Faculty Bibliography

Background While there is overwhelming evidence for the beneficial role of hydroxychloroquine (HCQ) in SLE, little is known about its economic impact. We estimated annual direct, indirect, and total costs (DC, IC, TC) associated with HCQ use. Methods A subset of patients from the Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) inception cohort were assessed annually between 2014 and 2019 for health resource use, lost work-force/non-work-force productivity and concurrent HCQ use. Resource use was costed using 2021 Canadian prices and lost productivity using Statistics Canada age-and-sex specific wages. At each assessment, HCQ dose over the past year and weight were documented and patients were stratified into 1 of 3 HCQ dosage groups: nonusers (0 mg/kg/day), low-intensity users (<= 5 mg/kg/day), or high-intensity users (>5 mg/kg/day). Costs associated with HCQ dose were calculated by averaging all observations within each dosage group. Multiple random effects linear regressions adjusted for the possible confounding of age at diagnosis, sex, race/ethnicity, disease duration, geographic region, education, alcohol use, and smoking on the association between annual DC and IC and HCQ dose. A possible mediating effect of disease damage (SLICC/ACR DI) on these associations was also investigated. Results 661 patients (89.4% female, 59.3% non-Caucasian race/ethnicity, mean age and mean disease duration at the start of economic assessments was 42.1 years and 9.5 years, respectively) were followed over a mean of 2.8 years. Across 1536 annual assessments, 36.1% of observations were provided by HCQ non-users, 43.1% by low-intensity users (mean dosage 3.4 mg/kg/day), and 20.8% by high-intensity users (mean dosage 5.9 mg/kg/day). Annual adjusted DC were higher in nonusers ($9599) versus low-intensity users ($6344) and highintensity users ($6333) (table 1). When disease damage was included in the regression, there were no significant differences in DC between dosage groups. While unadjusted IC were higher in non-users ($37,610) versus low-intensity users ($32,480) and high-intensity users ($31,418), adjusted IC did not differ. Adjusted TC were higher in non-users ($46,157) versus low-intensity users ($39,257) and high-intensity users ($37,634). Conclusion SLE patients reported higher adjusted annual DC and TC during periods of HCQ non-use versus periods of use, regardless of the intensity of use. There was no additional cost savings in those using high intensity dosages. The cost-savings effect of HCQ could potentially be partially mediated through reduced damage. In addition to its well-established therapeutic potential, there may be an economic imperative for HCQ use in SLE patients

In this issue of Arthritis & Rheumatology, the paper by Isenberg et al, entitled Efficacy, Safety, and Pharmacodynamic Effects of the Bruton's Tyrosine Kinase Inhibitor, Fenebrutinib (GDC-0853), in Systemic Lupus Erythematosus reports results of a Phase 2 trial of fenebrutinib, an inhibitor of Bruton's tyrosine kinase (BTK). This treatment met expected pharmacodynamic targets, decreasing phosphorylated BTK, dampening plasmablast signals, and lowering anti-dsDNA and IgG. No concerning safety signal was observed.

OBJECTIVES/OBJECTIVE:To determine predictors for change in neuropsychiatric (NP) event status in a large, prospective, international, inception cohort of SLE patients 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 onset and resolution of NP events were determined by time-to-event analysis using a multistate modelling structure. RESULTS:NP events occurred in 955/1,827 (52.3%) patients and 592/1910 (31.0%) unique events were attributed to SLE. For SLE NP events multivariate analysis revealed positive associations with male sex, concurrent non-SLE NP events excluding headache, active SLE and corticosteroids. There was a negative association with Asian race/ethnicity, post-secondary education, and immunosuppressive or anti-malarial drugs. For non-SLE NP events, excluding headache, there was a positive association with concurrent SLE NP events and negative associations with African and Asian race/ethnicity. NP events attributed to SLE had a higher resolution rate than non-SLE NP events, with the exception of headache that had comparable resolution rates. For SLE NP events, multivariate analysis revealed resolution was more common with Asian race/ethnicity and for central/focal NP events. For non-SLE NP events resolution was more common with African race/ethnicity and less common with older age at SLE diagnosis. CONCLUSIONS: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.

OBJECTIVE:To assess cancer risk factors in incident SLE. METHODS:Clinical variables and cancer outcomes were assessed annually among incident SLE patients. Multivariate hazard regression models (over-all risk, and most common cancers) included demographics and time-dependent medications (corticosteroids, antimalarial drugs, immunosuppressants), smoking, and adjusted mean SLE Disease Activity Index-2K. RESULTS:Among 1668 patients (average 9 years follow-up), 65 cancers occurred: 15 breast, 10 non-melanoma skin, seven lung, six hematological, six prostate, five melanoma, three cervical, three renal, two each gastric, head and neck, and thyroid, and one each rectal, sarcoma, thymoma, and uterine cancers. Half of cancers (including all lung cancers) occurred in past/current smokers, versus one-third of patients without cancer. Multivariate analyses indicated over-all cancer risk was related primarily to male sex and older age at SLE diagnosis. In addition, smoking was associated with lung cancer. For breast cancer risk, age was positively and anti-malarial drugs were negatively associated. Anti-malarial drugs and higher disease activity were also negatively associated with non-melanoma skin cancer (NMSC) risk, whereas age and cyclophosphamide were positively associated. Disease activity was associated positively with hematologic and negatively with NMSC risk. CONCLUSIONS:Smoking is a key modifiable risk factor, especially for lung cancer, in SLE. Immunosuppressive medications were not clearly associated with higher risk except for cyclophosphamide and NMSC. Antimalarials were negatively associated with breast cancer and NMSC risk. SLE activity was associated positively with hematologic cancer and negatively with NMSC. Since the absolute number of cancers was small, additional follow-up will help consolidate these findings.

OBJECTIVE:Anti-beta 2 glycoprotein I IgA is a common isotype of anti-beta 2 glycoprotein I in SLE. Anti-beta 2 glycoprotein I was not included in the American College of Rheumatology (ACR) SLE classification criteria, but was included in the Systemic Lupus International Collaborating Clinics (SLICC) criteria. We aimed to evaluate the prevalence of anti-beta 2-glycoprotein I IgA in SLE versus other rheumatic diseases. In addition, we examined the association between anti-beta 2 glycoprotein I IgA and disease manifestations in SLE. METHODS:The dataset consisted of 1384 patients, 657 with a consensus physician diagnosis of SLE and 727 controls with other rheumatic diseases. Anti-beta 2 glycoprotein I isotypes were measured by ELISA. Patients with a consensus diagnosis of SLE were compared to controls with respect to presence of anti-beta 2 glycoprotein I. Among patients with SLE, we assessed the association between anti-beta 2 glycoprotein I IgA and clinical manifestations. RESULTS:The prevalence of anti-beta 2 glycoprotein I IgA was 14% in SLE patients and 7% in rheumatic disease controls (odds ratio, OR 2.3, 95% CI: 1.6, 3.3). It was more common in SLE patients who were younger patients and of African descent (p = 0.019). Eleven percent of SLE patients had anti-beta 2 glycoprotein I IgA alone (no anti-beta 2 glycoprotein I IgG or IgM). There was a significant association between anti-beta 2 glycoprotein I IgA and anti-dsDNA (p = 0.001) and the other antiphospholipid antibodies (p = 0.0004). There was no significant correlation of anti-beta 2 glycoprotein I IgA with any of the other ACR or SLICC clinical criteria for SLE. Those with anti-beta 2 glycoprotein I IgA tended to have a history of thrombosis (12% vs 6%, p = 0.071), but the difference was not statistically significant. CONCLUSION/CONCLUSIONS:We found the anti-beta 2 glycoprotein I IgA isotype to be more common in patients with SLE and in particular, with African descent. It could occur alone without other isotypes.

BACKGROUND:Outcome measures of clinical trials in cutaneous lupus erythematosus (CLE) should reflect clinically meaningful improvement in disease activity, as measured by the Cutaneous Lupus Disease Area and Severity Index activity score (CLASI-A). OBJECTIVE:We aim to define the degree of improvement in disease activity meaningful to a patient's quality of life (QoL). METHODS:The change in the CLASI-A in 126 patients needed to predict meaningful change in QoL, as defined by the Emotions and Symptoms subscales of Skindex-29, was evaluated by linear regression models. RESULTS:In patients with an initial CLASI-A ≥8, a 42.1% or ≥7-point and a 31.0% or ≥5-point decrease in CLASI-A predicts meaningful improvement in the Emotions and the Symptoms subscales, respectively. LIMITATIONS/CONCLUSIONS:This is a retrospective study of prospectively collected data at a single site. CONCLUSIONS:A CLASI-A score ≥8 for trial entry allows for inclusion of patients with milder disease where CLASI-A improvement by ≥50% is clinically significant and meaningful.

OBJECTIVE:The Systemic Lupus International Collaborating Clinics (SLICC) 2012 SLE classification criteria and the revised American College of Rheumatology (ACR) 1997 criteria are list-based, counting each SLE manifestation equally. We derived a classification rule based on giving variable weights to the SLICC criteria, and compared its performance to the revised ACR 1997, unweighted SLICC 2012 and the newly reported European League Against Rheumatism (EULAR)/ACR 2019 criteria. METHODS:The physician-rated patient scenarios used to develop the SLICC 2012 classification criteria were re-employed to devise a new weighted classification rule using multiple linear regression. The performance of the rule was evaluated on an independent set of expert-diagnosed patient scenarios and compared to the performance of the previously reported classification rules. RESULTS:Weighted SLICC criteria and the EULAR/ACR 2019 criteria had less sensitivity but better specificity compared to the list-based revised ACR 1997 and SLICC 2012 classification criteria. There were no statistically significant differences between any pair of rules with respect to overall agreement with the physician diagnosis. CONCLUSION/CONCLUSIONS:The two new weighted classification rules did not perform better than the existing list-based rules in terms of overall agreement on a dataset originally generated to assess the SLICC criteria. Given the added complexity of summing weights, researchers may prefer the unweighted SLICC criteria. However, the performance of a classification rule will always depend on the populations from which the cases and non-cases are derived, and whether the goal is to prioritize sensitivity or specificity.

OBJECTIVE:Low disease activity (LDA) and remission are emerging treat-to-target (T2T) endpoints in SLE. However, the rates at which these endpoints are met in patients with high disease activity (HDA) are unknown. Atacicept, which targets B lymphocyte stimulator and a proliferation-inducing ligand, improved disease outcomes in SLE patients with HDA (SLEDAI-2K ≥10) at baseline in the phase 2b ADDRESS II study. This is a post hoc analysis of T2T endpoints in these patients. METHODS:Patients received weekly atacicept (75 or 150 mg s.c.) or placebo for 24 weeks (1:1:1 randomization). Attainment of three T2T endpoints, LDA (SLEDAI-2K ≤ 2), Lupus Low Disease Activity State (LLDAS) and remission (clinical SLEDAI-2K = 0, prednisone-equivalent ≤5mg/day and Physician's Global Assessment <0.5), was assessed and compared with SLE Responder Index (SRI)-4 and SRI-6 response. RESULTS:Of 306 randomized patients, 158 (51.6%) had baseline HDA. At week 24, 37 (23.4%) HDA patients attained LDA, 25 (15.8%) LLDAS and 17 (10.8%) remission. Each of these endpoints was more stringent than SRI-4 (n = 87; 55.1%) and SRI-6 (n = 67; 42.4%). Compared with placebo (n = 52), at week 24, patients treated with atacicept 150 mg (n = 51) were more likely to attain LDA [odds ratio (OR) 3.82 (95% CI: 1.44, 10.15), P = 0.007], LLDAS [OR 5.03 (95% CI: 1.32, 19.06), P = 0.018] or remission [OR 3.98 (95% CI: 0.78, 20.15), P = 0.095]. CONCLUSION:At week 24, LDA, LLDAS and remission were more stringent than SRI-4 and SRI-6 response, were attainable in the HDA population and discriminated between treatment with atacicept 150 mg and placebo. These results suggest that T2T endpoints are robust outcome measures in SLE clinical trials and support further evaluation of atacicept in SLE. TRAIL REGISTRATION:ClinicalTrials.gov, http://clinicaltrials.gov, NCT01972568.

Background/UNASSIGNED:The clinical and pathologic diversity of systemic lupus erythematosus (SLE) hinders diagnosis, management, and treatment development. This study addresses heterogeneity in SLE through comprehensive molecular phenotyping and machine learning clustering. Methods/UNASSIGNED: = 13) were assessed by multiplex bead-based assays and ELISAs. Patient clusters were identified by machine learning combining K-means clustering and random forest analysis of co-expression module scores and soluble mediators. Findings/UNASSIGNED:SLEDAI scores correlated with interferon, plasma cell, and select cell cycle modules, and with circulating IFN-α, IP10, and IL-1α levels. Co-expression modules and soluble mediators differentiated seven clusters of SLE patients with unique molecular phenotypes. Inflammation and interferon modules were elevated in Clusters 1 (moderately) and 4 (strongly), with decreased T cell modules in Cluster 4. Monocyte, neutrophil, plasmablast, B cell, and T cell modules distinguished the remaining clusters. Active clinical features were similar across clusters. Clinical SLEDAI trended highest in Clusters 3 and 4, though Cluster 3 lacked strong interferon and inflammation signatures. Renal activity was more frequent in Cluster 4, and rare in Clusters 2, 5, and 7. Serology findings were lowest in Clusters 2 and 5. Musculoskeletal and mucocutaneous activity were common in all clusters. Interpretation/UNASSIGNED:Molecular profiles distinguish SLE subsets that are not apparent from clinical information. Prospective longitudinal studies of these profiles may help improve prognostic evaluation, clinical trial design, and precision medicine approaches. Funding/UNASSIGNED:US National Institutes of Health.