Real-World Adherence and Drug Survival of Biologics among Patients with Ankylosing Spondylitis.

Objectives: The objective of this study was to evaluate the real-world drug survival, adherence, and discontinuation risk of biologics disease-modifying anti-rheumatic drugs (bDMARDs) among patients with ankylosing spondylitis (AS). Methods: This was a retrospective study using a computerized database. Biologic-naïve and biologic-experienced AS patients who initiated treatment with bDMARDs (tumor necrosis factor alpha inhibitors {TNF-αis} or interleukin-17 inhibitor {IL-17i}) during 2015-2018 were included. Adherence was assessed using the proportion of days covered (PDC) method. Drug survival was analyzed using Kaplan-Meier estimates. Risk of discontinuation was estimated by the Cox proportional hazard model. Results: We identified 343 eligible patients utilizing 481 lines of therapy. The mean age was 44.6 years (SD ± 13.4), 57.7% were males, and 69.7% were biologic-naïve at baseline. The proportion of highly adherent patients (PDC ≥ 0.8) in the biologic-naïve group was 63.5% for golimumab, 69.2% for etanercept, and 71.6% for adalimumab (p > 0.9). Among the biologic-experienced group, secukinumab had the highest proportion of adherent patients (75.7%) and etanercept the lowest (50.0%) reaching statistical difference (p < 0.001). The Kaplan-Meier analysis did not show a significant difference in drug survival in either the biologic-naïve or the biologic-experienced groups (p = 0.85). Multivariable analysis demonstrated a similar risk for discontinuation for etanercept, golimumab, and secukinumab compared with adalimumab, regardless of biologic-experience status. Conclusions: Adherence, drug survival, and risk for discontinuation were similar for all TNF-αis and the IL-17i SEC, regardless of biologic-experience status. As drug survival is an indirect measure of drug efficacy, n, in real-world settings, we believe caregivers can integrate these results into treatment considerations.

Risk factors for psoriatic arthritis development in psoriasis patients: myths, pitfalls, and pearls.

Psoriatic arthritis (PsA) predominantly emerges in individuals previously diagnosed with psoriasis (PsO), offering a unique opportunity to study the transition from PsO to PsA. This progression provides a window to identify characteristics of PsO patients who may develop PsA, facilitating early intervention and potentially informing prevention and treatment strategies. This review evaluates a wide array of research focusing on various risk factors for PsA development. These factors span demographic characteristics, concomitant diseases and habits, characteristics of skin and nail psoriatic disease, and symptoms and imaging abnormalities associated with PsA. By summarising the existing literature, this review critically examines each risk factor, highlighting the strengths and limitations inherent in the studies. Each section of the review not only summarises the current state of knowledge but also includes an expert opinion, culminating in a final concluding remark. This integration allows physicians to utilise the confluence of established literature and ongoing clinical experience, facilitating a rationalised decision-making process that is deeply informed by both empirical evidence and practical insights.

Subclinical psoriatic arthritis and disease interception-where are we in 2024?

Psoriatic arthritis (PsA) is a chronic rheumatic disease that usually appears in patients with skin psoriasis, making it a model for detection of joint disease in the pre-clinical phases in a setting where therapy for cutaneous disease may ameliorate or prevent arthritis development. Such PsA prevention appears credible due to the increasingly recognized closely shared immunopathology between the skin and joints, especially the entheses. Recently, several initiatives have explored the concept of pre-clinical PsA, and nomenclatures have been developed with the recent EULAR nomenclature proposing a simplified three stages from psoriasis to clinical PsA development, namely at risk of PsA, subclinical PsA and early PsA. A better comprehension of early PsA and the identification of individuals predisposed to its development could enable interventions to 'prevent' the appearance of PsA. Several recent retrospective observational studies have demonstrated disease interception feasibility, i.e. treatment of people with psoriasis may prevent the appearance of PsA, in particular using biologic disease-modifying drugs. However, further data is urgently required due to unexpected findings in some studies where TNF inhibition for psoriasis does not reduce the rate of PsA development. In this review we address the current challenges in early PsA, including comparisons of pre-PsA nomenclature sets, its risk factors, and the potential for disease interception.

GRAPPA 2023 Debate: Is Psoriatic Disease Really a Primary Enthesitis That Drives Joint Synovitis? The Enthesitis Hypothesis 25 Years On.

The enthesitis hypothesis posits that enthesitis is a primary lesion and that inflammation at the enthesis initiates the musculoskeletal symptoms of psoriatic arthritis (PsA) and spondyloarthropathies (SpA). The hypothesis suggested that inflamed entheseal tissue near the synovium could trigger cytokine-mediated synovitis, that enthesis bone anchorage could explain osteitis, and that the location of entheses at the soft tissue interface could explain dactylitis. Advances in imaging techniques that allow better visualization of enthesitis lesions and the development of animal models have allowed evolution of the concept of enthesitis as a central mechanistic driver of musculoskeletal symptoms in PsA and SpA. A debate between Drs. Dennis McGonagle and Bruce Kirkham at the Group for Research on Psoriasis and Psoriatic Arthritis (GRAPPA) 2023 annual meeting discussed the data supporting and refuting this hypothesis in PsA and SpA, respectively. The major points of this debate are summarized in this article.

From Psoriasis to Psoriatic Arthritis: Decoding the Impact of Treatment Modalities on the Prevention of Psoriatic Arthritis.

INTRODUCTION: Biologic therapies are licensed for both psoriasis (PsO) and psoriatic arthritis (PsA) with some electronic medical record data suggest that IL (Interleukin)-23 blockers might be more protective in PsA prevention than TNF blockers; however, the findings have been inconsistent. Higher Psoriasis Area and Severity Index (PASI) scores have also been linked to an increased PsA risk. To clarify these unresolved issues we investigated biologic agents, methotrexate, phototherapy, and topical therapy for PsA prevention in patients with psoriasis. METHODS: This retrospective cohort study analyzed data from 58,671 patients with psoriasis from the Israeli Meuhedet Health Services Organization database was evaluated for incident PsA. Patients were categorized on the basis of treatment: group 1, topical therapy; group 2, phototherapy; group 3, conventional disease-modifying antirheumatic drugs (cDMARDs; methotrexate); group 4, biologic DMARDs which was also stratified according to biologic class. RESULTS: The PsA incidence rate was lower in the biologic agents' group versus the methotrexate group (HR 0.46 [95% CI 0.35-0.62]). The incidence rates per 100 person-years varied across biologic treatment groups, with the anti­IL­12/23 or anti­IL­23p19 group at 4.57, the anti-IL-17 group at 4.35, and the TNF inhibitor group at 2.55. No differences were found between various biological agents in terms of preventing PsA. The phototherapy group exhibited a higher PsA development rate than the topical therapy group (HR 1.85 [95% CI 1.65-2.07]). CONCLUSION: Biological agents are more effective than methotrexate in reducing incident PsA in patients with psoriasis. This lower rate of PsA on topical therapy compared to phototherapy supports the importance of psoriasis severity as a risk factor.

Enthesitis and Dactylitis Resolution with Risankizumab for Active Psoriatic Arthritis: Integrated Analysis of the Randomized KEEPsAKE 1 and 2 Trials.

INTRODUCTION: The presence (vs absence) of enthesitis/dactylitis is associated with greater psoriatic arthritis (PsA) activity and reduced health-related quality of life. Risankizumab, an interleukin 23 antagonist, demonstrated superior treatment efficacy over placebo in patients with PsA, including enthesitis/dactylitis. Herein, we report the efficacy of risankizumab on complete resolution of enthesitis and/or dactylitis and improvements in patient-reported outcomes in patients with PsA. METHODS: This integrated post hoc analysis of data from KEEPsAKE 1 and KEEPsAKE 2 included patients with baseline enthesitis (Leeds Enthesitis Index > 0) and/or dactylitis (Leeds Dactylitis Index > 0). Efficacy outcomes at weeks 24 and 52 included proportion of patients achieving enthesitis and/or dactylitis resolution and minimal clinically important differences (MCID) in pain, Health Assessment Questionnaire-Disability Index, and Functional Assessment of Chronic Illness Therapy-Fatigue. RESULTS: Of 1407 patients, approximately 63%, 28%, and 20% had baseline enthesitis, dactylitis, and both enthesitis/dactylitis, respectively. At week 24, higher response rates were observed for risankizumab vs placebo for resolution of enthesitis, dactylitis, and both enthesitis/dactylitis (differences of 13.9%, 16.9%, and 13.3%, respectively; p < 0.05). By week 52, risankizumab treatment resulted in complete resolution of enthesitis, dactylitis, and both enthesitis and dactylitis in 55.0%, 76.1%, and 52.3% of patients; similar resolution rates occurred among patients who switched from placebo to risankizumab. Among risankizumab-treated patients who achieved resolution of enthesitis and/or dactylitis, MCIDs were also attained in patient-reported pain, disability, and fatigue at week 24 (all p < 0.05; except fatigue in patients with resolution of both enthesitis/dactylitis); responses were sustained through week 52. CONCLUSIONS: Higher proportions of risankizumab-treated (vs placebo-treated) patients achieved enthesitis and/or dactylitis resolution and meaningful improvements in patient-reported outcomes at week 24 and generally sustained responses at week 52. Thus, risankizumab may result in sustained alleviation of PsA-related pathognomonic musculoskeletal lesions of enthesitis/dactylitis. GOV IDENTIFIERS: NCT03675308, and NCT03671148.

Pronounced benefits of JAK inhibition with baricitinib in COVID-19 pneumonia in obese but not lean subjects.

OBJECTIVE: Obesity and age are strongly linked to severe COVID-19 pneumonia where immunomodulatory agents including Janus kinase inhibitors have shown benefits but the efficacy of such therapy in viral pneumonia is not well understood. We evaluated the impact of obesity and age on survival following baricitinib therapy for severe COVID-19. METHODS: A post hoc analysis of the COV-BARRIER multicentre double-blind randomised study of baricitinib versus placebo (PBO) with an assessment of 28-day mortality was performed. All-cause mortality by day 28 was evaluated in a Cox regression analysis (adjusted to age) in three different groups according to body mass index (BMI) (<25 kg/m2, 25-30 kg/m2 and >30 kg/m2) and age <65 years and ≥65 years. RESULTS: In the high BMI group (>25 kg/m2), baricitinib therapy showed a significant survival advantage compared with PBO (incidence rate ratio (IRR) for mortality by day 28 0.53 (95% CI 0.32 to 0.87)) and 0.66 (95% CI 0.46 to 0.94) for the respective <65 years and ≥65 years, respectively. The 28-day all-cause-mortality rates for BMI over 30 were 5.62% for baricitinib and 9.22% for PBO (HR=0.6, p<0.05). For BMI under 25 kg/m2, irrespective of age, baricitinib therapy conferred no survival advantage (IRR of 1.89 (95% CI 0.49 to 7.28) and 0.95 (95% CI 0.46 to 1.99) for <65 years and ≥65 years, respectively) ((mortality 6.6% baricitinib vs 8.1 in PBO), p>0.05). CONCLUSION: The efficacy of baricitinib in COVID-19 pneumonia is linked to obesity suggesting that immunomodulatory therapy benefit is associated with obesity-associated inflammation.

MDA5-autoimmunity and interstitial pneumonitis contemporaneous with the COVID-19 pandemic (MIP-C).

BACKGROUND: Anti-MDA5 (Melanoma differentiation-associated protein-5) positive dermatomyositis (MDA5+-DM) is characterised by rapidly progressive interstitial lung disease (ILD) and high mortality. MDA5 is an RNA sensor and a key pattern recognition receptor for the SARS-CoV-2 virus. METHODS: This is a retrospective observational study of a surge in MDA5 autoimmunity, as determined using a 15 muscle-specific autoantibodies (MSAs) panel, between Janurary 2018 and December 2022 in Yorkshire, UK. MDA5-positivity was correlated with clinical features and outcome, and regional SARS-CoV-2 positivity and vaccination rates. Gene expression patterns in COVID-19 were compared with autoimmune lung disease and idiopathic pulmonary fibrosis (IPF) to gain clues into the genesis of the observed MDA5+-DM outbreak. FINDINGS: Sixty new anti-MDA5+, but not other MSAs surged between 2020 and 2022, increasing from 0.4% in 2019 to 2.1% (2020), 4.8% (2021) and 1.7% (2022). Few (8/60) had a prior history of confirmed COVID-19, peak rates overlapped with regional SARS-COV-2 community positivity rates in 2021, and 58% (35/60) had received anti-SARS-CoV-2 vaccines. 25/60 cases developed ILD which rapidly progression with death in 8 cases. Among the 35/60 non-ILD cases, 14 had myositis, 17 Raynaud phenomena and 10 had dermatomyositis spectrum rashes. Transcriptomic studies showed strong IFIH1 (gene encoding for MDA5) induction in COVID-19 and autoimmune-ILD, but not IPF, and IFIH1 strongly correlated with an IL-15-centric type-1 interferon response and an activated CD8+ T cell signature that is an immunologic hallmark of progressive ILD in the setting of systemic autoimmune rheumatic diseases. The IFIH1 rs1990760TT variant blunted such response. INTERPRETATION: A distinct pattern of MDA5-autoimmunity cases surged contemporaneously with circulation of the SARS-COV-2 virus during COVID-19. Bioinformatic insights suggest a shared immunopathology with known autoimmune lung disease mechanisms. FUNDING: This work was supported in part by the National Institute for Health Research (NIHR) Leeds Biomedical Research Centre (BRC), and in part by the National Institutes of Health (NIH) grant R01-AI155696 and pilot awards from the UC Office of the President (UCOP)-RGPO (R00RG2628, R00RG2642 and R01RG3780) to P.G. S.S was supported in part by R01-AI141630 (to P.G) and in part through funds from the American Association of Immunologists (AAI) Intersect Fellowship Program for Computational Scientists and Immunologists.

Increased Risk for Pulmonary Embolism among Patients with Ankylosing Spondylitis-Results from a Large Database Analysis.

Background: Axial spondyloarthropathy(AS) is a chronic inflammatory disease primarily affecting the axial skeleton, often characterized by sacroiliitis. While pulmonary embolism (PE), a potentially lethal condition, has been linked to several autoimmune diseases, limited data exist regarding PE risk among patients with AS. Methods: This retrospective cohort study utilized the Clalit Healthcare Services (CHS) database, including 5825 patients with AS and 28,356 matched controls. Follow-up began at the date of first AS diagnosis for patients and at the matched patient's diagnosis date for controls and continued until PE diagnosis, death, or study end date. Results: Prevalence of PE before AS diagnosis in patients compared to controls was 0.4% vs. 0.2% (p < 0.01). The incidence rate of PE was 11.6 per 10,000 person-years for patients with AS and 6.8 per 10,000 person-years for controls. The adjusted hazard ratio (HR) for PE in patients with AS was 1.70 (p < 0.001). Subgroup analysis demonstrated excess risk for PE in patients with AS regardless of gender and age, with variations among AS treatment categories. Discussion: Our findings highlight a significant association between AS and PE, indicating an increased risk in patients with AS independent of age and sex and suggests a subclinical level of inflammation. Preliminary results suggest a protective role of immunosuppressing drugs. Further research into the impact of treatment strategies should be conducted and could inform clinical management and reduce the life-threatening risk of PE in Patients with AS.

Risk of developing psoriatic arthritis in psoriasis cohorts with arthralgia: exploring the subclinical psoriatic arthritis stage.

OBJECTIVE: Subjects with subclinical psoriatic arthritis (PsA), defined as the presence of arthralgia in psoriasis (PsO), are at higher risk of PsA but scant real-world data exist. Our aims were to (1) estimate the probability of PsA development in subclinical PsA, (2) characterise subclinical PsA symptoms and (3) determine the clinical patterns at PsA diagnosis. METHODS: Patients with PsO, mainly subclinical PsA, were evaluated longitudinally in two European cohorts. The key outcome was new-onset PsA. Musculoskeletal symptoms including inflammatory and non-inflammatory symptoms before PsA diagnosis were collected. Occurrence of PsA was analysed with survival analysis and cumulative incidence functions (CIFs). RESULTS: 384 patients with PsO were included with a mean follow-up of 33.0 (±20.9) months. 311 of 384 (80.9%) had subclinical PsA with a PsA incidence rate of 7.7 per 100 patient-years. Subclinical PsA displayed a higher risk of PsA development compared with PsO (HR=11.7 (95% CI 1.57 to 86.7), p=0.016). The probability of new-onset PsA estimated by the CIF was 9.4% (95% CI 4.7% to 10.6%) at month 12 and 22.7% (95% CI 17.2% to 28.6%) at month 36. 58.9% of cases reported inflammatory symptoms in the months immediately prior to PsA diagnosis but prior non-inflammatory symptoms were evident in 83.9% prior to PsA diagnosis. Peripheral joint swelling was the predominant PsA presentation pattern (82.1%). CONCLUSIONS: The probability of PsA development among subclinical PsA was relatively high, emphasising the importance of emergent musculoskeletal symptoms when aiming for PsA prevention. Joint swelling was the dominant feature in new-onset PsA, likely reflecting clinical confidence in recognising joint swelling.

High prevalence of radiographic erosions in early, untreated PsA: results from the SpARRO cohort.

AIMS: To investigate the prevalence and distribution of bone erosions in an early psoriatic arthritis (PsA) population using conventional radiography (CR) and to explore the agreement between CR and ultrasound (US) detected bone erosions. METHODS: Newly diagnosed, treatment naïve PsA patients fulfilling the ClASsification for Psoriatic Arthritis (CASPAR) classification criteria of ≤5 years symptom duration were recruited as part of the Leeds Spondyloarthropathy Register for Research and Observation and underwent CR and US examination of hands and feet. RESULTS: Overall, 4655 hand and feet joints were assessed in 122 patients. CR erosions were detected in 24.6% (n=30) with lowest prevalence seen below 8 months of symptoms (17.5% vs 24.3%>24 months). The number of erosions was higher on CR (1.55% (63/4,655); US 1.04% (34/3,270)), with 5th metatarsophalangeal (MTP) joint being the most affected site in both CR (5.21% (11/211)) and US (7.14% (15/210)). Erosions in CR were more evenly distributed compared with US where three-quarters of the total number of bone erosions were detected in wrists, second metacarpophalangeal (MCP) and fifth MTP joints. Most joints had almost perfect prevalence-adjusted bias-adjusted kappa values ranging from 0.91 to 1. CONCLUSIONS: Erosions were seen in a quarter of patients with newly diagnosed, untreated PsA with a declining trend around the 8-month symptom duration cut-off. High levels of agreement between CR and US were seen with CR detecting more erosions. A focused US assessment of the wrist, second MCP and fifth MTP joints may be useful to detect bone erosions in early PsA.

Association between enthesitis/dactylitis resolution and patient-reported outcomes in guselkumab-treated patients with psoriatic arthritis.

OBJECTIVES: To evaluate the association between enthesitis resolution (ER) and dactylitis resolution (DR) and meaningful improvements in patient-reported outcomes (PROs) among biologic-naïve patients with PsA receiving guselkumab in the DISCOVER-2 study. METHODS: Enthesitis and dactylitis, characteristic lesions of PsA, were evaluated by independent assessors using the Leeds Enthesitis Index (range, 0-6) and Dactylitis Severity Score (range, 0-60). Proportions of patients with ER or DR (score = 0) among those with score > 0 at baseline were determined at weeks 24, 52, and 100. PROs included: fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-Fatigue]), pain (0-100 visual analog scale), physical function (Health Assessment Questionnaire-Disability Index [HAQ-DI]), and health-related quality of life (36-item Short-Form Health Survey physical/mental component summary [SF-36 PCS/MCS]). Meaningful responses were defined as: improvements of ≥ 4 for FACIT-Fatigue, ≥ 0.35 for HAQ-DI, and ≥ 5 for SF-36 PCS/MCS and absolute scores of ≤ 15 for minimal pain and ≤ 0.5 for normalized HAQ-DI. Associations between ER/DR status and PRO response status were tested using a Chi-square test. RESULTS: Guselkumab-treated patients with ER were more likely than those without ER to achieve minimal pain (p < 0.001), normalized HAQ-DI (p < 0.001), and PCS response (p < 0.05) at weeks 24, 52, and 100. Patients with DR were more likely than those without DR to achieve FACIT-Fatigue response at week 24 and week 52 (both p ≤ 0.01) and minimal pain at week 24 and normalized HAQ-DI at week 52 (both p ≤ 0.03). CONCLUSION: In biologic-naïve patients with active PsA treated with guselkumab, achieving ER or DR was associated with durable improvements in selected PROs, including those of high importance to patients. TRIAL REGISTRATION: ClinicalTrials.gov ( https://clinicaltrials.gov ) NCT03158285; Registered: May 16, 2017. Key Points • At week 100, 65% and 76% of guselkumab-treated patients achieved enthesitis and dactylitis resolution (ER/DR). • Achieving ER was associated with achieving DR and vice versa through the end of study. • Achieving ER or DR was associated with durable and meaningful improvements in selected patient-reported outcomes.

EULAR recommendations for the management of psoriatic arthritis with pharmacological therapies: 2023 update.

OBJECTIVE: New modes of action and more data on the efficacy and safety of existing drugs in psoriatic arthritis (PsA) required an update of the EULAR 2019 recommendations for the pharmacological treatment of PsA. METHODS: Following EULAR standardised operating procedures, the process included a systematic literature review and a consensus meeting of 36 international experts in April 2023. Levels of evidence and grades of recommendations were determined. RESULTS: The updated recommendations comprise 7 overarching principles and 11 recommendations, and provide a treatment strategy for pharmacological therapies. Non-steroidal anti-inflammatory drugs should be used in monotherapy only for mild PsA and in the short term; oral glucocorticoids are not recommended. In patients with peripheral arthritis, rapid initiation of conventional synthetic disease-modifying antirheumatic drugs is recommended and methotrexate preferred. If the treatment target is not achieved with this strategy, a biological disease-modifying antirheumatic drug (bDMARD) should be initiated, without preference among modes of action. Relevant skin psoriasis should orient towards bDMARDs targeting interleukin (IL)-23p40, IL-23p19, IL-17A and IL-17A/F inhibitors. In case of predominant axial or entheseal disease, an algorithm is also proposed. Use of Janus kinase inhibitors is proposed primarily after bDMARD failure, taking relevant risk factors into account, or in case bDMARDs are not an appropriate choice. Inflammatory bowel disease and uveitis, if present, should influence drug choices, with monoclonal tumour necrosis factor inhibitors proposed. Drug switches and tapering in sustained remission are also addressed. CONCLUSION: These updated recommendations integrate all currently available drugs in a practical and progressive approach, which will be helpful in the pharmacological management of PsA.

Efficacy and safety of pharmacological treatment of psoriatic arthritis: a systematic literature research informing the 2023 update of the EULAR recommendations for the management of psoriatic arthritis.

OBJECTIVES: To obtain an overview of recent evidence on efficacy and safety of pharmacological treatments in psoriatic arthritis (PsA). METHODS: This systematic literature research (SLR) investigated the efficacy and safety of conventional synthetic (cs), biological (b) and targeted synthetic (ts) disease-modifying antirheumatic drugs (DMARDs) in patients with PsA. A systematic database search using Medline, EMBASE, Cochrane CENTRAL was conducted to identify relevant articles published since the previous update in 2019 until 28 December 2022. Efficacy was assessed in trials while for safety observational data were also considered. Adverse events of special interest were infections (including herpes zoster, influenza and tuberculosis), malignancies, major adverse cardiovascular events, venous thromboembolisms, liver disease, laboratory changes and psychiatric adverse events. No meta-analyses were performed. RESULTS: For efficacy, of 3946 articles screened, 38 articles (30 trials) were analysed. The compounds investigated included csDMARDs (leflunomide, methotrexate), bDMARDs inhibiting IL17 (bimekizumab, brodalumab, ixekizumab, izokibep, secukinumab,), IL-23 (guselkumab, risankizumab, tildrakizumab), IL-12/23 (ustekinumab) as well as TNF (adalimumab, certolizumab-pegol, etanercept, infliximab, golimumab) and Janus Kinase inhibitors (JAKi) (brepocitinib, deucravacitinib, tofacitinib, upadacitinib). The compounds investigated were efficacious in improving signs and symptoms of PsA, improving physical functioning and quality of life. For safety, 2055 abstracts were screened, and 24 articles analysed: 15 observational studies and 9 long-term follow-ups of trials, assessing glucocorticoids, TNFi, IL-17i, JAKi, IL-12/23i and PDE4i (apremilast). Safety indicators were generally coherent with the previous SLR in 2019. CONCLUSION: The results of this SLR informed the task force responsible for the 2023 update of the European Alliance of Associations for Rheumatology recommendations for pharmacological management of PsA.

Real-world experience of IL-17Ai drug survival in a large cohort of axial spondyloarthritis and psoriatic arthritis.

Objective: The aim was to assess the use and drug survival of IL-17Ai in a real-world cohort of axial SpA (axSpA) and PsA patients. Methods: Patients ever commenced on an IL-17Ai (secukinumab or ixekizumab) for axSpA or PsA at the Leeds Specialist Spondyloarthritis Service were identified. Demographics, IL-17Ai treatment length and reason for cessation were collected. Drug survival data were plotted as a Kaplan-Meier curve, with log rank test of median survival compared between axSpA and PsA. Cox regression analysis was performed to investigate the relationship between diagnosis and length of drug survival. Results: In total, 228 patients (91 axSpA and 137 PsA) were exposed to IL-17Ai. Drug survival for all patients at 12 months was 69% (95% Confidence Interval (CI) 63, 75%) and at 24 months 60% (95% CI 54, 67%). In axSpA and PsA, drug survival at 12 months was 63% (CI 54, 74%) and 73% (CI 66, 81%), respectively, and at 24 months it was 53% (CI 44, 65%) and 65% (CI 57, 75%), respectively. Median survival did not differ significantly between both diseases (log rank test 0.65). There was no association between diagnosis and survival (hazard ratio 0.92, 95% CI 0.63, 1.33), including when adjusting for age, previous biologic DMARD usage and sex (hazard ratio 0.89, 95% CI 0.61, 1.13). Conclusion: This is the first study, to our knowledge, to analyse and compare real-world IL-17Ai drug survival in patients with axSpA and PsA from a single centre. We demonstrate that there is no difference in IL-17Ai survival rates and no relationship between diagnosis and drug survival. These results contribute to the body of real-world evidence confirming the role of IL-17Ai in the management of axSpA and PsA.

Systematic Review and Metaanalysis of Pharmacological Interventions in Adult-Onset Still Disease and the Role of Biologic Disease-Modifying Antirheumatic Drugs.

OBJECTIVE: To conduct a systematic review of the effectiveness and safety of pharmacological treatments for adult-onset Still disease (AOSD). METHODS: Six databases, 2 trial registries, and conference abstracts were searched from January 2012 to February 2023 for studies of pharmacological interventions in people with AOSD. Outcomes were rates of remission and response, discontinuation of concurrent treatments, complications of AOSD, and treatment-related adverse events. Risk of bias was assessed with the Cochrane risk of bias tool and the Joanna Briggs Institute tool for case series. RESULTS: Forty-four studies evaluated treatments, including nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids (CS), conventional synthetic disease-modifying antirheumatic drugs (DMARDs), and biologic DMARDs (bDMARDs). For bDMARDs, tocilizumab (TCZ), anakinra (ANK), and canakinumab (CNK) had the most available data. Although 3 randomized controlled trials did not show statistically significant benefits of bDMARDs, metaanalyses showed high rates of complete remission and CS discontinuation. Complete remission was 80% (95% CI 59-92%, I 2 36%), 73% (95% CI 58-84%, I 2 66%), and 77% (95% CI 29-97%, I 2 82%) and CS discontinuation was 57% (95% CI 29-81%, I 2 66%), 47% (95% CI 18-78%, I 2 79%), and 34% (95% CI 6-81%, I 2 59%), respectively, for TCZ, ANK, and CNK. Studies with a higher proportion of patients previously treated with bDMARDs showed a trend toward lower rates of CS discontinuation (P = 0.05). The analyses had high clinical heterogeneity, largely because treatments were prescribed as different lines of therapy. CONCLUSION: Evidence supports TCZ, ANK, and CNK therapy for AOSD. However, the magnitude of effect and comparative effectiveness of treatments is uncertain.

In Vitro Osteogenesis Study of Shell Nacre Cement with Older and Young Donor Bone Marrow Mesenchymal Stem/Stromal Cells.

Bone void-filling cements are one of the preferred materials for managing irregular bone voids, particularly in the geriatric population who undergo many orthopedic surgeries. However, bone marrow mesenchymal stem/stromal cells (BM-MSCs) of older-age donors often exhibit reduced osteogenic capacity. Hence, it is crucial to evaluate candidate bone substitute materials with BM-MSCs from the geriatric population to determine the true osteogenic potential, thus simulating the clinical situation. With this concept, we investigated the osteogenic potential of shell nacre cement (SNC), a bone void-filling cement based on shell nacre powder and ladder-structured siloxane methacrylate, using older donor BM-MSCs (age > 55 years) and young donor BM-MSCs (age < 30 years). Direct and indirect cytotoxicity studies conducted with human BM-MSCs confirmed the non-cytotoxic nature of SNC. The standard colony-forming unit-fibroblast (CFU-F) assay and population doubling (PD) time assays revealed a significant reduction in the proliferation potential (p < 0.0001, p < 0.05) in older donor BM-MSCs compared to young donor BM-MSCs. Correspondingly, older donor BM-MSCs contained higher proportions of senescent, ß-galactosidase (SA-ß gal)-positive cells (nearly 2-fold, p < 0.001). In contrast, the proliferation capacity of older donor BM-MSCs, measured as the area density of CellTrackerTM green positive cells, was similar to that of young donor BM-MSCs following a 7-day culture on SNC. Furthermore, after 14 days of osteoinduction on SNC, scanning electron microscopy with energy-dispersive spectroscopy (SEM-EDS) showed that the amount of calcium and phosphorus deposited by young and older donor BM-MSCs on SNC was comparable. A similar trend was observed in the expression of the osteogenesis-related genes BMP2, RUNX2, ALP, COL1A1, OMD and SPARC. Overall, the results of this study indicated that SNC would be a promising candidate for managing bone voids in all age groups.

Effects of upadacitinib on enthesitis in patients with psoriatic arthritis: a post hoc analysis of SELECT-PsA 1 and 2.

OBJECTIVES: To characterize the effect of upadacitinib 15 mg once daily (UPA15) on enthesitis in patients with psoriatic arthritis from the SELECT-PsA Phase 3 trials. METHODS: Patients with an inadequate response/intolerance to ≥ 1 non-biologic DMARD (SELECT-PsA 1) or ≥ 1 biologic DMARD (SELECT-PsA 2) received UPA15, adalimumab 40 mg every other week or placebo (weeks 0-24) switched to UPA15 (week 24 onward). The Leeds Enthesitis Index (LEI) and Spondyloarthritis Research Consortium of Canada (SPARCC) index were used to assess improvement in enthesitis, enthesitis resolution, maintenance of enthesitis resolution, and protection from enthesitis development through week 56. RESULTS: Data from 639 patients receiving UPA15 and 635 patients receiving placebo (including 317 patients who switched from placebo to UPA15) were analysed. UPA15 led to higher rates of enthesitis resolution vs placebo at week 24 (LEI: 59.8% vs 38.0%; SPARCC index: 50.6% vs 31.5%, respectively) and greater improvements in the LEI (-1.7 vs -1.0) and SPARCC index (-3.4 vs -1.9); improvements were maintained through week 56. Improvements were observed after 12 weeks of UPA15 treatment. Over 90% of patients without enthesitis (LEI = 0) at baseline receiving UPA15 were enthesitis-free at week 56, and UPA15 prevented recurrence of enthesitis at week 56 in > 80% of patients with enthesitis at baseline who achieved resolution (LEI = 0) at week 24. CONCLUSIONS: UPA15 is associated with a comprehensive improvement in enthesitis, with improvements observed after 12 weeks of treatment. Additionally, treatment with UPA15 was associated with maintaining an enthesitis-free state after resolution and protection against new-onset enthesitis. CLINICALTRIALS.GOV IDENTIFIERS: NCT03104400 (SELECT-PsA 1) and NCT03104374 (SELECT-PsA 2).

Association of the clinical components in the distal interphalangeal joint synovio-entheseal complex and subsequent response to ixekizumab or adalimumab in psoriatic arthritis.

OBJECTIVES: To assess the frequency of simultaneous distal interphalangeal (DIP) joint disease and adjacent nail psoriasis (finger unit) among patients with psoriatic arthritis (PsA) and compare the efficacy of the interleukin (IL)-17A antagonist ixekizumab (IXE) and the tumour necrosis factor (TNF)-α inhibitor adalimumab (ADA). METHODS: This post hoc analysis evaluated the simultaneous occurrence of DIP joint involvement (tenderness and/or swelling) and adjacent nail psoriasis among patients with PsA from the SPIRIT-H2H (NCT03151551) trial comparing IXE to ADA. Among patients with simultaneous DIP joint involvement and adjacent nail psoriasis in ≥ 1 digit at baseline, treatment effects were assessed through week 52 for each affected finger unit; 'finger unit' defines the connected DIP joint and adjacent nail of an individual digit. RESULTS: A total of 354 patients had simultaneous DIP joint involvement and adjacent nail psoriasis in ≥ 1 finger unit at baseline. Among them, 1309 (IXE = 639, ADA = 670) finger units had baseline DIP joint tenderness and/or swelling and adjacent nail psoriasis. Proportions of affected finger units achieving complete resolution were significantly higher with IXE vs ADA as early as week 12 (38.8% vs 28.4%, p< 0.0001) and at all post-baseline assessments through week 52 (64.9% vs 57.5%, p= 0.0055). CONCLUSIONS: In this study cohort, patients with DIP joint involvement almost always had adjacent nail psoriasis. Greater resolution of DIP joint tenderness, swelling, and adjacent nail psoriasis was achieved at all timepoints over 52 weeks through targeting IL-17A with IXE than TNF-α with ADA, which is noteworthy given prior comparable musculoskeletal outcomes for both drug classes.