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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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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.

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.

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.

Objective: To determine nephritis outcomes in a prospective multi-ethnic/racial SLE inception cohort., Methods: Patients in the Systemic Lupus International Collaborating Clinics inception cohort (≤15 months of SLE diagnosis) were assessed annually for estimated glomerular filtration rate (eGFR), proteinuria and end-stage renal disease (ESRD). Health-related quality of life was measured by the Short Form (36 questions) health survey questionnaire (SF-36) subscales, mental and physical component summary scores., Results: There were 1827 patients, 89% females, mean (s.d.) age 35.1 (13.3) years. The mean (s.d.) SLE duration at enrolment was 0.5 (0.3) years and follow-up 4.6 (3.4) years. LN occurred in 700 (38.3%) patients: 566/700 (80.9%) at enrolment and 134/700 (19.1%) during follow-up. Patients with nephritis were younger, more frequently men and of African, Asian and Hispanic race/ethnicity. The estimated overall 10-year incidence of ESRD was 4.3% (95% CI: 2.8%, 5.8%), and with nephritis was 10.1% (95% CI: 6.6%, 13.6%). Patients with nephritis had a higher risk of death (HR = 2.98, 95% CI: 1.48, 5.99; P = 0.002) and those with eGFR <30 ml/min at diagnosis had lower SF-36 physical component summary scores (P < 0.01) and lower Physical function, Physical role and Bodily pain scores. Over time, patients with abnormal eGFR and proteinuria had lower SF-36 mental component summary (P ≤ 0.02) scores compared to patients with normal values., Conclusion: LN occurred in 38.3% of SLE patients, frequently as the initial presentation, in a large multi-ethnic inception cohort. Despite current standard of care, nephritis was associated with ESRD and death, and renal insufficiency was linked to lower health-related quality of life. Further advances are required for the optimal treatment of LN., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: The aim of this study was to describe the outcomes and predictors for development of damage in a large inception cohort of SLE patients., Methods: This was a prospective longitudinal study of a cohort of SLE patients. SLE patients were included if they were recruited within 3 years of achieving the fourth ACR criterion for SLE. Data were collected on disease activity, damage and treatment. Information on death was provided by the Office for National Statistics. The censoring date for analysis was 31 December 2010. A standardized mortality ratio was calculated. Poisson regression was used to determine the incidence rate for damage accrual. Multistate Markov modelling was used to determine predictors for development of damage., Results: There were 382 patients (92.4% females, 51.6% Caucasian, 22% South Asian, 20.7% Afro-Caribbean) with 12 072 assessments and total follow-up of 2958 patient-years. There were 300 items of damage (in 143 patients) and 37 deaths. The overall standardized mortality ratio was 2.0 (95% CI 1.5, 2.8) and the most common causes of death were infection (37.8%), cardiovascular (27%) and malignancy (13.5%). The predictors for damage accrual were higher prior damage, older age at diagnosis, active disease, systemic corticosteroid exposure and CYC exposure. Patients were more likely to develop new damage earlier in their disease than later. Ethnicity was not predictive of damage accrual or death in this cohort., Conclusion: SLE patients have premature mortality. Active disease, corticosteroid exposure and CYC exposure were independently associated with the development of damage. Damage accrual is more likely to occur in early disease., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

A generic random effects formulation for the Dirichlet negative multinomial distribution is developed together with a convenient regression parameterization. A simulation study indicates that, even when somewhat misspecified, regression models based on the Dirichlet negative multinomial distribution have smaller median absolute error than generalized estimating equations, with a particularly pronounced improvement when correlation between observations in a cluster is high. Estimation of explanatory variable effects and sources of variation is illustrated for a study of clinical trial recruitment.

Objective: This was an exploratory analysis to develop a new way of representing BILAG-2004 system scores longitudinally that would be clinically meaningful and easier to analyse in comparison with multiple categorical variables., Methods: Data from a multicentre longitudinal study of SLE patients (the BILAG-2004 index and therapy collected at every visit) were used. External responsiveness analysis of the index suggested the possibility of using counts of systems with specified transitions in scores as a basis to analyse the system scores. Exploratory analyses with multinomial logistic regression were used to examine the appropriateness of this new method of analysing BILAG-2004 system scores. Receiver operating characteristic (ROC) curve analysis was used to assess the performance of this approach., Results: There were 1414 observations from 347 patients. A novel method was devised based on counts of systems with defined transitions in score (BILAG-2004 systems tally, BST). It has six components (systems with major deterioration, systems with minor deterioration, systems with persistent significant activity, systems with major improvement, systems with minor improvement and systems with persistent minimal or no activity). This was further simplified (simplified BST, sBST) into three components (systems with active/worsening disease, systems with improving disease and systems with persistent minimal or no activity). Both versions had expected associations with change in therapy. ROC curve analyses demonstrated that both versions had similar good performance characteristics (areas under the curve >0.80) in predicting increase in therapy., Conclusion: The BST and sBST provide alternative approaches to representing BILAG-2004 disease activity longitudinally. Further validation of their use is required.

Objective: To assess the inter-rater reliability of the BILAG2004-Pregnancy index for assessment of SLE disease activity in pregnancy., Methods: Pregnant SLE patients were recruited from four centres and assessed separately by two raters/physicians in routine clinical practice. Disease activity was determined using the BILAG2004-Pregnancy index. Reliability was assessed using level of agreement, κ-statistics and analysis of disagreement. Major disagreement was defined as a score difference of A and C/D/E or B and D/E between the two raters, and minor disagreement was a score difference of A and B or B and C between raters., Results: A total of 30 patients (63.3% Caucasian, 13.3% Afro-Caribbean, 16.7% South Asian) were recruited. The majority of patients had low-level disease activity according to the local rater's assessment, and there was no grade A activity, with grade B activity present in the following systems: mucocutaneous (nine patients), musculoskeletal (two patients), cardiorespiratory (one patient) and renal (one patient). The distribution of disease activity was similar to the external rater's assessment. Good levels of agreement (>70%) were achieved in all systems. κ-statistics were not appropriate for use in the gastrointestinal, ophthalmic, constitutional and neuropsychiatric systems, as there was minimal variation between patients but good levels of agreement otherwise. There were three major disagreements (0.1 per patient, all differences between B and D/E) and five minor disagreements (0.17 per patient)., Conclusion: The BILAG2004-Pregnancy index is reliable for assessment of disease activity in pregnant SLE patients.

In psoriatic arthritis, permanent joint damage characterizes disease progression and represents a major debilitating aspect of the disease. Understanding the process of joint damage will assist in the treatment and disease management of patients. Multistate models provide a means to examine patterns of disease, such as symmetric joint damage. Additionally, the link between damage and the dynamic course of disease activity (represented by joint swelling and stress pain) at both the individual joint level and otherwise can be represented within a correlated multistate model framework. Correlation is reflected through the use of random effects for progressive models and robust variance estimation for non-progressive models. Such analyses, undertaken with data from a large psoriatic arthritis cohort, are discussed and the extent to which they permit causal reasoning is considered. For this, emphasis is given to the use of the Bradford Hill criteria for causation in observational studies and the concept of local (in)dependence to capture the dynamic nature of the relationships.

Objectives: To examine SLEDAI-2000 cut-off scores for definition of active SLE and to determine the sensitivity to change of SLEDAI-2000 for the assessment of SLE disease activity and minimal clinically meaningful changes in score., Methods: Data from two multi-centre studies were used in the analysis: in a cross-sectional and a longitudinal fashion. At every assessment, data were collected on SLEDAI-2000 and treatment. The cross-sectional analysis with receiver operating characteristic (ROC) curves was used to examine the appropriate SLEDAI-2000 score to define active disease and increase in therapy was the reference standard. In the longitudinal analysis, sensitivity to change of SLEDAI-2000 was assessed with multinomial logistic regression. ROC curves analysis was used to examine possible cut-points in score changes associated with change in therapy, and mean changes were estimated., Results: In the cross-sectional analysis, the most appropriate cut-off scores for active disease were 3 or 4. In the longitudinal analysis, the best model for predicting treatment increase was with the change in SLEDAI-2000 score and the score from the previous visit as continuous variables. The use of cut-points was less predictive of treatment change than the use of continuous score. The mean difference in the change in SLEDAI-2000 scores, adjusted for prior score, between patients with treatment increase and those without was 2.64 (95% CI 2.16, 3.14)., Conclusions: An appropriate SLEDAI-2000 score to define active disease is 3 or 4. SLEDAI-2000 index is sensitive to change. The use of SLEDAI-2000 as a continuous outcome is recommended for comparative purposes.

Time-to-event and similar analyses can be problematic if the event of interest is operationally defined by some condition being true for a prolonged period of time. A particular example of this, remission in psoriatic arthritis, is considered in detail for illustration. A 3-state model is proposed for characterizing the transition rates into and out of remission. Remission is linked to an initial and subsequent state for the purpose of introducing the condition that remission must be of some duration to be clinically meaningful. The model is compared with alternative approaches that have been used in such situations. These involve 2-state models where the duration of remission is allowed for through different definitions for the time of entry into remission. Both definitions are linked to prolonged observation of a particular clinical state.

Objective: To develop an additive numerical scoring scheme for the BILAG-2004 index., Methods: SLE patients were recruited into this multi-centre cross-sectional study. At every assessment, data were collected on disease activity and therapy. Logistic regression was used to model an increase in therapy, as an indicator of active disease, by the BILAG-2004 index score in the nine systems. As both indicate inactivity, scores of D and E were set to 0 and used as the baseline in the fitted model. The models were used to determine the numerical values for Grades A-C. Different scoring schemes were compared., Results: There were 1510 assessments from 369 SLE patients. The coding schemes suggested for the Classic BILAG index (A = 12, B = 5, C = 1, D/E = 0 and A = 9, B = 3, C = 1, D/E = 0) did not fit the data well. A coding scheme (A = 12, B = 8, C = 1 and D/E = 0) was recommended, based on analysis results and consistency with the numerical coding scheme of the Classic BILAG index., Conclusion: A reasonable additive numerical scoring scheme based on treatment decision for the BILAG-2004 index is A = 12, B = 8, C = 1, D = 0 and E = 0.

Objective: To develop an additive numerical scoring scheme for the Classic BILAG index., Methods: SLE patients were recruited into this multi-centre cross-sectional study. At every assessment, data were collected on disease activity and therapy. Logistic regression was used to model an increase in therapy, as an indicator of active disease, by the Classic BILAG score in eight systems. As both indicate inactivity, scores of D and E were set to 0 and used as the baseline in the fitted model. The coefficients from the fitted model were used to determine the numerical values for Grades A, B and C. Different scoring schemes were then compared using receiver operating characteristic (ROC) curves. Validation analysis was performed using assessments from a single centre., Results: There were 1510 assessments from 369 SLE patients. The currently used coding scheme (A = 9, B = 3, C = 1 and D/E = 0) did not fit the data well. The regression model suggested three possible numerical scoring schemes: (i) A = 11, B = 6, C = 1 and D/E = 0; (ii) A = 12, B = 6, C = 1 and D/E = 0; and (iii) A = 11, B = 7, C = 1 and D/E = 0. These schemes produced comparable ROC curves. Based on this, A = 12, B = 6, C = 1 and D/E = 0 seemed a reasonable and practical choice. The validation analysis suggested that although the A = 12, B = 6, C = 1 and D/E = 0 coding is still reasonable, a scheme with slightly less weighting for B, such as A = 12, B = 5, C = 1 and D/E = 0, may be more appropriate., Conclusions: A reasonable additive numerical scoring scheme based on treatment decision for the Classic BILAG index is A = 12, B = 5, C = 1, D = 0 and E = 0.

Joint damage in psoriatic arthritis can be measured by clinical and radiological methods, the former being done more frequently during longitudinal follow-up of patients. Motivated by the need to compare findings based on the different methods with different observation patterns, we consider longitudinal data where the outcome variable is a cumulative total of counts that can be unobserved when other, informative, explanatory variables are recorded. We demonstrate how to calculate the likelihood for such data when it is assumed that the increment in the cumulative total follows a discrete distribution with a location parameter that depends on a linear function of explanatory variables. An approach to the incorporation of informative observation is suggested. We present analyses based on an observational database from a psoriatic arthritis clinic. Although the use of the new statistical methodology has relatively little effect in this example, simulation studies indicate that the method can provide substantial improvements in bias and coverage in some situations where there is an important time varying explanatory variable.

Objective: To determine if the BILAG-2004 index is sensitive to change for assessment of SLE disease activity., Methods: This was a prospective multi-centre longitudinal study of SLE patients. At every assessment, data were collected on disease activity (BILAG-2004 index) and treatment. Analyses were performed using overall BILAG-2004 index score (as determined by the highest score achieved by any of the individual systems) and all the systems scores. Sensitivity to change was assessed by determining the relationship between change in disease activity and change in therapy between two consecutive visits. Statistical analyses were performed using multinomial logistic regression., Results: There were 1761 assessments from 347 SLE patients that contributed 1414 observations for analysis. An increase in therapy between visits occurred in 22.7% observations, while 37.3% had a decrease in therapy and in 40.0% therapy was unchanged. Increase in overall BILAG-2004 index score was associated with increase in therapy and inversely associated with decrease in therapy. Decrease in overall BILAG-2004 index score was associated with decrease in therapy and was inversely associated with increase in therapy. Changes in overall BILAG-2004 index score were differentially related to change in therapy, with greater change in score having greater predictive power. Increase in the scores of most systems was independently associated with an increase in treatment and there was no significant association between decreases in the score of any system with an increase in therapy., Conclusions: The BILAG-2004 index is sensitive to change and is suitable for use in longitudinal studies of SLE.

Semicontinuous data in the form of a mixture of zeros and continuously distributed positive values frequently arise in biomedical research. Two-part mixed models with correlated random effects are an attractive approach to characterize the complex structure of longitudinal semicontinuous data. In practice, however, an independence assumption about random effects in these models may often be made for convenience and computational feasibility. In this article, we show that bias can be induced for regression coefficients when random effects are truly correlated but misspecified as independent in a 2-part mixed model. Paralleling work on bias under nonignorable missingness within a shared parameter model, we derive and investigate the asymptotic bias in selected settings for misspecified 2-part mixed models. The performance of these models in practice is further evaluated using Monte Carlo simulations. Additionally, the potential bias is investigated when artificial zeros, due to left censoring from some detection or measuring limit, are incorporated. To illustrate, we fit different 2-part mixed models to the data from the University of Toronto Psoriatic Arthritis Clinic, the aim being to examine whether there are differential effects of disease activity and damage on physical functioning as measured by the health assessment questionnaire scores over the course of psoriatic arthritis. Some practical issues on variance component estimation revealed through this data analysis are considered.