Probability of Response in the First Sixteen Weeks After Starting Biologics: An Analysis of Juvenile Idiopathic Arthritis Biologics Trials.

OBJECTIVES: Most juvenile idiopathic arthritis (JIA) biologic disease-modifying antirheumatic drugs (bDMARDs) trials used an open-label run-in period followed by randomized medication withdrawal. We used data from the run-in period of 4 bDMARD trials to 1) delineate early response trajectory to bDMARDs and 2) identify predictors of early response. METHODS: Data from the first 16 weeks of 4 bDMARD trials were used. The primary outcome was the American College of Rheumatology (ACR) Pediatric 50 (Pedi 50) response criteria: clinically significant response defined as ACR Pedi 50 or greater. The secondary outcome was the clinical Juvenile Arthritis Disease Activity Score in 10 joints (cJADAS10) minimal disease activity state. Response transition rates and predictors were modeled using an inhomogeneous Markov multistate model. RESULTS: Five hundred thirty-two participants (70% receiving methotrexate, 41% prednisone) were included. By month 4, the probability of attaining ACR Pedi 50 or greater was 0.698. If ACR Pedi 50 or more was not achieved by month 1, the probability of achieving it by month 4 was 0.60. If ACR Pedi 50 or more was not achieved by month 3, the probability of achieving this by month 4 was 0.31. Age at diagnosis, disease duration, baseline rheumatoid factor, and active joint counts predicted ACR and cJADAS state transitions, adjusted for concomitant treatment. CONCLUSIONS: No response ACR Pedi 50 or more by month 1 after treatment was associated with a 0.60 probability of responding by month 4, but not responding by month 3 was associated with a 0.31 probability of response by month 4. Baseline disease duration, rheumatoid factor, and active joint counts predicted early treatment response (ACR and cJADAS10 states).

Latent classes of early response trajectories to biologics initiation in juvenile idiopathic arthritis: an analysis of four trials.

AIMS: 1) To delineate latent classes of treatment response to biologics in juvenile idiopathic arthritis (JIA) patients in the first 16 weeks after initiation. 2) To identify predictors of early disease response. METHODS: The study population was drawn from four biologics trials in polyarticular course JIA: Etanercept 2000, Abatacept 2008, TRial of Early Aggressive Therapy (TREAT) 2012 and Tocilizumab 2014. The outcome was active joint counts (AJC). Semiparametric latent class trajectory analysis was applied to identify latent classes of response to treatment; AJC was transformed for this modelling. We tested baseline disease and treatment characteristics for their abilities to predict class membership of response. RESULTS: There were 480 participants, 74% females. At baseline, 26% were rheumatoid factor positive. 67% were on methotrexate at enrollment. Three latent class solution provided the best fit. Baseline AJC was the sole best predictor of class membership. Participants classified by their highest membership probabilities into high baseline AJC (> 30) and slow response (26.5%), low baseline AJC (< 10), early and sustained response (29.7%), and moderate baseline AJC progressive response (43.8%). Participants were classified into the latent classes with a mean class membership posterior probability of 0.97. Those on methotrexate at baseline were less likely to belong to high baseline AJC class. CONCLUSIONS: Three latent classes of responses were detectable in the first 16 weeks of biologics therapy. Those with the highest baseline AJC demonstrated very slow response in this window and were less likely to be on concomitant methotrexate. TRIALS REGISTRATION: TREAT 2012 (NCT NCT00443430 ) (Wallace et. al, Arthritis Rheum 64:2012-21, 2012), tocilizumab trial 2014 ( NCT00988221 ), abatacept trial 2008 ( NCT00095173 ). Etanercept 2000 from Amgen does not have a trial registration number.

Joint trajectories of disease activity, and physical and mental health-related quality of life in an inception lupus cohort.

OBJECTIVES: To examine for latent patterns of SLE disease activity trajectories that associate with specific latent patterns of health-related quality of life (HRQoL; Medical Outcomes Study Short Form-36), and to determine baseline predictors of class membership. METHODS: In this retrospective longitudinal inception cohort of 222 SLE adults over 10 years, trajectories of three outcomes were studied jointly: Short Form-36 physical (PCS) and mental (MCS) component summaries and adjusted mean SLEDAI-2000 (AMS). Group-based joint trajectory modelling was used to model latent classes; univariable and multivariable analyses were used to identify predictors of class membership. RESULTS: Four latent classes were identified: Class 1 (C1) (24%) had moderate AMS, and persistently low PCS and MCS; C2 (26%) had low AMS, moderate PCS and improved then worsened MCS; C3 (38%) had moderate AMS, and persistently high PCS and MCS; and C4 (11%) had high AMS, moderate-low PCS and improving MCS. Baseline older age was associated with lower HRQoL trajectories. Higher AMS trajectories did not associate with a particular pattern of HRQoL trajectory. A higher prevalence of fibromyalgia (44% in C1) was associated with worse HRQoL trajectories. Disease manifestations, organ damage and cumulative glucocorticoid were not differentially distributed across the latent classes. CONCLUSION: High disease activity did not necessarily associate with low HRQoL. More patients with worse HRQoL trajectories had fibromyalgia. Older age at diagnosis increased the probability of belonging to a class with low HRQoL trajectories. The care of SLE patients may be improved through addressing fibromyalgia in addition to disease activity.

Real-World Effectiveness of Common Treatment Strategies for Juvenile Idiopathic Arthritis: Results From a Canadian Cohort.

OBJECTIVE: Undervaluing the effectiveness of conventional treatments may lead to overtreatment with biologic medications in children with juvenile idiopathic arthritis (JIA). Using data from a nationwide inception cohort and strict methods to control bias, the aim of our study was to estimate the real-world effectiveness of simple JIA treatment strategies recommended in current guidelines. METHODS: Children with JIA who were recruited at 16 Canadian centers from 2005 to 2010 were followed for up to 5 years. For each child, all observed treatment changes over time were assessed by independent physicians using prospectively collected data and published response criteria. Success was defined as attainment of inactive disease or maintenance of this state when stepping down treatment; minimally active disease was deemed acceptable for children with polyarticular JIA. Success rates were calculated for treatments tried ≥25 times, and logistic regression analysis identified features associated with success. RESULTS: A total of 4,429 treatment episodes were observed in 1,352 children. Nonsteroidal antiinflammatory drug (NSAID) monotherapy was attempted 697 times, mostly as initial treatment when <5 joints were involved, with a 54.4% success rate (95% confidence interval [95% CI] 50.3-58.6). NSAIDs plus joint injections had a 64.7% success rate (95% CI 59.8-69.7). Adding methotrexate to NSAIDs and/or joint injections (attempted 566 times) had a 60.5% success rate (95% CI 55.7-65.3). In adjusted analyses, each additional active joint reduced chances of success for treatment with NSAIDs (odds ratio [OR] 0.90 [95% CI 0.85-0.94]) and for methotrexate combinations (OR 0.96 [95% CI 0.94-0.99]). Each additional year after disease onset reduced chances of success for treatment with methotrexate combinations (OR 0.83 [95% CI 0.72-0.95]). CONCLUSION: These real-world effectiveness estimates show that conventional nonbiologic treatment strategies that are recommended in current guidelines are effective in achieving treatment targets in many children with JIA.

Using Registry Data to Understand Disease Evolution in Inflammatory Myositis and Other Rheumatic Diseases.

PURPOSE OF REVIEW: While rheumatic disease registries collect longitudinal patient information, longitudinal analytic methods are usually not applied to these data. This review will showcase advances in longitudinal designs/analyses, and ways to leverage digital technologies to recruit and retain more registry participants. RECENT FINDINGS: We will show how the accelerated cohort and longitudinal multiform methods are more efficient than traditional longitudinal designs. We illustrate how a smartphone app is used to recruit participants for a new rheumatic disease registry in the USA. Examples of newer longitudinal techniques applied in myositis and childhood-onset lupus are also presented. Applying high-efficiency longitudinal design and analysis let investigators leverage the rich registry information collected over time. They allow more sophisticated and precise questions to be asked about the disease course of myositis and other rheumatic diseases, which in turn will inform the practice of clinicians and important decisions made by stakeholders.

Alternative Design and Analytical Techniques for Longitudinal Rheumatology Studies: Improved Understanding of Outcomes.

Longitudinal cohort designs (with three or more measurement occasions) are invaluable to investigate between- and within-individual variation in outcomes. However, traditional longitudinal designs require a lengthy implementation and data collection period and impose a substantial burden on participants and investigators. We discuss alternative longitudinal designs, including planned missing data designs and retrospective cohort studies with secondary data, which require a shorter period for data accrual and reduce participant burden while maintaining statistical power. We also discuss analysis strategies to maximize data use and produce unbiased estimates of treatment effectiveness, including models for recurrent or multistate events and time-varying covariates.

From Childhood to Adulthood: Disease Activity Trajectories in Childhood-Onset Systemic Lupus Erythematosus.

OBJECTIVE: No previous study has studied the longitudinal disease course of childhood-onset systemic lupus erythematosus (cSLE). Our objectives are to assess distinguishable differences in disease activity trajectories in cSLE patients, determine baseline factors predictive of disease trajectory membership, and assess if the different disease activity trajectories are associated with different damage trajectories. METHODS: This is a retrospective, longitudinal inception cohort of cSLE patients. Patients were followed from diagnosis as children, until they were adults. SLE disease activity was modeled as a latent characteristic, jointly using the Systemic Lupus Erythematosus Disease Activity Index 2000 and prednisone in a Bayesian growth mixture model. Baseline factors were tested for membership prediction of the latent classes of disease trajectories. Differences in damage trajectories by disease activity classes were tested using a mixed model. RESULTS: A total of 473 patients (82% females), with median age at diagnosis of 14.1 years, were studied. We studied 11,992 visits (2,666 patient-years). We identified 5 classes of disease activity trajectories. Baseline major organ involvement, number of American College of Rheumatology criteria, and age at diagnosis predicted memberships into different classes. A higher proportion of Asians was in class 2 compared to class 5. Class 1 was associated with the most accrual of damage, while class 5 was associated with no significant damage accrual, even after 10 years. CONCLUSION: There are 5 distinct latent classes of disease trajectory in patients with cSLE. Membership within disease trajectories is predicted by baseline clinical and demographic factors. Membership in different disease activity trajectory classes is associated with different damage trajectories.

Methods for analyzing observational longitudinal prognosis studies for rheumatic diseases: a review & worked example using a clinic-based cohort of juvenile dermatomyositis patients.

Most outcome studies of rheumatic diseases report outcomes ascertained on a single occasion. While single assessments are sufficient for terminal or irreversible outcomes, they may not be sufficiently informative if outcomes change or fluctuate over time. Consequently, longitudinal studies that measure non-terminal outcomes repeatedly afford a better understanding of disease evolution.Longitudinal studies require special analytic methods. Newer longitudinal analytic methods have evolved tremendously to deal with common challenges in longitudinal observational studies. In recent years, an increasing number of studies have used longitudinal design. This review aims to help readers understand and apply the findings from longitudinal studies. Using a cohort of children with juvenile dermatomyositis (JDM), we illustrate how to study evolution of disease activity in JDM using longitudinal methods.

Risk Factors for Symptomatic Avascular Necrosis in Childhood-onset Systemic Lupus Erythematosus.

OBJECTIVE: To examine the frequency and risk factors for symptomatic avascular necrosis (AVN) in childhood-onset systemic lupus erythematosus (cSLE). METHODS: A single-center, nested, matched, case-control design was used. There were 617 patients with cSLE followed at the Hospital for Sick Children (SickKids) Lupus Clinic between July 1982 and June 2013 included in the study. The AVN cohort consisted of 37 patients identified with clinical findings of symptomatic AVN and diagnosis was confirmed by 1 or more imaging modalities. Three controls were matched to each patient with AVN by date and age at diagnosis. Baseline clinical, laboratory, and treatment characteristics were compared between patients with AVN and controls by univariable analyses and if statistically significant, were included in a multivariable logistic regression model. RESULTS: A total of 37/617 patients (6%) developed symptomatic AVN in 91 joints during followup at SickKids. The mean duration to disease was 2.3 years. The hip was the most commonly involved joint (26/37, 70%). Compared with the matched non-AVN cohort, patients with AVN had a higher incidence of central nervous system (CNS) involvement and nephritis, required greater cumulative prednisone (PRED) from cSLE diagnosis to AVN, received a greater maximal daily PRED dose, and had more frequent use of pulse methylprednisolone therapy. Multivariable regression analysis confirmed major organ involvement (CNS disease and/or nephritis) and maximal daily PRED dose as significant predictors of symptomatic AVN development. CONCLUSION: Patients with cSLE with severe organ involvement including nephritis and CNS disease and higher maximal daily dose of PRED are more likely to develop symptomatic AVN.

Longterm outcomes and damage accrual in patients with childhood systemic lupus erythematosus with psychosis and severe cognitive dysfunction.

OBJECTIVE: (1) To describe the clinical course and response to treatment; and (2) to evaluate and compare damage accrual of distinct phenotypic subgroups of patients with clinically important psychiatric illness of pediatric systemic lupus erythematosus (pSLE). METHODS: A single-center cohort study of patients with pSLE followed at a pediatric lupus clinic from 1985 to July 2009. Clinical course and response to treatment were studied. Remission was defined by absence of psychiatric/cognitive symptoms while receiving minimal doses of prednisone. Disease activity and damage were measured using SLE Disease Activity Index and SLE Damage Index. RESULTS: Fifty-three children were included: 40 with psychosis and cognitive dysfunction (PSYC group) and 13 with isolated cognitive dysfunction (COG group). All received immunosuppressive treatment. Eighteen of 32 treated with azathioprine required a change to cyclophosphamide for poor response but none on cyclophosphamide required a change. The median times to remission were 72 weeks (PSYC) and 70 weeks (COG). Eight patients (7 PSYC, 1 COG) experienced flare following response/remission. New damage was noted in 50% of children at a median of 11 months: 57% of PSYC group, 31% of COG group. Persistent cognitive dysfunction was seen in 16% of PSYC patients and 15% of COG patients. CONCLUSION: Most patients responded to immunosuppressive treatment, although median time to remission was > 1 year. Roughly half the patients acquired a new damage item, most of which did not interfere with functional abilities. Fewer than 20% of patients developed neuropsychiatric damage. Both phenotypes of psychiatric pSLE responded equally well to current treatment.

Psychiatric illness of systemic lupus erythematosus in childhood: spectrum of clinically important manifestations.

OBJECTIVE: To determine the spectrum of manifestations in clinically important (i.e., requiring alterations of immunosuppressive therapy) psychiatric illness of pediatric systemic lupus erythematosus (pSLE) and to describe the laboratory and imaging features associated with psychiatric illness of pSLE (psySLE). METHODS: This was a single-center cohort study of patients with pSLE followed at a pediatric SLE clinic from August 1985 to July 2009. Patients with organic psychiatric disease due to SLE were included. Data regarding psychiatric features at initial presentation and during followup were obtained from psychiatry and rheumatology visits. Data regarding concomitant SLE disease activity and laboratory results were obtained from the institutional SLE database. Information from imaging studies was abstracted from patients' charts. RESULTS: Our cohort consisted of 53 pediatric patients (87% female) diagnosed with psySLE, representing 12% of the total pSLE cohort of 447 in the same time period. The median age at diagnosis of pSLE was 15.0 years and 16.1 years for psySLE. All patients reported symptoms of cognitive dysfunction and 75% of patients had additional psychotic features. Insight was preserved in 64% of patients with psychosis at diagnosis of psySLE. Visual distortion was observed among 32% of children with psySLE. Eighty-two percent of patients demonstrated clinical response to the institutional protocol of immunosuppression. CONCLUSION: Cognitive dysfunction was present in all and additional psychosis present in 75% of pediatric patients with psySLE. Visual distortion and early preservation of insight were unique features of psychosis observed in this cohort of children/adolescents with psySLE.

The risky business of studying prognosis.

Prognosis studies provide important healthcare information. Clinicians use prognostic factors to predict disease progress, thus allowing individualization of disease management. Prognosis is the issue in many translational studies that aim to identify biomarkers to predict outcomes. In a clinical trial, researchers may use prognostic factors to sort patients into risk groups, to clarify the effects of a new therapeutic agent. Prognosis studies can have significant effects on clinical practice.

Predicting longitudinal trajectory of bone mineral density in paediatric systemic lupus erythematosus patients.

OBJECTIVES: (1) To identify the average lumbar spine (LS) bone mineral density (BMD) trajectory in paediatric systemic lupus erythematosus (pSLE) patients, and (2) to identify predictors of BMD trajectory. METHODS: 68 consecutive newly diagnosed pSLE patients prospectively followed in our lupus cohort with three annual dual energy x-ray absorptiometry (DEXA) examinations were studied. Low LS BMD was defined as z-score ≤-2.0. Baseline and longitudinal clinical features including disease activity, treatment and bone physiology markers were collected. Hierarchical linear modelling was used to model trajectory of LS BMD and identify predictors. RESULTS: Women constituted 84% of the cohort and median age at diagnosis was 13.1 years. The mean LS BMD z-scores decreased over time (-0.42 at first, -1.02 at second and -1.11 at third DEXA). Initially 9% of patients had a low BMD, which increased to 19% by 3 years after diagnosis. 35% of patients deteriorated in BMD category from the first to third DEXA. LS BMD (adjusted by height-for-age z-score) followed a general deteriorating trajectory of -0.06 z-score/year from diagnosis. Increased rate of deterioration of BMD trajectory was predicted by pubertal status at diagnosis, increased interval cumulative steroid exposure and decreased weight z-scores. CONCLUSIONS: The LS BMD of pSLE patients followed a general deteriorating trend over time and could be predicted by a combination of pubertal status at diagnosis, interval cumulative doses of steroids and weight z-scores. Interval cumulative steroid dose represents an important target that clinicians may modify to ameliorate deteriorating BMD trajectory over time.