Remission and low disease activity are associated with lower healthcare costs: results from the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort.

OBJECTIVES: This study aims to determine the independent impact of definitions of remission/low disease activity (LDA) on direct/indirect costs (DCs, ICs) in a multicentre inception cohort. METHODS: Patients from 31 centres in 10 countries were enrolled within 15 months of diagnosis and assessed annually. Five mutually exclusive disease activity states (DAS) were defined as (1) remission off-treatment: clinical (c) SLEDAI-2K=0, without prednisone/immunosuppressants; (2) remission on-treatment: cSLEDAI-2K=0, prednisone ≤5 mg/day and/or maintenance immunosuppressants; (3) LDA-Toronto Cohort (TC): cSLEDAI-2K≤2, without prednisone/immunosuppressants; (4) modified lupus LDA state (mLLDAS): SLEDAI-2K≤4, no activity in major organs/systems, no new activity, prednisone ≤7.5 mg/day and/or maintenance immunosuppressants and (5) active: all remaining assessments.At each assessment, patients were stratified into the most stringent DAS fulfilled and the proportion of time in a DAS since cohort entry was determined. Annual DCs/ICs (2021 Canadian dollars) were based on healthcare use and lost workforce/non-workforce productivity over the preceding year.The association between the proportion of time in a DAS and annual DC/IC was examined through multivariable random-effects linear regressions. RESULTS: 1692 patients were followed a mean of 9.7 years; 49.0% of assessments were active. Remission/LDA (per 25% increase in time in a remission/LDA state vs active) were associated with lower annual DC/IC: remission off-treatment (DC -$C1372; IC -$C2507), remission on-treatment (DC -$C973; IC -$C2604,) LDA-TC (DC -$C1158) and mLLDAS (DC -$C1040). There were no cost differences between remission/LDA states. CONCLUSIONS: Our data suggest that systemic lupus erythematosus patients who achieve remission, both off and on-therapy, and reductions in disease activity incur lower costs than those experiencing persistent disease activity.

Predictors of British Isles Lupus Assessment Group-based outcomes in patients with systemic lupus erythematosus: Analysis from the Systemic Lupus International Collaborating Clinics Inception Cohort.

BACKGROUND: We aimed to identify factors associated with a significant reduction in SLE disease activity over 12 months assessed by the BILAG Index. METHODS: In an international SLE cohort, we studied patients from their 'inception enrolment' visit. We also defined an 'active disease' cohort of patients who had active disease similar to that needed for enrolment into clinical trials. Outcomes at 12 months were; Major Clinical Response (MCR: reduction to classic BILAG C in all domains, steroid dose of ≤7.5 mg and SLEDAI ≤ 4) and 'Improvement' (reduction to ≤1B score in previously active organs; no new BILAG A/B; stable or reduced steroid dose; no increase in SLEDAI). Univariate and multivariate logistic regression with Least Absolute Shrinkage and Selection Operator (LASSO) and cross-validation in randomly split samples were used to build prediction models. RESULTS: 'Inception enrolment' (n = 1492) and 'active disease' (n = 924) patients were studied. Models for MCR performed well (ROC AUC = .777 and .732 in the inception enrolment and active disease cohorts, respectively). Models for Improvement performed poorly (ROC AUC = .574 in the active disease cohort). MCR in both cohorts was associated with anti-malarial use and inversely associated with active disease at baseline (BILAG or SLEDAI) scores, BILAG haematological A/B scores, higher steroid dose and immunosuppressive use. CONCLUSION: Baseline predictors of response in SLE can help identify patients in clinic who are less likely to respond to standard therapy. They are also important as stratification factors when designing clinical trials in order to better standardize overall usual care response rates.

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.

Valuing Health Gain from Composite Response Endpoints for Multisystem Diseases.

OBJECTIVES: This study aimed to demonstrate how to estimate the value of health gain after patients with a multisystem disease achieve a condition-specific composite response endpoint. METHODS: Data from patients treated in routine practice with an exemplar multisystem disease (systemic lupus erythematosus) were extracted from a national register (British Isles Lupus Assessment Group Biologics Register). Two bespoke composite response endpoints (Major Clinical Response and Improvement) were developed in advance of this study. Difference-in-differences regression compared health utility values (3-level version of EQ-5D; UK tariff) over 6 months for responders and nonresponders. Bootstrapped regression estimated the incremental quality-adjusted life-years (QALYs), probability of QALY gain after achieving the response criteria, and population monetary benefit of response. RESULTS: Within the sample (n = 171), 18.2% achieved Major Clinical Response and 49.1% achieved Improvement at 6 months. Incremental health utility values were 0.0923 for Major Clinical Response and 0.0454 for Improvement. Expected incremental QALY gain at 6 months was 0.020 for Major Clinical Response and 0.012 for Improvement. Probability of QALY gain after achieving the response criteria was 77.6% for Major Clinical Response and 72.7% for Improvement. Population monetary benefit of response was £1 106 458 for Major Clinical Response and £649 134 for Improvement. CONCLUSIONS: Bespoke composite response endpoints are becoming more common to measure treatment response for multisystem diseases in trials and observational studies. Health technology assessment agencies face a growing challenge to establish whether these endpoints correspond with improved health gain. Health utility values can generate this evidence to enhance the usefulness of composite response endpoints for health technology assessment, decision making, and economic evaluation.

Early infection risk in patients with systemic lupus erythematosus treated with rituximab or belimumab from the British Isles Lupus Assessment Group Biologics Register (BILAG-BR): a prospective longitudinal study.

BACKGROUND: Patients with systemic lupus erythematosus (SLE) are at an increased risk of infection relative to the general population. We aimed to describe the frequency and risk factors for serious infections in patients with moderate-to-severe SLE treated with rituximab, belimumab, and standard of care therapies in a large national observational cohort. METHODS: The British Isles Lupus Assessment Group Biologics Register (BILAG-BR) is a UK-based prospective register of patients with SLE. Patients were recruited by their treating physician as part of their scheduled care from 64 centres across the UK by use of a standardised case report form. Inclusion criteria for the BILAG-BR included age older than 5 years, ability to provide informed consent, a diagnosis of SLE, and starting a new biological therapy within the last 12 months or a new standard of care drug within the last month. The primary outcome for this study was the rate of serious infections within the first 12 months of therapy. Serious infections were defined as those requiring intravenous antibiotic treatment, hospital admission, or resulting in morbidity or death. Infection and mortality data were collected from study centres and further mortality data were collected from the UK Office for National Statistics. The relationship between serious infection and drug type was analysed using a multiple-failure Cox proportional hazards model. FINDINGS: Between July 1, 2010, and Feb 23, 2021, 1383 individuals were recruited to the BILAG-BR. 335 patients were excluded from this analysis. The remaining 1048 participants contributed 1002·7 person-years of follow-up and included 746 (71%) participants on rituximab, 119 (11%) participants on belimumab, and 183 (17%) participants on standard of care. The median age of the cohort was 39 years (IQR 30-50), 942 (90%) of 1048 patients were women and 106 (10%) were men. Of the patients with available ethnicity data, 514 (56%) of 911 were White, 169 (19%) were Asian, 161 (18%) were Black, and 67 (7%) were of multiple-mixed or other ethnic backgrounds. 118 serious infections occurred in 76 individuals during the 12-month study period, which included 92 serious infections in 58 individuals on rituximab, eight serious infections in five individuals receiving belimumab, and 18 serious infections in 13 individuals on standard of care. The overall crude incidence rate of serious infection was 117·7 (95% CI 98·3-141·0) per 1000 person-years. Compared with standard of care, the serious infection risk was similar in the rituximab (adjusted hazard ratio [HR] 1·68 [0·60-4·68]) and belimumab groups (1·01 [0·21-4·80]). Across the whole cohort in multivariate analysis, serious infection risk was associated with prednisolone dose (>10 mg; 2·38 [95%CI 1·47-3·84]), hypogammaglobulinaemia (<6 g/L; 2·16 [1·38-3·37]), and multimorbidity (1·45 [1·17-1·80]). Additional concomitant immunosuppressive use appeared to be associated with a reduced risk (0·60 [0·41-0·90]). We found no significant safety signals regarding atypical infections. Six infection-related deaths occurred at a median of 121 days (IQR 60-151) days from cohort entry. INTERPRETATION: In patients with moderate-to-severe SLE, rituximab, belimumab, and standard immunosuppressive therapy have similar serious infection risks. Key risk factors for serious infections included multimorbidity, hypogammaglobulinaemia, and increased glucocorticoid doses. When considering the risk of serious infection, we propose that immunosupppressives, rituximab, and belimumab should be prioritised as mainstay therapies to optimise SLE management and support proactive minimisation of glucocorticoid use. FUNDING: None.

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.

Lupus clinical trial eligibility in a real-world setting: results from the British Isles Lupus Assessment Group-Biologics Register (BILAG-BR).

OBJECTIVE: To quantify how well phase III randomised clinical trials in both SLE and lupus nephritis (LN) represents a real-world SLE cohort. METHODS: Literature reviews were performed of major published phase III SLE (n=12) and LN (n=6) clinical trials (ClinicalTrials.gov). Inclusion and exclusion criteria common across these trials were collated for non-renal SLE or LN trials, and applied to patients recruited to the British Isles Lupus Assessment Group-Biologics Register (BILAG-BR) starting either biological or standard-of-care (SOC) therapies. RESULTS: We recruited 837 patients to the BILAG-BR from September 2010 to June 2018, starting either SOC (n=125, 15%) or a biological medication (n=712, 85%). Active LN, defined as a BILAG A in the renal domain occurred in 20% (n=166). Overall, 530 (63%) patients were ineligible to participate in non-renal SLE clinical trials and 72 (43%) patients with active LN would be ineligible for LN trials. The most common reasons for ineligibility from the non-renal lupus trials included active renal involvement (n=166, 20%) and low disease activity (n=114, 15%). For LN trials, the most common exclusion met was pre-existing renal impairment (n=15, 9%). Patients with fewer comorbidities were more likely to be eligible to participate in non-renal SLE trials. CONCLUSIONS: In this national register of patients with moderate-to-severe SLE, nearly two-thirds would not be eligible for recruitment to key SLE clinical trials nor would almost half of those with active LN. Eligibility criteria may excessively constrain enrolment and thus, how we can generalise trial results in a real-world setting.

What Does It Mean to Be a British Isles Lupus Assessment Group-Based Composite Lupus Assessment Responder? Post Hoc Analysis of Two Phase III Trials.

OBJECTIVE: The British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) is a validated global measure of treatment response in systemic lupus erythematosus (SLE) clinical trials. To understand the relevance of BICLA in clinical practice, we investigated relationships between BICLA response and routine SLE assessments, patient-reported outcomes (PROs), and medical resource utilization. METHODS: This was a post hoc analysis of pooled data from the phase III, randomized, placebo-controlled, 52-week TULIP-1 (ClinicalTrials.gov identifier: NCT02446912; n = 457) and TULIP-2 (ClinicalTrials.gov identifier: NCT02446899; n = 362) trials of intravenous anifrolumab (150/300 mg once every 4 weeks) in patients with moderate-to-severe SLE. Changes from baseline to week 52 in clinical assessments, PROs, and medical resource use were compared in BICLA responders versus nonresponders, regardless of treatment assignment. RESULTS: BICLA responders (n = 318) achieved significantly improved outcomes compared with nonresponders (n = 501), including lower flare rates, higher rates of attainment of sustained oral glucocorticoid taper to ≤7.5 mg/day, greater improvements in PROs (Functional Assessment of Chronic Illness Therapy-Fatigue, Short Form 36 Health Survey), and fewer SLE-related hospitalizations/emergency department visits (all nominal P < 0.001). Compared with nonresponders, BICLA responders had greater improvements in global and organ-specific disease activity (Physician's Global Assessment, SLE Disease Activity Index 2000, Cutaneous Lupus Erythematosus Disease Area and Severity Index Activity, and joint counts; all nominal P < 0.001). BICLA responders had fewer lupus-related serious adverse events than nonresponders. CONCLUSION: BICLA response is associated with clinical benefit in SLE assessments, PROs, and medical resource utilization, confirming its value as a clinical trial end point that is associated with measures important to patient care.

Translating research into clinical practice: quality improvement to halve non-adherence to methotrexate.

OBJECTIVE: MTX remains the cornerstone for therapy for RA, yet research shows that non-adherence is significant and correlates with response to therapy. This study aimed to halve self-reported non-adherence to MTX at the Kellgren Centre for Rheumatology. METHODS: An anonymous self-report adherence questionnaire was developed and data collected for 3 months prior to the introduction of interventions, and then regularly for the subsequent 2.5 years. A series of interventions were implemented, including motivational interviewing training, consistent information about MTX and development of a summary bookmark. Information on clinic times was collected for consultations with and without motivational interviewing. Surveys were conducted to ascertain consistency of messages about MTX. A biochemical assay was used to test MTX serum levels in patients at two time points: before and 2.8 years following introduction of the changes. Remission rates at 6 and 12 months post-MTX initiation were retrieved from patient notes and cost savings estimated by comparing actual numbers of new biologic starters compared with expected numbers based on the numbers of consultants employed at the two time points. RESULTS: Between June and August 2016, self-reported non-adherence to MTX was 24.7%. Following introduction of the interventions, self-reported non-adherence rates reduced to an average of 7.4% between April 2018 and August 2019. Clinic times were not significantly increased when motivational interviewing was employed. Consistency of messages by staff across three key areas (benefits of MTX, alcohol guidance and importance of adherence) improved from 64% in September 2016 to 94% in January 2018. Biochemical non-adherence reduced from 56% (September 2016) to 17% (June 2019), whilst remission rates 6 months post-initiation of MTX improved from 13% in 2014/15 to 37% in 2017/18, resulting is estimated cost savings of £30 000 per year. CONCLUSION: Non-adherence to MTX can be improved using simple measures including focussing on the adherence and the benefits of treatment, and providing consistent information across departments.

Generating evidence to inform health technology assessment of treatments for SLE: a systematic review of decision-analytic model-based economic evaluations.

This study aimed to understand and appraise the approaches taken to handle the complexities of a multisystem disease in published decision-analytic model-based economic evaluations of treatments for SLE. A systematic review was conducted to identify all published model-based economic evaluations of treatments for SLE. Treatments that were considered for inclusion comprised antimalarial agents, immunosuppressive therapies, and biologics including rituximab and belimumab. Medline and Embase were searched electronically from inception until September 2018. Titles and abstracts were screened against the inclusion criteria by two reviewers; agreement between reviewers was calculated according to Cohen's κ. Predefined data extraction tables were used to extract the key features, structural assumptions and data sources of input parameters from each economic evaluation. The completeness of reporting for the methods of each economic evaluation was appraised according to the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement. Six decision-analytic model-based economic evaluations were identified. The studies included azathioprine (n=4), mycophenolate mofetil (n=3), cyclophosphamide (n=2) and belimumab (n=1) as relevant comparator treatments; no economic evaluation estimated the relative cost-effectiveness of rituximab. Six items of the CHEERS statement were reported incompletely across the sample: target population, choice of comparators, measurement and valuation of preference-based outcomes, estimation of resource use and costs, choice of model, and the characterisation of heterogeneity. Complexity in the diagnosis, management and progression of disease can make decision-analytic model-based economic evaluations of treatments for SLE a challenge to undertake. The findings from this study can be used to improve the relevance of model-based economic evaluations in SLE and as an agenda for research to inform future health technology assessment and decision-making.

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.

Short-term efficacy and safety of rituximab therapy in refractory systemic lupus erythematosus: results from the British Isles Lupus Assessment Group Biologics Register.

Objectives: To describe the baseline characteristics of SLE patients requiring biologic therapy in the UK and to explore short term efficacy and infection rates associated with rituximab (RTX) use. Methods: Patients commencing biologic therapy for refractory SLE and who consented to join BILAG-BR were analysed. Baseline characteristics, disease activity (BILAG 2004/SLEDAI-2K) and rates of infection over follow-up were analysed. Response was defined as loss of all A and B BILAG scores to ⩽ 1 B score with no new A/B scores in other organ systems at 6 months. Results: Two hundred and seventy SLE patients commenced biologic therapy from September 2010 to September 2015, most commonly RTX (n = 261). Two hundred and fifty (93%) patients were taking glucocorticoids at baseline at a median [interquartile range (IQR)] oral dose of 10 mg (5-20 mg) daily. Response rates at 6 months were available for 68% of patients. The median (IQR) BILAG score was 15 (10-23) at baseline and 3 (2-12) at 6 months (P < 0.0001). The median (IQR) SLEDAI-2K reduced from 8 (5-12) to 4 (0-7) (P < 0.001). Response was achieved in 49% of patients. There was also a reduction in glucocorticoid use to a median (IQR) dose of 7.5 mg (5-12 mg) at 6 months (P < 0.001). Serious infections occurred in 26 (10%) patients, being more frequent in the first 3 months post-RTX therapy. A higher proportion of early infections were non-respiratory (odds ratio = 1.98, 95% CI: 0.99, 3.9; P = 0.049). Conclusion: RTX is safe and is associated with improvement in disease activity in refractory SLE patients with concomitant reductions in glucocorticoid use. Early vigilance for infection post-infusion is important to further improve treatment risks and benefits.

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.

American College of Rheumatology criteria at inception, and accrual over 5 years in the SLICC inception cohort.

OBJECTIVE: To determine the frequency of each American College of Rheumatology (ACR) criterion met at time of enrollment, and the increase in each of the criteria over 5 years. METHODS: In 2000 the Systemic Lupus International Collaborating Clinics (SLICC) recruited an international inception cohort of patients with systemic lupus erythematosus (SLE; ≥ 4 ACR criteria) who were followed at yearly intervals according to a standard protocol. Descriptive statistics were used to assess the total and cumulative number of ACR criteria met at each visit. Regression models were done to compare the increase of individual and cumulative criteria as a function of race/ethnicity group, and sex. RESULTS: In all, 768 patients have been followed for a minimum of 5 years. Overall, 59.1% of the patients had an increase in the number of ACR criteria they met over the 5-year period. The mean number of ACR criteria met at enrollment was 5.04 ± 1.13 and at year 5 was 6.03 ± 1.42. At enrollment, nonwhite patients had a higher number of ACR criteria (5.19 ± 1.23) than white patients. The total number of criteria increased in both white and nonwhite ethnicities, but increased more among whites. Males had a slightly lower number of criteria at enrollment compared to females and males accrued fewer criteria at 5 years. CONCLUSION: In this international inception cohort of SLE patients with at least 4 ACR criteria at entry, there was an accumulation of ACR criteria over the following 5 years. The distribution of criteria both at inception and over 5 years is affected by sex and ethnicity.

Comprehensive assessment of rheumatoid arthritis susceptibility loci in a large psoriatic arthritis cohort.

OBJECTIVE: A number of rheumatoid arthritis (RA) susceptibility genes have been identified in recent years. Given the overlap in phenotypic expression of synovial joint inflammation between RA and psoriatic arthritis (PsA), the authors explored whether RA susceptibility genes are also associated with PsA. METHODS: 56 single nucleotide polymorphisms (SNPs) mapping to 41 genes previously reported as RA susceptibility loci were selected for investigation. PsA was defined as an inflammatory arthritis associated with psoriasis and subjects were recruited from the UK and Ireland. Genotyping was performed using the Sequenom MassArray platform and frequencies compared with data derived from large UK control collections. RESULTS: Significant evidence for association with susceptibility to PsA was found toa SNP mapping to the REL (rs13017599, p(trend)=5.2×10(4)) gene, while nominal evidence for association (p(trend)<0.05) was found to seven other loci including PLCL2 (rs4535211, p=1.7×10(-3)); STAT4 (rs10181656, p=3.0×10(-3)) and the AFF3, CD28, CCL21, IL2 and KIF5A loci. Interestingly, three SNPs demonstrated opposite effects to those reported for RA. CONCLUSIONS: The REL gene, a key modulator of the NFκB pathway, is associated with PsA but the allele conferring risk to RA is protective in PsA suggesting that there are fundamental differences in the aetiological mechanisms underlying these two types of inflammatory arthritis.

Access to the next wave of biologic therapies (Abatacept and Tocilizumab) for the treatment of rheumatoid arthritis in England and Wales: addressing treatment outside the current NICE guidance.

Patients in England and Wales with rheumatoid arthritis (RA) receive treatment from the National Health Service (NHS) with therapies approved by the European Medicines Agency (EMA), under guidance from the National Institute for Health and Clinical Excellence (NICE). This document overviews the current NICE guidelines for the treatment of RA and identifies scenarios when such guidance may not represent the optimum management strategy for individual patients. Specifically, we consider the use of tocilizumab or abatacept as the most appropriate treatments for some patients. In such scenarios, it may be possible for the clinician to secure access to the required therapy through an application procedure known as an 'individual funding request', the process of which is described in detail here. At present, it is unclear the extent to which the proposed reform of the NHS will affect the role of NICE in providing guidance and setting standards of care. Until the full impact of the proposed changes are realized, individual funding requests will remain a valuable way of securing the optimal treatment for all patients suffering from RA.

Golimumab for the treatment of psoriatic arthritis: a NICE single technology appraisal.

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of golimumab (Schering-Plough/Centocor) to submit evidence for the clinical and cost effectiveness of this drug for the treatment of active and progressive psoriatic arthritis (PsA) in patients who have responded inadequately to previous disease-modifying anti-rheumatic drugs (DMARDs). The Centre for Reviews and Dissemination and the Centre for Health Economics at the University of York were commissioned to act as the Evidence Review Group (ERG) to critically appraise the evidence presented by the manufacturer. This article provides a description of the company submission, the ERG review and the resulting NICE guidance. The ERG critically reviewed the evidence presented in the manufacturer's submission and identified areas requiring clarification, for which the manufacturer provided additional evidence. The main clinical effectiveness data were derived from a single phase III randomized controlled trial (GO-REVEAL) that compared golimumab with placebo for the treatment of active and progressive patients who were symptomatic despite the use of previous DMARDs or NSAIDs. The 14-week data showed that, compared with placebo, golimumab 50 mg significantly improved joint disease response as measured by American College of Rheumatology (ACR) 20 (relative risk [RR] 5.73, 95% CI 3.24, 10.56) and Psoriatic Arthritis Response Criteria (PsARC) [RR 3.45, 95% CI 2.49, 4.87], and significantly improved skin disease response as measured by Psoriasis Area and Severity Index (PASI) 75 (RR 15.95, 95% CI 4.62, 59.11). The 24-week absolute data showed that these treatment benefits were maintained. There was a significant improvement in patients' functional status as measured by Health Assessment Questionnaire change from baseline at 24 weeks (-0.33; p < 0.001). The open-label extension data showed that these beneficial effects were also maintained at 52 and 104 weeks. The ERG identified several issues relating to the clinical effectiveness results. Analyses of the 24-week data were less robust, failing to adjust for treatment contamination due to patient crossover at week 16. It was also unclear if these results were generalizable to clinical practice. No randomized controlled trial compared the effectiveness of different biologic therapies head-to-head. To compare the effectiveness of the biologics etanercept, infliximab, adalimumab and golimumab, the manufacturer conducted a network meta-analysis, including the comparator palliative care (usual care including use of NSAIDs or DMARDs). The ERG considered the assumption of exchangeability between the trials for the purpose of the network meta-analysis to be acceptable and the statistical approach to be reliable. The results indicated somewhat lower efficacy with golimumab than with comparator biologics. The ERG identified a number of issues relating to the cost-effectiveness results. The manufacturer calculated incremental cost-effectiveness ratios (ICERs) incorrectly by comparing golimumab with palliative care instead of the most cost-effective alternative (etanercept). Despite the manufacturer's claim that golimumab was a cost-effective treatment option, the manufacturer's own model showed that golimumab was unlikely to be cost effective, relative to currently accepted thresholds, when the ICERs were correctly calculated using an incremental analysis (i.e. comparing each treatment to the next best alternative). None of the sensitivity analyses carried out by the manufacturer or the ERG regarding uncertainty in the estimates of clinical effectiveness, the acquisition and administration cost of drugs, the cost of treating psoriasis and the utility functions estimated to generate health outcomes changed this conclusion. However, a key area in determining the cost effectiveness of biologics was whether they should be treated as a class. The ERG concluded that if all biologics were considered equally effective, then etanercept, adalimumab and golimumab had almost equal costs and equal QALYs, and all had an ICER of about £15 000 per QALY versus palliative care, whilst infliximab, with a higher acquisition cost, was dominated by the other biologics. The Appraisal Committee altered its position between the Appraisal Consultation Document and the Final Appraisal Determination. It ultimately recommended that golimumab be provided as an option for the treatment of active and progressive PsA in adults only if (i) it is used as described for other tumour necrosis factor inhibitor treatments in 'Etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis' (NICE clinical guideline 199); and (ii) the manufacturer provides the 100 mg dose of golimumab at the same cost as the 50 mg dose.