JAK-inhibitors. New players in the field of immune-mediated diseases, beyond rheumatoid arthritis

Janus kinase (JAK)/signal transducers and activators of transcription (STATs) are a group of molecules associated with one of the major pathways through which many cytokines exert and integrate their function, and as such they are increasingly recognized as playing critical role in the pathogenesis subserving various immune-mediated diseases, including RA, PsA, SpAs, IBD, skin disorders (e.g. alopecia areata, atopic dermatitis), single-gene disorders like interferonopathies, and others. JAKs are the key initiating players of the JAK/STAT pathway. Upon binding of their respective effector molecules (cytokines, IFNs, growth factors and others) to type I and type II receptors, JAKs are activated, and through phosphorylation of themselves and of other molecules (including STATs), they mediate signal transduction to the nucleus. A class of drugs—called JAK inhibitors or JAKinibs—that block one or more JAKs has been developed in the last decade, and now numbers >20 members. Although, so far, JAK inhibitors have been marketed only for RA and PsA, these drugs have been tested in phase 2 and phase 3 clinical trials for other inflammatory conditions and beyond. In this review, we summarize the clinical data, including efficacy and safety, available for JAK inhibitors used in some immune-mediated conditions other than RA

The role of IL-23 and the use IL-23 inhibitors in psoriatic arthritis

Background: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis characterised by musculoskeletal and extra-articular manifestations, most notably psoriasis. While the underlying pathogenetic mechanisms are not yet fully understood, a central role has been identified for the IL-23/IL-17 pathway. Objectives: We aimed to briefly describe the role of IL-23 in the pathogenesis of PsA and to describe the available anti-IL-23 agents and their place in the management of PsA. Methods: This is a narrative review of the current literature, focussing on the results of the phase 3 studies in PsA for the IL-23 p40 inhibitor ustekinumab and the more recent IL-23 p19 inhibitors guselkumab, risankizumab and tildrakizumab. Results: IL-23 triggers expression of IL-17 and other effector cytokines in a variety of cells, leading to tissue inflammation and injury. Targeting IL-23, particularly with p19 inhibitors, appears to be an effective and safe strategy for multiple clinical domains in PsA, most notably the skin, with some differences in efficacy emerging between these agents. Conclusion: The development of IL-23 inhibitors represents a significant advance in the management of psoriatic disease. In the absence of head-to-head studies, future data emerging from real-world experiences of individual IL-23 p19 inhibitors will help inform the use of these agents in relation to other biologics in PsA

HBV reactivation in patients with rheumatoid arthritis treated with anti-interleukin-6:a systematic review and meta-analysis

OBJECTIVE: The objective of this study was to assess the possibility of HBV reactivation (HBVr) in patients with RA under anti-IL-6 treatment.METHODS: Using PubMed, Scopus and EMBASE, we performed a systematic literature search for articles related to HBVr in RA patients under anti-IL-6 treatment. The search was performed with no date limits and was last updated 28 January 2023. The results from all the databases were combined and duplicates were excluded, as were non-English articles, case reports, position articles, comments, and paediatric studies.RESULTS: Our initial search led to 427 articles; 28 were duplicates, 46 non-English, 169 reviews, 31 books/letters, 25 case reports, and 88 irrelevant to the meta-analysis aim; 21 were excluded due to inadequate information, leaving 19 articles, with a sum of 372 RA patients with chronic HBV (CHB) or resolved HBV infection, for further analysis. The overall risk for HBVr in RA patients with CHB was 6.7%, increasing to 37% when only RA patients with CHB and no antiviral prophylaxis were included. On the contrary, HBVr was close to 0% in RA patients with resolved HBV infection, irrespective of antiviral prophylaxis. All RA patients experiencing HBVr in these studies were successfully managed with antiviral treatment and/or drug withdrawal.CONCLUSION: Overall, anti-IL-6 treatment comes with a significant risk of HBVr in RA patients with CHB; risk is diminished when antiviral prophylaxis is used. In contrast, in RA patients with resolved HBV infection, the risk of HBVr seems to be extremely low. Large, well-designed studies (either controlled trials or multicentre/international observational studies) are warranted to further validate these results.</p

Neutropaenia in early rheumatoid arthritis: frequency, predicting factors, natural history and outcome

Objectives To determine the frequency, severity and natural history of neutropaenia in early rheumatoid arthritis (RA), explore its associations with clinical features and assess its impact on clinical management. Methods: The Scottish Early Rheumatoid Arthritis inception cohort prospectively recruited patients with newly diagnosed RA and followed them up every 6 months. Patients with RA who developed at least one episode of neutropaenia (grade 1: &lt;2.0×10^9/L; grade 2: &lt;1.5×10^9/L; grade 3: &lt;1.0×10^9/L; grade 4: &lt;0.5×10^9/L) were compared with those who did not. Comparisons were also made between patients who experienced one or more episodes of neutropaenia and between patients with different neutropaenia grades. Results: 77 neutropaenia episodes were recorded in 58 of 771 (7.5%) patients with RA, who were followed up for a median (range) of 18 (6–48) months. Neutropaenia occurred at a median (range) of 12 (0–120) months after RA diagnosis. The majority had mild neutropaenia (grade 1: n=42; grade 2: n=14; grade 3: n=1; grade 4: n=1). Neutropaenia was transient (single episode) in the majority (44; 75.8%) of cases but led to treatment discontinuation in 14 (24.1%) patients. Patients who developed neutropaenia were more likely to be female (p=0.01) and non-smokers (p=0.007) and had lower baseline neutrophil levels (p&lt;0.0001). Binomial regression analysis confirmed the latter (p&lt;0.0001, B: −0.491) as neutropaenia predictor. The rate of infections did not differ between patients who developed neutropaenia and those who did not (p=0.878). Conclusion: Neutropaenia was a common finding in this cohort. It was usually mild, transient and not associated with increased infection rates. Neutropaenia occurrence was associated with non-smoking, female gender and lower baseline neutrophil levels

Selective JAK-inhibitors in spondyloarthritis

As our research interest and knowledge increases in the field of Spondyloarthritis, new aspects also emerge as regards to their therapeutic approach. JAK inhibitors (JAKi) are a relatively new treatment option, aiming molecules in the JAK-STAT pathway, which has a leading role in the pathophysiology of both Psoriatic Arthritis and Axial Spondyloarthritis. JAKi exhibit different selectivity towards the four different members of the JAK family (namely JAK1, JAK2, JAK3, and TYK2), possibly reflecting different efficacy and safety profile. Although knowledge is more consolidated for rheumatoid arthritis in which JAKi are being used for more than 10 years, data are still accumulating for PsA/SpA. In this review we aim to present and assess current knowledge about the efficacy of JAKi (with a focus on selective JAKi) in the treatment of patients with SpA and evaluate their safety profile as some concerns may arise around this therapeutic option

Depression and anxiety in an Early Rheumatoid Arthritis inception cohort. Associations with demographic, socioeconomic and disease features

Objective: Depression and anxiety are not uncommon in Rheumatoid arthritis (RA). It is increasingly recognised that they are associated with high disease activity and worse disease outcomes. We aimed to examine the frequency of depression and anxiety in an early RA inception cohort and to explore associations with disease-related measures. Methods: The Scottish Early Rheumatoid Arthritis inception cohort recruited newly diagnosed RA patients followed-up 6-monthly. Anxiety and depression were assessed using the hospital anxiety and depression scale. Associations with demographic characteristics and disease-related measures were examined at baseline, 6 months and 12 months. Results: 848 RA patients were included. The prevalence of anxiety and depression at baseline was 19.0% and 12.2%, respectively. Depression and anxiety scores correlated with DAS28 at all time-points (all p&lt;0.0001). In multivariable linear regression, anxiety score at baseline was associated with younger age and Health Assessment Questionnaire (HAQ) score. Anxiety scores at 6 months and 12 months were associated with low body mass index (BMI), baseline anxiety score and current patient global score and HAQ. Depression score at baseline was associated with younger age, being single and HAQ, while depression scores at 6 months and 12 months were associated with male gender (only at 6 months), baseline anxiety and depression scores and current patient global score, HAQ and C-reactive protein (CRP) levels. Conclusion: Depression and anxiety are associated with disease activity, worse functional status and other variables in early RA. There is a close relationship between CRP and depression but not anxiety

2019 EULAR recommendations for the generic core competences of health professionals in rheumatology

© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ. Background/objectives: To maintain and optimise the quality of care provided by health professionals in rheumatology (HPRs), adequate educational offerings are needed. This task force (TF) aimed to develop evidence-based recommendations for the generic core competences of HPRs, with specific reference to nurses, physical therapists (PTs) and occupational therapists (OTs) to serve as a basis for their postgraduate education. Methods: The EULAR standardised operating procedures for the development of recommendations were followed. A TF including rheumatologists, nurses, PTs, OTs, patient-representatives, an educationalist, methodologists and researchers from 12 countries met twice. In the first TF meeting, 13 research questions were defined to support a systematic literature review (SLR). In the second meeting, the SLR evidence was discussed and recommendations formulated. Subsequently, level of evidence and strength of recommendation were assigned and level of agreement (LoA) determined (0-10 rating scale). Results: Three overarching principles were identified and 10 recommendations were developed for the generic core competences of HPRs. The SLR included 79 full-text papers, 20 of which addressed the competences, knowledge, skills, attitudes and/or educational needs of HPRs from multiple professions. The average LoA for each recommendation ranged from 9.42 to 9.79. Consensus was reached both on a research and educational agenda. Conclusion: Evidence and expert opinion informed a set of recommendations providing guidance on the generic core competences of HPRs. Implementation of these recommendations in the postgraduate education of HPRs at the international and national level is advised, considering variation in healthcare systems and professional roles

Type-I interferon pathway and DNA damage accumulation in peripheral blood of patients with psoriatic arthritis

ObjectivesThe abnormal DNA damage response is associated with upregulation of the type-1 interferon (IFN-I) pathway in certain rheumatic diseases. We investigated whether such aberrant mechanisms operate in psoriatic arthritis (PsA).MethodsDNA damage levels were measured by alkaline comet assay in peripheral blood mononuclear cells from 52 PsA patients and age-sex-matched healthy individuals. RNA expression of IFIT1, MX1 and IFI44, which are selectively induced by IFN-I, was quantitated by real-time polymerase chain reaction and their composite normalized expression resulted in IFN-I score calculation. RNA expression of IL1β, IL6, TNF, IL17A and IL23A was also assessed in PsA and control subgroups.ResultsIn PsA, DNA damage accumulation was increased by almost two-fold compared to healthy individuals (olive tail moment arbitrary units, mean ± SD; 9.42 ± 2.71 vs 4.88 ± 1.98, p&lt;0.0001). DNA damage levels significantly correlated with serum C-Reactive-protein and IL6 RNA expression in PBMCs. Despite increased DNA damage, the IFN-I score was strikingly lower in PsA patients compared to controls (-0.49 ± 6.99 vs 4.24 ± 4.26; p&lt;0.0001). No correlation was found between IFN-I pathway downregulation and DNA damage. However, the IFN-I score in a PsA subgroup was lower in those patients with higher IL1β expression, as well as in those with higher TNF/IL23A PBMCs expression.ConclusionDNA damage in PsA correlates with measures of inflammation but is not associated with the IFN-I pathway induction. The unexpected IFN-I downregulation, albeit reminiscent to findings in experimental models of spondyloarthritis, may be implicated in PsA pathogenesis and explained by operation of other cytokines

Late-onset psoriatic arthritis: are there any distinct characteristics? A retrospective cohort data analysis

As life expectancy increases, psoriatic arthritis (PsA) in older individuals becomes more prevalent. We explored whether late-onset versus earlier-onset PsA patients display different clinical features at diagnosis and/or during the disease course, as well as different treatment approaches and comorbidity profiles. We retrospectively collected data from consecutive PsA patients attending two rheumatology centers (December 2017–December 2022). Late-onset PsA patients (diagnosis-age: ≥60 years) were compared to those diagnosed before 60 years old. Univariate analyses and logistic regression were performed to examine for factors associated with late-onset PsA. For sensitivity analyses, the cohort’s mean diagnosis age was used as the cut-off value. Overall, 281 PsA patients were included (mean ± SD diagnosis-age: 46.0 ± 13.3 years). Of them, 14.2% (N = 40) had late-onset PsA. At diagnosis, after controlling for confounders, no demographic and clinical differences were identified. During the disease course, the late-onset group exhibited 65% fewer odds of manifesting enthesitis (adjusted Odds-ratio—adOR 0.35; 95% confidence interval 0.13–0.97), but higher frequency of dyslipidemia (adOR 3.01; 1.30–6.95) and of major adverse cardiovascular events (adOR 4.30; 1.42–12.98) compared to earlier-onset PsA group. No differences were found in the treatment approaches. In sensitivity analyses, PsA patients diagnosed after 46 (vs. ≤46) years old had an increased frequency of hypertension (adOR 3.18; 1.70–5.94) and dyslipidemia (adOR 2.17; 1.25–3.74). The present study underpins that late-onset PsA is not uncommon, while the age at PsA onset may affect the longitudinal clinical expression of the disease. Patients with late-onset PsA were less likely to manifest enthesitis but displayed increased cardiovascular risk

Synthesis of guidance available for assessing methodological quality and grading of evidence from qualitative research to inform clinical recommendations: a systematic literature review

Objective To understand (1) what guidance exists to assess the methodological quality of qualitative research; (2) what methods exist to grade levels of evidence from qualitative research to inform recommendations within European Alliance of Associations for Rheumatology (EULAR). Methods A systematic literature review was performed in multiple databases including PubMed/Medline, EMBASE, Web of Science, COCHRANE and PsycINFO, from inception to 23 October 2020. Eligible studies included primary articles and guideline documents available in English, describing the: (1) development; (2) application of validated tools (eg, checklists); (3) guidance on assessing methodological quality of qualitative research and (4) guidance on grading levels of qualitative evidence. A narrative synthesis was conducted to identify key similarities between included studies. Results Of 9073 records retrieved, 51 went through to full-manuscript review, with 15 selected for inclusion. Six articles described methodological tools to assess the quality of qualitative research. The tools evaluated research design, recruitment, ethical rigour, data collection and analysis. Seven articles described one approach, focusing on four key components to determine how much confidence to place in findings from systematic reviews of qualitative research. Two articles focused on grading levels of clinical recommendations based on qualitative evidence; one described a qualitative evidence hierarchy, and another a research pyramid. Conclusion There is a lack of consensus on the use of tools, checklists and approaches suitable for appraising the methodological quality of qualitative research and the grading of qualitative evidence to inform clinical practice. This work is expected to facilitate the inclusion of qualitative evidence in the process of developing recommendations at EULAR level