Increasing number of Janus kinase (JAK) inhibitors have been approved for chronic haematopoietic neoplasms and inflammatory/autoimmune diseases. We aimed to assess safety of the first three approved ...JAK inhibitors: ruxolitinib, tofacitinib and baricitinib. In this retrospective observational study, pharmacovigilance data were extracted from the World Health Organization database. Adverse events are classified according to Medical Dictionary for Regulatory Activities hierarchy. Until February 28, 2021, all Individual Case Safety Reports ICSRs with the suspected drug ruxolitinib, tofacitinib or baricitinib were included. Disproportionality analysis was performed and the information component (IC) was estimated. Adverse events were considered a significant signal if the lower end of the 95% credibility interval of the IC (IC025) was positive. We identified 126,815 ICSRs involving JAK inhibitors. Ruxolitinib, tofacitinib and baricitinib were associated with infectious adverse events (IC025 1.7, especially with viral herpes and influenza, fungal, and mycobacterial infectious disorders); musculoskeletal and connective tissue disorders (IC025 1.1); embolism and thrombosis (IC025 0.4); and neoplasms (IC025 0.8, especially malignant skin neoplasms). Tofacitinib was associated with gastrointestinal perforation events (IC025 1.5). We did not find a significant increase in the reporting of major cardiovascular events. We identified significant association between adverse events and ruxolitinib, tofacinitib and baricitinib in international pharmacovigilance database.
To compare the clinical manifestations, disease activity and disease burden between patients with radiographic (r-axSpA) and non-radiographic axial spondyloarthritis (nr-axSpA) over a 5-year ...follow-up period in the Devenir des Spondylarthropathies Indifferénciées Récentes (DESIR) cohort.
Patients from the DESIR cohort who had X-ray images of the sacroiliac joints available at baseline and did not leave the study during the 5-year follow-up period because of a diagnosis other than axSpA were included. A unilateral rating of 'obvious sacroiliitis' by the local reader was considered sufficient for classification as r-axSpA. The incidence of first episodes of peripheral and extra-rheumatic manifestations was compared between the two groups using the incidence rate ratio and Cox regressions adjusted for sex, age and tumour necrosis factor blocker (TNFb) intake. Mean values of patient-reported outcomes (PROs) and days of sick leave over 5 years of follow-up were compared using mixed models adjusted for sex, age, TNFb intake and baseline values.
In total, 669 patients were included, of whom 185 (27.7%) and 484 (72.3%) were classified as r-axSpA and nr-axSpA, respectively. At baseline, the r-axSpA patients showed a significantly higher prevalence of males. After adjusting for age, sex and TNFb intake, Cox regressions for peripheral and extra-rheumatic manifestations did not show any significant differences between groups. Mixed models also showed similar mean levels in PROs and days of sick leave between groups over time.
The incidence of peripheral and extra-rheumatic manifestations as well as the disease burden over time remained similar between r-axSpA and nr-axSpA groups after adjusting for intermediate variables.
NCT01648907.
Abstract New bone formation of the entheses with possible progression to ankylosis is among the hallmarks of axial spondyloarthritis. Radiographic scores are available for evaluating axial new bone ...formation. The complex systems that underlie new bone formation involve Wnt bone-formation signaling and the natural Wnt inhibitors DKK-1 and sclerostin, as well as growth factors such as the bone morphogenetic proteins (BMPs); these systems are modulated by proinflammatory cytokines, most notably TNF. Factors that predict progressive new bone formation include the presence of syndesmophytes, various biological markers (CRP, MMP-3, sclerostin, DKK-1, and BMP), smoking, and prior vertebral corner abnormalities (inflammation and, above all, resolved inflammation). Nonsteroidal antiinflammatory agents seem able to slow the pace of radiographic progression, an effect not documented to date with TNF antagonists in patients with axial spondyloarthritis.
We evaluated the effectiveness and safety of adalimumab in a large cohort of patients with active ankylosing spondylitis (AS) and identified clinical predictors of good clinical response.
Patients ...with active AS Bath AS Disease Activity Index (BASDAI)>or=4 received adalimumab 40 mg every other week in addition to their standard antirheumatic therapies in a multinational 12-week, open-label study. We used 3 definitions of good clinical response: 50% improvement in the BASDAI (BASDAI=50), 40% improvement in the ASsessments of SpondyloArthritis International Society criteria (ASAS40), or ASAS partial remission. Response predictors were determined by logistic regression with backward elimination (selection level 5%).
Of 1250 patients, 1159 (92.7%) completed 12 weeks of adalimumab treatment. At Week 12, 57.2% of patients achieved BASDAI 50, 53.7% achieved ASAS40, and 27.7% achieved ASAS partial remission. Important predictors of good clinical response (BASDAI 50, ASAS40, and partial remission) were younger age (p<0.001), and greater C-reactive protein (CRP) concentration (p<or=0.001), HLA-B27 positivity (p<or=0.01), and tumor necrosis factor (TNF) antagonist naivety (p<0.001).
Adalimumab was effective in this large cohort of patients with AS, with more than half of patients achieving a BASDAI 50 or ASAS40 response and more than a quarter of patients reaching partial remission at Week 12.Younger age, greater CRP concentrations, HLA-B27 positivity, and TNF antagonist naivety were strongly associated with BASDAI 50, ASAS40, and partial remission responses. ClinicalTrials.gov identifier: NCT00478660.
Abstract Spondyloarthritis raises considerable diagnostic challenges. The mean time from symptom onset to the definitive diagnosis was 8 years in classical studies. This diagnostic delay has a ...deleterious impact not only for the patient, but also potentially on the course of the disease and therefore on its social and economic costs. In addition, delays in diagnosis translate into delays in management. The main reason for diagnostic delays is that early classification criteria sets include marked radiographic changes, which require time to develop. New criteria are now available that should allow earlier patient classification and that recognize the existence of non-radiographic forms of spondyloarthritis. Results from prospective cohort studies of early spondyloarthritis, on the one hand, and continuing medical education efforts aimed at informing all healthcare professionals of changes in concepts, on the other, should prove effective in decreasing the time to diagnosis, thereby optimizing patient management.
To investigate the association between 12 single nucleotide polymorphisms (SNPs) located on ERAP1 and IL23R with the presence of inflammation on the sacroiliac joint (SIJ) or spinal magnetic ...resonance imagery (MRI) in an early onset spondyloarthritis (SpA) cohort.
All the patients included in the DESIR cohort with an axial SpA and available DNA at baseline were enrolled in this study (n = 645 patients) and underwent a clinical examination, CRP assay, SIJ and spinal MRI scans. Six SNPs located on ERAP1 (rs30187, rs27044, rs27434, rs17482078, rs10050860, rs2287987) and six SNPs located on IL23R (rs1004819, rs10489629, rs1343151, rs2201841, rs10889677, rs11209032) were genotyped. Univariable analyses were performed to test the association between the genotypes and SIJ and spinal MRI inflammation, as well as disease activity based on Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Ankylosing Spondylitis Disease Activity Score-C-Reactive Protein (ASDAS-CRP) and CRP.
One SNP located on ERAP1 (rs27434) and haplotype CCT of ERAP1 were associated with SIJ inflammation detected by MRI, but these associations were below the Bonferroni corrected threshold of significance. However, one SNP (rs1004819) located on IL23R was associated with SIJ MRI inflammation (rs1004819: TT 42.3%, CT 40.5%, CC 26.5%, p = 0.0005). This locus was also significantly associated with Spondyloarthritis Research Consortium of Canada scores while no association with another inflammatory parameter such as BASDAI, ASDAS-CRP, CRP or Berlin MRI score was identified in this population.
One locus of the IL23R gene was associated with SIJ MRI inflammation and might be a marker of more active disease in recent onset SpA.
clinicaltrials.gov, NCTO 164 8907.
ObjectiveTo assess the risk of serious infection associated with different targeted therapies for psoriatic arthritis (PsA) in real-world settings.MethodsThis nationwide cohort study used the ...administrative healthcare database of the French health insurance scheme linked to the hospital discharge database to identify all adults with PsA who were new users of targeted therapies (adalimumab, etanercept, golimumab, certolizumab pegol, infliximab, secukinumab, ixekizumab, ustekinumab, and tofacitinib) from 1 January 2015 to 30 June 2021. The primary outcome was a serious infection (ie, requiring hospitalisation), in a time-to-event analysis using propensity score-weighted Cox models, with adalimumab as the comparator, estimating weighted HRs (wHRs) and their 95% CIs.ResultsA total of 12 071 patients were included (mean age 48.7±12.7 years; 6965 (57.7%) women). We identified 367 serious infections (3.0% of patients), with a crude incidence rate of 17.0 per 1000 person-years (95% CI, 15.2 to 18.7). After inverse propensity score weighting and adjustment for time-dependent covariates and calendar year, risk of serious infection was significantly lower for new users of etanercept (wHR 0.72; 95% CI, 0.53 to 0.97) or ustekinumab (wHR, 0.57; 95% CI, 0.35 to 0.93) than adalimumab new users. This risk was not statistically modified with the other targeted therapies.ConclusionsThe incidence of serious infection was low for PsA patients who were new users of targeted therapies in real-world settings. Relative to adalimumab new users, this risk was lower among new users of etanercept and ustekinumab and unmodified for the other molecules.
BackgroundSex differences in phenotype presentation, disease trajectory and treatment response in psoriatic arthritis (PsA) have been reported. Nevertheless, whether classes of targeted therapies ...differentially affect men and women with PsA remains unclear.ObjectivesTo assess the effect of sex on the long-term persistence of each class of targeted therapies in PsA.MethodsThis nationwide cohort study involved the administrative healthcare database of the French health insurance scheme linked to the hospital discharge database. We included all adults with PsA who were new users of targeted therapies (not in the year before the index date) during 2015–2021 and studied all treatment lines during the study period. Persistence was defined as the time from treatment initiation to discontinuation and was estimated by the Kaplan-Meier method. Comparison of persistence by sex involved multivariate frailty models with conventional synthetic disease-modifying antirheumatic drugs and prednisone as time-dependant variables.ResultsWe included 14 778 patients with PsA who were new users of targeted therapies: 8475 (57%) women (mean age 50±13 years; 15 831 lines), 6303 (43%) men (mean age 51±13 years; 10 488 lines). Overall, 1-year persistence was 52% for women and 62% for men and at 3 years it was 27% and 39%, respectively. After adjustments, persistence was lower for women than men for inhibitors of tumour necrosis factor (TNFi) (adjusted HR (HRa) 1.4, 99% CI 1.3 to 1.5) and interleukin 17 inhibitor (IL17i) (HRa 1.2, 99% CI 1.1 to 1.3) but not IL12/23i (HRa 1.1, 99% CI 0.9 to 1.3), IL23i (HRa 1.1, 99% CI 0.7 to 1.5) or Janus kinase inhibitor (JAKi) (HRa 1.2, 99% CI 0.9 to 1.6).ConclusionThe treatment persistence was lower for women than men for TNFi and IL17i but not for IL12/23i, IL23i or JAKi.
Limited information is available on the impact of treatment with a tumor necrosis factor inhibitor (TNFi) on structural lesions in patients with recent-onset axial spondyloarthritis (axSpA). We ...compared 2-year structural lesion changes on magnetic resonance imaging (MRI) in the sacroiliac joints (SIJ) of patients with recent-onset axSpA receiving etanercept in a clinical trial (EMBARK) to similar patients not receiving biologics in a cohort study (DESIR). We also evaluated the relationship between the Ankylosing Spondylitis Disease Activity Score (ASDAS) and change in MRI structural parameters.
The difference between etanercept (EMBARK) and control (DESIR) in the net percentage of patients with structural lesion change was determined using the SpondyloArthritis Research Consortium of Canada SIJ Structural Score, with and without adjustment for baseline covariates. The relationship between sustained ASDAS inactive disease, defined as the presence of ASDAS < 1.3 for at least 2 consecutive time points 6 months apart, and structural lesion change was evaluated.
This study included 163 patients from the EMBARK trial and 76 from DESIR. The net percentage of patients with erosion decrease was significantly greater for etanercept vs control: unadjusted: 23.9% vs 5.3%; P = 0.01, adjusted: 23.1% vs 2.9%; P = 0.01. For the patients attaining sustained ASDAS inactive disease on etanercept, erosion decrease was evident in significantly more than erosion increase: 34/104 (32.7%) vs 5/104 (4.8%); P < 0.001. A higher proportion had erosion decrease and backfill increase than patients in other ASDAS status categories. However, the trend across ASDAS categories was not significant and decrease in erosion was observed even in patients without a sustained ASDAS response.
These data show that a greater proportion of patients achieved regression of erosion with versus without etanercept. However, the link between achieving sustained ASDAS inactive disease and structural lesion change on MRI could not be clearly established.
EMBARK: ClinicalTrials.gov identifier: NCT01258738 , Registered 13 December 2010; DESIR: ClinicalTrials.gov identifier: NCT01648907 , Registered 24 July 2012.
Abstract Objectives To evaluate and compare four composite indices for assessing the activity of rheumatoid arthritis (RA). Methods We conducted a systematic literature review by searching Medline ...via PubMed and Embase and Cochrane databases for articles published up to March 2009. We selected studies that directly compared at least two of the four composite indices. The DAS (Disease Activity Score), DAS28, Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI) were evaluated in terms of reproducibility, construct validity, discriminative performance, and sensitivity to change. Results We included 61 articles. The only study that directly compared the intraobserver reproducibility of the DAS28, SDAI, and CDAI found comparable intraclass correlation coefficients ranging from 0.85 to 0.89. Concordance among indices was good (kappa values of ∼0.7), except between the DAS28 and the other indices in definition of remission (kappa 0.48–0.63). The indices had good construct validity by their similar fair-to-good correlations with the Health Assessment Questionnaire (HAQ) score and structural damage. Discriminative performance was comparable and satisfactory for treatment changes or remission according to the American College of Rheumatology (ACR). Two studies evaluated the sensitivity to change of the SDAI and CDAI; both indices detected a difference between responders and non-responders according to ACR definitions. Conclusion The DAS, DAS28, SDAI, and CDAI are valid tools for evaluating the activity of RA. The DAS28 is less conservative in defining remission than are the other three indices. Longitudinal studies of individual patients are needed to confirm these results.
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