 y at baseline were identified over a median follow-up of 11.5 y. Dietary fiber was estimated from country-specific dietary questionnaires. Multivariable Cox proportional hazards regression models were used to quantify the association between dietary variables and BC risk with energy adjustment by using the residual method. Subgroup analyses were performed by menopausal status and estrogen receptor (ER) and progesterone receptor (PR) expression in tumors. RESULTS BC risk was inversely associated with intakes of total dietary fiber [hazard ratio comparing fifth quintile to first quintile (HR(Q5-Q1)): 0.95; 95% CI: 0.89, 1.01; P-trend = 0.03] and fiber from vegetables (0.90; 0.84, 0.96; P-trend < 0.01) but not with fiber from fruit, cereals, or legumes. Overall, associations were homogeneous by menopausal status and ER and PR expression in tumors. For vegetable fiber, stronger associations were observed for estrogen receptor-negative and progesterone receptor-negative (HR(Q5-Q1):0.74; 95% CI: 0.59, 0.93; P-trend = 0.01) than for estrogen receptor-positive and progesterone receptor-positive tumors (0.92: 0.81, 1.03; P-trend = 0.05), with P-heterogeneity = 0.09. CONCLUSION Diets rich in dietary fiber and, particularly, fiber from vegetables may be associated with a small reduction in risk of BC, independently of menopausal status.

Look Beyond the Disease Activity Score of 28 Joints (DAS28): Tender Points Influence the DAS28 in Patients with Rheumatoid Arthritis

Objective. To explore the influence of tender points (TP) on the Disease Activity Score assessing 28 joints (DAS28) in patients with rheumatoid arthritis (RA). Methods. In 200 consecutive patients with RA from the outpatient clinic, DAS28 and its components, tender and swollen joint counts (TJC, SJC, respectively), visual analog scale (VAS) for patient’s general health (GH), and erythrocyte sedimentation rate (ESR), along with a tender point count (TPC) were assessed. Patients were categorized according to 4 TPC classes: zero, 1–5, 6–10, and ≥ 11 TP. The influence of TPC classes on DAS28 and its individual components was determined with Kruskal-Wallis tests and correlations between TP and DAS28 and its components were calculated. Results. In 196 eligible patients, 70% were female, mean age was 59 years, and median disease duration was 3.9 years; median DAS28 was 3.1; and 49% had active disease, defined as DAS28 > 3.2. In 15% of patients, the TPC was ≥ 11, in 12% 6–10, in 30% 1–5, and in 43% zero. TPC significantly influenced the DAS28 and its less objective components TJC and VAS-GH (i.e., based on patient’s report), but not the more objective DAS28 components SJC and ESR (i.e., observer- and laboratory-based). Conclusion. DAS28 is influenced by tender points, even in the non-fibromyalgia range, falsely suggesting higher disease activity and decreasing the sensitivity of the DAS28 criterion of low disease activity or remission. When applying DAS28-guided “tight control” or “treat-to-target” treatment strategies in RA, evaluation of not only the DAS28, but also its individual components along with a full joint and physical evaluation including assessment of TP is required to reliably estimate the individual’s disease activity, which guides therapeutic decisions.

Early clinical response to treatment predicts 5-year outcome in RA patients: follow-up results from the CAMERA study

Objective To investigate the long-term effects of the tight control (TC) and conventional (CT) methotrexate-based strategies of the Computer Assisted Management in Early Rheumatoid Arthritis trial in early rheumatoid arthritis and evaluate the predictive value of an early response to treatment. Methods Clinical and radiographic 5-year outcome was compared between initial strategies. Patients were classified according to the EULAR response criteria. The prognostic value of early response to treatment in addition to established predictors was analysed by multiple linear regression analyses. Results 5 years of data were available for 205 of 299 patients, with no indication for selective drop-out. At 5 years there was no longer any significant difference for clinical and radiographic outcomes between treatment strategies applied during the first 2 years. Good-responders had a mean disease activity score of 2.39 (1.2) and median yearly radiographic progression rate of 0.6 (0.0 to 2.2) at 5 years; significantly lower (both p<0.02) when compared to moderate- and non-responders. Multiple regression analysis showed that early response to treatment is an independent predictor of 5-year outcome, irrespective of treatment strategy. Conclusions The difference in disease activity between treatment strategies disappeared over the years. Good-response to treatment independently predicts significantly better 5-year clinical and radiographic outcome. The TC principle probably should be continued in the long-term.

Adverse events and factors associated with toxicity in patients with early rheumatoid arthritis treated with methotrexate tight control therapy: the CAMERA study

Objective To evaluate toxicity profiles in patients with rheumatoid arthritis (RA) treated either according to an intensive or a conventional treatment strategy approach with methotrexate (MTX) and to study factors associated with MTX-related toxicity. Methods Data were used from the Computer-Assisted Management in Early Rheumatoid Arthritis (CAMERA) study, in which clinical efficacy of an intensive treatment strategy with MTX was more beneficial than a conventional treatment strategy approach. In this study, data on adverse events (AEs) were compared between the two strategy groups. Logistic regression analyses were used to identify possible associations between factors assessed at baseline and withdrawal due to MTX-related AEs or liver toxicity at follow-up. Results Although significantly more patients in the intensive strategy group experienced MTX-related AEs than in the conventional strategy group, all recorded AEs were relatively mild. A higher body mass index (BMI) was significantly associated with withdrawal due to MTX-related AEs in the multiple regression analyses (odds ratio=1.207, 95% confidence interval 1.02 to 1.44, p=0.033). There was a trend towards an association between diminished creatinine clearance and MTX withdrawal. For liver toxicity, increased serum liver enzymes at baseline were associated with liver toxicity during follow-up. Conclusion Although the occurrence of AEs in the intensive strategy group was higher than in the conventional strategy group, the previously observed clinical efficacy of an intensive treatment strategy seems to outweigh the observed toxicity profiles. When starting MTX, attention should be given to patients with a high BMI and those with increased levels of liver enzymes and decreased renal function.

Are switches from oral to subcutaneous methotrexate or addition of ciclosporin to methotrexate useful steps in a tight control treatment strategy for rheumatoid arthritis? A post hoc analysis of the CAMERA study

Objective To investigate the effects of a switch from oral methotrexate (MTX) to subcutaneous MTX (scMTX) or adding ciclosporin to oral MTX with a simultaneous reduction of the MTX dose, in case of adverse events (AE) or insufficient effect (IE) in rheumatoid arthritis (RA). Methods The tight control treatment arm of the Computer Assisted Management in Early RA (CAMERA) trial was evaluated. The change in 28-joint Disease Activity Score (DAS28) after taking scMTX (over 1 month) or adding ciclosporin (over 3 months) was compared to the average monthly change in the preceding 3 months. Analyses were performed separately for strategy steps because of AE or IE. Results Of 151 patients, 57 needed the scMTX strategy step (21 because of AE, 36 because of IE) and 40 the following ciclosporin strategy step (20 and 20, respectively). The decrease in DAS28 after taking the scMTX strategy step was 0.30 points (p<0.05); no significant change in DAS28 was seen after the ciclosporin strategy step. In both strategy steps for AE or IE, quite similar observations were made. Of the patients who took the scMTX strategy step, 63% showed improvement. Conclusion scMTX seems a useful treatment step after oral MTX in a tight control strategy, whereas the ciclosporin step seems ineffective.

Misclassification of disease activity when assessing individual patients with early rheumatoid arthritis using disease activity indices that do not include joints of feet

Objective To study whether assessment of rheumatoid arthritis (RA) disease activity in individual patients using the disease activity score in 28 joints (DAS28) or other instruments excluding joints of feet may lead to misclassification of disease activity. Methods A cohort of RA patients was classified into three ‘regional radiographic damage progression’ groups: predominantly progression in feet, similar progression in hands and feet and predominantly progression in hands; both in early (0–2 years) and later (2–5 years) disease. Baseline and mean DAS28, individual DAS28 variables and tender joint counts (TJC) and swollen joint counts (SJC) of the feet were compared between groups. The longitudinal relation of DAS28 with radiographic damage was investigated using a mixed model analysis with rheumatoid factor status, baseline joint damage and TJC and SJC of the feet as covariates. Results Early (n=265) and later (n=200) in the disease course, by definition, the classification procedure resulted in 25% as predominantly foot, 25% as predominantly hand and 50% as similar progressors. In early RA predominantly foot progressors had higher TJC and SJC of the feet compared with predominantly hand progressors (p<0.001), but DAS28 was similar. This was not seen in later disease. The longitudinal relation between DAS28 and radiographic progression was influenced by the region of progression (predominantly foot progressors vs others, p<0.001), suggesting that DAS28 underestimates disease activity in predominantly foot progressors. In this group, joint counts for the feet were independently related to radiographic progression. Conclusions DAS28 underestimates actual disease activity and expected joint damage of individual early RA patients predominantly with disease in the feet.

Weight change in middle adulthood and breast cancer risk in the EPIC-PANACEA study

Long‐term weight gain (i.e., weight gain since age 20) has been related to higher risk of postmenopausal breast cancer, but a lower risk of premenopausal breast cancer. The effect of weight change in middle adulthood is unclear. We investigated the association between weight change in middle adulthood (i.e., women aged 40–50 years) and the risk of breast cancer before and after the age of 50. We included female participants of the European Prospective Investigation into Cancer and Nutrition cohort, with information on anthropometric measures at recruitment and after a median follow‐up of 4.3 years. Annual weight change was categorized using quintiles taking quintile 2 and 3 as the reference category (−0.44 to 0.36 kg/year). Multivariable Cox proportional hazards regression analysis was used to examine the association. 205,723 women were included and 4,663 incident breast cancer cases were diagnosed during a median follow‐up of 7.5 years (from second weight assessment onward). High weight gain (Q5: 0.83–4.98 kg/year) was related to a slightly, but significantly higher breast cancer risk (HRQ5_versus_Q2/3: 1.09, 95% CI: 1.01−1.18). The association was more pronounced for breast cancer diagnosed before or at age 50 (HRQ5_versus_Q2/3: 1.37, 95% CI: 1.02−1.85). Weight loss was not associated with breast cancer risk. There was no evidence for heterogeneity by hormone receptor status. In conclusion, high weight gain in middle adulthood increases the risk of breast cancer. The association seems to be more pronounced for breast cancer diagnosed before or at age 50. Our results illustrate the importance of avoiding weight gain in middle adulthood.