Effect of tapered versus stable treatment with tumour necrosis factor inhibitors on disease flares in patients with rheumatoid arthritis in remission: a randomised, open label, non-inferiority trial.

OBJECTIVES: Many patients with rheumatoid arthritis (RA) require treatment with tumour necrosis factor inhibitor (TNFi) to reach remission. It is debated whether tapering of TNFi to discontinuation should be considered in sustained remission. The aim of ARCTIC REWIND TNFi was to assess the effect of tapering TNFi to withdrawal compared with stable treatment on the risk of disease activity flares in patients with RA in remission ≥1 year. METHODS: This randomised, open-label, non-inferiority trial was undertaken at nine Norwegian rheumatology departments. Patients with RA in remission ≥12 months on stable TNFi therapy were allocated by computer-based block-randomisation to tapering to discontinuation of TNFi or stable TNFi. Conventional synthetic disease-modifying antirheumatic co-medication was unchanged. The primary endpoint was disease flare during the 12-month study period (non-inferiority margin 20%), assessed in the per-protocol population. RESULTS: Between June 2013 and January 2019, 99 patients were enrolled and 92 received the allocated treatment strategy. Eighty-four patients were included in the per-protocol population. In the tapering TNFi group, 27/43 (63%) experienced a flare during 12 months, compared with 2/41 (5%) in the stable TNFi group; risk difference (95% CI) 58% (42% to 74%). The tapering strategy was not non-inferior to continued stable treatment. The number of total/serious adverse events was 49/3 in the tapering group, 57/2 in the stable group. CONCLUSION: In patients with RA in remission for more than 1 year while using TNFi, an increase in flare rate was reported in those who tapered TNFi to discontinuation. However, most regained remission after reinstatement of full-dose treatment. TRIAL REGISTRATION NUMBERS: EudraCT: 2012-005275-14 and clinicaltrials.gov: NCT01881308.

First step in the development of an ultrasound joint inflammation score for rheumatoid arthritis using a data-driven approach.

OBJECTIVES: To develop and validate candidate sets of joints and tendons for assessment of ultrasound (US) joint inflammation in rheumatoid arthritis (RA). METHODS: Patients were included in one of two cohorts from 2010 to June 2013: disease-modifying antirheumatic drug naïve early RA or established RA starting/switching biologics. An extensive US examination was performed by experienced sonographers using a validated grey-scale (GSUS) and power Doppler (PDUS) semiquantitative scoring system with scores 0-3 for both GSUS and PDUS in 36 joints and four tendons. We performed factor analysis in the early RA US data and selected candidate joint/tendon sets based on these results. The proportion of information in the total US scores retained in these candidate sets was assessed by R(2) from linear regression analysis. Finally, the candidate sets and previously proposed joint scores were tested in the established RA cohort, and we also evaluated the sensitivity to change with standardised response means. RESULTS: 227 patients with early RA and 212 patients with established RA were included. We identified two candidate sets of joints/tendons: candidate set A consisted of seven joints/two tendons (meatacarpophalangeal 1 (MCP1), MCP2, proximal interphalangeal 3, radiocarpal, elbow, metatarsophalangeal 1 (MTP1), MTP2, tibialis posterior tendon, extensor carpi ulnaris tendon) and set B of nine joints/two tendons (MCP5 and MTP5 added to set A). Unilateral reduced scores retained 78%-85% of the information in total score, while bilateral reduced scores retained 89%-93%, and both sets performed better than previously proposed reduced joint scores, and similar or slightly better regarding sensitivity to change. CONCLUSIONS: The reduced GSUS and PDUS scores retained most of the information from the total score and performed well in a validation cohort of established RA. TRIAL REGISTATION NUMBER: NCT01205854, ACTRN12610000284066.

The role of methotrexate co-medication in TNF-inhibitor treatment in patients with psoriatic arthritis: results from 440 patients included in the NOR-DMARD study.

BACKGROUND: The role of co-medication with tumour necrosis factor inhibitors (TNFi) is well established in rheumatoid arthritis and ankylosing spondylitis. In psoriatic arthritis (PsA) there is little evidence available on this issue. MATERIAL AND METHODS: The analyses were based on data from the Norwegian longitudinal observational study on disease-modifying antirheumatic drugs (NOR-DMARD). Patients with PsA starting their first TNFi, either as monotherapy or with concomitant methotrexate (MTX), were selected. Baseline characteristics, responses after 3, 6 and 12 months, and drug survival were compared between those with and without MTX co-medication. A secondary analysis was performed on patients who had confirmed swollen joints at baseline. Cox regression was used to identify predictors of discontinuation. RESULTS: We included 440 patients, 170 receiving TNFi as monotherapy and 270 receiving concomitant MTX. The groups had similar baseline characteristics, except for number of swollen joints, which was higher in the concomitant MTX group. Responses were similar in the two groups in both analyses. Drug survival analyses revealed a borderline significant difference in favour of patients receiving co-medication (p=0.07), and this was most prominent for patients receiving infliximab (IFX) (p=0.01). In the Cox regression analysis lack of concomitant MTX and current smoking were independent predictors of discontinuation of TNFi. CONCLUSIONS: We found similar responses to TNFi in patients with and without concomitant MTX, but drug survival was superior in patients receiving co-medication. The effect of MTX on drug survival was most prominent in patients receiving IFX. Smoking at baseline and use of TNFi as monotherapy were identified as independent predictors of drug discontinuation.

Switching between TNF inhibitors in psoriatic arthritis: data from the NOR-DMARD study.

BACKGROUND: Tumour necrosis factor inhibitors (TNFi) are efficacious in patients with psoriatic arthritis (PsA), but some patients do not respond or do not tolerate their first TNFi, and are switched to a different TNFi. Evidence supporting this practice is limited, and we wanted to investigate the effectiveness of switching to a second TNFi. MATERIAL AND METHODS: From a longitudinal observational study (LOS) we selected patients with PsA who were starting their first TNFi, and identified patients who had switched to a second TNFi ('switchers'). Three-month responses and 3-year drug-survival were compared between switchers and non-switchers, and within switchers. RESULTS: Switchers (n=95) receiving their second TNFi had significantly poorer responses compared with non-switchers (n=344) (ACR50 response: 22.5% vs 40.0%, DAS28 remission: 28.2% vs 54.1%). There was a trend towards poorer responses to the second TNFi compared with the first TNFi within switchers. Estimated 3-year drug-survival was 36% for the second TNFi compared with 57% for the first TNFi overall. CONCLUSIONS: 20-40% of patients had a response on a second TNFi after having failed one TNFi in this LOS. This observation highlights the need for treatments with other mechanisms of action than TNF inhibition in patients with PsA.

Prevalence of pulmonary hypertension in an unselected, mixed connective tissue disease cohort: results of a nationwide, Norwegian cross-sectional multicentre study and review of current literature.

OBJECTIVES: The aim of this study was to assess the overall prevalence of pulmonary hypertension (PH) in an unselected MCTD cohort and review the current knowledge with a systematic database search. METHODS: A nationwide multicentre cohort of 147 adult MCTD patients were initially screened for PH by echocardiography, high-resolution computed tomography (HRCT), pulmonary function tests and N-terminal pro-brain natriuretic peptide (NT-proBNP) and then followed up for a mean of 5.6 years. Right-sided heart catheterization was performed when estimated pulmonary artery systolic pressure was >40 mmHg on echocardiography. PH was diagnosed according to the 2009 European Society of Cardiology and European Respiratory Society guidelines. RESULTS: At inclusion, 2.0% (3/147) had established PH. Two additional PH patients were identified during follow-up, giving a total PH frequency in the cohort of 3.4% (5/147). All five had elevated serum NT-proBNP. Two had isolated pulmonary arterial hypertension (PAH) and three PH associated with interstitial lung disease (PH-ILD). Three PH patients died during follow-up. Nine other patients in the cohort also died, but none of them had echocardiographic signs of PH prior to death. CONCLUSION: The data from the current unselected MCTD cohort suggest that the prevalence of PH is much lower than expected from previous studies but confirm the seriousness of the disease complication.

Prevalence and severity of interstitial lung disease in mixed connective tissue disease: a nationwide, cross-sectional study.

BACKGROUND: Mixed connective tissue disease (MCTD) is an immune-mediated, systemic disorder of unknown cause. OBJECTIVE: To assess the prevalence, pattern and severity of interstitial lung disease (ILD) in a cross-sectional study of the nationwide, Norwegian MCTD cohort. METHODS: 126 patients with MCTD were systematically examined for ILD by high-resolution CT (HRCT), pulmonary function tests (PFT), 6 min walk test (6MWT) and by the New York Heart Association (NYHA) functional classification of dyspnoea. The extent and type of HRCT lung abnormalities were scored according to the CT criteria of ILD recommended by the Fleischner Society. RESULTS: All 126 patients were Caucasian, 75% women. At the time of the cross-sectional ILD study, the patients had a mean disease duration of 9.0 years. 52% of the patients had abnormal HRCT findings, most commonly reticular patterns consistent with lung fibrosis (35%). Lung fibrosis was quantified as minor in 7%, moderate in 9% and severe in 19% of the patients. Fibrosis was uniformly concentrated in the lower parts of the lungs and was not associated with smoking. Patients with severe lung fibrosis had lower PFT values, shorter 6MWT and a higher mean NYHA functional class. After a mean 4.2 years' follow-up, overall mortality was 7.9%. Mortality in patients with normal HRCT was 3.3%, as compared with 20.8% in patients with severe lung fibrosis (p<0.01). CONCLUSIONS: Severe lung fibrosis is common in MCTD, has an impact on pulmonary function and overall physical capacity and is associated with increased mortality.

Physician participation in quality improvement work- interest and opportunity: a cross-sectional survey.

BACKGROUND: Lack of physician involvement in quality improvement threatens the success and sustainability of quality improvement measures. It is therefore important to assess physicians´ interests and opportunities to be involved in quality improvement and their experiences of such participation, both in hospital and general practice. METHODS: A cross-sectional postal survey was conducted on a representative sample of physicians in different job positions in Norway in 2019. RESULTS: The response rate was 72.6% (1513 of 2085). A large proportion (85.7%) of the physicians wanted to participate in quality improvement, and 68.6% had actively done so in the last year. Physicians' interest in quality improvement and their active participation was significantly related to the designated time for quality improvement in their work-hour schedule (p < 0.001). Only 16.7% reported time designated for quality improvement in their own work hours. When time was designated, 86.6% of the physicians reported participation in quality improvement, compared to 63.7% when time was not specially designated. CONCLUSIONS: This study shows that physicians want to participate in quality improvement, but only a few have designated time to allow continuous involvement. Physicians with designated time participate significantly more. Future quality programs should involve physicians more actively by explicitly designating their time to participate in quality improvement work. We need further studies to explore why managers do not facilitate physicians´ participation in quality improvement.

Treat to target strategy in early rheumatoid arthritis versus routine care - A comparative clinical practice study.

OBJECTIVE: To assess the 2-year effect on disease activity and health-related quality of life (HRQoL) of implementing a clinical practice treat-to-target (T2T) strategy in patients with rheumatoid arthritis (RA). METHODS: Patients in the Norwegian Very Early Arthritis Cohort 2.0 (NOR-VEAC 2.0), included 2010-2015, were treated according to T2T principles with visits at baseline, 3, 6, 9, 12 months, then every 6 months plus monthly visits until DAS28 <2.6. These patients were compared to a pre-T2T cohort of patients included in the Norwegian Disease Modifying Anti-Rheumatic Drug (NOR-DMARD) register 2006-2009. Both groups had a clinical diagnosis of RA (≤1 year) and were DMARD naïve. Disease activity and HRQoL outcomes were analysed, and the primary outcome was SDAI remission (≤3.3) at 2years. RESULTS: The T2T cohort included 293 patients (mean (SD) age 54 (13) years, 66% females, disease duration median (25,75 perc) 98 (57,164) days) and the routine care cohort 392 patients (age 54 (13) years, 68% females, 4 (0,30) days since diagnosis). At 2years, the proportion of patients achieving SDAI remission was 46% in the T2T cohort compared to 31% in the routine care cohort. EQ-5D was similar at baseline, but differed significantly between groups at 2years (median (25,75 perc) 0.77 (0.69, 0.85) vs 0.73 (0.59, 0.80), p < 0.001). Methotrexate monotherapy was the dominant DMARD regimen used to achieve SDAI remission in both cohorts. CONCLUSION: Higher remission rates and better HRQoL were achieved in patients following a T2T strategy in clinical practice compared to routine care.

Achievement of Remission and Low Disease Activity Definitions in Patients with Rheumatoid Arthritis in Clinical Practice: Results from the NOR-DMARD Study.

OBJECTIVE: To examine the frequency of 6 definitions for remission and 4 definitions for low disease activity (LDA) after starting a disease-modifying antirheumatic drug (DMARD) in patients with rheumatoid arthritis (RA) in clinical practice, and to study whether predictors for achieving remission after 6 months are similar for these definitions. METHODS: Remission and LDA were calculated according to the 28-joint Disease Activity Score (DAS28), the Clinical Disease Activity Index (CDAI), the Simplified Disease Activity Index (SDAI), the Routine Assessment of Patient Index Data (RAPID3), and both the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Boolean remission definitions 3 and 6 months after 4992 DMARD prescriptions for patients enrolled in the NOR-DMARD, a 5-center Norwegian register. Prediction of remission after 6 months was also studied. RESULTS: After 3 months, remission rates varied between definitions from 8.7% to 22.5% and for LDA from 35.5% to 42.7%, and increased slightly until 6 months of followup. DAS28 and RAPID3 gave the highest and ACR/EULAR, SDAI, and CDAI the lowest proportions for remission. Positive predictors for remission after 6 months were similar across the definitions and included lower age, male sex, short disease duration, high level of education, current nonsmoking, nonerosive disease, treatment with a biological DMARD, being DMARD-naive, good physical function, little fatigue, and LDA. CONCLUSION: In daily clinical practice, the DAS28 and RAPID3 definitions identified remission about twice as often as the ACR/EULAR Boolean, SDAI, and CDAI. Predictors of remission were similar across remission definitions. These findings provide additional evidence to follow treatment recommendations and treat RA early with a DMARD.

Development of a feasible and responsive ultrasound inflammation score for rheumatoid arthritis through a data-driven approach.

OBJECTIVE: To develop and validate a responsive and feasible ultrasound inflammation score for rheumatoid arthritis (RA). METHODS: We used data from cohorts of early RA (development) and established RA starting/switching biologic therapy (validation). 4 tendons and 36 joints were examined by a grey scale (GSUS) and power Doppler semiquantitative ultrasound (PDUS) scoring system (full score). Ultrasound score components were selected based on factor analyses of 3-month change in the development cohort. Responsiveness was assessed by standardised response means (SRMs). We assessed the proportion of information retained from the full score by linear regression. RESULTS: 118 patients with early and 212 patients with established RA were included. The final ultrasound score included 8 joints (metacarpophalangeal 1-2-3, proximal interphalangeal 2-3, radiocarpal, metatarsophalangeal 2-3) and 1 tendon (extensor carpi ulnaris) examined bilaterally. The 6-month SRMs for the final score were -1.24 (95% CI -1.47 to -1.02) for GSUS, and -1.09 (-1.25 to -0.92) for PDUS in early RA, with 87% of total information retained for GSUS and 90% for PDUS. The new score performed somewhat better than formerly proposed scores in the validation cohort. CONCLUSIONS: The Ultrasound in Rheumatoid Arthritis 9 joint/tendon score (USRA9) inflammation score showed good responsiveness, retained most of the information from the original full score and overall performed better than previous scores in a validation cohort. TRIAL REGISTRATION NUMBERS: NCT01205854, ACTRN12610000284066; Post-results.

Ultrasound in management of rheumatoid arthritis: ARCTIC randomised controlled strategy trial.

OBJECTIVE:  To determine whether a treatment strategy based on structured ultrasound assessment would lead to improved outcomes in rheumatoid arthritis, compared with a conventional strategy. DESIGN:  Multicentre, open label, two arm, parallel group, randomised controlled strategy trial. SETTING:  Ten rheumatology departments and one specialist centre in Norway, from September 2010 to September 2015. PARTICIPANTS:  238 patients were recruited between September 2010 and April 2013, of which 230 (141 (61%) female) received the allocated intervention and were analysed for the primary outcome. The main inclusion criteria were age 18-75 years, fulfilment of the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis, disease modifying anti-rheumatic drug naivety with indication for disease modifying drug therapy, and time from first patient reported swollen joint less than two years. Patients with abnormal kidney or liver function or major comorbidities were excluded. INTERVENTIONS:  122 patients were randomised to an ultrasound tight control strategy targeting clinical and imaging remission, and 116 patients were randomised to a conventional tight control strategy targeting clinical remission. Patients in both arms were treated according to the same disease modifying anti-rheumatic drug escalation strategy, with 13 visits over two years. MAIN OUTCOME MEASURES:  The primary endpoint was the proportion of patients with a combination between 16 and 24 months of clinical remission, no swollen joints, and non-progression of radiographic joint damage. Secondary outcomes included measures of disease activity, radiographic progression, functioning, quality of life, and adverse events. All participants who attended at least one follow-up visit were included in the full analysis set. RESULTS:  26 (22%) of the 118 analysed patients in the ultrasound tight control arm and 21 (19%) of the 112 analysed patients in the clinical tight control arm reached the primary endpoint (mean difference 3.3%, 95% confidence interval -7.1% to 13.7%). Secondary endpoints (disease activity, physical function, and joint damage) were similar between the two groups. Six (5%) patients in the ultrasound tight control arm and seven (6%) patients in the conventional arm had serious adverse events. CONCLUSIONS:  The systematic use of ultrasound in the follow-up of patients with early rheumatoid arthritis treated according to current recommendations is not justified on the basis of the ARCTIC results. The findings highlight the need for randomised trials assessing the clinical application of medical technology.Trial registration Clinical trials NCT01205854.