Assessing the Costs of Neuropsychiatric Disease in the Systemic Lupus International Collaborating Clinics Cohort Using Multistate Modeling.

OBJECTIVE: To estimate direct and indirect costs associated with neuropsychiatric (NP) events in the Systemic Lupus International Collaborating Clinics inception cohort. METHODS: NP events were documented annually using American College of Rheumatology definitions for NP events and attributed to systemic lupus erythematosus (SLE) or non-SLE causes. Patients were stratified into 1 of 3 NP states (no, resolved, or new/ongoing NP event). Change in NP status was characterized by interstate transition rates using multistate modeling. Annual direct costs and indirect costs were based on health care use and impaired productivity over the preceding year. Annual costs associated with NP states and NP events were calculated by averaging all observations in each state and adjusted through random-effects regressions. Five- and 10-year costs for NP states were predicted by multiplying adjusted annual costs per state by expected state duration, forecasted using multistate modeling. RESULTS: A total of 1,697 patients (49% White race/ethnicity) were followed for a mean of 9.6 years. NP events (n = 1,971) occurred in 956 patients, 32% attributed to SLE. For SLE and non-SLE NP events, predicted annual, 5-, and 10-year direct costs and indirect costs were higher in new/ongoing versus no events. Direct costs were 1.5-fold higher and indirect costs 1.3-fold higher in new/ongoing versus no events. Indirect costs exceeded direct costs 3.0 to 5.2 fold. Among frequent SLE NP events, new/ongoing seizure disorder and cerebrovascular disease accounted for the largest increases in annual direct costs. For non-SLE NP events, new/ongoing polyneuropathy accounted for the largest increase in annual direct costs, and new/ongoing headache and mood disorder for the largest increases in indirect costs. CONCLUSION: Patients with new/ongoing SLE or non-SLE NP events incurred higher direct and indirect costs.

The BILAG-2004 index is associated with development of new damage in SLE.

OBJECTIVE: To determine whether BILAG-2004 index is associated with the development of damage in a cohort of SLE patients. Mortality and development of damage were examined. METHODS: This was a multicentre longitudinal study. Patients were recruited within 12 months of achieving fourth ACR classification criterion for SLE. Data were collected on disease activity, damage, SLE-specific drug exposure, cardiovascular risk factors, antiphospholipid syndrome status and death at every visit. This study ran from 1 January 2005 to 31 December 2017. Descriptive statistics were used to analyse mortality and development of new damage. Poisson regression was used to examine potential explanatory variables for development of new damage. RESULTS: A total of 273 SLE patients were recruited with total follow-up of 1767 patient-years (median 73.4 months). There were 6348 assessments with disease activity scores available for analysis. During follow-up, 13 deaths and 114 new damage items (in 83 patients) occurred. The incidence rate for development of damage was higher in the first 3 years before stabilizing at a lower rate. Overall rate for damage accrual was 61.1 per 1000 person-years (95% CI: 50.6, 73.8). Analysis showed that active disease scores according to BILAG-2004 index (systems scores of A or B, counts of systems with A and BILAG-2004 numerical score) were associated with development of new damage. Low disease activity (LDA) states [BILAG-2004 LDA and BILAG Systems Tally (BST) persistent LDA] were inversely associated with development of damage. CONCLUSIONS: BILAG-2004 index is associated with new damage. BILAG-2004 LDA and BST persistent LDA can be considered as treatment targets.

Comparison of Responsiveness of British Isles Lupus Assessment Group 2004 Index, Systemic Lupus Erythematosus Disease Activity Index 2000, and British Isles Lupus Assessment Group 2004 Systems Tally.

OBJECTIVE: To compare the responsiveness of the British Isles Lupus Assessment Group 2004 index (BILAG-2004) and the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) disease activity indices and to determine whether there was any added value in combining BILAG-2004, BILAG-2004 system tally (BST), or simplified BST (sBST) with SLEDAI-2K. METHODS: This was a multicenter longitudinal study of SLE patients. Data were collected on BILAG-2004, SLEDAI-2K, and therapy on consecutive assessments in routine practice. The external responsiveness of the indices was assessed by determining the relationship between change in disease activity and change in therapy between 2 consecutive visits. Comparison of indices and their derivatives was performed by assessing the main effects of the indices using logistic regression. Receiver operating characteristic curves analysis was used to describe the performance of these indices individually and in various combinations, and comparisons of area under the curve were performed. RESULTS: There were 1,414 observations from 347 patients. Both BILAG-2004 and SLEDAI-2K maintained an independent relationship with change in therapy when compared. There was some improvement in responsiveness when continuous SLEDAI-2K variables (change in score and score of previous visit) were combined with BILAG-2004 system scores. Dichotomization of BILAG-2004 or SLEDAI-2K resulted in poorer performance. BST and sBST had similar responsiveness as the combination of SLEDAI-2K variables and BILAG-2004 system scores. There was little benefit in combining SLEDAI-2K with BST or sBST. CONCLUSION: The BILAG-2004 index had comparable responsiveness to SLEDAI-2K. There was some benefit in combining both indices. Dichotomization of BILAG-2004 and SLEDAI-2K leads to suboptimal performance. BST and sBST performed well on their own; sBST is recommended for its simplicity and clinical meaningfulness.

Impact of glucocorticoids on the incidence of lupus-related major organ damage: a systematic literature review and meta-regression analysis of longitudinal observational studies.

OBJECTIVE: In systemic lupus erythematosus (SLE), disease activity and glucocorticoid (GC) exposure are known to contribute to irreversible organ damage. We aimed to examine the association between GC exposure and organ damage occurrence. METHODS: We conducted a literature search (PubMed (Medline), Embase and Cochrane January 1966-October 2021). We identified original longitudinal observational studies reporting GC exposure as the proportion of users and/or GC use with dose information as well as the occurrence of new major organ damage as defined in the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. Meta-regression analyses were performed. Reviews, case-reports and studies with <5 years of follow-up, <50 patients, different outcomes and special populations were excluded. RESULTS: We selected 49 articles including 16 224 patients, 14 755 (90.9%) female with a mean age and disease duration of 35.1 years and of 37.1 months. The mean follow-up time was 104.9 months. For individual damage items, the average daily GC dose was associated with the occurrence of overall cardiovascular events and with osteoporosis with fractures. A higher average cumulative dose adjusted (or not)/number of follow-up years and a higher proportion of patients on GC were associated with the occurrence of osteonecrosis. CONCLUSIONS: We confirm associations of GC use with three specific damage items. In treating patients with SLE, our aim should be to maximise the efficacy of GC and to minimise their harms.

Neuropsychiatric Events in Systemic Lupus Erythematosus: Predictors of Occurrence and Resolution in a Longitudinal Analysis of an International Inception Cohort.

OBJECTIVE: To determine predictors of change in neuropsychiatric (NP) event status in a large, prospective, international inception cohort of patients with systemic lupus erythematosus (SLE). METHODS: Upon enrollment and annually thereafter, NP events attributed to SLE and non-SLE causes and physician-determined resolution were documented. Factors potentially associated with the onset and resolution of NP events were determined by time-to-event analysis using a multistate modeling structure. RESULTS: NP events occurred in 955 (52.3%) of 1,827 patients, and 593 (31.0%) of 1,910 unique events were attributed to SLE. For SLE-associated NP (SLE NP) events, multivariate analysis revealed a positive association with male sex (P = 0.028), concurrent non-SLE NP events excluding headache (P < 0.001), active SLE (P = 0.012), and glucocorticoid use (P = 0.008). There was a negative association with Asian race (P = 0.002), postsecondary education (P = 0.001), and treatment with immunosuppressive drugs (P = 0.019) or antimalarial drugs (P = 0.056). For non-SLE NP events excluding headache, there was a positive association with concurrent SLE NP events (P < 0.001) and a negative association with African race (P = 0.012) and Asian race (P < 0.001). NP events attributed to SLE had a higher resolution rate than non-SLE NP events, with the exception of headache, which had comparable resolution rates. For SLE NP events, multivariate analysis revealed that resolution was more common in patients of Asian race (P = 0.006) and for central/focal NP events (P < 0.001). For non-SLE NP events, resolution was more common in patients of African race (P = 0.017) and less common in patients who were older at SLE diagnosis (P < 0.001). CONCLUSION: In a large and long-term study of the occurrence and resolution of NP events in SLE, we identified subgroups with better and worse prognosis. The course of NP events differs greatly depending on their nature and attribution.

The Pulmonary Metastasectomy in Colorectal Cancer cohort study: Analysis of case selection, risk factors and survival in a prospective observational study of 512 patients.

AIM: We wanted to examine survival in patients with resected colorectal cancer (CRC) whose lung metastases are or are not resected. METHODS: Teams participating in the study of Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC) identified potential candidates for lung metastasectomy and invited their consent to join Stage 1. Baseline data related to CRC and fitness for surgery were collected. Eligible patients were invited to consent for randomization in the PulMiCC randomized controlled trial (Stage 2). Sites were provided with case report forms for non-randomized patients to record adverse events and death at any time. They were all reviewed at 1 year. Baseline and survival data were analysed for the full cohort. RESULTS: Twenty-five clinical sites recruited 512 patients from October 2010 to January 2017. Data collection closed in October 2020. Before analysis, 28 patients with non-CRC lung lesions were excluded and three had withdrawn consent leaving 481. The date of death was known for 292 patients, 136 were alive in 2020 and 53 at earlier time points. Baseline factors and 5-year survival were analysed in three strata: 128 non-randomized patients did not have metastasectomy; 263 had elective metastasectomy; 90 were from the randomized trial. The proportions of solitary metastases for electively operated and non-operated patients were 69% and 35%. Their respective 5-year survivals were 47% and 22%. CONCLUSION: Survival without metastasectomy was greater than widely presumed. Difference in survival appeared to be largely related to selection. No inference can be drawn about the effect of metastasectomy on survival in this observational study.

Pulmonary metastasectomy in colorectal cancer: health utility scores by EQ-5D-3L in a randomized controlled trial show no benefit from lung metastasectomy.

AIM: The aim was to assess the health utility of lung metastasectomy in the treatment of patients with colorectal cancer (CRC) using the EQ-5D-3L questionnaire. METHODS: Multidisciplinary CRC teams at 14 sites recruited patients to a two-arm randomized controlled trial-Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC). Remote randomization was used, stratified by site and with minimization for seven known confounders. Participants completed the EQ-5D-3L questionnaire together with other patient reported outcome measures at randomization and then again at 3, 6, 12 and 24 months. These were returned by post to the coordinating centre. RESULTS: Between December 2010 and December 2016, 93 participants were randomized, 91 of whom returned questionnaires. Survival and patient reported quality of life have been published previously, revealing no significant differences between the trial arms. Described here are patient reported data from the five dimensions of the EQ-5D-3L and the visual analogue scale (VAS) health state. No significant difference was seen at any time point. The estimated difference between control and metastasectomy patients was -0.23 (95% CI -0.113, 0.066) for the composite 0 to 1 index scale based on the descriptive system and 0.123 (95% CI -7.24, 7.49) for the 0 to 100 VAS scale. CONCLUSIONS: Following lung metastasectomy for CRC, no benefit was demonstrated for health utility, which alongside a lack of a survival or quality of life benefit calls into question the widespread use of the procedure.

Accrual of Atherosclerotic Vascular Events in a Multicenter Inception Systemic Lupus Erythematosus Cohort.

OBJECTIVE: In previous studies, atherosclerotic vascular events (AVEs) were shown to occur in ~10% of patients with systemic lupus erythematosus (SLE). We undertook this study to investigate the annual occurrence and potential risk factors for AVEs in a multinational, multiethnic inception cohort of patients with SLE. METHODS: A large 33-center cohort of SLE patients was followed up yearly between 1999 and 2017. AVEs were attributed to atherosclerosis based on SLE being inactive at the time of the AVE as well as typical atherosclerotic changes observed on imaging or pathology reports and/or evidence of atherosclerosis elsewhere. Analyses included descriptive statistics, rate of AVEs per 1,000 patient-years, and univariable and multivariable relative risk regression models. RESULTS: Of the 1,848 patients enrolled in the cohort, 1,710 had ≥1 follow-up visit after enrollment, for a total of 13,666 patient-years. Of these 1,710 patients, 3.6% had ≥1 AVEs attributed to atherosclerosis, for an event rate of 4.6 per 1,000 patient-years. In multivariable analyses, lower AVE rates were associated with antimalarial treatment (hazard ratio [HR] 0.54 [95% confidence interval (95% CI) 0.32-0.91]), while higher AVE rates were associated with any prior vascular event (HR 4.00 [95% CI 1.55-10.30]) and a body mass index of >40 kg/m2 (HR 2.74 [95% CI 1.04-7.18]). A prior AVE increased the risk of subsequent AVEs (HR 5.42 [95% CI 3.17-9.27], P < 0.001). CONCLUSION: The prevalence of AVEs and the rate of AVE accrual demonstrated in the present study is much lower than that seen in previously published data. This may be related to better control of both the disease activity and classic risk factors.

Neuropsychiatric events in systemic lupus erythematosus: a longitudinal analysis of outcomes in an international inception cohort using a multistate model approach.

OBJECTIVES: Using a reversible multistate model, we prospectively examined neuropsychiatric (NP) events for attribution, outcome and association with health-related quality of life (HRQoL), in an international, inception cohort of systemic lupus erythematosus (SLE) patients. METHODS: Annual assessments for 19 NP events attributed to SLE and non-SLE causes, physician determination of outcome and patient HRQoL (short-form (SF)-36 scores) were measured. Time-to-event analysis and multistate modelling examined the onset, recurrence and transition between NP states. RESULTS: NP events occurred in 955/1827 (52.3%) patients and 592/1910 (31.0%) unique events were attributed to SLE. In the first 2 years of follow-up the relative risk (95% CI) for SLE NP events was 6.16 (4.96, 7.66) and non-SLE events was 4.66 (4.01, 5.43) compared with thereafter. Patients without SLE NP events at initial assessment had a 74% probability of being event free at 10 years. For non-SLE NP events the estimate was 48%. The majority of NP events resolved over 10 years but mortality was higher in patients with NP events attributed to SLE (16%) versus patients with no NPSLE events (6%) while the rate was comparable in patients with non-SLE NP events (7%) compared with patients with no non-SLE events (6%). Patients with NP events had lower SF-36 summary scores compared with those without NP events and resolved NP states (p<0.001). CONCLUSIONS: NP events occur most frequently around the diagnosis of SLE. Although the majority of events resolve they are associated with reduced HRQoL and excess mortality. Multistate modelling is well suited for the assessment of NP events in SLE.

Economic Evaluation of Damage Accrual in an International Systemic Lupus Erythematosus Inception Cohort Using a Multistate Model Approach.

OBJECTIVE: There is a paucity of data regarding health care costs associated with damage accrual in systemic lupus erythematosus. The present study was undertaken to describe costs associated with damage states across the disease course using multistate modeling. METHODS: Patients from 33 centers in 11 countries were enrolled in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort within 15 months of diagnosis. Annual data on demographics, disease activity, damage (SLICC/American College of Rheumatology Damage Index [SDI]), hospitalizations, medications, dialysis, and selected procedures were collected. Ten-year cumulative costs (Canadian dollars) were estimated by multiplying annual costs associated with each SDI state by the expected state duration using a multistate model. RESULTS: A total of 1,687 patients participated; 88.7% were female, 49.0% were white, mean ± SD age at diagnosis was 34.6 ± 13.3 years, and mean time to follow-up was 8.9 years (range 0.6-18.5 years). Mean annual costs were higher for those with higher SDI scores as follows: $22,006 (Canadian) (95% confidence interval [95% CI] $16,662, $27,350) for SDI scores ≥5 versus $1,833 (95% CI $1,134, $2,532) for SDI scores of 0. Similarly, 10-year cumulative costs were higher for those with higher SDI scores at the beginning of the 10-year interval as follows: $189,073 (Canadian) (95% CI $142,318, $235,827) for SDI scores ≥5 versus $21,713 (95% CI $13,639, $29,788) for SDI scores of 0. CONCLUSION: Patients with the highest SDI scores incur 10-year cumulative costs that are ~9-fold higher than those with the lowest SDI scores. By estimating the damage trajectory and incorporating annual costs, data on damage can be used to estimate future costs, which is critical knowledge for evaluating the cost-effectiveness of novel therapies.

Peripheral Nervous System Disease in Systemic Lupus Erythematosus: Results From an International Inception Cohort Study.

OBJECTIVE: To determine the frequency, clinical characteristics, associations, and outcomes of different types of peripheral nervous system (PNS) disease in a multiethnic/multiracial, prospective inception cohort of systemic lupus erythematosus (SLE) patients. METHODS: Patients were evaluated annually for 19 neuropsychiatric (NP) events including 7 types of PNS disease. SLE disease activity, organ damage, autoantibodies, and patient and physician assessment of outcome were measured. Time to event and linear regressions were used as appropriate. RESULTS: Of 1,827 SLE patients, 88.8% were female, and 48.8% were white. The mean ± SD age was 35.1 ± 13.3 years, disease duration at enrollment was 5.6 ± 4.2 months, and follow-up was 7.6 ± 4.6 years. There were 161 PNS events in 139 (7.6%) of 1,827 patients. The predominant events were peripheral neuropathy (66 of 161 [41.0%]), mononeuropathy (44 of 161 [27.3%]), and cranial neuropathy (39 of 161 [24.2%]), and the majority were attributed to SLE. Multivariate Cox regressions suggested longer time to resolution in patients with a history of neuropathy, older age at SLE diagnosis, higher SLE Disease Activity Index 2000 scores, and for peripheral neuropathy versus other neuropathies. Neuropathy was associated with significantly lower Short Form 36 (SF-36) physical and mental component summary scores versus no NP events. According to physician assessment, the majority of neuropathies resolved or improved over time, which was associated with improvements in SF-36 summary scores for peripheral neuropathy and mononeuropathy. CONCLUSION: PNS disease is an important component of total NPSLE and has a significant negative impact on health-related quality of life. The outcome is favorable for most patients, but our findings indicate that several factors are associated with longer time to resolution.

Partially hidden multi-state modelling of a prolonged disease state defined by a composite outcome.

For rheumatic diseases, Minimal Disease Activity (MDA) is usually defined as a composite outcome which is a function of several individual outcomes describing symptoms or quality of life. There is ever increasing interest in MDA but relatively little has been done to characterise the pattern of MDA over time. Motivated by the aim of improving the modelling of MDA in psoriatic arthritis, the use of a two-state model to estimate characteristics of the MDA process is illustrated when there is particular interest in prolonged periods of MDA. Because not all outcomes necessary to define MDA are measured at all clinic visits, a partially hidden multi-state model with latent states is used. The defining outcomes are modelled as conditionally independent given these latent states, enabling information from all visits, even those with missing data on some variables, to be used. Data from the Toronto Psoriatic Arthritis Clinic are analysed to demonstrate improvements in accuracy and precision from the inclusion of data from visits with incomplete information on MDA. An additional benefit of this model is that it can be extended to incorporate explanatory variables, which allows process characteristics to be compared between groups. In the example, the effect of explanatory variables, modelled through the use of relative risks, is also summarised in a potentially more clinically meaningful manner by comparing times in states, and probabilities of visiting states, between patient groups.

Psychosis in Systemic Lupus Erythematosus: Results From an International Inception Cohort Study.

OBJECTIVE: To determine, in a large, multiethnic/multiracial, prospective inception cohort of patients with systemic lupus erythematosus (SLE), the frequency, attribution, clinical, and autoantibody associations with lupus psychosis and the short- and long-term outcomes as assessed by physicians and patients. METHODS: Patients were evaluated annually for 19 neuropsychiatric (NP) events including psychosis. Scores on the Systemic Lupus Erythematosus Disease Activity Index 2000, the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, and the Short Form 36 (SF-36) were recorded. Time to event and linear regressions were used as appropriate. RESULTS: Of 1,826 SLE patients, 88.8% were female and 48.8% were Caucasian. The mean ± SD age was 35.1 ± 13.3 years, the mean ± SD disease duration was 5.6 ± 4.2 months, and the mean ± SD follow-up period was 7.4 ± 4.5 years. There were 31 psychotic events in 28 of 1,826 patients (1.53%), and most patients had a single event (26 of 28 [93%]). In the majority of patients (20 of 25 [80%]) and events (28 of 31 [90%]), psychosis was attributed to SLE, usually either in the year prior to or within 3 years of SLE diagnosis. Positive associations (hazard ratios [HRs] and 95% confidence intervals [95% CIs]) with lupus psychosis were previous SLE NP events (HR 3.59 [95% CI 1.16-11.14]), male sex (HR 3.0 [95% CI 1.20-7.50]), younger age at SLE diagnosis (per 10 years) (HR 1.45 [95% CI 1.01-2.07]), and African ancestry (HR 4.59 [95% CI 1.79-11.76]). By physician assessment, most psychotic events resolved by the second annual visit following onset, in parallel with an improvement in patient-reported SF-36 summary and subscale scores. CONCLUSION: Psychosis is an infrequent manifestation of NPSLE. Generally, it occurs early after SLE onset and has a significant negative impact on health status. As determined by patient and physician report, the short- and long-term outlooks are good for most patients, although careful follow-up is required.

Cerebrovascular Events in Systemic Lupus Erythematosus: Results From an International Inception Cohort Study.

OBJECTIVE: To determine the frequency, characteristics, and outcomes of cerebrovascular events (CerVEs), as well as clinical and autoantibody associations in a multiethnic/racial inception cohort of patients with systemic lupus erythematosus (SLE). METHODS: A total of 1,826 patients were assessed annually for 19 neuropsychiatric (NP) events, including 5 types of CerVEs: 1) stroke, 2) transient ischemia, 3) chronic multifocal ischemia, 4) subarachnoid/intracranial hemorrhage, and 5) sinus thrombosis. Global disease activity (Systemic Lupus Erythematosus Disease [SLE] Activity Index 2000), damage scores (SLE International Collaborating Clinics/American College of Rheumatology Damage Index), and Short Form 36 (SF-36) scores were collected. Time to event, linear and logistic regressions, and multistate models were used as appropriate. RESULTS: CerVEs were the fourth most frequent NP event: 82 of 1,826 patients had 109 events; of these events, 103 were attributed to SLE, and 44 were identified at the time of enrollment. The predominant events were stroke (60 of 109 patients) and transient ischemia (28 of 109 patients). CerVEs were associated with other NP events attributed to SLE, non-SLE-attributed NP events, African ancestry (at US SLICC sites), and increased organ damage scores. Lupus anticoagulant increased the risk of first stroke and sinus thrombosis and transient ischemic attack. Physician assessment indicated resolution or improvement in the majority of patients, but patients reported sustained reduction in SF-36 summary and subscale scores following a CerVE. CONCLUSION: CerVEs, the fourth most frequent NP event in SLE, are usually attributable to lupus. In contrast to good physician-reported outcomes, patients reported a sustained reduction in health-related quality of life following a CerVE.

Clustered multistate models with observation level random effects, mover-stayer effects and dynamic covariates: modelling transition intensities and sojourn times in a study of psoriatic arthritis.

In psoriatic arthritis, it is important to understand the joint activity (represented by swelling and pain) and damage processes because both are related to severe physical disability. The paper aims to provide a comprehensive investigation into both processes occurring over time, in particular their relationship, by specifying a joint multistate model at the individual hand joint level, which also accounts for many of their important features. As there are multiple hand joints, such an analysis will be based on the use of clustered multistate models. Here we consider an observation level random-effects structure with dynamic covariates and allow for the possibility that a subpopulation of patients is at minimal risk of damage. Such an analysis is found to provide further understanding of the activity-damage relationship beyond that provided by previous analyses. Consideration is also given to the modelling of mean sojourn times and jump probabilities. In particular, a novel model parameterization which allows easily interpretable covariate effects to act on these quantities is proposed.

Correlated multistate models for multiple processes: an application to renal disease progression in systemic lupus erythematosus.

Bidirectional changes over time in the estimated glomerular filtration rate and in urine protein content are of interest for the treatment and management of patients with lupus nephritis. Although these processes may be modelled by separate multistate models, the processes are likely to be correlated within patients. Motivated by the lupus nephritis application, we develop a new multistate modelling framework where subject-specific random effects are introduced to account for the correlations both between the processes and within patients over time. Models are fitted by using bespoke code in standard statistical software. A variety of forms for the random effects are introduced and evaluated by using the data from the Systemic Lupus International Collaborating Clinics.

Economic Evaluation of Lupus Nephritis in the Systemic Lupus International Collaborating Clinics Inception Cohort Using a Multistate Model Approach.

OBJECTIVE: Little is known about the long-term costs of lupus nephritis (LN). The costs were compared between patients with and without LN using multistate modeling. METHODS: Patients from 32 centers in 11 countries were enrolled in the Systemic Lupus International Collaborating Clinics inception cohort within 15 months of diagnosis and provided annual data on renal function, hospitalizations, medications, dialysis, and selected procedures. LN was diagnosed by renal biopsy or the American College of Rheumatology classification criteria. Renal function was assessed annually using the estimated glomerular filtration rate (GFR) or estimated proteinuria. A multistate model was used to predict 10-year cumulative costs by multiplying annual costs associated with each renal state by the expected state duration. RESULTS: A total of 1,545 patients participated; 89.3% were women, the mean ± age at diagnosis was 35.2 ± 13.4 years, 49% were white, and the mean followup duration was 6.3 ± 3.3 years. LN developed in 39.4% of these patients by the end of followup. Ten-year cumulative costs were greater in those with LN and an estimated glomerular filtration rate (GFR) <30 ml/minute ($310,579 2015 Canadian dollars versus $19,987 if no LN and estimated GFR >60 ml/minute) or with LN and estimated proteinuria >3 gm/day ($84,040 versus $20,499 if no LN and estimated proteinuria <0.25 gm/day). CONCLUSION: Patients with estimated GFR <30 ml/minute incurred 10-year costs 15-fold higher than those with normal estimated GFR. By estimating the expected duration in each renal state and incorporating associated annual costs, disease severity at presentation can be used to anticipate future health care costs. This is critical knowledge for cost-effectiveness evaluations of novel therapies.

Exploring the existence of a stayer population with mover-stayer counting process models: application to joint damage in psoriatic arthritis.

Many psoriatic arthritis patients do not progress to permanent joint damage in any of the 28 hand joints, even under prolonged follow-up. This has led several researchers to fit models that estimate the proportion of stayers (those who do not have the propensity to experience the event of interest) and to characterize the rate of developing damaged joints in the movers (those who have the propensity to experience the event of interest). However, when fitted to the same data, the paper demonstrates that the choice of model for the movers can lead to widely varying conclusions on a stayer population, thus implying that, if interest lies in a stayer population, a single analysis should not generally be adopted. The aim of the paper is to provide greater understanding regarding estimation of a stayer population by comparing the inferences, performance and features of multiple fitted models to real and simulated data sets. The models for the movers are based on Poisson processes with patient level random effects and/or dynamic covariates, which are used to induce within-patient correlation, and observation level random effects are used to account for time varying unobserved heterogeneity. The gamma, inverse Gaussian and compound Poisson distributions are considered for the random effects.

Multiple Imputation of Missing Composite Outcomes in Longitudinal Data.

In longitudinal randomised trials and observational studies within a medical context, a composite outcome-which is a function of several individual patient-specific outcomes-may be felt to best represent the outcome of interest. As in other contexts, missing data on patient outcome, due to patient drop-out or for other reasons, may pose a problem. Multiple imputation is a widely used method for handling missing data, but its use for composite outcomes has been seldom discussed. Whilst standard multiple imputation methodology can be used directly for the composite outcome, the distribution of a composite outcome may be of a complicated form and perhaps not amenable to statistical modelling. We compare direct multiple imputation of a composite outcome with separate imputation of the components of a composite outcome. We consider two imputation approaches. One approach involves modelling each component of a composite outcome using standard likelihood-based models. The other approach is to use linear increments methods. A linear increments approach can provide an appealing alternative as assumptions concerning both the missingness structure within the data and the imputation models are different from the standard likelihood-based approach. We compare both approaches using simulation studies and data from a randomised trial on early rheumatoid arthritis patients. Results suggest that both approaches are comparable and that for each, separate imputation offers some improvement on the direct imputation of a composite outcome.