Towards developing diagnostic criteria for early knee osteoarthritis: data from the CHECK study.

OBJECTIVES: There is a general consensus that a shift in focus towards early diagnosis and treatment of knee OA is warranted. However, there are no validated and widely accepted diagnostic criteria for early knee OA available. The current study aimed to take the first steps towards developing diagnostic criteria for early knee OA. METHODS: Data of 761 individuals with 1185 symptomatic knees at baseline were selected from the CHECK study. For CHECK, individuals with pain/stiffness of the knee, aged 45-65 years, who had no prior consultation or a first consultation with the general practitioner for these symptoms in the past 6 months were recruited and followed for 10 years. A group of 36 experts (17 general practitioners and 19 secondary care physicians) evaluated the medical records in pairs to diagnose the presence of clinically relevant knee OA 5-10 years after enrolment. A backward selection methods was used to create predictive models based on pre-defined baseline factors from history taking, physical examination, radiography and blood testing, using the experts' diagnoses as gold standard outcome. RESULTS: Prevalence of clinically relevant knee OA during follow-up was 37%. Created models contained 7-11 baseline factors and obtained an area under the curve between 0.746 (0.002) and 0.764 (0.002). CONCLUSION: The obtained diagnostic models for early knee OA had 'fair' predictive ability in individuals presenting with knee pain in primary care. Further modelling and validation of the identified predictive factors is required to obtain clinically feasible and relevant diagnostic criteria for early knee OA.

The multi-biomarker disease activity test for assessing response to treatment strategies using methotrexate with or without prednisone in the CAMERA-II trial.

OBJECTIVES: The CAMERA-II trial compared two tight-control, treat-to-target strategies, initiating methotrexate with prednisone (MTX+pred) or MTX with placebo (MTX+plac), in early RA-patients. The multi-biomarker disease activity (MBDA) blood test objectively measures RA disease activity with a score of 1-100. In CAMERA-II, response profiles of the MBDA score, its individual biomarkers, and DAS28 were assessed. METHODS: We evaluated 92 patients from CAMERA-II of whom clinical data and serum for MBDA testing at baseline and ≥ 1 time-point from months 1, 2, 3, 4, 5, 6, 9, or 12 were available. Changes (∆) from baseline for DAS28 and MBDA score and comparisons of ∆DAS28 and ∆MBDA score over time within the MTX+pred versus the MTX+plac strategy were tested for significance with t tests. Changes in biomarker concentration from baseline to months 1-5 were tested with Wilcoxon signed rank test and tested for difference between treatment arms by Mann-Whitney U test. RESULTS: MBDA and DAS28 showed similar response profiles, with gradual improvement over the first 6 months in the MTX+plac group, and in the MTX+pred group faster improvement during month 1, followed by gradual improvement. The 12 MBDA biomarkers could be grouped into 4 categories of response profiles, with significant responses for 4 biomarkers during the MTX+plac strategy and 9 biomarkers during the MTX+pred strategy. CONCLUSIONS: MBDA tracked treatment response in CAMERA-II similarly to DAS28. More individual MBDA biomarkers tracked treatment response to MTX+pred than to MTX+plac. Four response profiles could be observed. TRIAL REGISTRATION: CAMERA-II International Standard Randomised Controlled Trial Number: ISRCTN 70365169 . Registered on 29 March 2006, retrospectively registered.

Effectiveness of Remission Induction Strategies for Early Rheumatoid Arthritis: a Systematic Literature Review.

PURPOSE OF REVIEW: To review the effectiveness of remission induction strategies compared to single csDMARD-initiating strategies according to current guidelines in early RA. RECENT FINDINGS: Twenty-nine studies, heterogeneous on, e.g., specific treatment strategy and remission outcome used, were identified. Using DAS28-remission over 12 months, 13 (76%) of 17 remission induction strategies showed significantly more patients achieving remission. Pooled relative "risk" was 1.73 [95%CI 1.59-1.88] for bDMARD-based remission induction strategies and 1.20 [95%CI 1.03-1.40] for combination csDMARD-based remission induction strategies compared to single csDMARD-initiating strategies. When additional glucocorticoid "bridging therapy" was used in single csDMARD-initiating strategies, the higher proportion patients achieving remission in remission induction strategies was no longer statistically significant (pooled RR 1.06 [95%CI 0.83-1.35]). For other remission outcomes, results were in line with above. Remission induction strategies are more effective in achieving remission compared to single csDMARD-initiating strategies, possibly more so in bDMARD-based induction strategies. However, compared to single csDMARD-initiating strategies with glucocorticoids, induction strategies may not be more effective.

Cross-sectional survey of the undergraduate rheumatology curriculum in European medical schools: a EULAR School of Rheumatology initiative.

OBJECTIVES: To survey the undergraduate rheumatic and musculoskeletal diseases (RMDs) curriculum content in a sample of medical schools across Europe. METHODS: The undergraduate musculoskeletal diseases and disability curriculum of University of Nottingham, UK, was used as a template to develop a questionnaire on curriculum content. The questionnaire elicited binary (yes/no) responses and included the option to provide additional information as free text. The survey was mailed to members of the European League Against Rheumatism (EULAR) School of Rheumatology (Undergraduate Classroom) and to EULAR Standing Committee on Education and Training members in January 2017, with a reminder in February 2017. RESULTS: Responses were received from 21 schools belonging to 11 countries. Assessment of gait, hyperalgesic tender site response and hypermobility were not included in many curricula. Similarly, interpretation of investigations undertaken on synovial fluid was taught in only 16 schools. While disease-modifying anti-rheumatic drugs and biological agents, and urate-lowering treatment were included in the curricula of 20 and 21 institutions, respectively, only curricula from 18 schools included core non-pharmacological interventions. Osteoarthritis, gout, rheumatoid arthritis, spondyloarthropathy, polymyalgia rheumatica and lupus were included in the curriculum of all institutions. However, common RMDs such as calcium pyrophosphate deposition, fibromyalgia, giant cell arteritis and bone and joint infection were included in 19 curricula. CONCLUSION: This survey highlights areas of similarities and differences in undergraduate curricula across Europe. It is hoped that the results of this survey will catalyse the development and agreement of a minimum core European Curriculum for undergraduate education in RMDs.

[Impaired immunity: risk groups and consequences for general practice]. / Verminderde afweer.

- Due to medication use, comorbidities and/or age, an increasing number of patients have an impaired immunity to infection.- Impaired immunity may lead to an increased risk of (opportunistic) infection, complications from infections, and difficulties in the diagnosis of infections.- Guided by clinical parameters, a general practitioner can classify an impaired immunity as 'clinically irrelevant', 'limitedly relevant' or 'potentially serious'.- Tocilizumab impairs the production of CRP, which makes it unreliable as an infection parameter.- In case of a suspected infection in patients with severe immunosuppression, it will often be necessary to consult a specialist as quickly as possible about further diagnostic procedures and the need for, type and administration route of antimicrobials.- In patients with an impaired immunity, adaptation of the antibiotic policy and prophylactic measures, such as vaccination, may be indicated.- Patients with (functional) asplenia should immediately start antibiotic treatment in case of fever, pending clinical evaluation by a physician.

A Personalized Approach to Biological Therapy Using Prediction of Clinical Response Based on MRP8/14 Serum Complex Levels in Rheumatoid Arthritis Patients.

OBJECTIVES: Measurement of MRP8/14 serum levels has shown potential in predicting clinical response to different biological agents in rheumatoid arthritis (RA). We aimed to develop a treatment algorithm based on a prediction score using MRP8/14 measurements and clinical parameters predictive for response to different biological agents. METHODS: Baseline serum levels of MRP8/14 were measured in 170 patients starting treatment with infliximab, adalimumab or rituximab. We used logistic regression analysis to develop a predictive score for clinical response at 16 weeks. MRP8/14 levels along with clinical variables at baseline were investigated. We also investigated how the predictive effect of MRP8/14 was modified by drug type. A treatment algorithm was developed based on categorizing the expected response per drug type as high, intermediate or low for each patient and optimal treatment was defined. Finally, we present the utility of using this treatment algorithm in clinical practice. RESULTS: The probability of response increased with higher baseline MRP8/14 complex levels (OR = 1.39), differentially between the TNF-blockers and rituximab (OR of interaction term = 0.78), and also increased with higher DAS28 at baseline (OR = 1.28). Rheumatoid factor positivity, functional disability (a higher HAQ), and previous use of a TNF-inhibitor decreased the probability of response. Based on the treatment algorithm 80 patients would have been recommended for anti-TNF treatment, 8 for rituximab, 13 for another biological treatment (other than TNFi or rituximab) and for 69 no recommendation was made. The predicted response rates matched the observed response in the cohort well. On group level the predicted response based on the algorithm resulted in a modest 10% higher response rate in our cohort with much higher differences in response probability in individual patients treated contrary to treatment recommendation. CONCLUSIONS: Prediction of response using MRP8/14 levels along with clinical predictors has potential in personalizing treatment for RA patients starting biological anti-rheumatic treatment, and might increase cost-effectiveness.

The OA Trial Bank: meta-analysis of individual patient data from knee and hip osteoarthritis trials show that patients with severe pain exhibit greater benefit from intra-articular glucocorticoids.

OBJECTIVE: To evaluate the efficacy of intra-articular (IA) glucocorticoids for knee or hip osteoarthritis (OA) in specific subgroups of patients with severe pain and inflammatory signs using individual patient data (IPD) from existing trials. DESIGN: Randomized trials evaluating one or more IA glucocorticoid preparation in patients with knee or hip OA, published from 1995 up to June 2012 were selected from the literature. IPD obtained from original trials included patient and disease characteristics and outcomes measured. The primary outcome was pain severity at short-term follow-up (up to 4 weeks). The subgroup factors assessed included severe pain (≥70 points, 0-100 scale) and signs of inflammation (dichotomized in present or not) at baseline. Multilevel regression analyses were applied to estimate the magnitude of the effects in the subgroups with the individuals nested within each study. RESULTS: Seven out of 43 published randomized clinical trials (n = 620) were included. Patients with severe baseline pain had a significantly larger reduction in short-term pain, but not in mid- and long-term pain, compared to those with less severe pain at baseline (Mean Difference 13.91; 95% Confidence Interval 1.50-26.31) when receiving IA glucocorticoid injection compared to placebo. No statistical significant interaction effects were found between inflammatory signs and IA glucocorticoid injections compared to placebo and to tidal irrigation at all follow-up points. CONCLUSIONS: This IPD meta-analysis demonstrates that patients with severe knee pain at baseline derive more benefit from IA glucocorticoid injection at short-term follow-up than those with less severe pain at baseline.

Assessment of disease activity in patients with rheumatoid arthritis using optical spectral transmission measurements, a non-invasive imaging technique.

OBJECTIVES: In rheumatoid arthritis (RA), treat-to-target strategies require instruments for valid detection of joint inflammation. Therefore, imaging modalities are increasingly used in clinical practice. Optical spectral transmission (OST) measurements are non-invasive and fast and may therefore have benefits over existing imaging modalities. We tested whether OST could measure disease activity validly in patients with RA. METHODS: In 59 patients with RA and 10 patients with arthralgia, OST, joint counts, Disease Activity Score (DAS) 28 and ultrasonography (US) were performed. Additionally, MRI was performed in patients with DAS28<2.6. We developed and validated within the same cohort an algorithm for detection of joint inflammation by OST with US as reference. RESULTS: At the joint level, OST and US performed similarly inproximal interphalangeal-joints (area under the receiver-operating curve (AUC) of 0.79, p<0.0001) andmetacarpophalangeal joints (AUC 0.78, p<0.0001). Performance was less similar in wrists (AUC 0.62, p=0.006). On the patient level, OST correlated moderately with clinical examination (DAS28 r=0.42, p=0.001), and US scores (r=0.64, p<0.0001). Furthermore, in patients with subclinical and low disease activity, there was a correlation between OST and MRI synovitis score (RAMRIS (Rheumatoid Arthritis MRI Scoring) synovitis), r=0.52, p=0.005. CONCLUSIONS: In this pilot study, OST performed moderately in the detection of joint inflammation in patients with RA. Further studies are needed to determine the diagnostic performance in a new cohort of patients with RA.

Crying Without Tears: Dimensions of Crying and Relations With Ocular Dryness and Mental Well-Being in Patients With Sjögren's Syndrome.

This study examined dimensions of crying and its relations with ocular dryness and mental well-being in patients with Sjögren's syndrome, a systemic autoimmune disease with dryness as primary symptom. Three-hundred patients with Sjögren's syndrome completed questionnaires on crying, dryness, and well-being. The crying questionnaire revealed four dimensions: "Cryability" (comprising both crying sensibility and ability to cry), Somatic consequences, Frustration, and Suppression. Compared to 100 demographically-matched control participants from the general population, patients scored low on Cryability and high on Somatic consequences and Frustration. The crying dimensions generally showed significant but weak associations with ocular dryness and mental well-being in patients. This is the first quantitative study indicating that crying problems are more common in patients with Sjögren's syndrome than in the general population. Perhaps, patients who experience problems with crying could be helped to rely on other ways of expressing emotions than crying in tear-inducing situations.

Novel glucocorticoids: where are we now and where do we want to go?

Glucocorticoid (GC) therapy is widely accepted as effective treatment for many inflammatory conditions. However, the potential of GC to produce adverse effects may prompt both patients and prescribing doctors to take a critical view on these important drugs. The increasing awareness of potential side effects suggests that the improvement of the benefit:risk ratio represents both a current need and an ongoing challenge. The developing and detailed knowledge on mechanisms of GC action has resulted in exploration of numerous approaches to optimise treatments with these important drugs. Most advanced is a chronotherapeutic formulation of prednisone (termed modified- or delayed-release prednisone) that has been recently approved in many European and other countries, and very recently also in the United States. Another interesting example is the development of selective GC receptor (GR) agonists, with clinical studies being currently underway. The development of so called liposomal GC is ongoing. However, another approach, the synergistic combination of prednisolone and dipyridamole, has been recently discontinued because a phase 2b study with the treatment in patients with rheumatoid arthritis showed a statistically significant improvement in disease activity score measured in 28 joints (DAS28) compared with placebo, but not compared with prednisolone alone. Other interesting developments and promising concepts include the development of nitrosteroids, targeting the membrane-bound GR and the use of extracts of the medicinal plant Tripterygium wilfordii Hook F.

Economic evaluation of a tight-control treatment strategy using an imaging device (handscan) for monitoring joint inflammation in early rheumatoid arthritis.

OBJECTIVES: To evaluate the cost-effectiveness of a tight-control treatment strategy using the handscan (TCHS) compared to using only clinical assessments (TC) and compared to a general non-tight-control treatment strategy (usual care; UC) in early rheumatoid arthritis (RA). METHODS: Data from 299 early RA patients from the CAMERA trial were used. Clinical outcomes were extrapolated to Quality Adjusted Life Years (QALYs) and costs using a Markov model. Costs and QALYs were compared between the TC and UC treatment strategy arm of the CAMERA trial and a simulated tight-control treatment strategy using the handscan (TCHS). Incremental Cost-Effectiveness Ratios (ICERs) were calculated and several scenario analyses performed. All analyses were performed probabilistically to obtain confidence intervals and costs-effectiveness planes and acceptability curves. RESULTS: In TCHS, €4,660 (95% CI -€11,516 to €2,045) was saved and 0.06 (95% CI 0.01 to 0.11) QALYs were gained when compared to UC, with an ICER of €77,670 saved per QALY gained. Ninety-one percent (91%) of simulations resulted in less costs and more QALYs. TCHS resulted in comparable costs or even limited savings €642 (95% CI -€6,903 to €5,601)) and comparable QALYs to TC. In all scenario analyses, TCHS and TC were found to be cost effective as compared to UC. CONCLUSIONS: A tight-control treatment strategy is highly cost-effective compared to a non-tight-control approach in early RA. Using the handscan as a monitoring device might facilitate implementation of tight-control treatment strategy at comparable costs and with comparable effects. This approach should be investigated further.

Anti-osteoporosis drug prescribing after hip fracture in the UK: 2000-2010.

UNLABELLED: The probability of initiating with anti-osteoporosis therapy increased from 7 % in 2000 to 46 % in 2010. This improvement was greater for patients over the age of 75 years. Men, those overweight, having dementia or exposed to antipsychotics, sedatives/hypnotics or opioid analgesics were significantly less likely to receive anti-osteoporosis drugs. INTRODUCTION: The objective of this study was to examine trends and determinants of anti-osteoporosis drug prescribing after hip fracture in the UK between 2000 and 2010. METHODS: Data were extracted from the UK Clinical Practice Research Datalink for patients ≥50 years who had a first hip fracture between 2000 and 2010 and who did not currently (≤6 months prior) receive anti-osteoporosis drugs (bisphosphonates, strontium ranelate, parathyroid hormone, calcitonin and raloxifene) (n = 27,542). The cumulative incidence probability of being prescribed anti-osteoporosis drugs within 1 year after hip fracture was estimated by Kaplan-Meier life-table analyses. Determinants for treatment initiation were estimated by Cox proportional hazards models. RESULTS: The probability of being prescribed any anti-osteoporosis drug after hip fracture increased from 7 % in 2000 to 46 % in 2010. This trend was more marked in patients ≥75 years. The increase in prescribing of anti-osteoporosis drugs was complemented by a similar increase in vitamin D/calcium provision. Cumulative incidence of receiving anti-osteoporosis therapy was greater at any given point in time in women (8 % in 2000, 51 % in 2010) compared to men (4 % in 2000, 34 % in 2010). In addition to male gender, multivariable Cox regression identified reduced likelihood of receiving anti-osteoporosis drugs for those being overweight, having dementia and exposed to psychotropic drugs (antipsychotics, sedatives/hypnotics) or opioid analgesics. CONCLUSION: Although the prescribing of anti-osteoporosis drugs after hip fracture has increased substantially since 2000, the overall rate remained inadequate, particularly in men. With the continuing increase in the absolute number of hip fractures, further research should be made into the barriers to optimise osteoporosis management.

Long-term persistence with anti-osteoporosis drugs after fracture.

UNLABELLED: Long-term persistence with anti-osteoporosis drugs and determinants for discontinuation among fracture patients were examined. Persistence was 75.0 and 45.3 % after 1 and 5 years, respectively. Those aged ≥80 years were at increased risk of early discontinuation. Within 1 year after discontinuation, 24.3 % restarted therapy, yet 47.0 % persisted for 1 year. INTRODUCTION: The risk of osteoporotic fracture can effectively be reduced with use of anti-osteoporosis drugs. However, little is known about persistence with these drugs after fracture where subsequent fracture risk is high. The aims were to determine long-term persistence with anti-osteoporosis drugs among fracture patients, including its determinants, and to describe restart and subsequent persistence. METHODS: A cohort study was conducted within the Dutch PHARMO Database Network. Patients aged ≥50 years (n = 961) who received anti-osteoporosis drugs within 1 year after fracture, but not in the preceding year, were included (2002-2011). Persistence (defined as the proportion on treatment) and the proportion restarting after discontinuation were estimated using Kaplan-Meier analyses. Time-dependent Cox regression was used to identify determinants of non-persistence including age, sex, initial dosage regime, fracture type, comorbidities, and drug use. RESULTS: Persistence with anti-osteoporosis drugs was 75.0 % (95 % confidence interval (CI) 72.0-77.7) and 45.3 % (95 % CI 40.4-50.0) after 1 and 5 years, respectively. A significant determinant of non-persistence was age ≥80 years (reference 50-59 years: adjusted hazard ratio [adj. HR] 1.65; 95 % CI 1.15-2.38). This effect was not constant over time (≤360 days following initiation: adj. HR 2.07; 95 % CI 1.27-3.37; >360 days: adj. HR 1.08; 95 % CI 0.62-1.88). Within 1 year after discontinuation, 24.3 % (95 % CI 20.1-29.2) restarted therapy, yet 47.0 % persisted for 1 year. CONCLUSIONS: This study identified suboptimal persistence with anti-osteoporosis drugs among fracture patients. Major target groups for measures aimed to improve persistence may be those aged >80 years and those restarting therapy.

The ability of systemic biochemical markers to reflect presence, incidence, and progression of early-stage radiographic knee and hip osteoarthritis: data from CHECK.

OBJECTIVE: To relate systemic biochemical markers of joint metabolism to presence, incidence, and progression of early-stage radiographic knee and/or hip osteoarthritis (OA). METHOD: The cartilage markers uCTX-II, sCOMP, sPIIANP, and sCS846, bone markers uCTX-I, uNTX-I, sPINP, and sOC, and synovial markers sHA and sPIIINP were assessed by enzyme-linked immunosorbent assay or radioactive immunoassay in baseline samples of CHECK (Cohort Hip and Cohort Knee), a cohort study of early-stage symptomatic knee and/or hip OA. Knee and hip radiographs were obtained at baseline and 5-year follow-up. Presence of OA at baseline was defined as Kellgren and Lawrence (K&L) = 1 (maximum observed). Incidence of OA was defined as K&L = 0 at baseline and K&L ≥ 1 at 5-year follow-up. Progression of OA was defined as K&L = 1 at baseline and K&L ≥ 2 at 5-year follow-up. RESULTS: Data were available for 801 subjects at baseline and for 723 subjects at both baseline and 5-year follow-up. Multiple cartilage and synovial markers showed positive associations with presence and progression of knee and hip OA and with incidence of hip OA, except for negative associations of uCTX-II and sCOMP with incidence of knee OA. uCTX-II and sCOMP showed multiple interactions with other biomarkers in their associations with knee and hip OA. Bone markers were positively associated with presence of radiographic knee OA, but negatively associated with progression of radiographic hip OA. CONCLUSION: Especially metabolism in cartilage and synovial matrix appear to be of relevance in knee and hip OA. The role of bone metabolism appears to differ between knee and hip OA.

Association between serum levels of the proinflammatory protein S100A8/A9 and clinical and structural characteristics of patients with established knee, hip, and hand osteoarthritis.

OBJECTIVES: To explore the association between S100A8/A9 serum levels with clinical and structural characteristics of patients with established knee, hip, or hand osteoarthritis (OA). METHOD: A cross-sectional exploratory study was conducted with 162 OA patients. Measures for pain, stiffness, and function included the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) questionnaire or the Australian Canadian Osteoarthritis Hand (AUSCAN) Index and for structural abnormalities, osteophytes and joint space narrowing grades. The association between S100A8/A9 and clinical or structural characteristics was analysed using linear regression or logistic regression where appropriate. RESULTS: The mean age of the OA patients was 56 years, 71% were female, and 61% had a Kellgren and Lawrence (K&L) score ≥ 2. The serum S100A8/A9 level did not differ between knee, hip, and hand OA patients and no association was found between serum S100A8/A9 and clinical characteristics. The serum S100A8/A9 level was negatively associated with the sum score of osteophytes after adjusting for sex and body mass index (BMI) [adjusted ß -0.015, 95% confidence interval (CI) -0.030 to 0.001, p = 0.062] and positively associated with erythrocyte sedimentation rate (ESR) > 12 mm/h (adjusted OR 1.002, 95% CI 1.000-1.004 p = 0.049) for each increase in S100A8/A9 of 1 ng/mL. For hand OA patients, a negative association of S100A8/A9 with sum score of joint space narrowing was found (adjusted ß -0.007, 95% CI -0.016 to 0.001, p = 0.099). CONCLUSIONS: The results from this cross-sectional exploratory study do not support an important role for serum S100A8/A9 levels as a biomarker for clinical and structural characteristics in established knee, hip, and hand OA patients. The inverse association with structural abnormalities and the positive association with ESR may reflect inflammatory synovial processes in patients with OA before structural abnormalities occur.

Personalised treatment using serum drug levels of adalimumab in patients with rheumatoid arthritis: an evaluation of costs and effects.

OBJECTIVE: To evaluate the cost-effectiveness of personalised treatment for rheumatoid arthritis (RA) using clinical response and serum adalimumab levels. METHODS: A personalised treatment algorithm defined, based on clinical (European League Against Rheumatism) response and drug levels at 6 months, whether adalimumab treatment should be continued in a specific dose or discontinued and/or switched to a next biological. Outcomes were simulated using a patient level Markov model, with 3 months cycles, based on a cohort of 272 adalimumab-treated patients with RA for 3 years and data of patients from the Utrecht Rheumatoid Arthritis Cohort. Costs, clinical effectiveness and quality adjusted life years (QALYs) were compared with outcomes as observed in usual care and incremental cost-effectiveness ratios were calculated. Analyses were performed probabilistically. RESULTS: Clinical effectiveness was higher for the cohort simulated to receive personalised care compared with usual care; the average difference in QALYs was 3.84 (95 percentile range -8.39 to 16.20). Costs were saved on drugs: €2 314 354. Testing costs amounted to €10 872. Mean total savings were €2 561 648 (95 percentile range -3 252 529 to -1 898 087), resulting in an incremental cost-effectiveness ratio of €666 500 or €646 266 saved per QALY gained from a societal or healthcare perspective, respectively. In 72% of simulations personalised care saved costs and resulted in more QALYs, in 28% it was cost saving with lower QALYs. Scenario analyses showed cost saving along with QALYs gain or limited loss. CONCLUSIONS: Tailoring biological treatment to individual patients with RA starting adalimumab using drug levels and short-term outcome is cost-effective. Results underscore the potential merit of personalised biological treatment in RA.

The efficacy of abatacept in reducing synovial T cell activation by CD1c myeloid dendritic cells is overruled by the stimulatory effects of T cell-activating cytokines.

OBJECTIVE: To investigate whether the potential of abatacept to inhibit vigorous CD1c myeloid dendritic cell (MDC)-driven activation of naive and memory CD4 T cells is abrogated in the presence of T cell-activating cytokines. METHODS: CD4 T cell subsets (naive [Tn], central memory [Tcm], and effector memory [Tem] T cells) were isolated from the peripheral blood (PB) of healthy controls and the PB and synovial fluid (SF) of rheumatoid arthritis (RA) patients. CD4 T cells were cocultured with autologous, thymic stromal lymphopoietin (TSLP)-primed CD1c MDCs in the presence or absence of abatacept (CTLA-4Ig) and/or interleukin-7 (IL-7) or IL-15. Subsequently, T cell proliferation and cytokine production were measured. RESULTS: The percentages of each CD4 T cell subset from the circulation of healthy controls and RA patients were comparable and mainly consisted of Tn and Tcm cells, whereas the SF of RA patients mainly consisted of Tcm and Tem cells. Activation of CD4 T cell subsets by TSLP-primed MDCs from the RA PB was completely blocked by abatacept. Addition of IL-7 or IL-15 to the cocultures strongly increased CD4 T cell activation and overruled the inhibitory capacity of abatacept. IL-7-induced reversal was associated with robust induction of interferon-γ, tumor necrosis factor α, and IL-17 secretion. Similarly, CD4 T cell proliferation induced by TSLP-primed MDCs from the SF of RA patients was strongly blocked by abatacept, but this inhibitory effect was vigorously overruled in the presence of IL-7. CONCLUSION: These findings indicate that the presence of T cell-activating cytokines such as IL-7 or IL-15 in the joints of RA patients reduces the capacity of abatacept to inhibit MDC-driven CD4 T cell activation. This mechanism may be one explanation for the partial, and sometimes absent, response to abatacept therapy in a subset of patients.

MRI assessment of early response to certolizumab pegol in rheumatoid arthritis: a randomised, double-blind, placebo-controlled phase IIIb study applying MRI at weeks 0, 1, 2, 4, 8 and 16.

OBJECTIVES: To identify the first time point of an MRI-verified response to certolizumab pegol (CZP) therapy in patients with rheumatoid arthritis (RA). METHODS: Forty-one patients with active RA despite disease-modifying antirheumatic drug therapy were randomised 2:1 to CZP (CZP loading dose 400 mg every 2 weeks at weeks 0-4; CZP 200 mg every 2 weeks at weeks 6-16) or placebo→CZP (placebo at weeks 0-2; CZP loading dose at weeks 2-6; CZP 200 mg every 2 weeks at weeks 8-16). Contrast-enhanced MRI of one hand and wrist was acquired at baseline (week 0) and weeks 1, 2, 4, 8 and 16. All six time points were read simultaneously, blinded to time, using the Outcome Measures in Rheumatology Clinical Trials RA MRI scoring system. Primary outcome was change in synovitis score in the CZP group; secondary outcomes were change in bone oedema (osteitis) and erosion scores and clinical outcome measures. RESULTS: Forty patients were treated (27 CZP, 13 placebo→CZP), and 36 (24 CZP, 12 placebo→CZP) completed week 16. In the CZP group, there were significant reductions from baseline synovitis (Hodges-Lehmann estimate of median change, -1.5, p=0.049) and osteitis scores (-2.5, p=0.031) at week 16. Numerical, but statistically insignificant, MRI inflammation reductions were observed at weeks 1-2 in the CZP group. No significant change was seen in bone erosion score. Improvements across all clinical outcomes were seen in the CZP group. CONCLUSIONS: CZP reduced MRI synovitis and osteitis scores at week 16, despite small sample size and the technical challenge of reading six time points simultaneously. This study provides essential information on optimal MRI timing for subsequent trials. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT01235598.