Classification of rheumatoid arthritis into active or inactive with a modified Disease Activity score, for future use as a treat-to-target tool, with a HandScan score replacing joint counts.

OBJECTIVES: To establish the value of a modified Disease Activity score with Optical Spectral Transmission score (DAS-OST) without joint counts but with a HandScan score, versus that of DAS28, to classify rheumatoid arthritis (RA) as active versus inactive, with as reference standard the rheumatologist's clinical classification. METHODS: RA patients with at least one HandScan and DAS28 measurement performed at the same visit were included. Data was extracted from medical records, as was the clinical interpretation as active or inactive RA by the rheumatologist. Logistic regression analyses were performed to calculate areas under the receiver operating characteristics (AU-ROC) curves. The clinical interpretation was used as reference standard in all analyses, and disease activity measures were used as predictor variables. The performance of predictor variables (AU-ROCs) was compared. RESULTS: The data of 1505 RA patients were used for analyses. The highest AU-ROC of 0.88 (95%CI 0.85-0.90) was shown for DAS28; AU-ROC of DAS-OST was 0.78 (95%CI 0.75-0.81), difference 0.10, p<0.01. CONCLUSIONS: Compared to DAS28, DAS-OST classified RA statistically significantly less well as active versus inactive, when using the clinical classification as reference standard. However, a DAS-modification without joint scores might have a place in strategies limiting routine outpatients' visits to the rheumatologist.

Revisiting the use of remission criteria for rheumatoid arthritis by excluding patient global assessment: an individual meta-analysis of 5792 patients.

OBJECTIVES: To determine the impact of excluding patient global assessment (PGA) from the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Boolean remission criteria, on prediction of radiographic and functional outcome of rheumatoid arthritis (RA). METHODS: Meta-analyses using individual patient data from randomised controlled trials testing the efficacy of biological agents on radiographic and functional outcomes at ≥2 years. Remission states were defined by 4 variants of the ACR/EULAR Boolean definition: (i) tender and swollen 28-joint counts (TJC28/SJC28), C reactive protein (CRP, mg/dL) and PGA (0-10=worst) all ≤1 (4V-remission); (ii) the same, except PGA >1 (4V-near-remission); (iii) 3V-remission (i and ii combined; similar to 4V, but without PGA); (iv) non-remission (TJC28 >1 and/or SJC28 >1 and/or CRP >1). The most stringent class achieved at 6 or 12 months was considered. Good radiographic (GRO) and functional outcome (GFO) were defined as no worsening (ie, change in modified total Sharp score (ΔmTSS) ≤0.5 units and ≤0.0 Health Assessment Questionnaire-Disability Index points, respectively, during the second year). The pooled probabilities of GRO and GFO for the different definitions of remission were estimated and compared. RESULTS: Individual patient data (n=5792) from 11 trials were analysed. 4V-remission was achieved by 23% of patients and 4V-near-remission by 19%. The probability of GRO in the 4V-near-remission group was numerically, but non-significantly, lower than that in the 4V-remission (78 vs 81%) and significantly higher than that for non-remission (72%; difference=6%, 95% CI 2% to 10%). Applying 3V-remission could have prevented therapy escalation in 19% of all participants, at the cost of an additional 6.1%, 4.0% and 0.7% of patients having ΔmTSS >0.0, >0.5 and >5 units over 2 years, respectively. The probability of GFO (assessed in 8 trials) in 4V-near-remission (67%, 95% CI 63% to 71%) was significantly lower than in 4V-remission (78%, 74% to 81%) and similar to non-remission (69%, 66% to 72%). CONCLUSION: 4V-near-remission and 3V-remission have similar validity as the original 4V-remission definition in predicting GRO, despite expected worse prediction of GFO, while potentially reducing the risk of overtreatment. This supports further exploration of 3V-remission as the target for immunosuppressive therapy complemented by patient-oriented targets.

The psychological impact of the COVID-19 pandemic on Dutch people with and without an inflammatory rheumatic disease.

OBJECTIVES: To determine the psychological impact of the COVID-19 pandemic on people with and without an inflammatory rheumatic disease and establish whether psychological flexibility buffers this impact. METHODS: From online surveys in the general Dutch population in 2018 and during the peak of the COVID-19 pandemic in 2020, we analysed data of people with (index group, n = 239) and without (control group, n = 1821) an inflammatory rheumatic disease. Worry, stress, mental well-being (SF-36) and psychological flexibility levels were subjected to covariate-adjusted analyses of variance or linear regression analyses. RESULTS: During the peak of the COVID-19 pandemic in 2020, as compared with the control group, the index group was more worried about getting infected with the virus (partial η2=0.098; medium effect) and more stressed (partial η2=0.040; small effect). However, as compared with data acquired in 2018, the level of mental well-being during the COVID-19 pandemic peak was not lower in both groups. Levels of psychological flexibility did not moderate associations of group or year with mental well-being. CONCLUSIONS: Although patients with an inflammatory rheumatic disease were more worried and stressed during the peak of the COVID-19 pandemic, their level of mental well-being was not reduced, which may have prevented us from finding a buffering effect of psychological flexibility. Overall, our results suggest that the psychological impact of the COVID-19 pandemic in patients with inflammatory rheumatic disease is modest, which could imply that common education and health care will do for most patients.

Effect of disease duration and other characteristics on efficacy outcomes in clinical trials of tocilizumab for rheumatoid arthritis.

OBJECTIVE: To determine the extent to which disease duration, alone or in combination with other baseline clinical and non-clinical factors, explains variations in outcome of tocilizumab initiated in biologic-naïve patients with established RA. METHODS: In this pooled analysis of phase 3 and 4 clinical trials conducted by the sponsor, predictors of response, including demographics, disease characteristics at baseline (start of tocilizumab dosing) and study characteristics (e.g. patient inclusion criteria, tocilizumab dosing regimen) were evaluated. Response was measured as change from baseline to week 24 in Clinical Disease Activity Index (CDAI) and HAQ-Disability Index (HAQ-DI) scores and as the proportions of patients who experienced ≥50% improvement based on ACR criteria (ACR50) and CDAI remission (≤2.8) rates at week 24. RESULTS: Improvements in all outcomes investigated were observed in patients receiving tocilizumab. Although disease duration was statistically significant in the models, it accounted for <2% of variation in CDAI and HAQ-DI score changes from baseline to week 24; baseline CDAI and HAQ-DI values accounted for 32% and 15% of variations, respectively. Doubling of disease duration reduced the odds of achieving an ACR50 response by only 9%, and each additional 5-year period of disease duration decreased the odds of achieving CDAI remission by only 15%. CONCLUSION: RA duration, alone or in combination with other baseline characteristics, had a statistically significant but clinically small effect on the outcomes of tocilizumab initiated in biologic-naïve patients with established RA.

Healthcare utilization and economic burden of difficult-to-treat rheumatoid arthritis: a cost-of-illness study.

OBJECTIVES: To determine the impact of difficult-to-treat rheumatoid arthritis (D2T RA) on (costs related to) healthcare utilization, other resource use and work productivity. METHODS: Data regarding healthcare utilization, other resource use and work productivity of 52 D2T (according to the EULAR definition) and 100 non-D2T RA patients were collected via a questionnaire and an electronic patient record review during a study visit. Annual costs were calculated and compared between groups. Multivariable linear regression analysis was performed to assess whether having D2T RA was associated with higher costs. RESULTS: Mean (95% CI) annual total costs were €37 605 (€27 689 - €50 378) for D2T and €19 217 (€15 647 - €22 945) for non-D2T RA patients (P<0.001). D2T RA patients visited their rheumatologist more frequently, were more often admitted to day-care facilities, underwent more laboratory tests and used more drugs (specifically targeted synthetic DMARDs), compared with non-D2T RA patients (P<0.01). In D2T RA patients, the main contributors to total costs were informal help of family and friends (28%), drugs (26%) and loss of work productivity (16%). After adjustment for physical functioning (HAQ), having D2T RA was no longer statistically significantly associated with higher total costs. HAQ was the only independent determinant of higher costs in multivariable analysis. CONCLUSIONS: The economic burden of D2T RA is significantly higher than that of non-D2T RA, indicated by higher healthcare utilization and higher annual total costs. Functional disability is a key determinant of higher costs in RA.

Difficult-to-treat rheumatoid arthritis: contributing factors and burden of disease.

OBJECTIVES: Treatment of difficult-to-treat (D2T) RA patients is generally based on trial-and-error and can be challenging due to a myriad of contributing factors. We aimed to identify risk factors at RA onset, contributing factors and the burden of disease. METHODS: Consecutive RA patients were enrolled and categorized as D2T, according to the EULAR definition, or not (controls). Factors potentially contributing to D2T RA and burden of disease were assessed. Risk factors at RA onset and factors independently associated with D2T RA were identified by logistic regression. D2T RA subgroups were explored by cluster analysis. RESULTS: Fifty-two RA patients were classified as D2T and 100 as non-D2T. Lower socioeconomic status at RA onset was found as an independent risk factor for developing D2T RA [odds ratio (OR) 1.97 (95%CI 1.08-3.61)]. Several contributing factors were independently associated with D2T RA, occurring more frequently in D2T than in non-D2T patients: limited drug options because of adverse events (94% vs 57%) or comorbidities (69% vs 37%), mismatch in patient's and rheumatologist's wish to intensify treatment (37% vs 6%), concomitant fibromyalgia (38% vs 9%) and poorer coping (worse levels). Burden of disease was significantly higher in D2T RA patients. Three subgroups of D2T RA patients were identified: (i) 'non-adherent dissatisfied patients'; (ii) patients with 'pain syndromes and obesity'; (iii) patients closest to the concept of 'true refractory RA'. CONCLUSIONS: This comprehensive study on D2T RA shows multiple contributing factors, a high burden of disease and the heterogeneity of D2T RA. These findings suggest that these factors should be identified in daily practice in order to tailor therapeutic strategies further to the individual patient.

Non-adherence in difficult-to-treat rheumatoid arthritis from the perspectives of patients and rheumatologists: a concept mapping study.

OBJECTIVES: Treatment non-adherence is more frequent among difficult-to-treat (D2T) than among non-D2T RA patients. Perceptions of non-adherence may differ. We aimed to thematically structure and prioritize barriers to (i.e. causes and reasons for non-adherence) and facilitators of optimal adherence from the patients' and rheumatologists' perspectives. METHODS: Patients' perceptions were identified in semi-structured in-depth interviews. Experts selected representative statements regarding 40 barriers and 40 facilitators. Twenty D2T and 20 non-D2T RA patients sorted these statements during two card-sorting tasks: first, by order of content similarity and, second, content applicability. Additionally, 20 rheumatologists sorted the statements by order of content applicability to the general RA population. The similarity sorting was used as input for hierarchical cluster analysis. The applicability sorting was analysed using descriptive statistics, prioritized and the results compared between D2T RA patients, non-D2T RA patients and rheumatologists. RESULTS: Nine clusters of barriers were identified, related to the healthcare system, treatment safety/efficacy, treatment regimen and patient behaviour. D2T RA patients prioritized adverse events and doubts about effectiveness as the most important barriers. Doubts about effectiveness were more important to D2T than to non-D2T RA patients (P = 0.02). Seven clusters of facilitators were identified, related to the healthcare system and directly to the patient. All RA patients and rheumatologists prioritized a good relationship with the healthcare professional and treatment information as the most helpful facilitators. CONCLUSIONS: D2T RA patients, non-D2T RA patients and rheumatologists prioritized perceptions of non-adherence largely similarly. The structured overviews of barriers and facilitators provided in this study may guide improvement of adherence.

Effect on efficacy and safety trial outcomes of also enrolling patients on ongoing glucocorticoid therapy in rheumatoid arthritis clinical trials of tocilizumab or adalimumab or methotrexate monotherapy.

BACKGROUND: In rheumatoid arthritis (RA) trials, inclusion of patients on background treatment with glucocorticoids (GCs) might impact efficacy and safety outcomes. OBJECTIVES: To determine if inclusion of patients on background GC use influenced efficacy and safety outcomes of RA randomised clinical trials on initiation of tocilizumab (TCZ) or adalimumab (ADA) or methotrexate (MTX) monotherapy. METHODS: Data of four double-blind RA randomised controlled trials (AMBITION, ACT-RAY, ADACTA and FUNCTION) with in total four TCZ, one ADA and two MTX monotherapy arms were analysed. Analyses of covariance of changes from baseline to week 24 in efficacy endpoints and radiographic progression up to week 104 were performed, correcting for relevant covariates. Incidence rates of serious adverse events (SAEs) were assessed. RESULTS: No statistically significant differences were found in efficacy parameters between background GC users and non-GC users, except for less radiographic progression associated with GC usage in one MTX arm. SAE rates were not statistically significantly different between GC users and non-GC users in the treatment arms. CONCLUSION: No effect of including patients on background GC treatment on efficacy and safety trial outcomes was found, with the exception of reduced radiological joint damage in one MTX arm.

The performance of dual-energy CT in the classification criteria of gout: a prospective study in subjects with unclassified arthritis.

OBJECTIVE: To establish the performance of (subsets of) the 2015 ACR/EULAR gout classification criteria in patients with unclassified arthritis, and to determine the value of dual-energy CT (DECT) herein. Reference was the MSU crystal detection result in SF at polarization microscopy. METHODS: We included subjects with acute, unclassified mono or oligoarthritis, who underwent SF analysis and DECT. Performance was assessed by calculating area under the receiver operating characteristic curve of (i) the clinical criteria subset, (ii) the clinical+serum urate subset and (iii) the full set (including DECT). RESULTS: Of the 89 subjects enrolled, 40 met the clinical+serum urate subset criteria, and 49 (55%) subjects did not. Of these 49, 30 had a negative microscopy result, of whom 15 had positive DECT; of these 15, 14 met the full set criteria only after adding the positive DECT result. For the clinical-only subset, the areas under the curves (AUCs) were 0.68 and 0.69 without and with DECT result, respectively, and for the clinical+serum urate subset without and with DECT, AUCs were 0.81 and 0.81, respectively (results not significant). CONCLUSION: Adding the serum urate results to the clinical subset improves the performance, but adding the DECT result does not, neither does adding the DECT results to the clinical+serum urate subset. However, DECT seems to have an additive value in gout classification, especially when microscopy of SF is negative; 14/89 of patients (16%) only met the classification criteria with the use of DECT. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT03038386.

Effectiveness and safety over 3 years after the 2-year U-Act-Early trial of the strategies initiating tocilizumab and/or methotrexate.

OBJECTIVES: U-Act-Early was a 2-year, randomized placebo controlled, double-blind trial, in which DMARD-naïve early RA patients were treated to the target of sustained remission (SR). Two strategies initiating tocilizumab (TCZ), with and without methotrexate (MTX), were more effective than a strategy initiating MTX. The aim of the current study was to determine longer-term effectiveness in daily clinical practice. METHODS: At the end of U-Act-Early, patients were included in a 3-year post-trial follow-up (PTFU), in which treatment was according to standard care and data were collected every 3 months during the first year and every 6 months thereafter. Primary end point was disease activity score assessing 28 joints (DAS28) over time. Mixed effects models were used to compare effectiveness between initial strategy groups, correcting for relevant confounders. Between the groups as randomized, proportions of patients were tested for DMARD use, SR and radiographic progression of joint damage. RESULTS: Of patients starting U-Act-Early, 226/317 (71%) participated in the PTFU. Over the total 5 years, mean DAS28 was similar between groups (P > 0.20). During U-Act-Early, biologic DMARD use decreased in both TCZ initiation groups and increased in the MTX initiation group, but during follow-up this trend did not continue. SR was achieved at least once in 99% of patients. Of the 226 patients, only 30% had any radiographic progression over 5 years, without significant differences between the groups. CONCLUSION: Although in the short-term the strategies initiating TCZ yielded the most clinical benefit, in the longer-term differences in important clinical outcomes between the strategies disappeared, probably due to continuation of the treat-to-target principle.

Cardiovascular risk in patients with new gout diagnosis: is monosodium urate volume at ankles and feet on dual-energy computed tomography associated with previous cardiovascular events?

OBJECTIVES: Chronic inflammation associated with hyperuricaemia and urate deposition may contribute to an increased risk of developing cardiovascular (CV) events (CVE) in patients with gout. The aim of this study was to explore whether urate deposition on dual-energy CT (DECT) present at the diagnosis of gout is associated with a history of CVE. METHODS: Patients from a study on clinical value of DECT with mono or oligoarthritis who had gout according the 2015 EULAR/ACR classification criteria were included in this cross-sectional study. Urate volume on DECT was calculated. Patients underwent a structured CV consultation, including assessment of CVE-history and of CV risk factors, scored with the Dutch risk prediction SCORE and the Framingham score. The data were analysed using logistic regression analyses. RESULTS: Sixty-eight patients were included. In the multivariable model, -next to significant associations of age (OR per year 1.1, 95% CI 1.04 to 1.02, p=0.02), HDLc per mmol/l (OR 0.04, 95% CI 0.002 to 0.8, p=0.03), and diabetes yes/no (OR 4, 95% CI 0.8 to 20.9, p=0.09)-, urate volumes at ankles/feet on DECT in the third and fourth quartile with first quartile as reference showed a trend of association (OR 4.8, 95% CI 0.6 to 42, p=0.1 and 6.4, 0.7 to 63, 0.1, respectively) with past CVE events (yes/ no). This association could be bidirectional. Almost two-third of newly classified gout patients had a high or very high CV risk. CONCLUSIONS: CVE history probably is associated with urate volumes already present at the time of diagnosis of gout. Our data corroborate the need of assessing and treating CV risk factors when diagnosing gout.

Cardiovascular risk in patients with new gout: should we reclassify the risk?

OBJECTIVES: Chronic inflammation, as seen in gout, may contribute to an increased risk of developing cardiovascular (CV) events (CVE). The aim of the study was to explore the effect of adding gout as a chronic inflammatory disease to the Dutch SCORE, a tool predicting 10-year CV mortality and morbidity. METHODS: This was a cross-sectional substudy including new patients with gout according the 2015 EULAR/ACR classification criteria who had participated in a trial on diagnostic accuracy of DECT with mono or oligoarthritis. Patients underwent a structured CV consultation, including assessment of CVE-history and of CV risk factors with the Dutch risk prediction SCORE. Chi-square test for trends was used to test for significance reclassification of the CV risk before and after adding gout to the Dutch SCORE. RESULTS: Seventy-six gout patients were included. SCORE was applied in 60 patients; 16 patients had experienced a prior CVE. The 10-year risk scores without gout as risk factor were high in 29 patients (48.3%), moderate in 6 (10%) and low in 25 (41.7%); with gout, the risk of 23/60 patients (38.3%) was reclassified from low to moderate in 6 patients (10%), from low to high in 11 (18.3%) and from moderate to high in 6 (10%), p<0.001 for trend. CONCLUSIONS: Adding gout to the risk prediction tools led to significant and clinically relevant reclassification of CV risk in new gout patients. Studies with large follow-up are warranted to validate these findings.

The diagnostic performance of dual energy CT for diagnosing gout: a systematic literature review and meta-analysis.

OBJECTIVE: This study aimed to assess the utility of dual energy CT (DECT) for diagnosing gout. METHODS: A systematic literature search was performed in PubMed, EMBASE and Cochrane Library. Studies evaluating the utility of DECT for diagnosing gout were included. Reference standards were detection of monosodium urate crystals at SF assessment or a validated set of criteria. The methodological quality of studies was evaluated according to the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 criteria. Data from person-based and joint-/localization-based evaluations were pooled separately, and subgroup analyses for disease stage/duration and reference standard were performed. RESULTS: Ten studies were included; in person-based evaluations, the pooled (95% CI) sensitivity and specificity were 0.81 (0.77, 0.86) and 0.91 (0.85, 0.95), respectively. In joint-based evaluations, they were 0.83 (0.79, 0.86) and 0.88 (0.83, 0.92), respectively. At short disease duration (⩽6 weeks), the pooled (95% CI) sensitivity and specificity at the joint level were 0.55 (0.46, 0.64) and 0.89 (0.84, 0.94), respectively. CONCLUSION: DECT has a high diagnostic accuracy in established gout, but its diagnostic sensitivity is low in subjects with recent onset gout.

Adalimumab drug and antidrug antibody levels do not predict flare risk after stopping adalimumab in RA patients with low disease activity.

OBJECTIVE: To establish whether serum adalimumab (ADA) trough level (ADA-TL) and antidrug antibody (ADA-ab) level predict flare after stopping ADA in established RA patients with long-standing low disease activity. METHODS: From the clinical trial Potential Optimalisation and Effectiveness of TNF-blockers, 210 RA patients stopping ADA, who had been using ADA (40 mg/2 weeks) for >1 year with conventional synthetic DMARDs and who had low disease activity (DAS28 < 3.2, or the rheumatologist's assessment of low disease activity with CRP < 10 mg/l) for at least 6 months prior to stopping, were followed for 1 year. The ADA-TL was measured (by ELISA) 12-17 days after the last ADA injection; if it was low, ADA-abs were measured (by an antigen-binding test). Association between time-to-flare and ADA-TL was evaluated by area under the receiver operating characteristic curve and Cox regression. RESULTS: A total of 106 (51%) patients flared within 1 year after stopping ADA. The area under the receiver operating characteristic curve for flare and ADA-TL was 0.50 (95% CI 0.42-0.58), P = 0.92. The hazard ratio for flare for ADA-TL ⩾ 5 µg/ml (adequate level) vs <5 µg/ml was 0.93 (95% CI: 0.63-1.36) (not significant). Of the 4 patients with high ADA-ab levels, 2 patients (50%) experienced a flare. CONCLUSION: Flare risk within the year following stopping ADA is not predicted by the ADA-TL or ADA-abs assessed at the moment of stopping. TRIAL REGISTRATION: Netherlands Trial Register, http://www.trialregister.nl, NTR3112.

Inadequate response to treat-to-target methotrexate therapy in patients with new-onset rheumatoid arthritis: development and validation of clinical predictors.

OBJECTIVE: To identify and validate clinical baseline predictors associated with inadequate response (IR) to methotrexate (MTX) therapy in newly diagnosed patients with rheumatoid arthritis (RA). METHODS: In U-Act-Early, 108 disease-modifying antirheumatic drug (DMARD)-naive patients with RA were randomised to initiate MTX therapy and treated to target until sustained remission (disease activity score assessing 28 joints (DAS28) <2.6 with four or less swollen joints for ≥24 weeks) was achieved. If no remission, hydroxychloroquine was added to the treatment regimen (ie, 'MTX+') and replaced by tocilizumab if the target still was not reached thereafter. Regression analyses were performed to identify clinical predictors for IR, defined as needing addition of a biological DMARD, to 'MTX+'. Data from the treatment in the Rotterdam Early Arthritis Cohort were used for external validation of the prediction model. RESULTS: Within 1 year, 56/108 (52%) patients in U-Act-Early showed IR to 'MTX+'. DAS28 (adjusted OR (ORadj) 2.1, 95% CI 1.4 to 3.2), current smoking (ORadj 3.02, 95% CI 1.1 to 8.0) and alcohol consumption (ORadj 0.4, 95% CI 0.1 to 0.9) were identified as baseline predictors. The area under the receiver operator characteristic curve (AUROC) of the prediction model was 0.75 (95% CI 0.66 to 0.84); the positive (PPV) and negative predictive value (NPV) were 65% and 80%, respectively. When applying the model to the validation cohort, the AUROC slightly decreased to 0.67 (95% CI 0.55 to 0.79) and the PPV and NPV to 54% and 80%, respectively. CONCLUSION: Higher DAS28, current smoking and no alcohol consumption are predictive factors for IR to step-up 'MTX+' in DMARD-naive patients with new-onset RA. TRIAL REGISTRATION: NCT01034137; Post-results, ISRCTN26791028; Post-results.

Characteristics of difficult-to-treat rheumatoid arthritis: results of an international survey.

OBJECTIVES: Patients with difficult-to-treat rheumatoid arthritis (RA) remain symptomatic despite treatment according to current European League Against Rheumatism (EULAR) management recommendations. These focus on early phases of the disease and pharmacological management. We aimed to identify characteristics of difficult-to-treat RA and issues to be addressed in its workup and management that are not covered by current management recommendations. METHODS: An international survey was conducted among rheumatologists with multiple-choice questions on disease characteristics of difficult-to-treat RA. Using open questions, additional items to be addressed and items missing in current management recommendations were identified. RESULTS: 410 respondents completed the survey: 50% selected disease activity score assessing 28 joints >3.2 OR presence of signs suggestive of active disease as characteristics of difficult-to-treat RA; 42% selected fatigue; 48% selected failure to ≥2 conventional synthetic disease-modifying antirheumatic drugs (DMARDs) AND ≥2 biological/targeted synthetic DMARDs; 89% selected inability to taper glucocorticoids below 5 mg or 10 mg prednisone equivalent daily. Interfering comorbidities, extra-articular manifestations and polypharmacy were identified as important issues missing in current management recommendations. CONCLUSIONS: There is wide variation in concepts of difficult-to-treat RA. Several important issues regarding these patients are not addressed by current EULAR recommendations.

Difficult-to-treat rheumatoid arthritis: an area of unmet clinical need.

Increased effectiveness of pharmacological treatments in early RA has led many to believe that difficult-to-treat, established RA is a condition of the past. However, there are still plenty of RA patients who continue to have signs and symptoms suggestive of inflammatory disease activity, despite consecutive treatment with multiple conventional synthetic and biological DMARDs. We argue that difficult-to-treat RA constitutes an area of unmet clinical need and propose a definition of this concept. An overview of what is known about the multiple contributory factors varying for each individual patient, and an approach towards improved patient-tailored management are presented. This management approach involves thorough assessment to determine whether persistence of signs and symptoms is based on inflammatory disease activity, and the role of comorbidities. Furthermore, it addresses medication-related issues, such as non-adherence, patient beliefs and expectations, and setting of realistic treatment goals.

Optical spectral transmission to assess inflammation in hand and wrist joints of rheumatoid arthritis patients.

Objective: To develop an optical spectral transmission (OST) model to measure joint inflammation, and thus disease activity, as well as to evaluate (patho-)physiological findings that could lead to misclassification of inflammation. Methods: Forty-six RA patients were included in this cross-sectional study, where US scores, duplicate OST measurements and 28-joint DAS (DAS28) were acquired. With US as a reference standard, the diagnostic performance of OST in detecting inflammation at the joint level was evaluated using receiver operating characteristic (ROC) curve analyses. At the patient level, correlations with US were analysed for DAS28 and OST, and at joint level for OST and tender and swollen joint counts (TJC and SJC, respectively). Joint pathology potentially influencing misclassification by OST [erosions, osteophytes, tendon (sheath) inflammation (ab)normal vasculature and chondrocalcinosis] was evaluated for significance in a multivariate nominal logistic regression model. Results: Diagnostic performance of OST was good for MCP [area under the ROC curve (AUC-ROC) 0.88], PIP (AUC-ROC 0.83) and wrist (AUC-ROC 0.74) joints and for all joints together (AUC-ROC 0.85). At the patient level, DAS28 correlated very poorly (ρ = 0.06) and OST moderately (ρ = 0.54) with US. At the joint level, US correlation with OST was strong (ρ = 0.64), with SJC it was weak (ρ = 0.30) and with TJC it was very weak (ρ = -0.02). Misclassification of inflammation by OST was relatively rare (17%). Dorsal erosions [odds ratio (OR) 4.0], osteophytes (OR 2.1) and extensor tendinitis (OR 4.6) increased the risk of underestimating inflammation of MCP and PIP joints and osteophytes (OR 3.0) also increased the risk of overestimating inflammation. Conclusion: OST is a sensitive, specific and objective technique to assess joints inflammation of the hands and wrists of RA patients, even though bone and tendon pathology increases the risk of misclassification.

Radiographic joint damage in early rheumatoid arthritis patients: comparing tocilizumab- and methotrexate-based treat-to-target strategies.

OBJECTIVE: To evaluate the progression of erosions and joint space narrowing (JSN) in feet and hands in the U-Act-Early trial. METHODS: In this trial, 317 newly diagnosed DMARD-naïve RA patients initiated randomly tocilizumab, or step-up MTX or a combination of the two. Radiographs were scored at baseline and after 52 and 104 weeks using the Sharp-van der Heijde erosion and JSN score. Between the strategy arms, changes from baseline and the proportions of patients without radiographic progression (change from baseline ≤0) were compared. RESULTS: Mean changes from baseline in erosion and JSN scores for the whole study population were after 52 weeks 0.59 and 0.18 and after 104 weeks 0.70 and 0.50, respectively. For JSN, at both time points no differences in progression were found between strategies (P ⩾ 0.09). For erosions, the progression was significantly lower at week 104 in both tocilizumab arms when compared with the MTX arm ((p≤0.023). Less progression of erosions in the feet was found after 104 weeks in both tocilizumab arms (P ⩽ 0.046); this was not significant for the hands (P ⩾ 0.11). The proportion of patients without progression in erosions was higher in the tocilizumab arms at week 52 (tocilizumab plus MTX: 87%, P = 0.038; tocilizumab: 81%, P = 0.29) and 104 (tocilizumab plus MTX: 85%, P = 0.001; tocilizumab: 77%, P = 0.028), compared with the MTX arm (74 and 60%, respectively). CONCLUSION: In DMARD-naïve early RA patients, initiating a tocilizumab-based treat-to-target strategy inhibits the progression of erosions, especially in the feet, more compared with initiation of a step-up MTX strategy. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT01034137.

Explorative analyses of protein biomarkers in patients with early rheumatoid arthritis achieving sustained drug-free remission after treatment with tocilizumab- or methotrexate-based strategies: from transcriptomics to proteomics.

OBJECTIVES: Previously, we identified networks of co-expressed genes related to achieving sustained drug-free remission (sDFR). The aim of the present exploratory analysis was to identify inflammatory proteins associated with achieving sDFR and their enriched biological pathways, and compare these pathways with those found in the previous transcriptomic analyses. METHODS: Serum samples were used from 60 patients who participated in the U-Act-Early trial and were treated-to-target with tocilizumab plus methotrexate, or tocilizumab or methotrexate; 37 achieved sDFR (≥3 months drug-free) and 23 did not (controls). Luminex® multi-analyte profiling (xMAP)® was used to measure 85 proteins. Partial least square discriminant analyses (PLSDA) identified proteins associated with achieving sDFR within each strategy arm, which were thereafter used for pathway analyses. RESULTS: PLSDA identified 9, 14 and 13 relevant proteins in the tocilizumab plus methotrexate, tocilizumab and methotrexate arm, respectively and pathway analyses thereafter identified respectively 49, 88 and 117 significantly enriched gene ontology (GO) terms. When comparing these terms with those previously found in the transcriptomic analyses, corresponding pathways were related in the tocilizumab arm to activity of leukocytes; in the methotrexate arm to response of stimuli and regulation of the Janus kinase signal transducer and activator of transcription (JAK-STAT) pathway. In the tocilizumab plus methotrexate arm, no corresponding enriched pathways were found. CONCLUSIONS: Multiple proteins were associated with achieving sDFR and several biological pathways corresponded, mainly in the methotrexate arm, with our previous transcriptomic findings potentially providing further insights into gene expression and protein translation in newly diagnosed RA patients.