PURPOSE:We used prospective data from a well-characterized urologic chronic pelvic pain syndrome (UCPPS) cohort (including interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome) to identify transitions between localized pelvic pain (LP) and widespread pain (WP) and characteristics associated with these transitions. MATERIAL AND METHODS:A total of 311 individuals (195 women; 116 men) with UCPPS were recruited from 6 sites and followed for 3 years. Participants completed 5 weekly "run-in" assessments at baseline, followed by quarterly symptom assessments. Responses on a self-reported body pain map were used to define LP vs WP (≥2 nonpelvic body map regions with pain). Multivariable modeling was used to evaluate 74 baseline characteristics related to transitions between LP and WP. RESULTS:At baseline, 126 participants (41%) reported LP, 13 (10.3%) of whom transitioned to WP. Conversely, 17 of the 66 participants (26%) with WP transitioned to LP at follow-up. Progression from LP to WP was associated with: (1) not living with a partner/spouse and (2) a higher Somatic Awareness Score on the complex multisymptom inventory. Conversely, transition from WP to LP was associated with: (3) lower urinary urgency symptoms on the complex multisymptom inventory and (4) higher frequency of sensation of not emptying bladder completely. CONCLUSIONS:Greater levels of baseline nonpainful somatic symptoms were associated with progression to WP, suggesting that high baseline somatic symptoms may predict the development of future pain. Not living with a spouse/partner was also associated with progression to WP, highlighting the importance of social support in UCPPS. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT02514265-MAPP Research Network: Trans-MAPP Study of UCPPS: Symptom Patterns Study.

PURPOSE:Urologic Chronic Pelvic Pain Syndrome (UCPPS) impacts millions of people in the United States but treatment options remain largely unsatisfying. A large number of neurobiological studies from the Multidisciplinary Approach to the study of chronic Pelvic Pain (MAPP) research network and others point to aberrant pain mechanisms in patients with UCPPS and widespread pain, but the clinical significance of widespread pain has been speculative. MATERIALS AND METHODS:In the current exploratory study we investigated whether pain and urologic symptoms responded to centrally-directed therapies (tricyclic antidepressants/gabapentinoids) versus peripherally-directed (pelvic floor physical therapy/hydrodistension) therapies depending on the presence or absence of widespread pain when the new treatment was initiated. RESULTS AND CONCLUSIONS:Forty UCPPS patients (n = 19 widespread) underwent an evaluation of UCPPS symptoms before and after twelve weeks of either centrally-directed (n = 16) or peripherally-directed therapy. Participants were stratified post hoc into widespread (two or more non-pelvic pain sites + pelvic pain) and localized pain categories. General linear models were used to test the group X treatment interaction effect, adjusting for age, sex, and baseline outcome levels. On average, patients with widespread pain receiving centrally-directed therapies improved more than six points on the 0-28 Pelvic Pain Severity scale, while those with localized pain showed no average improvement (interaction p = 0.005). Similar effects were observed for the bladder symptom impact score (interaction p = 0.011) but not urologic symptom severity (interaction p = 0.72). While these findings are exploratory, they provide preliminary evidence for phenotype X treatment interactions in UCPPS and should be followed by confirmatory studies. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT02514265-MAPP Research Network: Trans-MAPP Study of Urologic Chronic Pelvic Pain: Symptom Patterns Study (SPS). CLINICALTRIALS:gov Identifier: NCT02898220-Trans-MAPP Study of Urologic Chronic Pelvic Pain: Control Study Protocol.xs.

OBJECTIVES:To characterise 3-year pelvic pain and urinary symptom trajectories and to identify baseline factors associated with urologic chronic pelvic pain syndrome (UCPPS) improvement. PATIENTS AND METHODS:The Trans-Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Symptom Patterns Study was a multicentre, prospective cohort study of UCPPS, including interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome. Patients completed four weekly run-in assessments, baseline visit, and quarterly visits up to 3 years, providing clinical and patient-reported data. A functional clustering approach, applied separately to Pelvic Pain Severity (PPS) and Urinary Symptom Severity (USS) longitudinal change scores, was used to generate symptom trajectory clusters dichotomised as Group 0 'improvers' vs Groups 1-3 'non-improvers'. Logistic regression models explored baseline factors associated with improvement and included run-in period average and baseline scores to adjust for regression to the mean effects. RESULTS:A total of 545 patients (66% female) were followed for a median (interquartile range) of 34 (23-35) months. Four trajectory clusters were identified for each of PPS and USS, consistent with moderate improvement (Group 0), slight improvement (Group 1), no change (Group 2), and slight worsening (Group 3). In all, 18% and 19% of patients were in the moderately improved PPS and USS groups, respectively, representing 30% of patients overall. Female sex, better sleep, and less opioid use were associated with PPS improvement (Group 0); younger age and baseline cystoscopic treatment were associated with USS improvement (Group 0). CONCLUSION:In all, 30% of patients with UCPPS demonstrated improvement in pain and/or urinary symptoms over 3 years. Baseline factors associated with improvement may represent markers of a milder or localised phenotype and/or treatment effects.

Abstract Pain clinical trials are notoriously complex and often inefficient in demonstrating efficacy, even for known efficacious treatments. A major issue is the difficulty in the a priori identification of specific phenotypes to include in the study population. Recent work has identified the extent of widespread pain as an important determinant of the likelihood of response to therapy, but it has not been tested in clinical trials for the treatment of interstitial cystitis/bladder pain syndrome (IC/BPS). We explored this hypothesis using data from 3 previously published trials testing treatments for IC/BPS, which suggested modest benefits but did not meet a priori primary outcome statistical significance criteria. Importantly, these studies also collected symptom questionnaire data that allowed us to retrospectively identify participants with and without widespread pain. Analyzing the treatment by the degree of widespread pain revealed a difference in outcome and statistical significance level for each trial. Participants with predominately local pain (ie, limited widespread pain symptoms) responded to therapy targeting local symptoms, whereas those with widespread pain did not. Alternatively, participants with widespread pain beyond their local pelvic pain responded to more centrally acting treatments. Our results suggest that differentiating patients based on widespread vs more localized pain is a key consideration for designing future clinical trials for conditions with variable pain profiles, such as IC/BPS and potentially other pain-based syndromic disorders.

Randomized clinical trials have resulted in few approved therapies for the treatment of interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome, collectively referred to as urologic chronic pelvic pain syndrome. Heterogenous patient populations, mismatches of treatments to patient phenotypes, non-specific outcomes and use of standard study designs not leveraging phenotypic heterogeneity might have contributed to the inability of previous trials to demonstrate existing efficacy. The Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network has identified important phenotypic characteristics associated with differential symptom severity and treatment responsiveness. Based on Multidisciplinary Approach to the Study of Chronic Pelvic Pain findings and external research, empirically informed strategies were generated for defining patient populations, specifying treatments and selecting primary outcomes for future randomized clinical trials in urologic chronic pelvic pain syndrome. Explicitly specifying the scope of eligibility criteria across heterogeneous patient subgroups defined by pain widespreadness, the presence of Hunner lesions, the presence of pain with bladder filling or relieved by voiding, the extent of chronic overlapping pain conditions, and pelvic floor tenderness is needed. Therapies should be selected based on the mechanism of action and relevance to the mechanism of pain and dominant symptomology that the patient experiences. Evidence suggests that pain and urinary symptoms should be evaluated separately. Promising trial designs for identifying effective therapies in this heterogeneous patient population include sequential multiple assignment randomized trials and adaptive designs. This Expert Recommendation from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network provides informed considerations and a greatly expanded foundation that can be used to refine the design of future therapeutic clinical trials in urologic chronic pelvic pain syndrome.

PURPOSE:This study tested the hypothesis that ecological momentary assessment (EMA) of pelvic pain (PP) and urinary urgency (UU) would reveal unique Urologic Chronic Pelvic Pain Syndrome (UCPPS) phenotypes that would be associated with disease specific quality of life (QOL) and illness impact metrics (IIM).MATERIALS AND METHODS:A previously validated smart phone app (M-app) was provided to willing Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) participants. M-app notifications were sent 4-times daily for 14 days inquiring about PP and UU severity. A clustering algorithm that accounted for variance placed participants into PP and UU variability? clusters. Associations between clusters and QOL and IIM were then determined.RESULTS:A total of 204 participants enrolled in the M-app study (64% female). M-app compliance was high (median 63% of surveys). Cluster analysis revealed k = 3 (high, low, none) PP clusters and k = 2 (high, low) UU clusters. When adjusting for baseline pain severity, high PP variability, but not UU variability, was strongly associated with QOL and IIM; specifically worse mood, worse sleep and higher anxiety. UU and PP clusters were associated with each other (p < 0.0001), but a large percentage (33%) of patients with high PP variability had low UU variability.CONCLUSIONS:PP variability is an independent predictor of worse QOL and more severe IIM in UCPPS participants after controlling for baseline pain severity and UU. These findings suggest alternative pain indices, such as pain variability and unpredictability, may be useful adjuncts to traditional measures of worst and average pain when assessing UCPPS treatment responses.

PURPOSE:In patients with urologic chronic pelvic pain syndrome (UCPPS), the presence of widespread pain appears to identify a distinct phenotype, with a different symptom trajectory and potentially different response to treatment than patients with pelvic pain only.MATERIALS AND METHODS:A 76-site body map was administered four times, at weekly intervals, to 568 male and female UCPPS participants in the MAPP Network protocol. The 76 sites were classified into 13 regions (1 pelvic region and 12 nonpelvic regions). The degree of widespread pain was scored from 0 to 12 based on the number of reported nonpelvic pain regions. This continuous body map score was regressed over other measures of widespread pain, with UCPPS symptom severity, and with psychosocial variables to measure level of association. These models were repeated using an updated body map score (0-12) that incorporated a threshold of pain ≥ 4 at each site.RESULTS:Body map scores showed limited variability over the 4 weekly assessments, indicating that a single baseline assessment was sufficient. The widespread pain score correlated highly with other measures of widespread pain and correlated with worsened UCPPS symptom severity and psychosocial functioning. Incorporating a pain severity threshold ≥4 resulted in only marginal increases in these correlations.CONCLUSIONS:These results support the use of this 13-region body map in the baseline clinical assessment of UCPPS patients. It provides reliable data about the presence of widespread pain and does not require measurement of pain severity, making it relatively simple to use for clinical purposes.

We pay tribute to Marshall Joffe, PhD, and his substantial contributions to the field of causal inference with focus in biostatistics and epidemiology. By compiling narratives written by us, his colleagues, we not only present highlights of Marshall's research and their significance for causal inference but also offer a portrayal of Marshall's personal accomplishments and character. Our discussion of Marshall's research notably includes (but is not limited to) handling of posttreatment variables such as noncompliance, employing G-estimation for treatment effects on failure-time outcomes, estimating effects of time-varying exposures subject to time-dependent confounding, and developing a causal framework for case-control studies. We also provide a description of some of Marshall's unpublished work, which is accompanied by a bonus anecdote. We discuss future research directions related to Marshall's research. While Marshall's impact in causal inference and the world outside of it cannot be wholly captured by our words, we hope nonetheless to present some of what he has done for our field and what he has meant to us and to his loved ones.

Cover: The cover image is from the Clinical Article Validation of a simple body map to measure widespread pain in urologic chronic pelvic pain syndrome: A MAPP Research Network study by Clemens JQ, Locke K, Landis JR, et al. Neurourol Urodyn. 2024;43(3):727-737. https://doi.org/10.1002/nau.25400. MAPP II body map: 76 sites (numbers), 13 regions (colors). Pelvic region = sites 23, 24, 26, and 27.

OBJECTIVE:To assess differences in clinical presentation and illness impact in men and women presenting with urologic chronic pelvic pain syndrome (UCPPS) and between men diagnosed with interstitial cystitis/bladder pain syndrome (IC/BPS) or chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). METHODS:356 men and 605 women from six sites across the United States were assessed using a comprehensive set of demographic, symptom, and illness impact measures. Multivariable regression analyses examined differences between men and women and between men previously diagnosed with CP/CPPS or IC/BPS. In a stepwise manner, analyses tested group differences, controlling for demographic variables including symptom duration and presence of bladder pain that varied with filling and voiding. RESULTS:Men diagnosed with IC/BPS had the most severe UCPPS symptoms, followed by women with IC/BPS, and then men with CP/CPPS only. While men and women showed similar patterns of symptoms across most of the variables, women had increased widespread non-pelvic pain, greater pelvic floor tenderness on exam, and higher self-reported sensory sensitivity compared to men. About 60% of men diagnosed with CP/CPPS only reported bladder symptoms of painful filling or relief with voiding. CONCLUSIONS:A generally shared symptom pattern was found across men and women irrespective of diagnostic labels suggesting the use of key marker symptoms, such as severity of bladder symptoms and widespread pain, to better identify subgroups of UCPPS rather than diagnostic category. Women may have an increased likelihood of increased sensitivity and central sensitization than men, including those men with IC/BPS. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT02514265 - MAPP Research Network: Trans-MAPP Study of Urologic Chronic Pelvic Pain: Symptom Patterns Study (SPS).

ABSTRACT:Interstitial cystitis/bladder pain syndrome (IC/BPS) is a common and debilitating disease with poor treatment outcomes. Studies from the multidisciplinary approach to the study of chronic pelvic pain research network established that IC/BPS patients with chronic overlapping pain conditions (COPCs) experience poorer quality of life and more severe symptoms, yet the neurobiological correlates of this subtype are largely unknown. We previously showed that ex vivo toll-like receptor 4 (TLR4) cytokine/chemokine release is associated with the presence of COPCs, as well as widespread pain and experimental pain sensitivity women with IC/BPS. Here, we attempt to confirm these findings in the multisite multidisciplinary approach to the study of chronic pelvic pain Symptom Patterns Study using TLR4-stimulated whole blood (female IC/BPS patients with COPC n = 99; without n = 36). Samples were collected in tubes preloaded with TLR4 agonist, incubated for 24 hours, and resulting supernatant assayed for 7 cytokines/chemokines. These were subject to a principal components analysis and the resulting components used as dependent variables in general linear models. Controlling for patient age, body mass index, and site of collection, we found that greater ex vivo TLR4-stimulated cytokine/chemokine release was associated with the presence of COPCs ( P < 0.01), extent of widespread pain ( P < 0.05), but not experimental pain sensitivity ( P > 0.05). However, a second component of anti-inflammatory, regulatory, and chemotactic activity was associated with reduced pain sensitivity ( P < 0.01). These results confirm that the IC/BPS + COPCs subtype show higher levels of ex vivo TLR4 cytokine/chemokine release and support a link between immune priming and nociplastic pain in IC/BPS.

PURPOSE:Symptom heterogeneity in interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome, collectively termed urological chronic pelvic pain syndrome, has resulted in difficulty in defining appropriate clinical trial endpoints. We determine clinically important differences for 2 primary symptom measures, pelvic pain severity and urinary symptom severity, and evaluate subgroup differences.MATERIALS AND METHODS:The Multidisciplinary Approach to the Study of Chronic Pelvic Pain Symptom Patterns Study enrolled individuals with urological chronic pelvic pain syndrome. We defined clinically important differences by associating changes in pelvic pain severity and urinary symptom severity over 3 to 6 months with marked improvement on a global response assessment using regression and receiver operating characteristic curves. We evaluated clinically important differences for absolute and percent change and examined differences in clinically important differences by sex-diagnosis, presence of Hunner lesions, pain type, pain widespreadness, and baseline symptom severity.RESULTS:An absolute change of -4 was clinically important in pelvic pain severity among all patients, but clinically important difference estimates differed by pain type, presence of Hunner lesions, and baseline severity. Pelvic pain severity clinically important difference estimates for percent change were more consistent across subgroups and ranged from 30% to 57%. The absolute change urinary symptom severity clinically important difference was -3 for female participants and -2 for male participants with chronic prostatitis/chronic pelvic pain syndrome only. Patients with greater baseline severity required larger decreases in symptoms to feel improved. Estimated clinically important differences had lower accuracy among participants with low baseline symptoms.CONCLUSIONS:A reduction of 30%-50% in pelvic pain severity is a clinically meaningful endpoint for future therapeutic trials in urological chronic pelvic pain syndrome. Urinary symptom severity clinically important differences are more appropriately defined separately for male and female participants.

You have accessJournal of UrologyCME1 May 2022PD08-11 USING A MOBILE PHONE APPLICATION TO DISCOVER PELVIC PAIN PROFILE CLUSTERS IN UROLOGIC CHRONIC PELVIC PAIN SYNDROME (UCPPS) Bradley Erickson, Bayley Taple, James Griffith, Mengying You, Wenghseng Guo, Catherine Bradley, John Farrar, Priyanka Gupta, Karl Kreder, Henry Lai, Bruce Naliboff, Diane Newman, Larissa Rodriguez, Theresa Spitznagle, Siobhan Sutcliffe, Suzette Sutherland, and Richard Landis Bradley EricksonBradley Erickson More articles by this author , Bayley TapleBayley Taple More articles by this author , James GriffithJames Griffith More articles by this author , Mengying YouMengying You More articles by this author , Wenghseng GuoWenghseng Guo More articles by this author , Catherine BradleyCatherine Bradley More articles by this author , John FarrarJohn Farrar More articles by this author , Priyanka GuptaPriyanka Gupta More articles by this author , Karl KrederKarl Kreder More articles by this author , Henry LaiHenry Lai More articles by this author , Bruce NaliboffBruce Naliboff More articles by this author , Diane NewmanDiane Newman More articles by this author , Larissa RodriguezLarissa Rodriguez More articles by this author , Theresa SpitznagleTheresa Spitznagle More articles by this author , Siobhan SutcliffeSiobhan Sutcliffe More articles by this author , Suzette SutherlandSuzette Sutherland More articles by this author , and Richard LandisRichard Landis More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002527.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Inter- and intra-day fluctuation in pelvic pain in patients with UCPPS is poorly understood. This study deployed a mobile phone application (mAPP) to assess ecological momentary assessments of pelvic pain. We hypothesized that 1) variations in pain severity, trajectory and stability would cluster into distinct phenotypes and 2) these clusters would be associated with quality of life (QOL) and illness impact (II) metrics. METHODS: A previously validated mAPP was provided to UCPPS patients enrolled in the Multidisciplinary Approach to Chronic Pelvic Pain Symptoms Pattern Study (MAPP II SPS) following a 6-month in-clinic visit. Notifications were sent to each mAPP participant 4-times daily for 14 consecutive days (t=56 sampling points) asking about the presence/severity of pelvic pain (PP). A functional mixed effects clustering algorithm in which subgroups are clustered both in terms of group-average trajectories and within-group variabilities, was applied to patient PP trajectories. Associations between demographic, urinary urgency, pain severity, QOL and II measures obtained at 6 months and functional cluster membership were estimated, adjusting for baseline PP severity. RESULTS: Longitudinal PP severity data from n=204 patients were utilized to generate K=3 PP clusters (Figure 1), that can be characterized as 1) no variability (NV, n=20); 2) low variability (LV, n=74); and 3) high variability (HV, n=110). Significant differences in clusters were noted (Table 1), with patients in the HV cluster being younger, more likely to be female, have higher baseline pain and urgency scores, report worse QOL and higher II versus NV and LV clusters. CONCLUSIONS: A 14-day study that assessed inter- and intra-day pain variability identified three distinct UCPPS PP clusters that differ significantly by demographics, baseline pain/urgency, QOL and II. Subjects with the highest variability had worse sleep, decreased mood and more anxiety relative to those with more stable pain scores. Source of Funding: NIH/NIDDK © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e109 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Bradley Erickson More articles by this author Bayley Taple More articles by this author James Griffith More articles by this author Mengying You More articles by this author Wenghseng Guo More articles by this author Catherine Bradley More articles by this author John Farrar More articles by this author Priyanka Gupta More articles by this author Karl Kreder More articles by this author Henry Lai More articles by this author Bruce Naliboff More articles by this author Diane Newman More articles by this author Larissa Rodriguez More articles by this author Theresa Spitznagle More articles by this author Siobhan Sutcliffe More articles by this author Suzette Sutherland More articles by this author Richard Landis More articles by this author Expand All Advertisement PDF downloadLoading ...

PURPOSE:We assessed the reliability and validity of an efficient severity assessment for pelvic pain and urinary symptoms in urological chronic pelvic pain syndrome, which consists of interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome.MATERIALS AND METHODS:A total of 578 patients were assessed using brief, empirically derived self-report scales for pelvic pain severity (PPS) and urinary symptom severity (USS) 4 times during a 1-month period and baseline clinic visit that included urological, pain and illness-impact measures. Mild, moderate and severe categories on each dimension were examined for measurement stability and construct validity.RESULTS:PPS and USS severity categories had adequate reliability and both discriminant validity (differential relationships with specific clinical and self-report measures) and convergent validity (common association with nonurological somatic symptoms). For example, increasing PPS was associated with pelvic tenderness and widespread pelvic pain, whereas USS was associated with urgency during a bladder filling test and increased sensory sensitivity. PPS and USS categories were independently associated with nonurological pain and emotional distress. A descriptive analysis identified higher likelihood characteristics associated with having moderate to severe PPS or USS or both. Lack of sex interactions indicated that the measures are comparable in interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome.CONCLUSIONS:Women and men with urological chronic pelvic pain syndrome can be reliably subgrouped using brief self-report measures of mild, moderate or severe pelvic pain and urinary symptoms. Comparisons with a broad range of clinical variables demonstrate the validity and potential clinical utility of these classifications, including use in clinical trials, health services and biological research.

By clustering patients with the urologic chronic pelvic pain syndromes (UCPPS) into homogeneous subgroups and associating these subgroups with baseline covariates and other clinical outcomes, we provide opportunities to investigate different potential elements of pathogenesis, which may also guide us in selection of appropriate therapeutic targets. Motivated by the longitudinal urologic symptom data with extensive subject heterogeneity and differential variability of trajectories, we propose a functional clustering procedure where each subgroup is modeled by a functional mixed effects model, and the posterior probability is used to iteratively classify each subject into different subgroups. The classification takes into account both group-average trajectories and between-subject variabilities. We develop an equivalent state-space model for efficient computation. We also propose a cross-validation based Kullback-Leibler information criterion to choose the optimal number of subgroups. The performance of the proposed method is assessed through a simulation study. We apply our methods to longitudinal bi-weekly measures of a primary urological urinary symptoms score from a UCPPS longitudinal cohort study, and identify four subgroups ranging from moderate decline, mild decline, stable and mild increasing. The resulting clusters are also associated with the one-year changes in several clinically important outcomes, and are also related to several clinically relevant baseline predictors, such as sleep disturbance score, physical quality of life and painful urgency.

Chronic inflammation is highly prevalent among patients receiving maintenance hemodialysis and is associated with morbidity and mortality. Inhibiting inflammation with anti-cytokine therapy has been proposed but not well studied in this population. Therefore, we conducted the ACTION trial, a pilot, multicenter, randomized, placebo-controlled trial of an IL-1 receptor antagonist, anakinra, to evaluate safety, tolerability, and feasibility, and explore efficacy. Eighty hemodialysis patients with plasma concentrations of high sensitivity C-reactive protein (hsCRP) 2 mg/L and above were randomized 1:1 to placebo or anakinra 100 mg, three times per week via the hemodialysis circuit for 24 weeks, with an additional 24 weeks of post-treatment safety monitoring. Efficacy outcomes included changes in hsCRP (primary), cytokines, and patient-reported outcomes. Rates of serious adverse events and deaths were similar with anakinra and placebo (serious adverse events: 2.71 vs 2.74 events/patient-year; deaths: 0.12 vs 0.22 events/patient-year). The rate of adverse events of interest (including infections and cytopenias) was significantly lower with anakinra than placebo (0.48 vs 1.40 events/patient-year). Feasibility was demonstrated by attaining the enrollment target, a retention rate of 80%, and administration of 72% of doses. The median decrease in hsCRP from baseline to Week 24 was 41% in the anakinra group and 6% in the placebo group, a between-group difference that was not statistically significant. For IL-6, the median decreases were significant: 25% and 0% in the anakinra and placebo groups, respectively. An effect of anakinra on patient-reported outcomes was not evident. Thus, anakinra was well tolerated and did not increase infections or cytopenias. The promising safety data and potential efficacy on CRP and IL-6 provide support for conducting definitive trials of IL-1 inhibition to improve outcomes in hemodialysis patients.

Background The intestinal microbiome is an appealing target for interventions in ESKD because of its likely contribution to uremic toxicity. Before conducting clinical trials of microbiome-altering treatments, it is necessary to understand the within-person and between-person variability in the composition and function of the gut microbiome in patients with ESKD. Methods We conducted a multicenter, nonrandomized, crossover feasibility study of patients on maintenance hemodialysis consisting of three phases: pretreatment (8 weeks); treatment, during which the prebiotic, p-inulin, was administered at a dosage of 8 g twice daily (12 weeks); and post-treatment (8 weeks). Stool samples were collected 1-2 times per week and blood was collected weekly for 28 weeks. The gut microbiome was characterized using 16S ribosomal-RNA sequencing and metabolomic profiling. Results A total of 11 of the 13 participants completed the 28-week study. Interparticipant variability was greater than intraparticipant variability for microbiome composition (P<0.001 by UniFrac distances) and metabolomic composition (P<0.001 by Euclidean distances). p-Inulin was well tolerated by 12 of 13 participants. Adherence to the frequent sample collection and self-aliquoting of stool samples were both 96%. A change in the microbiome composition from pretreatment to post-treatment was evident by the overall shifts in weighted UniFrac distances (P=0.004) and a progressive decrease in prevalence of high intraclass correlations, indicating an increase in intraparticipant microbiome diversity during and after p-inulin treatment. An effect of p-inulin on the metabolomic profile was not evident. Conclusions The intraparticipant stability of the gut microbiome under no-treatment conditions, the tolerability of p-inulin, the signals of increased diversity of the microbiome with p-inulin treatment, and the willingness of participants to provide stool samples all support the feasibility of a larger trial to investigate interventions targeting the gut microbiome in patients with ESKD. Whether or not p-inulin has sufficient efficacy as an intervention requires evaluation in larger studies. Clinical Trial registry name and registration number Gut Microbiome and p-Inulin in Hemodialysis, NCT02572882.

Background:The semi-quantitative Outcome Measures in Rheumatology (OMERACT) Psoriatic Arthritis Magnetic Resonance Imaging Score (PsAMRIS) was developed for the evaluation of inflammatory and destructive changes in PsA,1 but has limited trial usage.Objectives:To retrospectively utilise the PsAMRIS in a multi-dose, randomised Phase IIb study of abatacept in patients with PsA who have inadequate response to DMARDs (NCT00534313).2Methods:Patients were randomised to abatacept (3, 10 or 30/10 mg/kg [the 30-mg/kg group switched to 10 mg/kg after the first two doses]) or placebo and treated for 169 days, after which all patients received abatacept 10 mg/kg through to Day 365. MRI scans of one hand or foot from 123 patients with PsA collected at baseline and on Days 85, 169 and 365 were centrally evaluated by two readers blinded to chronological order and treatment arm. Synovitis, bone oedema, tenosynovitis, periarticular inflammation, bone erosion, bone proliferation and joint space narrowing were assessed as per OMERACT PsAMRIS; a novel total inflammation score was calculated from the sum of synovitis, bone oedema, tenosynovitis and periarticular inflammation. Variables were analysed using all cases (hand or foot) and by hand and foot cases separately.Results:At Day 169, the abatacept 30/10 mg/kg or 10 mg/kg group showed the most decrease (improvement) in each inflammatory assessment (Figure 1). The Day 169 change from baseline severity in synovitis and tenosynovitis in the abatacept 30/10 mg/kg and 10 mg/kg groups, respectively, were significantly reduced (improved) compared with placebo (estimated differences of –0.966 [p=0.039] and –1.652 [p=0.014], respectively) (Table 1). Patients originally randomised to placebo and then switched to abatacept 10 mg/kg at Day 169 showed significant improvements in synovitis, tenosynovitis and total inflammation from Day 169 to Day 365 (Table 1, Figure 1). The structural outcomes joint space narrowing and bone erosion remained stable within each treatment group, showing little change from baseline to Days 85, 169 and 365. After separating hand and foot analyses (72 hand and 51 foot cases), only hand tenosynovitis in the 10-mg/kg group and foot synovitis in the 3-mg/kg group were significantly reduced (improved) at Day 169 compared with placebo (differences of –2.331 [p=0.017] and –1.689 [p=0.010], respectively). In general, more comparisons in the hand analysis were statistically significant versus in the foot analysis.Conclusion:This analysis confirmed the efficacy of abatacept 10 and 30/10 mg/kg when assessed with the OMERACT PsAMRIS. The inflammatory pathologies, synovitis and tenosynovitis, appeared to be the most responsive MRI outcomes. Analysing hand and foot cases together yielded results consistent with the primary clinical efficacy endpoint (ACR20 response rate), as the abatacept 10- and 30/10-mg/kg groups showed significant differences versus placebo at Day 169;2 reduced sample size in separate hand and foot assessments may have prevented finding significant results corresponding to the combined analysis. These results also demonstrate the responsiveness of the PsAMRIS in PsA randomised clinical trials.References:[1]Glinatsi D, et al. J Rheumatol 2015;42:2473–2479.[2]Mease P, et al. Arthritis Rheum 2011;63:939–948.Table 1.MRI variables showing significant treatment effectsaBetween groups at Day 169MRI scoreComparatorComparatorDifferenceSEp valueSynovitisPlaceboAbatacept 30/10 mg/kg–0.9660.4610.039TenosynovitisPlaceboAbatacept 10 mg/kg–1.6520.6620.014Placebo group before/after switchbMRI scoreTreatment, Day 169Treatment, Day 365DifferenceSEp valueSynovitisPlaceboAbatacept 10 mg/kg–1.0180.4580.029TenosynovitisPlaceboAbatacept 10 mg/kg–0.9400.3900.018Total inflammationPlaceboAbatacept 10 mg/kg–2.2751.0670.036aBased on change from baseline at the stated time points (unadjusted p values).bPatients were switched to abatacept 10 mg/kg after Day 169.Acknowledgements:Professional medical writing and editorial assistance was provided by Rob Coover, MPH, at Caudex and was funded by Bristol Myers Squibb.Disclosure of Interests:Mikkel Østergaard Speakers bureau: AbbVie, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, Roche, Sanofi, UCB, Consultant of: AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, UCB, Grant/research support from: AbbVie, Bristol Myers Squibb, Celgene, Merck, Novartis, Paul Bird Speakers bureau: AbbVie, Bristol Myers Squibb, Eli Lilly, Novartis, Pfizer, UCB, Grant/research support from: Gilead, Chahin Pachai Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Shuyan Du Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Chun Wu Employee of: Bristol Myers Squibb, Jessica Landis Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Thomas Fuerst Employee of: Bioclinica, Inc., a contract research service providing radiology central reading services to pharmaceutical, biotech and medical device companies, Harris A Ahmad Employee of: Bristol Myers Squibb, Sean Connolly Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Philip G Conaghan Speakers bureau: AbbVie, Novartis, Consultant of: AstraZeneca, Bristol Myers Squibb, Eli Lilly, EMD Serono, Flexion Therapeutics, Galapagos, Gilead, Novartis, Pfizer.

BACKGROUND:CKD is a heterogeneous condition with multiple underlying causes, risk factors, and outcomes. Subtyping CKD with multidimensional patient data holds the key to precision medicine. Consensus clustering may reveal CKD subgroups with different risk profiles of adverse outcomes. METHODS:We used unsupervised consensus clustering on 72 baseline characteristics among 2696 participants in the prospective Chronic Renal Insufficiency Cohort (CRIC) study to identify novel CKD subgroups that best represent the data pattern. Calculation of the standardized difference of each parameter used the cutoff of ±0.3 to show subgroup features. CKD subgroup associations were examined with the clinical end points of kidney failure, the composite outcome of cardiovascular diseases, and death. RESULTS:The algorithm revealed three unique CKD subgroups that best represented patients' baseline characteristics. Patients with relatively favorable levels of bone density and cardiac and kidney function markers, with lower prevalence of diabetes and obesity, and who used fewer medications formed cluster 1 (n=1203). Patients with higher prevalence of diabetes and obesity and who used more medications formed cluster 2 (n=1098). Patients with less favorable levels of bone mineral density, poor cardiac and kidney function markers, and inflammation delineated cluster 3 (n=395). These three subgroups, when linked with future clinical end points, were associated with different risks of CKD progression, cardiovascular disease, and death. Furthermore, patient heterogeneity among predefined subgroups with similar baseline kidney function emerged. CONCLUSIONS:Consensus clustering synthesized the patterns of baseline clinical and laboratory measures and revealed distinct CKD subgroups, which were associated with markedly different risks of important clinical outcomes. Further examination of patient subgroups and associated biomarkers may provide next steps toward precision medicine.