Synøve Kalstad

Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): a 52-week, randomised, double-blind, non-inferiority trial

BACKGROUND TNF inhibitors have improved treatment of Crohns disease, ulcerative colitis, spondyloarthritis, rheumatoid arthritis, psoriatic arthritis, and chronic plaque psoriasis, but are expensive therapies. The aim of NOR-SWITCH was to examine switching from originator infliximab to the less expensive biosimilar CT-P13 regarding efficacy, safety, and immunogenicity. METHODS The study is a randomised, non-inferiority, double-blind, phase 4 trial with 52 weeks of follow-up. Adult patients on stable treatment with infliximab originator treated in a hospital setting for at least 6 months were eligible for participation. Patients with informed consent were randomised in a 1:1 ratio to either continued infliximab originator or to switch to CT-P13 treatment, with unchanged dosing regimen. Data were collected at infusion visits in 40 Norwegian study centres. Patients, assessors, and patient care providers were masked to treatment allocation. The primary endpoint was disease worsening during 52-week follow-up. 394 patients in the primary per-protocol set were needed to show a non-inferiority margin of 15%, assuming 30% disease worsening in each group. This trial is registered with ClinicalTrials.gov, number NCT02148640. FINDINGS Between Oct 24, 2014, and July 8, 2015, 482 patients were enrolled and randomised (241 to infliximab originator, 241 to CT-P13 group; one patient was excluded from the full analysis and safety set for CT-P13) and 408 were included in the per-protocol set (202 in the infliximab originator group and 206 in the CT-P13 group). 155 (32%) patients in the full analysis set had Crohns disease, 93 (19%) had ulcerative colitis, 91 (19%) had spondyloarthritis, 77 (16%) had rheumatoid arthritis, 30 (6%) had psoriatic arthritis, and 35 (7%) had chronic plaque psoriasis. Disease worsening occurred in 53 (26%) patients in the infliximab originator group and 61 (30%) patients in the CT-P13 group (per-protocol set; adjusted treatment difference -4·4%, 95% CI -12·7 to 3·9). The frequency of adverse events was similar between groups (for serious adverse events, 24 [10%] for infliximab originator vs 21 [9%] for CT-P13; for overall adverse events, 168 [70%] vs 164 [68%]; and for adverse events leading to discontinuation, nine [4%] vs eight [3%], respectively). INTERPRETATION The NOR-SWITCH trial showed that switching from infliximab originator to CT-P13 was not inferior to continued treatment with infliximab originator according to a prespecified non-inferiority margin of 15%. The study was not powered to show non-inferiority in individual diseases. FUNDING Norwegian Ministry of Health and Care Services.

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.

Time trends in disease activity, response and remission rates in rheumatoid arthritis during the past decade: results from the NOR-DMARD study 2000–2010

Objectives To investigate whether baseline disease activity levels and responses in patients with rheumatoid arthritis (RA) changed during the period 2000–2010. Methods Data were provided by the Norwegian disease-modifying antirheumatic drug (NOR-DMARD) study. Patients with inflammatory joint diseases starting new treatment with disease-modifying antirheumatic drugs (DMARDs) were consecutively included and followed longitudinally. Time trend analyses were performed in methotrexate (MTX)-naïve RA patients starting MTX monotherapy (MTX mono) and biologic DMARD (bDMARD)-naïve RA patients starting tumour necrosis factor inhibitors+MTX (TNFi+MTX). Results A total of 2573 patients were included in the analyses: MTX mono n=1866 (69.9% female, 62.0% RF+, mean (SD) age 56.0 (13.7) years, median (25–75 percentile) time from diagnosis 0.2 (0.01–2.8) years); TNFi+MTX n=707 (70.3% female, 75.0% RF+, mean (SD) age 52.1 (13.2) years, median (25–75 percentile) time from diagnosis 5.7 (2.0–13.7) years). Significant time trends towards lower baseline disease activity score 28 (DAS28) as well as other disease activity measures were found in both groups (DAS28 from 5.17 to 4.75 in MTX mono and from 5.88 to 4.64 in TNFi+MTX), and disease duration became shorter. Six-month DAS28 remission rates increased significantly over the years (from 17.8 to 37.6 in MTX mono and from 16.9 to 46.3 in TNFi+MTX). Conclusions During the last decade, baseline RA disease activity level at the time of starting MTX as well as TNFi+MTX decreased from high to moderate. A more than twofold increase in 6-month remission rates was observed in both groups. Our findings indicate that clinicians have implemented modern, more aggressive treatment strategies, which hopefully will lead to better long-term disease outcomes.

Treatment strategies in patients with rheumatoid arthritis for whom methotrexate monotherapy has failed: data from the NOR-DMARD register

Objectives To compare the effectiveness of adding synthetic disease-modifying antirheumatic drugs (sDMARDs) versus tumour necrosis factor α inhibitors (TNFi) to methotrexate (MTX) in patients with rheumatoid arthritis (RA) who were MTX inadequate responders (IR). Second, to examine outcomes in patients receiving MTX+TNFi for whom the MTX+sDMARD combination had also failed. Methods Patients with RA (disease duration ≤ 5 years, MTX IR and naïve to other DMARDs) starting treatment with MTX+TNFi or MTX+sDMARDs were included. From the latter group a subgroup of patients who went on to receive MTX+TNFi was identified. Results Patients receiving MTX+TNFi (n=98) and MTX+sDMARDs (n=129) had similar baseline disease activity when starting combination therapy (mean Disease Activity Score 28 (DAS28) = 4.90 and 4.96, respectively). Three- and 6-month effectiveness and 2-year drug survival were better for MTX+TNFi than for MTX+sDMARDs: mean ∆DAS28 was −1.61 versus −0.85 after 3 months (p<0.001) and −1.91 versus −1.03 after 6 months (p=0.01); DAS28<2.6 was reached by 29.0% versus 11.6% after 3 and 34.5% versus 12.9% after 6 months. Effectiveness was somewhat better with triple therapy than other MTX+sDMARD combinations but was generally inferior compared with MTX+TNFi. For the patients who received MTX+TNFi as a third step after MTX+sDMARDs had failed (n=38) there was a tendency towards lower remission rates, worse disease activity states and inferior drug survival compared with patients who received MTX+TNFi directly after the failure of MTX. Conclusions Effectiveness was better for MTX+TNFi than for MTX+sDMARDs. Patients who started MTX+TNFi after two synthetic DMARD regimens had failed had a tendency to less favourable disease states after 3 months than patients who switched directly from MTX to MTX+TNFi.

Do depression and anxiety reduce the likelihood of remission in rheumatoid arthritis and psoriatic arthritis? Data from the prospective multicentre NOR-DMARD study

Objective To investigate the predictive value of baseline depression/anxiety on the likelihood of achieving joint remission in rheumatoid arthritis (RA) and psoriatic arthritis (PsA) as well as the associations between baseline depression/anxiety and the components of the remission criteria at follow-up. Methods We included 1326 patients with RA and 728 patients with PsA from the prospective observational NOR-DMARD study starting first-time tumour necrosis factor inhibitors or methotrexate. The predictive value of depression/anxiety on remission was explored in prespecified logistic regression models and the associations between baseline depression/anxiety and the components of the remission criteria in prespecified multiple linear regression models. Results Baseline depression/anxiety according to EuroQoL-5D-3L, Short Form-36 (SF-36) Mental Health subscale ≤56 and SF-36 Mental Component Summary ≤38 negatively predicted 28-joint Disease Activity Score <2.6, Simplified Disease Activity Index ≤3.3, Clinical Disease Activity Index ≤2.8, ACR/EULAR Boolean and Disease Activity Index for Psoriatic Arthritis ≤4 remission after 3 and 6 months treatment in RA (p≤0.008) and partly in PsA (p from 0.001 to 0.73). Baseline depression/anxiety was associated with increased patient’s and evaluator’s global assessment, tender joint count and joint pain in RA at follow-up, but not with swollen joint count and acute phase reactants. Conclusion Depression and anxiety may reduce likelihood of joint remission based on composite scores in RA and PsA and should be taken into account in individual patients when making a shared decision on a treatment target.

Brief Report: No Excess Risks in Offspring With Paternal Preconception Exposure to Disease-Modifying Antirheumatic Drugs

To examine pregnancy outcomes in the partners of male patients with inflammatory joint disease who were or were not exposed to disease‐modifying antirheumatic drugs (DMARDs) before conception compared with the outcomes in reference subjects from the general population.

No excess risks in offspring with paternal preconception exposure to disease-modifying antirheumatic drugs.

To examine pregnancy outcomes in the partners of male patients with inflammatory joint disease who were or were not exposed to disease‐modifying antirheumatic drugs (DMARDs) before conception compared with the outcomes in reference subjects from the general population.

Discordance between tender and swollen joint count as well as patient's and evaluator's global assessment may reduce likelihood of remission in patients with rheumatoid arthritis and psoriatic arthritis: data from the prospective multicentre NOR-DMARD study

Objective To investigate the predictive value of discordance between (1) tender and swollen joint count and (2) patients and evaluators global assessment on remission in patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Methods From the prospective, multicentre Norwegian-Disease-Modifying Antirheumatic Drug study, we included patients with RA and PsA starting first-time tumour necrosis factor inhibitors and DMARD-naïve patients starting methotrexate between 2000 and 2012. The predictive value of ΔTSJ (tender minus swollen joint counts) and ΔPEG (patients minus evaluators global assessment) on remission was explored in prespecified logistic regression models adjusted for age, sex, disease duration and smoking. Results A total of 2735 patients with RA and 1236 patients with PsA were included (mean (SD) age 55.0 (13.5)/48.3 (12.4) years, median(range) disease duration 0.7 (0.0–58.0)/1.3 (0.0–48.3) years, 69.7/48.4% females). Baseline ΔTSJ/ΔPEG reduced the likelihood of achieving DAS28<2.6, SDAI≤3.3, CDAI≤2.8, ACR/EULAR Boolean and DAPSA<4 remission after 3 and 6 months in RA (OR 0.95–0.97, p<0.001/OR 0.96–0.99, p≤0.01) and PsA (OR 0.91–0.94, p≤0.004/OR 0.89–0.99, p≤0.002), except for ΔPEG and 6-month DAS28 remission in PsA. Conclusions Discordance between patients and physicians evaluation of disease activity reflected through ΔTSJ and partly ΔPEG may reduce likelihood of remission in RA and PsA. The findings are relevant for use of the treat-to-target strategy in individual patients.

First-time prescriptions of biological disease-modifying antirheumatic drugs in rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis 2002–2011: data from the NOR-DMARD register

Biological disease-modifying antirheumatic drugs (bDMARD) have constituted a major advance in the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA). In Norway, access to these therapies has been good since their introduction, with full reimbursement and no requirements of disease activity measures above certain cut-offs. With increasing focus on early and aggressive therapy, one could expect increasing prescription of bDMARDs, including use in patients with moderate disease activity. Our objectives were to examine if prescription rates of bDMARDs in RA, PsA and axSpA continue to increase or have reached a plateau, and whether disease activity at initiation of therapy has changed over the years. Data for these analyses were provided by the NOR-DMARD register, which was established by three Norwegian rheumatology departments in 2000, with two more centres joining in 2002. The register has aimed for longitudinal follow-up of all patients with inflammatory joint diseases starting a new DMARD regimen.1 For the current analyses we included all prescriptions of bDMARDs in previously bDMARD-naive patients with …