Risk of neuroinflammatory events in arthritis patients treated with tumour necrosis factor alpha inhibitors: a collaborative population-based cohort study from Denmark and Sweden.

To investigate whether tumour necrosis factor alpha inhibitors (TNFis) are associated with an increased risk of neuroinflammatory diseases among patients with arthritic diseases. Cohorts of patients with rheumatoid arthritis (RA, n=25 796), psoriatic arthritis (PsA, n=8586) and ankylosing spondylitis (AS, n=9527) who initiated a TNFi treatment year 2000-2017 were identified from nationwide clinical rheumatology registers in Sweden and Denmark. Information on demyelinating disease and inflammatory neuropathy diagnoses was retrieved from prospective linkage to National Patients Register. A Cox proportional hazard model was used to estimate HRs and 95% CI comparing TNFi exposed and non-exposed, by disease and country. Among 111 455 patients with RA, we identified 270 (Sweden) and 51 (Denmark) events (all types of neuroinflammatory diseases combined), corresponding to crude incidence rates (per 1000 person-years) of 0.37 (Sweden) and 0.39 (Denmark) in TNFi-treated patients vs 0.39 (Sweden) and 0.28 (Denmark) in unexposed patients, and an age-sex-calendar-period-adjusted HR (95% CI) of 0.97 (0.72 to 1.33) (Sweden) and 1.45 (0.74 to 2.81) (Denmark) in TNFi exposed compared with non-exposed patients. For a total of 64 065 AS/PsA patients, the corresponding numbers were: 196 and 32 events, crude incidence rates of 0.59 and 0.87 in TNFi-treated patients vs 0.40 and 0.19 in unexposed patients, and HRs of 1.50 (1.07 to 2.11) and 3.41 (1.30 to 8.96), for Sweden and Denmark, respectively. For multiple sclerosis, the patterns of HRs were similar. Use of TNFi in AS/PsA, but not in RA, was associated with increased risk of incident neuroinflammatory disease, though the absolute risk was below one in 1000 patients/year.

Kopp TI ，Delcoigne B ，Arkema EV ，Jacobsen RK ，Magyari M ，Ibfelt EH ，Locht H ，Sellebjerg F ，Cordtz RL ，Jensen DV ，Askling J ，Dreyer L ... -  《-》

Cancer risk in patients with spondyloarthritis treated with TNF inhibitors: a collaborative study from the ARTIS and DANBIO registers.

Safety data on cancer risks following tumour necrosis factor α inhibitors (TNFi) in patients with spondyloarthritis (SpA) (here defined as ankylosing spondylitis (AS), undifferentiated spondarthropaties (SpA UNS), psoriatic arthritis (PsA)) are scarce. Our objective was to assess risks for cancer overall and for common subtypes in patients with SpA treated with TNFi compared with TNFi-naïve patients with SpA and to the general population. From the Swedish (Anti-Rheumatic Therapy in Sweden (ARTIS)) and Danish (DANBIO) biologics registers, we assembled 8703 (ARTIS=5448, DANBIO=3255) patients with SpA initiating a first TNFi 2001-2011. From the Swedish National Patient and Population Registers we assembled a TNFi-naïve SpA cohort (n=28,164) and a Swedish age-matched and sex-matched general population comparator cohort (n=131 687). We identified incident cancers by linkage with the nationwide Swedish and Danish Cancer Registers 2001-2011, and calculated age-standardised and sex-standardised incidence ratios as measures of relative risk (RR). Based on 1188 cancers among the TNFi-naïve patients with SpA, RR of cancer overall was 1.1 (95% CI 1.0 to 1.2). Based on 147 cancers among TNFi initiators with SpA, RR versus TNFi-naïve was 0.8 (95% CI 0.7 to 1.0) and results were similar for AS and PsA when analysed separately. Site-specific cancer RRs: prostate 0.5 (95% CI 0.3 to 0.8), lung 0.6 (95% CI 0.3 to 1.3), colorectal 1.0 (95% CI 0.5 to 2.0), breast 1.3 (95% CI 0.9 to 2.0), lymphoma 0.8 (95% CI 0.4 to 1.8) and melanoma 1.4 (95% CI 0.7 to 2.6). In patients with SpA, treatment with TNFi was not associated with increased risks of cancer, neither overall nor for the six most common cancer types.

Hellgren K ，Dreyer L ，Arkema EV ，Glintborg B ，Jacobsson LT ，Kristensen LE ，Feltelius N ，Hetland ML ，Askling J ，ARTIS Study Group, For the DANBIO Study Group ... -  《-》

Serious infections in patients with rheumatoid arthritis and psoriatic arthritis treated with tumour necrosis factor inhibitors: data from register linkage of the NOR-DMARD study.

To estimate the incidence of serious infections (SIs) in patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) treated with tumour necrosis factor inhibitor (TNFi), and compare risk of SIs between patients with RA and PsA. We included patients with RA and PsA from the NORwegian-Disease Modifying Anti-Rheumatic Drug registry starting TNFi treatment. Crude incidence rates (IRs) and IR ratio for SIs were calculated. The risk of SIs in patients with RA and PsA was compared using adjusted Cox-regression models. A total of 3169 TNFi treatment courses (RA/PsA: 1778/1391) were identified in 2359 patients. Patients with RA were significantly older with more extensive use of co-medication. The crude IRs for SIs were 4.17 (95% CI 3.52 to 4.95) in patients with RA and 2.16 (95% CI 1.66 to 2.81) in patients with PsA. Compared with the patients with RA, patients with PsA had a lower risk of SIs (HR 0.59, 95% CI 0.41 to 0.85, p=0.004) in complete set analysis. The reduced risk in PsA versus RA remained significant after multiple adjustments and consistent across strata based on age, gender and disease status. Compared with patients with RA, the risk of SIs was significantly lower in patients with PsA during TNFi exposure.

Christensen IE ，Lillegraven S ，Mielnik P ，Bakland G ，Loli L ，Sexton J ，Uhlig T ，Kvien TK ，Provan SA ... -  《-》

Diagnostic delay in patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis: results from the Danish nationwide DANBIO registry.

Early diagnosis of inflammatory rheumatic diseases is important in order to improve long-term outcome. We studied whether delay in diagnosis (time between onset of symptoms and establishment of diagnosis) in patients with rheumatoid arthritis (RA), psoriatic arthritis (PSA) and ankylosing spondylitis (AS) changed from year 2000 to 2011. Month and year of initial symptoms and diagnosis, gender, hospital, year of birth and date of first data entry were obtained for 13,721 patients with RA, PSA or AS who had been registered in the DANBIO registry. Time between symptom onset and diagnosis was modelled using generalised linear regression to predict the average duration for each calendar year of initial symptoms with adjustments for gender, year of birth and date of DANBIO entry. Patients with valid data (RA: 10,416 (73%); PSA: 1970 (68%); AS: 1335 (65%)) did not differ significantly from the whole DANBIO population, except more missing data in early years. The regression model showed that the mean duration from initial symptoms to diagnosis for RA, PSA and AS declined steadily from 30, 53 and 66 months (year 2000), respectively, to 3-4 months (year 2011). Sensitivity analyses including patients who were included after 2005, patients who had received biological treatment or had symptom onset less than 2 and 5 years prior to first entry into DANBIO showed similar results. Since the year 2000, a significant reduction in diagnostic delay was observed in this large cohort of patients with RA, PSA or AS, probably reflecting a stronger awareness of the importance of early diagnosis.

Sørensen J ，Hetland ML ，all departments of rheumatology in Denmark 《-》

Tumor necrosis factor (TNF) inhibitors for psoriatic arthritis.

Psoriatic arthritis (PsA) is a chronic arthritis affecting people with psoriasis. If untreated, it may lead to disability. Recommended drugs are non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), biologic DMARDs (bDMARDs), and targeted synthetic DMARDs (tsDMARDs). Tumour necrosis factor inhibitors (TNFi) are the first choice bDMARDs. To assess the benefits and harms of TNFi in adults with psoriatic arthritis. We searched CENTRAL, MEDLINE, Embase, ClinicalTrials.gov and the World Health Organization trials portal up to 28 March 2024. We included randomized controlled trials (RCTs) in adults with PsA, comparing TNFi to placebo, physiotherapy, NSAIDs, corticosteroids, and cs/b/tsDMARDs. Major outcomes included clinical improvement, minimal disease activity, physical function, health-related quality of life, radiographic progression, serious adverse events, and withdrawals due to adverse events. We used standard Cochrane methods. The primary comparison was TNFi versus placebo. The primary time point was 12 weeks for clinical improvement; 24 weeks for minimal disease activity, function, quality of life, and radiographic progression; and the end of the trial period for serious adverse events and withdrawals due to adverse events. We included 25 RCTs randomizing 7857 participants. Four studies compared TNFi to methotrexate and one to ustekinumab in DMARD-naïve participants. In csDMARD-inadequate responders, 11 studies compared TNFi to placebo; four studies compared TNFi to placebo and ixekizumab, bimekizumab, tofacitinib, or upadacitinib; and three studies compared TNFi to ixekizumab, secukinumab, and ustekinumab. Two studies compared different TNFi. We found no studies with b/tsDMARD-inadequate responders (b/tsDMARD-IR). No studies compared TNFi to NSAIDs, corticosteroids, or physiotherapy. Performance (32%), detection (56%) and reporting (80%) biases were at high or unclear risk across studies. Only one study had a low risk of bias in all domains. We limit reporting to the primary comparison, TNFi versus placebo. DMARD-naïve We found no studies comparing TNFi with placebo in DMARD-naïve participants. csDMARD-inadequate responders TNFi probably result in a large clinical improvement compared to placebo. At 12 weeks, 149/1926 (8%) participants in the placebo group showed a clinical improvement (ACR50) compared to 784/2141 (37%) participants in the TNFi group (risk ratio (RR) 5.63, 95% confidence interval (CI) 3.98 to 7.96; I2 = 65%; 14 studies, 4067 participants; moderate-certainty evidence). TNFi probably result in a higher proportion of participants in minimal disease activity. At 24 weeks, 95/1017 (9%) participants in the placebo group were in minimal disease activity compared to 428/1336 (32%) participants in the TNFi group (RR 3.76, 95% CI 2.39 to 5.92; I2 = 72%; 5 studies, 2353 participants; moderate-certainty evidence). At 24 weeks, TNFi may improve function compared to placebo. The mean change in function from baseline (assessed with the Health Assessment Questionnaire; score from 0 to 3, 0 = no disability; minimal clinically important difference (MCID) = 0.35) was -0.14 points with placebo and 0.33 points lower (0.41 lower to 0.25 lower) with TNFi (I2 = 72%; 8 studies, 2949 participants; low-certainty evidence). TNFi probably result in a clinically important improvement in health-related quality of life. The mean change in quality of life from baseline (assessed with the Short Form 36-item Mental Component Summary questionnaire; score from 0 to 100, 100 = best score; MCID = 1.7) was 2.4 points with placebo and 3.29 points higher (2.18 points higher to 4.40 points higher) with TNFi (I2 = 52%; 8 studies, 2928 participants; moderate-certainty evidence). TNFi probably slightly reduce radiographic progression. The mean change in radiographic progression (assessed with the Sharp/Van der Heijde-PsA score; scale from 0 to 528, 0 = no damage) was 0.25 points with placebo and 0.37 points lower with TNFi (0.48 lower to 0.25 lower) (I2 = 32%; 7 studies, 2478 participants; moderate-certainty evidence) at 24 weeks. We downgraded the evidence to moderate certainty for clinical improvement, minimal disease activity, quality of life, and radiographic progression due to risk of bias. For function, we downgraded the evidence to low certainty for risk of bias and imprecision. TNFi may result in little to no difference in serious adverse events, but may slightly increase withdrawals due to adverse events, compared to placebo. At the end of follow-up: 56/1826 participants (3%) given placebo and 69/1900 (4%) participants given TNFi experienced serious adverse events (RR 1.00, 95% CI 0.70 to 1.42; I2 = 0%; 13 studies, 3866 participants; low-certainty evidence); and 35/1926 (2%) participants given placebo and 65/2140 (3%) given TNFi withdrew due to adverse events (RR 1.53, 95% CI 1.01 to 2.33; I2 = 0%; 14 studies, 4066 participants; low-certainty evidence). We downgraded the evidence to low certainty for risk of bias and imprecision. In csDMARD-inadequate responders, moderate-certainty evidence showed that TNFi probably result in a large clinical improvement, lower disease activity, small decrease in radiographic progression, and better quality of life compared to placebo. Low-certainty evidence showed that TNFi may lead to a slight improvement in physical function compared to placebo. Low-certainty evidence suggested that TNFi may lead to a slight increase in withdrawals due to adverse events, whereas they may result in little to no difference in serious adverse events compared to placebo. No trials assessed TNFi compared to placebo in DMARD-naïve participants or in b/tsDMARD-IR.

Cagnotto G ，Bruschettini M ，Stróżyk A ，Scirè CA ，Compagno M ... -  《Cochrane Database of Systematic Reviews》