Tanja Stamm

Acute phase reactants add little to composite disease activity indices for rheumatoid arthritis: validation of a clinical activity score

IntroductionFrequent assessments of rheumatoid arthritis (RA) disease activity allow timely adaptation of therapy, which is essential in preventing disease progression. However, values of acute phase reactants (APRs) are needed to calculate current composite activity indices, such as the Disease Activity Score (DAS)28, the DAS28-CRP (i.e. the DAS28 using C-reactive protein instead of erythrocyte sedimentation rate) and the Simplified Disease Activity Index (SDAI). We hypothesized that APRs make limited contribution to the SDAI, and that an SDAI-modification eliminating APRs – termed the Clinical Disease Activity Index (CDAI; i.e. the sum of tender and swollen joint counts [28 joints] and patient and physician global assessments [in cm]) – would have comparable validity in clinical cohorts.MethodData sources comprised an observational cohort of 767 RA patients (average disease duration 8.1 ± 10.6 years), and an independent inception cohort of 106 patients (disease duration 11.5 ± 12.5 weeks) who were followed prospectively.ResultsOur clinically based hypothesis was statistically supported: APRs accounted only for 15% of the DAS28, and for 5% of the SDAI and the DAS28-CRP. In both cohorts the CDAI correlated strongly with DAS28 (R = 0.89–0.90) and comparably to the correlation of SDAI with DAS28 (R = 0.90–0.91). In additional analyses, the CDAI when compared to the SDAI and the DAS28 agreed with a weighted kappa of 0.70 and 0.79, respectively, and comparably to the agreement between DAS28 and DAS28-CRP. All three scores correlated similarly with Health Assessment Questionnaire (HAQ) scores (R = 0.45–0.47). The average changes in all scores were greater in patients with better American College of Rheumatology response (P < 0.0001, analysis of variance; discriminant validity). All scores exhibited similar correlations with radiological progression (construct validity) over 3 years (R = 0.54–0.58; P < 0.0001).ConclusionAPRs add little information on top (and independent) of the combination of clinical variables included in the SDAI. A purely clinical score is a valid measure of disease activity and will have its greatest merits in clinical practice rather than research, where APRs are usually always available. The CDAI may facilitate immediate and consistent treatment decisions and help to improve patient outcomes in the longer term.

Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force

Background Reaching the therapeutic target of remission or low-disease activity has improved outcomes in patients with rheumatoid arthritis (RA) significantly. The treat-to-target recommendations, formulated in 2010, have provided a basis for implementation of a strategic approach towards this therapeutic goal in routine clinical practice, but these recommendations need to be re-evaluated for appropriateness and practicability in the light of new insights. Objective To update the 2010 treat-to-target recommendations based on systematic literature reviews (SLR) and expert opinion. Methods A task force of rheumatologists, patients and a nurse specialist assessed the SLR results and evaluated the individual items of the 2010 recommendations accordingly, reformulating many of the items. These were subsequently discussed, amended and voted upon by >40 experts, including 5 patients, from various regions of the world. Levels of evidence, strengths of recommendations and levels of agreement were derived. Results The update resulted in 4 overarching principles and 10 recommendations. The previous recommendations were partly adapted and their order changed as deemed appropriate in terms of importance in the view of the experts. The SLR had now provided also data for the effectiveness of targeting low-disease activity or remission in established rather than only early disease. The role of comorbidities, including their potential to preclude treatment intensification, was highlighted more strongly than before. The treatment aim was again defined as remission with low-disease activity being an alternative goal especially in patients with long-standing disease. Regular follow-up (every 1–3 months during active disease) with according therapeutic adaptations to reach the desired state was recommended. Follow-up examinations ought to employ composite measures of disease activity that include joint counts. Additional items provide further details for particular aspects of the disease, especially comorbidity and shared decision-making with the patient. Levels of evidence had increased for many items compared with the 2010 recommendations, and levels of agreement were very high for most of the individual recommendations (≥9/10). Conclusions The 4 overarching principles and 10 recommendations are based on stronger evidence than before and are supposed to inform patients, rheumatologists and other stakeholders about strategies to reach optimal outcomes of RA.

Autoantibody profiling as early diagnostic and prognostic tool for rheumatoid arthritis

Background: Early treatment prevents progression of joint damage in rheumatoid arthritis (RA), but diagnosis in early disease is impeded by lack of appropriate diagnostic criteria. Objective: To study the value of rheumatoid factor (RF), anti-cyclic citrullinated peptide autoantibodies (anti-CCP), and anti-RA33 autoantibodies for diagnosis of RA and prediction of outcome in patients with very early arthritis. Methods: The prospective follow up inception cohort included 200 patients with very early (<3 months) inflammatory joint disease. Autoantibodies were measured at baseline and analysed in a tree based model which aimed at determining the added diagnostic value of testing for anti-CCP and anti-RA33 as compared with RF alone. Results: RA was diagnosed in 102 patients, while 98 developed other inflammatory arthropathies. Receiver operator curve analysis showed an optimum cut off level for RF at 50 U/ml, above which anti-CCP and anti-RA33 had no additional diagnostic value. Remarkably, RF ⩾50 U/ml and anti-CCP showed similar sensitivity and high specificity for RA, but overlapped considerably. Anti-RA33 was less specific and did not correlate with RF or anti-CCP. Among patients with RA, 72% showed at least one of these three autoantibodies, compared with 15% of non-RA patients. RF ⩾50 U/ml and anti-CCP were predictors of erosive disease, whereas anti-RA33 was associated with mild disease. Conclusions: Stepwise autoantibody testing in early inflammatory joint disease, starting with RF, followed by anti-CCP (in patients with RF <50 U/ml), and finally anti-RA33, should be used as a sensitive and effective strategy for distinguishing patients with RA at high risk for poor outcome.

Evidence for treating rheumatoid arthritis to target: results of a systematic literature search update

Objective A systematic literature review (SLR; 2009–2014) to compare a target-oriented approach with routine management in the treatment of rheumatoid arthritis (RA) to allow an update of the treat-to-target recommendations. Methods Two SLRs focused on clinical trials employing a treatment approach targeting a specific clinical outcome were performed. In addition to testing clinical, functional and/or structural changes as endpoints, comorbidities, cardiovascular risk, work productivity and education as well as patient self-assessment were investigated. The searches covered MEDLINE, EMBASE, Cochrane databases and Clinicaltrial.gov for the period between 2009 and 2012 and separately for the period of 2012 to May of 2014. Results Of 8442 citations retrieved in the two SLRs, 176 articles underwent full-text review. According to predefined inclusion/exclusion criteria, six articles were included of which five showed superiority of a targeted treatment approach aiming at least at low-disease activity versus routine care; in addition, publications providing supportive evidence were also incorporated that aside from expanding the evidence provided by the above six publications allowed concluding that a target-oriented approach leads to less comorbidities and cardiovascular risk and better work productivity than conventional care. Conclusions The current study expands the evidence that targeting low-disease activity or remission in the management of RA conveys better outcomes than routine care.

Validation of the International Classification of Functioning, Disability and Health (ICF) Core Set for rheumatoid arthritis from the patient perspective using focus groups

Functioning is recognized as an important study outcome in rheumatoid arthritis (RA). The Comprehensive ICF Core Set for RA is an application of the International Classification of Functioning, Disability and Health (ICF) of the World Health Organisation with the purpose of representing the typical spectrum of functioning of patients with RA. To strengthen the patient perspective, persons with RA were explicitly involved in the validation of the Comprehensive ICF Core Set for RA using qualitative methodology. The objective of the study was twofold: to come forward with a proposal for the most appropriate methodology to validate Comprehensive ICF Core Sets from the patient perspective; and to add evidence to the validation of the Comprehensive ICF Core Set for RA from the perspective of patients. The specific aims were to explore the aspects of functioning and health important to patients with RA using two different focus group approaches (open approach and ICF-based approach) and to examine to what extent these aspects are represented by the current version of the Comprehensive ICF Core Set for RA. The sampling of patients followed the maximum variation strategy. Sample size was determined by saturation. The focus groups were digitally recorded and transcribed verbatim. The meaning condensation procedure was used for the data analysis. After qualitative data analysis, the resulting concepts were linked to ICF categories according to established linking rules. Forty-nine patients participated in ten focus groups (five in each approach). Of the 76 ICF categories contained in the Comprehensive ICF Core Set for RA, 65 were reported by the patients based on the open approach and 71 based on the ICF-based approach. Sixty-six additional categories (open approach, 41; ICF-based approach, 57) that are not covered in the Comprehensive ICF Core Set for RA were raised. The existing version of the Comprehensive ICF Core Set for RA could be confirmed almost entirely by the two different focus group approaches applied. Focus groups are a highly useful qualitative method to validate the Comprehensive ICF Core Set for RA from the patient perspective. The ICF-based approach seems to be the most appropriate technique.

The development of a preliminary ultrasonographic scoring system for features of hand osteoarthritis

Objectives: Painful osteoarthritis (OA) of the hand is common and a validated ultrasound (US) scoring system would be valuable for epidemiological and therapeutic outcome studies. US is increasingly used to assess peripheral joints, though most of the US focus in rheumatic diseases has been on rheumatoid arthritis. We aimed to develop a preliminary US hand OA scoring system, initially focusing on relevant pathological features with potentially high reliability. Methods: A group of experts in the fields of OA, US and novel tool development agreed on domains and suggested scaling of the items to be used in US hand OA scoring systems. A multi-observer reliability exercise was then performed to evaluate the draft items. Results: Synovitis (grey scale and Power Doppler) and osteophytes (representing activity and damage domains) were included and evaluated as the initial components of the scoring system. All three features were evaluated for their presence/absence and if present were scored using a 1–3 scale. The reliability exercise demonstrated intra-reader κ values of 0.444–1.0, 0.211–1.0 and 0.087–1.0 for grey scale synovitis, power Doppler and osteophytes respectively. Inter-reader reliability κ values were 0.398, 0.327 and 0.530 grey-scale synovitis, power Doppler and osteophytes respectively. Without extensive standardisation, both intra- and inter-reader reliability were moderately good. Conclusions: The draft scoring system demonstrated substantive to almost perfect percentage exact agreement on the presence/absence of the selected OA features and moderate to substantive percentage exact agreement on semi-quantitative grading. This preliminary process provides a good basis from which to further develop an US outcome tool for hand OA that has the potential to be utilised in multicentre clinical trials.

A patient-derived and patient-reported outcome measure for assessing psoriatic arthritis: elaboration and preliminary validation of the Psoriatic Arthritis Impact of Disease (PsAID) questionnaire, a 13-country EULAR initiative

Introduction The objective was to develop a questionnaire that can be used to calculate a score reflecting the impact of psoriatic arthritis (PsA) from the patients’ perspective: the PsA Impact of Disease (PsAID) questionnaire. Methods Twelve patient research partners identified important domains (areas of health); 139 patients prioritised them according to importance. Numeric rating scale (NRS) questions were developed, one for each domain. To combine the domains into a single score, relative weights were determined based on the relative importance given by 474 patients with PsA. An international cross-sectional and longitudinal validation study was performed in 13 countries to examine correlations of the PsAID score with other PsA or generic disease measures. Test–retest reliability and responsiveness (3 months after a treatment change) were examined in two subsets of patients. Results Two PsAID questionnaires were developed with both physical and psychological domains: one for clinical practice (12 domains of health) and one for clinical trials (nine domains). Pain, fatigue and skin problems had the highest relative importance. The PsAID scores correlated well with patient global assessment (N=474, Spearman r=0.82–0.84), reliability was high in stable patients (N=88, intraclass correlation coefficient=0.94–0.95), and sensitivity to change was also acceptable (N=71, standardised response mean=0.90–0.91). Conclusions A questionnaire to assess the impact of PsA on patients’ lives has been developed and validated. Two versions of the questionnaire are available, one for clinical practice (PsAID-12) and one for clinical trials (PsAID-9). The PsAID questionnaires should allow better assessment of the patients perspective in PsA. Further validation is needed.

The Stop Arthritis Very Early (SAVE) trial, an international multicentre, randomised, double-blind, placebo-controlled trial on glucocorticoids in very early arthritis

Background Glucocorticoids (GCs) are often used as early arthritis treatment and it has been suggested that they induce remission or at least delay the development of rheumatoid arthritis (RA) and the need to start disease-modifying antirheumatic drugs (DMARDs). Objective To test the effect of GCs on patients with very early arthritis (symptom duration of <16 weeks) in a randomised controlled trial. Methods Patients received a single intramuscular injection of 120 mg methylprednisolone or placebo (PL) and were followed up for 52 weeks. Primary end point was drug-free clinical remission, both at weeks 12 and 52. Among secondary outcomes were fulfilment of remission criteria at weeks 2, 12 or 52, time course of ‘core set variables’ and proportion of patients starting DMARDs. Results 17.0% of all analysed subjects (65/383) achieved persistent remission: 17.8% (33/185) of the PL group, 16.2% (32/198) of the patients receiving methylprednisolone (OR=1.13, 95% CI 0.66 to 1.92, p=0.6847). Analyses of secondary end points showed significant clinical benefits of the GC only at week 2. These differences subsequently disappeared. DMARDs were started in 162 patients: 50.3% methylprednisolone and 56.7% PL patients had to start DMARD treatment (OR=0.78, 95% CI 0.49 to 1.22, p=0.30). Significantly more patients with polyarthritis than with oligoarthritis received DMARDs (OR=2.84, 95% CI 1.75 to 4.60, p<0.0001). Conclusions Neither remission nor development of RA is delayed by GC treatment. Remission is rare in the first year of very early arthritis, occurring in <20% of the patients. Also, the need to start DMARDs was not influenced by GC treatment.

Estimation of a numerical value for joint damage-related physical disability in rheumatoid arthritis clinical trials

Background Joint damage is an important outcome in trials of rheumatoid arthritis (RA), usually assessed by Total Sharp Score (TSS). It is currently unknown how it translates numerically into disability by the Health Assessment Questionnaire (HAQ). Objective To determine the units of HAQ score corresponding to one TSS unit. Methods A short-term observational trial of glucocorticoids in RA (the ‘BEst LIfe with Rheumatoid Arthritis’ (BELIRA) trial) was evaluated, using randomised controlled clinical trial (RCT) data for confirmation. For each trial arm HAQ, TSS and the Simplified Disease Activity Index (SDAI) were assessed. Based on the hypothesis that short-term HAQ changes will mostly be due to changes of disease activity, activity HAQ (ACT-HAQ) at end point (EP) was determined and remaining disability defined as damage related (DAM-HAQ). Using TSS at EP, the HAQ units corresponding to a TSS unit were estimated. Results In BELIRA, one TSS unit corresponded to a mean of 0.017 HAQ units; to account for other causes of irreversible disability, the 25th percentile was used: 0.011 HAQ units/TSS unit. In RCT trial arms, the HAQ/TSS were similar (0.013 and 0.015 in established and early RA, respectively; 25th percentile: 0.010). The correlation between DAM-HAQEP and TSS was r=0.829. Over 5 years, damage would amount to an increase of irreversible HAQ of 0.33 on placebo, 0.13 on disease-modifying antirheumatic drugs (DMARDs) and 0.03 on TNF inhibitors+methotrexate (MTX). Conclusion An approach to estimate the numerical relationship between HAQ and damage as 0.01 HAQ points/TSS unit is presented, although the linear relationship may not be generally valid. This allows the assessment of functional correlates of radiographic changes in trials.

Thumb base involvement in symptomatic hand osteoarthritis is associated with more pain and functional disability

Objective To assess the impact of different subsets of symptomatic hand osteoarthritis (OA) on pain and disability. Methods From 308 patients with hand OA a group with carpometacarpal joint (CMCJ) symptoms only (group I, n=20) was identified as well as groups with symptoms at the interphalangeal joints (IPJs) only (group II, n=138), and symptoms at both sites (group III, n=150). Hand pain and function, assessed with the AUSCAN, were compared between groups using linear mixed models. Radiological OA was assessed using the Kellgren–Lawrence grading scale. Results Mean (SD) AUSCAN scores for groups I, II and III were 23.1 (11.7), 18.3 (11.9) and 26.4 (12.5), respectively. After adjustment for age, gender, body mass index, family effects and number of symptomatic hand joints, significant differences in AUSCAN scores of 7.4 (95% CI 1.8 to 13.0) between groups I and II, and 5.7 (95% CI 2.7 to 8.6) between groups II and III were found. AUSCAN scores were 5.8 (95% CI 3.1 to 8.6) higher for patients with versus patients without CMCJ symptoms. Kellgren–Lawrence scores did not differ between groups. Conclusion In symptomatic hand OA, CMCJ OA contributes more to pain and disability than IPJ OA. Hence, treatment of CMCJ OA should be emphasised, even if it coincides with IPJ OA.