Leslie J Crofford’s research while affiliated with Vanderbilt University and other places

Objectives To identify phenotype clusters and their trajectories in psoriatic arthritis (PsA) and examine the association of the clusters with treatment response in a real-world setting. Methods In the multicentre PsA Research Consortium (PARC) study, we applied factor analysis of mixed data to reduce dimensionality and collinearity, followed by hierarchical clustering on principal components. We then evaluated the transition of PsA clusters and their response to new immunomodulatory therapy and tumour necrosis factor inhibitor (TNFi). Results Among 627 patients with PsA, three clusters were identified: mild PsA and psoriasis only (PsO) (Cluster 1, 47.4%), severe PsA and mild PsO (Cluster 2, 34.3%) and severe PsA and severe PsO (Cluster 3, 18.3%). Among 339 patients starting or changing, significant differences in response were observed (mean follow-up of 0.7 years, SD 0.8), with Cluster 3 showing the largest improvements in cDAPSA and PsAID. No differences were found among those starting TNFi (n=218). cDAPSA remission and PsAID patient acceptable symptom state were achieved in 10% and 54%, respectively. Clusters remained stable over time despite treatment changes, though some transitions occurred, notably from Cluster 3 to milder clusters. Conclusion Data-driven clusters with distinct therapy responses identified in this real-world study highlight the extensive heterogeneity in PsA and the central role of psoriasis and musculoskeletal severity in treatment outcomes. Concurrently, these findings underscore the need for better outcome measures, particularly for individuals with lower disease activity.

Background The NIH Pragmatic Trials Collaboratory supports the design and conduct of 31 embedded pragmatic clinical trials, and many of these trials use patient-reported outcome measures (PROMs) to provide valuable information about the patients' health and wellness. Often these trials enroll medically underserved patients, including people with incomes below the federal poverty threshold, racial or ethnic minority groups, or rural or frontier communities. Objectives In this series of trial case reports, we provide lessons learned about collecting PROMs in these populations. Unbiased collection of PROM data is critical to increase the generalizability of trial outcomes and to address health inequities. Use of electronic health records (EHRs) and other digital modes of PROM administration has gained traction. However, engagement with these modes is often low among populations prone to disparity due to lower digital proficiency, device access, and uptake of EHR portals and web interfaces. Methods To maximize the completeness and representativeness of their trial outcome data, study teams tested a range of strategies to improve PROM response rates with emphasis on disparities prone and underserved patient groups. This manuscript describes the approaches, their implementation, and the targeted populations. Conclusion Optimized PROM collection required hybrid approaches with multiple outreach modes, high-touch methods, creativity in promoting digital uptake, multimodal participant engagement, and text messaging.

Objective In the randomized Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial, myeloablation, followed by hematopoietic stem cell transplantation (HSCT), led to the normalization of systemic sclerosis (SSc) peripheral blood cell (PBC) gene expression signature at the 26‐month visit. Herein, we examined long‐term molecular changes ensuing 54 months after randomization for individuals receiving an HSCT or 12 months of intravenous cyclophosphamide (CYC). Methods Global PBC transcript studies were performed in study participants at pretreatment baseline and at 38 months and 54 months after randomization, as well as in healthy controls using Illumina HT‐12 arrays. Results Thirty (HSCT = 19 and CYC = 11) participants had 38‐month samples available, and 26 (HSCT = 16 and CYC = 11) had 54‐month samples available. In the paired comparison to baseline, a significant down‐regulation of interferon modules and an up‐regulation of cytotoxic/natural killer module were observed at the 38‐month and 54‐month visits in the HSCT arm, indicating a long‐term normalization of baseline SSc gene expression signature. No differentially expressed modules were detected in the CYC arm. In comparison to samples from healthy controls, 38‐month visit samples in the HSCT arm showed an up‐regulation of B cell and plasmablast modules and a down‐regulation of myeloid and inflammation modules. Importantly, 54‐month HSCT samples did not show any differentially expressed modules compared to healthy control samples, suggesting completion of immune reconstitution. Participants in the CYC arm continued to show an SSc transcript signature in comparison to controls at both time points. Conclusion Paralleling the observed clinical benefit, HSCT leads to durable long‐term normalization of the molecular signature in SSc, with completion of immune resetting to 54 months after HSCT. image

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating urologic pain condition with few treatment advances in the past 25 years. Individuals with IC/BPS often experience significant psychological distress, which worsens symptoms and functioning. To date, there have been no large-scale, randomized controlled trials (RCTs) of comprehensive psychological interventions for IC/BPS. We conducted a 2:1 RCT of an 8-session patient-informed cognitive-behavioral therapy (CBT) intervention designed for IC/BPS for reducing pain-related symptoms and improving quality of life, delivered through telemedicine. Individuals with IC/BPS (N = 78) were randomized to receive either 8 weeks of CBT specifically designed for IC/BPS (n = 52) or an attention control condition (n = 26). Urologic symptoms (Genitourinary Pain Index, GUPI), pain-related symptoms, affective distress, and quality of life were evaluated before, immediately after, and 3 months posttreatment. Both conditions reported significant but similar reductions ( P = 0.922) in the a priori primary outcome of genitourinary symptoms at posttreatment (GUPI reduction = 6.6 vs 4.8, for CBT and control, respectively) and long-term follow-up (8.1 vs 6.6, for CBT and control). However, the CBT group had significantly greater improvement in Patient Global Impression of Change (PGIC) scores and was significantly more likely to be treatment responders (PGIC ≥ 6) (37% vs 8%, P = 0.019 for CBT and control), with a large relative effect size (OR = 6.68). A subgroup analysis of CBT recipients showed that responders (PGIC 6) displayed significant reductions in genitourinary symptoms ( P = 0.023), pain intensity ( P = 0.027), and pain interference ( P = 0.013) posttreatment. Telemedicine-delivered pain CBT for IC/BPS shows promise for improving outcomes, and this trial demonstrates the need for larger RCTs of CBT for IC/BPS.

Objective Sleep quality and duration are important for biological restoration and promotion of psychological well-being. Optimism may facilitate or result from sufficient sleep, but questions remain as to directionality. The present study tested how optimism is associated with levels of and variability in sleep quantity and quality in a longitudinal burst design. Methods Midlife and older women (N = 199) reported their sleep quantity and quality in online diaries for a 7-day period, every 3 months for 2 years. Optimism was measured at baseline and end-of-study. Multilevel models tested the effects of optimism on sleep. Linear regression models tested the effect of sleep on optimism. Results Baseline optimism was associated with higher sleep quality (γ = 2.13 [1.16, 3.11], p < .0001) and lower intraindividual variability (IIV; night-to-night and wave-to-wave) in sleep quantity (night-to-night: γ = -0.07 [-0.13, -0.005], p = .03; wave-to-wave: b = -.07 [-.12, -.02], p = .003). In turn, higher average sleep quality (but not quantity) was associated with higher optimism at end-of-study ( b = .02 [.007, .03], p = .002). Variability in sleep was unrelated to optimism. Conclusions Optimism may play an important role in maintaining sleep quality and consistency in sleep quantity, perhaps by buffering stress. Similarly, sleep quality may play an important role in maintaining optimism. The cycle whereby optimism and sleep enhance one another could improve physical health and psychological well-being among aging adults.

The Advances in Targeted Therapies meets annually, convening experts in the field of rheumatology to both provide scientific updates and identify existing scientific gaps within the field. To review the major unmet scientific needs in rheumatology. The 23rd annual Advances in Targeted Therapies meeting convened with more than 100 international basic scientists and clinical researchers in rheumatology, immunology, infectious diseases, epidemiology, molecular biology and other specialties relating to all aspects of immune-mediated inflammatory diseases. We held breakout sessions in five rheumatological disease-specific groups including: rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis (axSpa), systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and vasculitis, and osteoarthritis (OA). In each group, experts were asked to identify and prioritise current unmet needs in clinical and translational research. An overarching theme across all disease states is the continued need for clinical trial design innovation with regard to therapeutics, endpoint and disease endotypes. Within RA, unmet needs comprise molecular classification of disease pathogenesis and activity, pre-/early RA strategies, more refined pain profiling and innovative trials designs to deliver on precision medicine. Continued scientific questions within PsA include evaluating the genetic, immunophenotypic, clinical signatures that predict development of PsA in patients with psoriasis, and the evaluation of combination therapies for difficult-to-treat disease. For axSpA, there continues to be the need to understand the role of interleukin-23 (IL-23) in pathogenesis and the genetic relationship of the IL-23-receptor polymorphism with other related systemic inflammatory diseases (eg, inflammatory bowel disease). A major unmet need in the OA field remains the need to develop the ability to reliably phenotype and stratify patients for inclusion in clinical trials. SLE experts identified a number of unmet needs within clinical trial design including the need for allowing endpoints that reflect pharmacodynamic/functional outcomes (eg, inhibition of type I interferon pathway activation; changes in urine biomarkers). Lastly, within SSc and vasculitis, there is a lack of biomarkers that predict response or disease progression, and that allow patients to be stratified for therapies. There remains a strong need to innovate clinical trial design, to identify systemic and tissue-level biomarkers that predict progression or response to therapy, endotype disease, and to continue developing therapies and therapeutic strategies for those with treatment-refractory disease. This document, based on expert consensus, should provide a roadmap for prioritising scientific endeavour in the field of rheumatology.

Osteoarthritis ( OA ) and rheumatoid arthritis ( RA ) are joint diseases that are associated with pain and lost quality of life. No disease modifying OA drugs are currently available. RA treatments are better established but are not always effective and can cause immune suppression. Here, an MMP13-selective siRNA conjugate was developed that, when delivered intravenously, docks onto endogenous albumin and promotes preferential accumulation in articular cartilage and synovia of OA and RA joints. MMP13 expression was diminished upon intravenous delivery of MMP13 siRNA conjugates, consequently decreasing multiple histological and molecular markers of disease severity, while also reducing clinical manifestations such as swelling (RA) and joint pressure sensitivity (RA and OA). Importantly, MMP13 silencing provided more comprehensive OA treatment efficacy than standard of care (steroids) or experimental MMP inhibitors. These data demonstrate the utility of albumin ‘hitchhiking’ for drug delivery to arthritic joints, and establish the therapeutic utility of systemically delivered anti-MMP13 siRNA conjugates in OA and RA. Editorial Summary Lipophilic siRNA conjugates optimized for albumin binding and “hitchhiking” can be leveraged to achieve preferential delivery to and gene silencing activity within arthritic joints. Chemical stabilization of the lipophilic siRNA enables intravenous siRNA delivery without lipid or polymer encapsulation. Using siRNA sequences targeting MMP13, a key driver of arthritis-related inflammation, albumin hitchhiking siRNA diminished MMP13, inflammation, and manifestations of osteoarthritis and rheumatoid arthritis at molecular, histological, and clinical levels, consistently outperforming clinical standards of care and small molecule MMP antagonists.