Evaluation of newly proposed remission cut-points for disease activity score in 28 joints (DAS28) in rheumatoid arthritis patients upon IL-6 pathway inhibition.

BACKGROUND: Stringent remission criteria are crucial in rheumatoid arthritis (RA) assessment. Disease activity score in 28 joints (DAS28)-remission has not been included among American College of Rheumatology/European League Against Rheumatism definitions, because of its association with significant residual disease activity, partly due to high weighting of acute-phase reactants (APR). New, more stringent cut-points for DAS28-remission have recently been proposed that are suggested to reflect remission by clinical and simplified disease activity indices (clinical disease activity index (CDAI), simple disease activity index (SDAI)). However, their stringency in therapies directly influencing APR, like IL-6-blockers, has not been tested. We tested the new cut-points in patients with RA receiving tocilizumab. METHODS: We used data from randomised controlled trials of tocilizumab and evaluated patients in remission according to new DAS28-C-reactive protein (DAS-CRP) and DAS-erythrocyte sedimentation rate (DAS-ESR) cut-points (1.9 and 2.2). We assessed their disease activity state using the CDAI, SDAI and Boolean criteria and analysed their individual residual core set variables, like swollen joint counts (SJC28). RESULTS: About 50% of patients in DAS28-CRP-remission (<1.9) fell into higher disease activity states when assessed with CDAI, SDAI or Boolean criteria. Also, 15% had three or more (up to eight) SJC. Even higher disease activity was seen in patients classified as being in DAS28-ESR-remission (<2.2). CONCLUSIONS: Even with new, more stringent cut-points, DAS28-remission is frequently associated with considerable residual clinical disease activity, indicating that this limitation of the DAS28 is related to score construction rather than the choice of cut-points.

[Rheumatoid arthritis]. / Rheumatoide Arthritis.

Therapy reduction in rheumatoid arthritis (RA) is still a challenge for physicians as well as for patients. Effective therapy with subsequent achievement of low disease activity or even remission is achievable for numerous patients using currently available treatment options. Therapy discontinuation has therefore become a hot topic and the risk of exacerbation of well-controlled RA must be weighed against the medical and economic benefits of reducing or even discontinuing therapy. This article gives a review of data regarding tapering of therapy in RA, focusing on conventional disease-modifying antirheumatic drug (DMARD) monotherapy, reduction of conventional therapy under continuing therapy with biologics and discontinuation of biologics. Important influencing factors for a safe and successful tapering procedure appear to be disease activity, disease duration and the tapering process itself (i.e. gradual dose reduction vs. abrupt discontinuation). Additionally, the so-called nocebo effect should also be taken into consideration for interpretation of drug tapering studies.

Disease activity states of the DAPSA, a psoriatic arthritis specific instrument, are valid against functional status and structural progression.

BACKGROUND: Recently, disease activity states were developed for the Disease Activity index for PSoriatic Arthritis (DAPSA). Here, we assess if different DAPSA disease activity states are associated with different degrees of functional impairment and different extents of joint damage progression in patients with psoriatic arthritis (PsA). METHODS: We used data from two pivotal trials of tumour necrosis factor (TNF) inhibitors in PsA (IMPACT II and GO-REVEAL) and identified patients in DAPSA remission (REM, ≤4), and low, moderate or high disease activity (LDA, ≤14; MDA, ≤28; HDA, >28) at 6 months. Across these groups we compared the functional scores (Health Assessment Questionnaire Disability Index, HAQ and physical component scale of the Short Form-36, PCS), and 1-year structural progression (PsA-modified Sharp/van der Heijde Score). RESULTS: We identified 310 from GO-REVEAL and 130 from IMPACT II, with a mean (SD) baseline DAPSA of 48.8 (26.4) and 44.6 (17.9), respectively. HAQ scores increased across patients groups in the four DAPSA disease activity states, while PCS decreased (p<0.001 for both). The mean progression in the combined cohort was -0.47 for REM, -0.28 for LDA, -0.14 for MDA and 0.51 for HDA (p<0.001). This association was also significant in the individual trial cohorts, and in the subgroups of patients treated with TNF inhibitors or placebo. Higher DAPSA scores were significantly and independently associated with probability of structural progression in multiple analyses. CONCLUSIONS: Disease activity states of the PsA specific DAPSA score are highly valid for future use as endpoints in clinical trials or as targets in clinical practice. TRIAL REGISTRATION NUMBERS: IMPACT 2: NCT02152254; GO-REVEAL: NCT00265096.

Clinical joint inactivity predicts structural stability in patients with established rheumatoid arthritis.

OBJECTIVES: Clinical joint activity is a strong predictor of joint damage in rheumatoid arthritis (RA), but progression of damage might increase despite clinical inactivity of the respective joint (silent progression). The aim of this study was to evaluate the prevalence of silent joint progression, but particularly on the patient level and to investigate the duration of clinical inactivity as a marker for non-progression on the joint level. METHODS: 279 patients with RA with any radiographic progression over an observational period of 3-5 years were included. We obtained radiographic and clinical data of 22 hand/finger joints over a period of at least 3 years. Prevalence of silent progression and associations of clinical joint activity and radiographic progression were evaluated. RESULTS: 120 (43.0%) of the patients showed radiographic progression in at least one of their joints without any signs of clinical activity in that respective joint. In only 7 (5.8%) patients, such silent joint progression would go undetected, as the remainder had other joints with clinical activity, either with (n=84; 70.0%) or without (n=29; 24.2%) accompanying radiographic progression. Also, the risk of silent progression decreases with duration of clinical activity. CONCLUSIONS: Silent progression of a joint without accompanying apparent clinical activity in any other joint of a patient was very rare, and would therefore be most likely detected by the assessment of the patient. Thus, full clinical remission is an excellent marker of structural stability in patients with RA, and the maintenance of this state reduces the risk of progression even further.

European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update.

BACKGROUND: Since the publication of the European League Against Rheumatism recommendations for the pharmacological treatment of psoriatic arthritis (PsA) in 2012, new evidence and new therapeutic agents have emerged. The objective was to update these recommendations. METHODS: A systematic literature review was performed regarding pharmacological treatment in PsA. Subsequently, recommendations were formulated based on the evidence and the expert opinion of the 34 Task Force members. Levels of evidence and strengths of recommendations were allocated. RESULTS: The updated recommendations comprise 5 overarching principles and 10 recommendations, covering pharmacological therapies for PsA from non-steroidal anti-inflammatory drugs (NSAIDs), to conventional synthetic (csDMARD) and biological (bDMARD) disease-modifying antirheumatic drugs, whatever their mode of action, taking articular and extra-articular manifestations of PsA into account, but focusing on musculoskeletal involvement. The overarching principles address the need for shared decision-making and treatment objectives. The recommendations address csDMARDs as an initial therapy after failure of NSAIDs and local therapy for active disease, followed, if necessary, by a bDMARD or a targeted synthetic DMARD (tsDMARD). The first bDMARD would usually be a tumour necrosis factor (TNF) inhibitor. bDMARDs targeting interleukin (IL)12/23 (ustekinumab) or IL-17 pathways (secukinumab) may be used in patients for whom TNF inhibitors are inappropriate and a tsDMARD such as a phosphodiesterase 4-inhibitor (apremilast) if bDMARDs are inappropriate. If the first bDMARD strategy fails, any other bDMARD or tsDMARD may be used. CONCLUSIONS: These recommendations provide stakeholders with an updated consensus on the pharmacological treatment of PsA and strategies to reach optimal outcomes in PsA, based on a combination of evidence and expert opinion.

Persistence of subclinical sonographic joint activity in rheumatoid arthritis in sustained clinical remission.

BACKGROUND: Sonographic assessment, measuring grey scale (GS) and power Doppler (PD) signals, is a sensitive tool for the evaluation of inflammatory joint activity in patients with rheumatoid arthritis (RA). We evaluated the persistence of PD and GS signals in previously clinically active RA joints that have reached a state of continuous clinical inactivity. METHODS: We performed sonographic imaging of 22 joints of the hands of patients with RA, selected all joints without clinical activity but showing ongoing sonographic signs of inflammation, and evaluated the time from last clinical joint activity. RESULTS: A total of 90 patients with RA with 1980 assessed joints were included in this study. When comparing the mean time from clinical swelling, we found a significantly longer period of clinical inactivity in joints showing low sonographic activity (mean±SD time from swelling of 4.1±3.2 vs 3.1±2.9 years for PD1 vs PD≥2, p=0.031 and 4.5±3.4 vs 3.3±3.2 years for GS1 vs GS≥2, p≤0.0001). CONCLUSIONS: We conclude that subclinical joint activity is long-lasting in RA joints in clinical remission, but attenuates over time. The latter conclusion is based on the observed shorter time duration from last clinical activity for strong compared with weaker sonographic signals.

Relationship between radiographic joint space narrowing, sonographic cartilage thickness and anatomy in rheumatoid arthritis and control joints.

OBJECTIVE: To validate ultrasound (US) for measuring metacarpal cartilage thickness (MCT), by comparing it with anatomical measurement using cadaver specimens. To correlate US MCT with radiographic joint space narrowing (JSN) or width (JSW) in patients with rheumatoid arthritis (RA). METHODS: Bilateral metacarpophalangeal (MCP) joints of 35 consecutive outpatients, with recent hand X-rays, were included in the analysis. Metacarpal and phalangeal cartilage of MCP 2-5 was assessed bilaterally by US. JSW and JSN were evaluated on X-rays by the van der Heijde modified Sharp method (vdHS). In addition, cadaver specimens of MCP 2-5 joints (n=19) were evaluated by anatomical measurement and US. RESULTS: The agreement (intraclass correlation coefficient) between sonographic and anatomical MCT on cadaver specimens of MCP joints was 0.61. MCT of individual MCP joints correlated with individual MCP JSN (r=-0.32, p<0.001) and individual MCP JSW (r=0.72, p<0.001). No correlation was found between phalangeal cartilage thickness and JSN in individual MCP joints. The US MCT summary score for MCP joints 2-5 correlated with summary scores for JSW (r=0.78, p<0.001), JSN (r=-0.5, p<0.001), erosion score of the vdHS (r=-0.39, p<0.001) and total vdHS (r=-0.47, p<0.001). CONCLUSIONS: Sonographic cartilage assessment in MCPs is closely related to anatomical cartilage thickness. Both JSW and JSN by radiography represent cartilage thickness in the MCP joints of patients with RA quite well. Thus, US is a valid tool for measuring MCT if radiographs are not available or in case of joint malalignment.

Scores for all seasons: SDAI and CDAI.

Disease activity assessment is one of the most pivotal aspects in the care of RA patients. Composite measures of disease activity are superior to individual measures, since they capture the multiple facets of the disease. Since swollen joint counts correlate with joint damage progression and tender joint counts with physical function, composite scores that include joint counts are preferable. The simplified and clinical disease activity indices (SDAI, CDAI) are easy to calculate and correlate well with joint damage and physical function. Cutpoints for disease activity states have been established and improvement criteria likewise. The SDAI and CDAI remission criteria (ACR-EULAR index-based remission) are stringent, usually associated with a halt of progression of damage and optimisation of physical function and can still be achieved in 1 of 4 clinic patients and up to one third of patients in trials of early arthritis.

European League Against Rheumatism recommendations for the management of psoriatic arthritis with pharmacological therapies.

BACKGROUND: Psoriatic arthritis (PsA) is a clinically heterogeneous disease. Clear consensual treatment guidance focused on the musculoskeletal manifestations of PsA would be advantageous. The authors present European League Against Rheumatism (EULAR) recommendations for the treatment of PsA with systemic or local (non-topical) symptomatic and disease-modifying antirheumatic drugs (DMARD). METHODS: The recommendations are based on evidence from systematic literature reviews performed for non-steroidal anti-inflammatory drugs (NSAID), glucocorticoids, synthetic DMARD and biological DMARD. This evidence was discussed, summarised and recommendations were formulated by a task force comprising 35 representatives, and providing levels of evidence, strength of recommendations and levels of agreement. RESULTS: Ten recommendations were developed for treatment from NSAID through synthetic DMARD to biological agents, accounting for articular and extra-articular manifestations of PsA. Five overarching principles and a research agenda were defined. CONCLUSION: These recommendations are intended to provide rheumatologists, patients and other stakeholders with a consensus on the pharmacological treatment of PsA and strategies to reach optimal outcomes, based on combining evidence and expert opinion. The research agenda informs directions within EULAR and other communities interested in PsA.

European League Against Rheumatism recommendations for the inclusion of patient representatives in scientific projects.

OBJECTIVE: To develop recommendations to enable successful inclusion of the patient perspective in European League Against Rheumatism (EULAR)-funded scientific research projects. METHODS: The EULAR standardised operational procedures for guideline development were followed. A systematic literature review was presented during a first task force meeting, including 3 rheumatologists, 1 rheumatologist/epidemiologist, 2 allied health professionals, 2 representatives of arthritis research organisations and 7 patient representatives, resulting in 38 statements. A Delphi method was carried out to reduce and refine the statements and agree on a set of eight. Next, a survey among a wider group of experts, professionals and patient representatives (n=42), was completed. Feedback from this wider group was discussed at the second meeting and integrated in the final wording of the recommendations. Subsequently, the level of agreement of the group of experts (n=81) was re-evaluated. RESULTS: The project resulted in a definition of patient research partner and agreement on a set of eight recommendations for their involvement in research projects. These recommendations provide practical guidance for organising patient participation, capturing (1) the role of patient research partners, (2) phase of involvement, (3) the recommended number, (4) recruitment, (5) selection, (6) support, (7) training and (8) acknowledgement. CONCLUSION: Collaboration between patients and professionals in research is relatively new. Trials or effectiveness studies are not yet available. Nevertheless, it is possible to define recommendations for the inclusion of patients in research following a solid expert opinion based consensus process.

Multinational evidence-based recommendations on how to investigate and follow-up undifferentiated peripheral inflammatory arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative.

OBJECTIVE: To develop evidence-based recommendations on how to investigate and follow-up undifferentiated peripheral inflammatory arthritis (UPIA). METHODS: 697 rheumatologists from 17 countries participated in the 3E (Evidence, Expertise, Exchange) Initiative of 2008-9 consisting of three separate rounds of discussions and modified Delphi votes. In the first round 10 clinical questions were selected. A bibliographic team systematically searched Medline, Embase, the Cochrane Library and ACR/EULAR 2007-2008 meeting abstracts. Relevant articles were reviewed for quality assessment, data extraction and synthesis. In the second round each country elaborated a set of national recommendations. Finally, multinational recommendations were formulated and agreement among the participants and the potential impact on their clinical practice was assessed. RESULTS: A total of 39,756 references were identified, of which 250 were systematically reviewed. Ten multinational key recommendations about the investigation and follow-up of UPIA were formulated. One recommendation addressed differential diagnosis and investigations prior to establishing the operational diagnosis of UPIA, seven recommendations related to the diagnostic and prognostic value of clinical and laboratory assessments in established UPIA (history and physical examination, acute phase reactants, autoantibodies, radiographs, MRI and ultrasound, genetic markers and synovial biopsy), one recommendation highlighted predictors of persistence (chronicity) and the final recommendation addressed monitoring of clinical disease activity in UPIA. CONCLUSIONS: Ten recommendations on how to investigate and follow-up UPIA in the clinical setting were developed. They are evidence-based and supported by a large panel of rheumatologists, thus enhancing their validity and practical use.

Evaluation of disease activity assessments in patients with rheumatoid arthritis and an inadequate response to anti-TNF therapy: analyses of abatacept clinical trial data.

OBJECTIVES: To assess the ability of efficacy measures that incorporate onset or sustainability to detect treatment effect or reflect patient satisfaction, using exploratory analyses of data from the ATTAIN (Abatacept Trial in Treatment of Anti-TNF INadequate Responders) trial. METHODS: 218 abatacept- and 99 placebo-treated patients were evaluated. Reporting methods included time to onset (first American College of Rheumatology [ACR] 50 response/Low Disease Activity State [LDAS; DAS28 < or =3.2]) and sustainability of ACR50/LDAS, both assessed according to discriminatory capacity (number of patients needed to study [NNS]) and patient satisfaction with treatment. RESULTS: Efficacy measures incorporating elements of sustainability or onset decreased discriminatory capacity, while sustainability, but not onset of action, was important in reflecting patient satisfaction. CONCLUSIONS: Optimal assessment methods depend on whether the outcome of interest is ability to detect treatment effects or to reflect patient satisfaction. Sustainability of response (and possibly, at a lower magnitude, fast onset of action) may be important when evaluating patient satisfaction with RA therapies in patients who have previously failed anti-TNF therapy.

Current evidence for a strategic approach to the management of rheumatoid arthritis with disease-modifying antirheumatic drugs: a systematic literature review informing the EULAR recommendations for the management of rheumatoid arthritis.

OBJECTIVES: To perform a systematic literature review of effective strategies for the treatment of rheumatoid arthritis (RA). METHODS: As part of a European League Against Rheumatism (EULAR) Task Force investigation, a literature search was carried out from January 1962 until February 2009 in PubMed/Ovid Embase/Cochrane and EULAR/American College of Rheumatism (ACR)) abstracts (2007/2008) for studies with a treatment strategy adjusted to target a predefined outcome. Articles were systematically reviewed and clinical outcome, physical function and structural damage were compared between intensive and less intensive strategies. The results were evaluated by an expert panel to consolidate evidence on treatment strategies in RA. RESULTS: The search identified two different kinds of treatment strategies: strategies in which the reason for treatment adjustment differed between the study arms ('steering strategies', n=13) and strategies in which all trial arms used the same clinical outcome to adjust treatment with different pharmacological treatments ('medication strategies', n=7). Both intensive steering strategies and intensive medication strategies resulted in better outcome than less intensive strategies in patients with early active RA. CONCLUSION: Intensive steering strategies and intensive medication strategies produce a better clinical outcome, improved physical function and less structural damage than conventional steering or treatment. Proof in favour of any steering method is lacking and the best medication sequence is still not known.

Rheumatoid arthritis joint progression in sustained remission is determined by disease activity levels preceding the period of radiographic assessment.

OBJECTIVE: Joint damage is related to disease activity in rheumatoid arthritis (RA), but the degree of its progression and the temporal associations between disease activity and joint damage are unclear. The aim of this study was to evaluate whether there is a latency in the effect of disease activity on radiographic progression in patients with RA. METHODS: Data were obtained from the PREMIER trial, a 2-year randomized, controlled clinical trial of adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in early RA. Radiographic progression of joint damage was calculated using the modified total Sharp score in a subset of patients whose disease was in remission (Simplified Disease Activity Index

Perception of improvement in patients with rheumatoid arthritis varies with disease activity levels at baseline.

OBJECTIVE: To analyze the minimum clinically important improvement (MCII) of disease activity measures in rheumatoid arthritis (RA) using patient-derived anchors, and to assess whether criteria for improvement differ with baseline disease activity. METHODS: We used data from a Norwegian observational database comprising 1,050 patients (73% women, 65% rheumatoid factor-positive, mean duration of RA 7.7 years). At 3 months after initiation of therapy, patients indicated whether their condition had improved, had considerably improved, was unchanged, had worsened, or had considerably worsened. We used receiver operating characteristic curve analysis to determine the MCII for the Disease Activity Score based on the assessment of 28 joints (DAS28), the Simplified Disease Activity Index (SDAI), and the Clinical Disease Activity Index (CDAI), and analyzed the effects of different levels of baseline disease activity on the MCII. RESULTS: On average, patients started with high disease activity and improved significantly during treatment (American College of Rheumatology 20%, 50%, and 70% improvement criteria responses were 37%, 17%, and 5%, respectively). The overall mean (95% confidence interval [95% CI]) thresholds for MCII after 3 months for the DAS28, SDAI, and CDAI were 1.20 (95% CI 1.18-1.22), 10.95 (95% CI 10.69-11.20), and 10.76 (95% CI 10.49-11.04), respectively, and the mean (95% CI) thresholds for major responses were 1.82 (95% CI 1.80-1.83), 15.82 (95% CI 15.65-16.00), and 15.00 (95% CI 14.82-15.18), respectively. With increasing disease activity, much higher changes in disease activity were needed to achieve MCII according to patient judgment. CONCLUSION: The perception of improvement of disease activity of patients with RA is considerably different depending on the disease activity level at which they start.

[Rheumatoid arthritis. Target outcome for treatment]. / Rheumatoide Arthritis. Zielkriterien der Behandlung.

Rheumatoid arthritis is a chronic disabling disease that results in considerable loss of physical function in patients over time. The ultimate goal of therapy is remission, a clinical state with a highly variable definition in the literature. For the purpose of achieving the best patient outcome, it is important to maintain the lowest possible disease activity. Therefore, stringent remission criteria should be chosen, which will lead to the best possible prevention of structural and functional decline. Standardised intensive therapeutic strategies and algorithms should form the basis for the administration of anti-rheumatic medication.

Does damage cause inflammation? Revisiting the link between joint damage and inflammation.

Rheumatoid arthritis (RA) is characterised by both inflammation, as manifested by pain and swelling, and destruction of the joints. Unequivocal evidence indicates that disease activity, and thus the inflammatory response, is linked to joint damage. From this viewpoint we suggest that, vice versa, joint damage might be a cause of the active disease process, thus leading to a vicious cycle of events. The background to this notion stems from the known autoimmune response in RA, the potential of cartilage and bone breakdown products to elicit inflammation and notions that in joints that have undergone surgery with cartilage removal RA does not flare. However, the clinical evidence for this relationship is still to be provided as proof of the concept.

Progression of radiographic joint damage in rheumatoid arthritis: independence of erosions and joint space narrowing.

OBJECTIVE: To compare the progression of erosions and joint space narrowing (JSN) in patients with early active rheumatoid arthritis (RA) using data obtained in the "Active-controlled Study of Patients receiving Infliximab for the treatment of Rheumatoid arthritis of Early onset" (ASPIRE) study. METHODS: This was a post hoc analysis of patients in ASPIRE who received placebo plus methotrexate (MTX) or infliximab (3 or 6 mg/kg) plus MTX. Radiographs of the hands (870 patients) and feet (871 patients) were obtained at baseline and week 54 and scored using the van der Heijde/Sharp method. In total, 7160 joints in the placebo plus MTX group and 18,908 joints in the combined infliximab plus MTX group were included in this analysis. RESULTS: At baseline, 83.4% of joints in the placebo plus MTX group had no radiographic damage, 8.5% had only erosions, 4.4% had only JSN and 3.7% had both. The distribution was similar in the infliximab plus MTX group. In the placebo plus MTX group, the majority of joints did not have development or progression of radiographic damage from baseline to week 54; among joints that did have development or progression of damage at week 54, erosions occurred more often than JSN. The same pattern was observed in the infliximab plus MTX group, although the proportions of joints with damage at week 54 were generally larger in the placebo plus MTX group. There was a tendency for joints with existing erosions or JSN to have progression of damage, rather than development of new damage. CONCLUSIONS: Erosions were the predominant type of damage observed in both treatment groups. Erosions and JSN are related but partly independent processes.