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

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

Educational readiness among health professionals in rheumatology: Low awareness of EULAR offerings and unfamiliarity with the course content as major barriers—results of a EULAR-funded European survey

Background Ongoing education of health professionals in rheumatology (HPR) is critical for high-quality care. An essential factor is education readiness and a high quality of educational offerings. We explored which factors contributed to education readiness and investigated currently offered postgraduate education, including the European Alliance of Associations for Rheumatology (EULAR) offerings.Methods and participants We developed an online questionnaire, translated it into 24 languages and distributed it in 30 European countries. We used natural language processing and the Latent Dirichlet Allocation to analyse the qualitative experiences of the participants as well as descriptive statistics and multiple logistic regression to determine factors influencing postgraduate educational readiness. Reporting followed the Checklist for Reporting Results of Internet E-Surveys guideline.Results The questionnaire was accessed 3589 times, and 667 complete responses from 34 European countries were recorded. The highest educational needs were ‘professional development’, ‘prevention and lifestyle intervention’. Older age, more working experience in rheumatology and higher education levels were positively associated with higher postgraduate educational readiness. While more than half of the HPR were familiar with EULAR as an association and the respondents reported an increased interest in the content of the educational offerings, the courses and the annual congress were poorly attended due to a lack of awareness, comparatively high costs and language barriers.Conclusions To promote the uptake of EULAR educational offerings, attention is needed to increase awareness among national organisations, offer accessible participation costs, and address language barriers

Hidradenitis suppurativa: Infection, autoimmunity or both?

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease mainly affecting areas rich in apocrine glands. Clinically, is characterized by painful subcutaneous nodules and if left untreated to pus secretion, abscess and fistula formation. Its frequency is estimated to be 0.5–4% of the general population, affecting women more often. Pathogenesis of HS is still not clearly defined. It seems to be a combination of genetic factors with alterations in the skin microbiome. Furthermore, at tissue (i.e. skin) as well as at serum level, several inflammatory cytokines are upregulated. The most important of the latter are tumor necrosis factor (TNF), interleukin (IL)-1, IL-17, and IL-23. Adding another level of complexity, it has been suggested that keratinocytes might be intrinsically activated, contributing also to the observed inflammation. Interestingly, it has been noted that frequency of HS is increased in some autoimmune rheumatic diseases, such as spondyloarthropathies (SpA). Of note, both HS and SpA have relatively strong association with metabolic diseases and obesity implying that there are indeed some common underlying pathophysiological pathways. Although no specific microbe has been identified, alterations in the microbiome of the skin of these patients have been reported. Of note, microbes with a capability for biofilm formation are abundant. Treatment of HS among others, include antibiotics as well as biologic drugs targeting TNF and other cytokines and used for autoimmune rheumatic diseases. Herein, we review the current evidence on links between HS and autoimmune diseases and infectious diseases with a focus on epidemiology and pathophysiology