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ObjectiveTo investigate the humoral and cellular immune response to messenger RNA (mRNA) COVID-19 vaccines in patients with immune-mediated inflammatory diseases (IMIDs) on immunomodulatory treatment.MethodsEstablished patients at New York University Langone Health with IMID (n=51) receiving the BNT162b2 mRNA vaccination were assessed at baseline and after second immunisation. Healthy subjects served as controls (n=26). IgG antibody responses to the spike protein were analysed for humoral response. Cellular immune response to SARS-CoV-2 was further analysed using high-parameter spectral flow cytometry. A second independent, validation cohort of controls (n=182) and patients with IMID (n=31) from Erlangen, Germany, were also analysed for humoral immune response.ResultsAlthough healthy subjects (n=208) and patients with IMID on biologic treatments (mostly on tumour necrosis factor blockers, n=37) demonstrate robust antibody responses (over 90%), those patients with IMID on background methotrexate (n=45) achieve an adequate response in only 62.2% of cases. Similarly, patients with IMID on methotrexate do not demonstrate an increase in CD8+ T-cell activation after vaccination.ConclusionsIn two independent cohorts of patients with IMID, methotrexate, a widely used immunomodulator for the treatment of several IMIDs, adversely affected humoral and cellular immune response to COVID-19 mRNA vaccines. Although precise cut-offs for immunogenicity that correlate with vaccine efficacy are yet to be established, our findings suggest that different strategies may need to be explored in patients with IMID taking methotrexate to increase the chances of immunisation efficacy against SARS-CoV-2 as has been demonstrated for augmenting immunogenicity to other viral vaccines.

Objectives Despite significant therapeutic advances in psoriatic arthritis (PsA), many patients do not achieve remission and cycle through multiple biologic (b)- or targeted synthetic (ts)- DMARDs. Identifying the underlying reasons for repetitive therapeutic failure remains a knowledge gap. Here we describe prescribing patterns and characteristics of PsA patients with multi-b/tsDMARD failure at the NYU Psoriatic Arthritis Center. Methods Nine hundred sixty PsA patients were enrolled in an observational, longitudinal registry. Demographics, medical history, medication use, and psoriatic disease phenotype were collected. Multi-b/tsDMARD failure was defined as requiring ≥ 4 b/tsDMARDs. Results Seven hundred twenty-five patients (75%) used ≥ 1 b/tsDMARD during their disease course. The initial b/tsDMARDs prescribed were predominately anti-TNF agents. 166 (17%) patients had multi-b/tsDMARD failure. Compared to those requiring 1 b/tsDMARD, female sex (OR 2.3; 95%CI 1.4–3.8), axial disease (OR 2.1; 95% CI 1.2–3.6), depression (OR 2.0; 95%CI 1.1–3.7), and obesity (OR 1.7; 95%CI 1.0–2.8) were risk factors for multi-b/tsDMARD failure disease after adjustment for age, disease duration, sex, depression, smoking, obesity, and skin severity. Patients with multi-b/tsDMARD failure PsA also had increased disease activity at their clinical visit (i.e., swollen joint count, p = 0.005). Conclusion In this cohort, 17% patients with PsA experienced multi-b/tsDMARD failure. These patients were more likely to be female, obese, and have higher rates of axial involvement and depression, along with higher active disease activity. This highlights the inflammatory and non-inflammatory drivers of multiple therapeutic failures, underscoring the need for precision medicine strategies and potential non-pharmacologic adjuvant therapies for patients with PsA to improve outcomes and quality of life.

Background Psoriatic arthritis (PsA) is a multi-domain, inflammatory disease impacting joints, soft tissues, and skin; tumor necrosis factor inhibitors (TNFi) are typically the first biologic following inadequate response (IR) to conventional therapies. Although guidance is lacking on therapy selection after initial TNFi failure, data suggest TNFi-IR PsA patients may benefit from switching to a different mechanism of action (MOA) vs. cycling to another TNFi. Guselkumab is a fully human monoclonal antibody targeting the interleukin-23p19 subunit. Emphasizing practicality and applicability to routine clinical practice, EVOLUTION will pragmatically evaluate whether switching to guselkumab is more effective than cycling to a second TNFi (subcutaneous [SC] golimumab) in TNFi-IR PsA patients. Methods The multicenter, longitudinal, prospective, observational Psoriatic Arthritis Research Consortium study guided eligibility criteria, outcome measures, and sample size estimates. Adults seen in clinical practice with active PsA (≥ 1 swollen joint) while receiving TNFi treatment will be eligible. Participants will be randomized (1:1:1) to guselkumab 100 mg every 4 weeks (Q4W); guselkumab 100 mg at Week 0, Week 4, and Q8W; or SC golimumab 50 mg Q4W (no washout period). The novel primary composite endpoint is achievement of clinical Disease Activity in Psoriatic Arthritis (cDAPSA) low disease activity (≤ 13) and an Investigator’s Global Assessment (IGA) of psoriasis score of 0/1 (scale: 0–4) at Month12. Secondary endpoints include cDAPSA + IGA 0/1 at Month 6; achievement of minimal disease activity, resolution of enthesitis and dactylitis (among patients affected at baseline) at Months 6/12; and mean changes at Months 6/12 in the 12-item PsA Impact of Disease, Dermatology Life Quality Index, Patient-Reported Outcomes Measurements Information System fatigue and depression questionnaires, and Bath Ankylosing Spondylitis Disease Activity Index (patients with physician-determined axial disease). The target sample size is 150 participants (50/treatment group); all analyses are considered exploratory. Discussion EVOLUTION will employ a pragmatic approach, including a novel primary endpoint relevant to clinical practice, to assess whether switching to an alternate MOA biologic with guselkumab is more effective than cycling to a second TNFi among TNFi-IR PsA patients. Trial registration This trial was registered at ClinicalTrials.gov, NCT05669833, on 3 January 2023, https://www.clinicaltrials.gov/study/NCT05669833?term=%20NCT05669833&rank=1 Graphical Abstract

Background: In children, C3 glomerulopathy (C3G) is a heterogeneous disease characterized by diverse clinicopathological profiles and kidney outcomes. However, diagnostic work-up in resource-limited settings is challenging because of the unavailability of complement assays and limited access to electron microscopy or genetic testing.Purpose: This study aimed to describe the clinicopathological features and response to immunosuppression and evaluate renal outcomes among children with C3G in a resource-limited setting.Methods: This retrospective cohort study involved a review of the hospital records of 46 children (2013–2021) diagnosed with C3G on kidney biopsy. Their clinical, laboratory, treatment, and outcome details at onset and follow-up were noted.Results: The mean (standard deviation) age was 9 (4) years. The common presentation was acute nephritis (27 [58.6%]), while 1 in 5 (19.5%) presented with rapidly progressive glomerulonephritis. Focal crescentic glomerulonephritis (14 [30.4%]) was the common histological pattern. Electron microscopy was performed in 22 (47.8%), of which 17 were C3 glomerulonephritis and 4 were dense deposit disease (DDD). None of the patients underwent complement assay or genetic testing. Almost two-thirds (63%) received empirical immunosuppressive therapy, most commonly steroids. Of the 31/46 who completed follow-up (median [interquartile range] duration, 11.5 [6–24] months), 6 (19.4%) demonstrated complete kidney recovery, while the other 25 (80.7%) had kidney sequelae; of them, 5 (16.1%) progressed to end-stage kidney disease and 2 (4.3%) died by the last follow-up.Conclusion: Pediatric C3G has a variable clinicopathological spectrum, while DDD is less common. Most patients present with glomerulonephritis and significant morbidities. The lack of genetic and C3Nephritic factor testing is a barrier to the comprehensive phenotyping and management of C3G in resource-limited settings.

The concept of psoriatic arthritis (PsA) prevention is gaining increased interest owing to the physical limitation, poor quality of life and low remission rates that are achieved with current therapies for PsA. The psoriasis-to-PsA transition offers a unique opportunity to identify individuals at increased risk of developing PsA and to implement preventive strategies. However, identifying individuals at increased risk of developing PsA is challenging as there is no consensus on how this population should be defined. This Consensus Statement puts forward recommended terminology from the Psoriasis and Psoriatic Arthritis Clinics Multicenter Advancement Network (PPACMAN) for defining specific subgroups of individuals during the preclinical and early clinical phases of PsA to be used in research studies. Following a three-round Delphi process, consensus was reached for three terms and definitions: ‘increased risk for PsA’, ‘psoriasis with asymptomatic synovio-entheseal imaging abnormalities’ and ‘psoriasis with musculoskeletal symptoms not explained by other diagnosis’. These terms and their definitions will enable improved identification and standardization of study populations in clinical research. In the future, as increasing evidence emerges regarding the molecular and clinical features of the psoriasis-to-PsA continuum, these terms and definitions will be further refined and updated.In this Consensus Statement, an expert panel from the Psoriasis and Psoriatic Arthritis Clinics Multicenter Advancement Network (PPACMAN) recommends terminology for defining specific subgroups of individuals during the preclinical and early clinical phases of psoriatic arthritis to be used in research studies.

Anti-tumor necrosis factors (Anti-TNFs) are a class of biologic disease-modifying anti-rheumatic drugs indicated for the treatment of moderate-to-severe psoriatic arthritis (PsA). Refractory patients are commonly managed by switching from one anti-TNF to another. To assess the evidence on the effectiveness of anti-TNF cycling in PsA patients, a systematic review of the literature was conducted. MEDLINE- and Embase-indexed English-language publications were systematically searched from 1995 to 2015 for studies assessing real-world effectiveness outcomes of anti-TNF cycling in PsA patients. Of 1086 citations identified, 18 studies were included; most conducted in Europe. Six of seven studies testing between lines found significant differences in effectiveness between earlier and subsequent lines of anti-TNF therapy. First-line therapy yielded better results compared with second-line therapy, and significant differences were observed between second- and third-line anti-TNF treatments. In the only study with multivariate regression testing for predictors of response, Danish registry patients were less likely to respond (American College of Rheumatology 20 % or 50 % response) to a second anti-TNF course if safety, rather than lack of effect, caused them to switch (odds ratio [OR] 0.04; p  = 0.003 and OR 0.05; p  = 0.03, respectively). Effectiveness of anti-TNFs at second line and later is reported in a small number of real-world studies of PsA patients. Subsequent treatment lines may be associated with less response in some measures. More research is needed to quantify the effectiveness of sequential anti-TNF lines in this progressive population‚ and to compare these effects with responses to drugs with different mechanisms of action.

IntroductionAn important consideration in the treatment of patients with psoriatic arthritis (PsA) is whether the addition of methotrexate (MTX) to biologics has greater efficacy than biologic monotherapy with respect to efficacy outcomes in these patients.ObjectivesTo conduct a network meta-analysis (NMA) comparing biologics by treatment class with and without MTX for treatment of adults with active PsA.MethodsA systematic literature review (SLR) identified randomised, double-blinded, controlled trials, and a Bayesian NMA compared biologics with and without MTX by treatment class (tumour necrosis factor inhibitors (TNFi), interleukin-23 inhibitors (IL-23i) and IL-17i). Efficacy outcomes included American College of Rheumatology 20%, 50% and 70% (ACR20, ACR50 and ACR70) improvement response.ResultsThe SLR initially identified 31 studies, of which 17 met feasibility criteria for the NMA by containing the ‘without MTX’ subgroup. For ACR20 efficacy (the most robust assessment examined), all active treatments were significantly better than placebo. No statistically significant differences were demonstrated between biologic monotherapy (for all classes examined) and biologics in combination with MTX for ACR20/50. IL-17i were comparable to IL-23i, and IL-17i were significantly better than TNFi for ACR20. Although limited by fewer trials, TNFi, IL-23i and IL-17i were not statistically different for ACR50/70.ConclusionsConcomitant use of MTX and biologics did not improve ACR efficacy outcomes versus biologic monotherapy. MTX does not appear to be necessary as a background therapy when biologics are used for the achievement of ACR20/50 responses in patients with PsA.

This study proposes an enhanced Smith Predictor (ESP) based Modified repetitive control (MRC) technique to develop a precise tracking performance of the input delayed double boost converter model, which is highly influenced by disturbances and saturation nonlinearity. A group of inequalities is derived on the basis of Lyapunov stability concept, which are in the form of linear-matrix-inequalities (LMIs) to guarantee the asymptotic stability and tracking performance of the considered delayed double boost converter. To be more specific, the proposed Lyapunov method not only provides the asymptotic stability of the system but also design the controller parameters when the feasibility of the derived LMIs are analyzed. The validation of the suggested ESP based MRC technique is confirmed through the simulation analysis and the corresponding outcomes from the considered double boost converter model. Moreover, the recommended control procedure yields better accuracy in tracking performance and disturbance elimination when comparing with the existing active disturbance methods such as improved equivalent-input-disturbance (IEID), parallel EID (PEID), higher-order EID (HEID) and EID based Smith predictor (SP) techniques.

Tissue Biomarkers are information written in the tissue and used in Pathology to recognize specific subsets of patients with diagnostic, prognostic or predictive purposes, thus representing the key elements of Personalized Medicine. The advent of Artificial Intelligence (AI) promises to further reinforce the role of Pathology in the scenario of Personalized Medicine: AI-based devices are expected to standardize the evaluation of tissue biomarkers and also to discover novel information, which would otherwise be ignored by human review, and use them to make specific predictions. In this review we will present how AI has been used to support Tissue Biomarkers evaluation in the specific field of Pathology, give an insight to the intriguing field of AI-based biomarkers and discuss possible advantages, risk and perspectives for Pathology.

Background Caregivers of children with chronic kidney disease (CKD) in low resource settings must provide complex medical care at home while being burdened by treatment costs often paid out-of-pocket. We hypothesize that caregiver burden in our low resource setting is greater than reported from high income countries and is associated with frequent catastrophic healthcare expenditure (CHE). Methods We conducted a mixed-methods study of primary caregivers of children with advanced CKD (stage 3b–5) in our private-sector referral hospital in a low resource setting. We assessed caregiver burden using the Pediatric Renal Caregiver Burden Scale (PRCBS) and measured financial burden by calculating the proportion of caregivers who experienced CHE (monthly out-of-pocket healthcare expenditure exceeding 10% of total household monthly expenditure). We performed a qualitative reflexive thematic analysis of caregiver interviews to explore sources of burden. Results Of the 45 caregivers included, 35 (78%) had children on maintenance dialysis (25 PD, 10 HD). Mean caregiver burden score was 141 (± 17), greater than previously reported. On comparative analysis, PRCBS scores were higher among caregivers of children with kidney failure ( p  = 0.005), recent hospitalization ( p  = 0.03), non-earning caregivers ( p  = 0.02), caring for > 2 dependents ( p  = 0.009), and with high medical expenditure ( p  = 0.006). CHE occurred in 43 (96%) caregivers of whom 37 (82%) paid out-of-pocket. The main themes derived relating to caregiver burden were severe financial burden , mental stress and isolation , and perpetual burden of concern . Conclusion Parents of children with CKD experienced severe caregiver burden with frequent CHE and relentless financial stress indicating an imminent need for social support interventions. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information