Flares after hydroxychloroquine reduction or discontinuation: results from the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort.

OBJECTIVES: To evaluate systemic lupus erythematosus (SLE) flares following hydroxychloroquine (HCQ) reduction or discontinuation versus HCQ maintenance. METHODS: We analysed prospective data from the Systemic Lupus International Collaborating Clinics (SLICC) cohort, enrolled from 33 sites within 15 months of SLE diagnosis and followed annually (1999-2019). We evaluated person-time contributed while on the initial HCQ dose ('maintenance'), comparing this with person-time contributed after a first dose reduction, and after a first HCQ discontinuation. We estimated time to first flare, defined as either subsequent need for therapy augmentation, increase of ≥4 points in the SLE Disease Activity Index-2000, or hospitalisation for SLE. We estimated adjusted HRs (aHRs) with 95% CIs associated with reducing/discontinuing HCQ (vs maintenance). We also conducted separate multivariable hazard regressions in each HCQ subcohort to identify factors associated with flare. RESULTS: We studied 1460 (90% female) patients initiating HCQ. aHRs for first SLE flare were 1.20 (95% CI 1.04 to 1.38) and 1.56 (95% CI 1.31 to 1.86) for the HCQ reduction and discontinuation groups, respectively, versus HCQ maintenance. Patients with low educational level were at particular risk of flaring after HCQ discontinuation (aHR 1.43, 95% CI 1.09 to 1.87). Prednisone use at time-zero was associated with over 1.5-fold increase in flare risk in all HCQ subcohorts. CONCLUSIONS: SLE flare risk was higher after HCQ taper/discontinuation versus HCQ maintenance. Decisions to maintain, reduce or stop HCQ may affect specific subgroups differently, including those on prednisone and/or with low education. Further study of special groups (eg, seniors) may be helpful.

Geographic access to buprenorphine prescribers for patients who use public transit.

OBJECTIVE: Urban Medicaid enrollees with opioid use disorder often rely on public transit to reach buprenorphine prescribers. Research has not shown whether public transit provides this population with adequate geographic access to buprenorphine prescribers. We examined travel times to buprenorphine prescribers by car and public transit in urban areas, and determined whether car-based Medicaid regulatory standards produce their intended geographic coverage. METHODS: We obtained data for this study from the Substance Abuse and Mental Health Services Administration's Buprenorphine Practitioner Locator, Microsoft Bing Maps, and the American Community Survey. We examined four urban counties at the centers of the metropolitan statistical areas with the highest 2017 accidental drug poisoning death rates: Kanawha, WV; Montgomery, OH; Philadelphia, PA; and St. Louis City, MO. These counties comprised 696 census tracts representing 1,038,564 households. We calculated travel times from each census tract center to the nearest buprenorphine prescribers by car and public transit, and compared that to 30-min regulatory standards and by whether census tracts had below median levels of car access. We calculated Global Moran's I statistics to determine whether spatial clustering was present among census tracts with limited access to buprenorphine prescribers. RESULTS: Households in all but two census tracts could access a buprenorphine prescriber within 30 min by car. However, households in 12.1% (84) of census tracts could not do so by public transit. The correlation between car- and public transit-based travel times to the nearest buprenorphine prescriber was 0.11 (95% CI = 0.07-0.22). More than 15% (47,918) of households in the two less densely populated counties could not travel to the nearest prescriber in 30 min and resided in census tracts where access to cars was relatively low. There was no evidence of spatial clustering among census tracts with public transit travel times exceeding 30 min, or among census tracts with public transit travel times exceeding 30 min and below median values of access to cars. CONCLUSIONS: Geographic access to buprenorphine prescribers is overestimated by regulatory standards that apply car-based travel time estimates, which are a weak proxy for public transit-based travel times. Since geographic areas with limited access to buprenorphine prescribers do not tend to cluster near one another, individually targeted interventions may be necessary to improve buprenorphine access and utilization.

Body image mediates the impact of pain on depressive symptoms in patients with systemic lupus erythematosus.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with treatment manifestations that can cause changes in appearance, including skin rashes, alopecia, vitiligo, and scars. SLE has been shown to adversely impact body image outcomes, and previous research has identified that greater disease activity is associated with worse body image outcomes which, in turn, are associated with greater depressive symptoms. For patients with SLE who also experience significant pain, poor body image outcomes may further compromise wellbeing and lead to greater depressive symptoms. The role of pain in body image has not been explored in SLE. Thus, the present study examined whether body image (specifically, body image-related quality of life) serves as a mediator of the relationship between pain and depressive symptoms among patients with SLE. METHODS: Multiple mediation analysis was used to examine the hypothesis that body image-related quality of life mediates the relationship between pain and depressive symptoms in a sample of patients with SLE (N = 135) from an urban region in Los Angeles, California. RESULTS: The sample was predominately female (92.6%) with a mean disease duration of approximately 17 years. Approximately one-quarter of the sample had elevated depressive symptoms. Body image-related quality of life was a significant mediator in the relationship between pain and depressive symptoms. The model accounted for 51% of the total variance in depressive symptoms (R2 = 0.51). CONCLUSION: This cross-sectional study suggested that body image-related quality of life may mediate the effects of pain on depressive symptoms among patients with SLE.

Screening characteristics for enrichment of individuals at higher risk for transitioning to classified SLE.

OBJECTIVE: Further prospective study is needed to elucidate the etiology and natural history of systemic lupus erythematosus development. The clinical complexity of this heterogeneous disease makes study design challenging. Our objective was to ascertain useful screening factors for identifying at-risk individuals for follow-up rheumatologic assessment or inclusion in prospective studies. METHODS: We attempted to re-contact 3823 subjects with a family history of systemic lupus erythematosus, who did not meet American College of Rheumatology systemic lupus erythematosus classification at a baseline study visit; 436 agreed to follow-up participation an average of 6.3 years after baseline. In total, 56 of these individuals had transitioned to classified systemic lupus erythematosus (≥ 4 cumulative American College of Rheumatology criteria, verified by medical record review) by the time of follow up. Generalized estimating equations assessed associations between our dichotomous outcome of transitioning to systemic lupus erythematosus with baseline characteristics, including ANA positivity, Connective Tissue Disease Screening questionnaire systemic lupus erythematosus score, and number of American College of Rheumatology criteria. We analyzed predictive accuracy of characteristics on transitioning. RESULTS: ANA positivity, Connective Tissue Disease Screening questionnaire systemic lupus erythematosus score categorization of possible or probable systemic lupus erythematosus, and greater number of American College of Rheumatology criteria at baseline were each associated with transitioning to systemic lupus erythematosus classification. Being ANA positive and having confirmed immunologic criteria at baseline had the highest positive predictive value and specificity for transitioning to systemic lupus erythematosus. American College of Rheumatology Connective Tissue Disease Screening questionnaire systemic lupus erythematosus score categorization of possible or probable systemic lupus erythematosus had a better positive predictive value, negative predictive value, sensitivity, and specificity than ANA positivity. CONCLUSION: Given limited resources, identifying individuals for follow up based on the systemic lupus erythematosus portion of the Connective Tissue Disease Screening questionnaire could be an efficient way to identify family members at highest risk of disease transition.

Psychometric validation of the Arthritis Helplessness Index in systemic lupus erythematosus.

Objective Helplessness is a relevant construct in systemic lupus erythematosus (SLE), an unpredictable chronic illness with no known cure characterized by relapsing and remitting features. However, no measure of helplessness has been validated in this population. The present study examined the structural validity, reliability, and convergent validity of the Arthritis Helplessness Index, a measure initially developed for rheumatoid arthritis populations, in a sample of patients with SLE. Methods Patients with SLE ( N = 136) receiving medical care at a private hospital completed the Arthritis Helplessness Index and other self-report measures. The structural validity of the Arthritis Helplessness Index was examined using confirmatory factor analysis. Internal consistency reliability was evaluated with Cronbach's coefficient alpha. Pearson product-moment correlations were used to examine convergent validity with measures of depression, anxiety and mastery. Results The five-item Arthritis Helplessness Index-Helplessness measure demonstrated a tenable factor structure (comparative fit index 0.98, root mean square error of approximation 0.06, standardized root mean residual 0.04). Internal consistency reliability was fair (α = 0.69). Convergent validity was evidenced by significant correlations with measures of depression, anxiety and mastery. Conclusion The five-item Arthritis Helplessness Index-Helplessness scale can confidently be used as a measure of helplessness in SLE.

Less than 7 hours of sleep per night is associated with transitioning to systemic lupus erythematosus.

Background The role of sleep in the etiology of systemic lupus erythematosus (SLE) has not been well studied. We examined whether sleep duration was associated with subsequent transitioning to SLE in individuals at risk for SLE. Methods Four hundred and thirty-six relatives of SLE patients who did not have SLE themselves at baseline were evaluated again an average of 6.3 (± 3.9) years later. Fifty-six individuals transitioned to SLE (≥ 4 cumulative American College of Rheumatology (ACR) criteria). Sleep duration, medication use and medical history were assessed by questionnaire; ACR criteria were confirmed by medical record review. Vitamin D was measured by ELISA. Generalized estimating equations, accounting for correlation within families, assessed associations between baseline sleep and the outcome of transitioning to SLE. Results Reporting sleeping less than 7 hours per night at baseline was more common in those who subsequently transitioned than those who did not transition to SLE (55% versus 32%, p = 0.0005; OR: 2.8, 95% CI 1.6-4.9). Those who transitioned to SLE were more likely to sleep less than 7 hours per night than those who did not transition to SLE adjusting for age, sex and race (OR: 2.8, 95% CI 1.6-5.1). This association remained after individual adjustment for conditions and early symptoms that could affect sleep, including prednisone use, vitamin D deficiency and number of ACR criteria (OR: 2.0, 95% CI 1.1-4.2). Conclusion Lack of sleep may be associated with transitioning to SLE, independent of early clinical manifestations of SLE that may influence sleep duration. Further evaluation of sleeping patterns and biomarkers in at-risk individuals is warranted.

Computerized planimetry to assess clinical responsiveness in a phase II randomized trial of topical R333 for discoid lupus erythematosus.

BACKGROUND: R333 is a topical janus kinase and spleen tyrosine kinase inhibitor being evaluated for discoid lupus erythematosus (DLE) treatment. There is no validated measure to assess the area of active DLE lesions. OBJECTIVES: To evaluate R333 efficacy and assess a technique to measure responsiveness. METHODS: Fifty-four patients with DLE were randomized in a double-blind design to R333 or placebo. Primary end point was the proportion of patients achieving ≥ 50% decrease in erythema and scale based on lesional Cutaneous Lupus Erythematosus Disease Area and Severity IndexTM for all treated lesions at week 4. Two-dimensional (2D) area measurements for each lesion were recorded at baseline and weeks 1-6. Eighty-eight photographs (44 pre- and 44 post-treatment) were obtained from the trial and change in size of active areas was analysed by computerized planimetry and physician-assessed area change (PAAC). RESULTS: Thirty-six patients were randomized to R333 and 18 patients were randomized to placebo. Primary end point was not achieved. There was a strong association between lesion activity and physician global assessment (P < 0·001). Photos of 42 patients assessed by computerized planimetry demonstrated excellent inter- and intra-rater reliability. Area change by computerized planimetry showed a strong correlation with PAAC (Spearman r = 0·72). Area change by 2D measurements showed a weak correlation with PAAC (Spearman r = 0·29). CONCLUSIONS: Four weeks of R333 treatment did not result in significant improvement in lesion activity. Lesion activity and area change using computerized planimetry are better determinants of responsiveness than area change using 2D measurements.

Study of Flare Assessment in Systemic Lupus Erythematosus Based on Paper Patients.

OBJECTIVE: To determine the level of agreement of disease flare severity (distinguishing severe, moderate, and mild flare and persistent disease activity) in a large paper-patient exercise involving 988 individual cases of systemic lupus erythematosus. METHODS: A total of 988 individual lupus case histories were assessed by 3 individual physicians. Complete agreement about the degree of flare (or persistent disease activity) was obtained in 451 cases (46%), and these provided the reference standard for the second part of the study. This component used 3 flare activity instruments (the British Isles Lupus Assessment Group [BILAG] 2004, Safety of Estrogens in Lupus Erythematosus National Assessment [SELENA] flare index [SFI] and the revised SELENA flare index [rSFI]). The 451 patient case histories were distributed to 18 pairs of physicians, carefully randomized in a manner designed to ensure a fair case mix and equal distribution of flare according to severity. RESULTS: The 3-physician assessment of flare matched the level of flare using the 3 indices, with 67% for BILAG 2004, 72% for SFI, and 70% for rSFI. The corresponding weighted kappa coefficients for each instrument were 0.82, 0.59, and 0.74, respectively. We undertook a detailed analysis of the discrepant cases and several factors emerged, including a tendency to score moderate flares as severe and persistent activity as flare, especially when the SFI and rSFI instruments were used. Overscoring was also driven by scoring treatment change as flare, even if there were no new or worsening clinical features. CONCLUSION: Given the complexity of assessing lupus flare, we were encouraged by the overall results reported. However, the problem of capturing lupus flare accurately is not completely solved.

Breast cancer in systemic lupus erythematosus (SLE): receptor status and treatment.

Objective There is a decreased risk of breast cancer in systemic lupus erythematosus (SLE) versus the general population; little is known regarding the receptor status of breast cancers in SLE, or treatment. Methods Breast cancer cases occurring after SLE diagnosis were ascertained through linkage with tumor registries. We determined breast cancer positivity for estrogen receptors (ER), progesterone receptors (PR), and/or Human Epidermal Growth Factor Receptor 2 (HER2), as well as cancer treatment. Results We obtained information on ER, PR, and/or HER2 status for 63 SLE patients with breast cancer. Fifty-three had information on ER and/or PR status; 36 of these (69%) were ER positive. Thirty-six of the 63 had information on HER2 status; of these, 26 had complete information on all three receptors. Twenty-one of these 26 (81%) were HER2 negative; seven of 26(27%) were triple negative. All but one patient underwent surgery; 11.5% received both non-tamoxifen chemotherapy and radiotherapy, 16.4% radiotherapy without non-tamoxifen chemotherapy, and 14.7% received non-tamoxifen chemotherapy without radiotherapy. Conclusion ER positivity was similar to historical general population figures, with a trend toward a higher proportion of triple-negative breast cancers in SLE (possibly reflecting the relatively young age of our SLE patients).

The prevalence and determinants of anti-DFS70 autoantibodies in an international inception cohort of systemic lupus erythematosus patients.

Autoantibodies to dense fine speckles 70 (DFS70) are purported to rule out the diagnosis of SLE when they occur in the absence of other SLE-related autoantibodies. This study is the first to report the prevalence of anti-DFS70 in an early, multinational inception SLE cohort and examine demographic, clinical, and autoantibody associations. Patients were enrolled in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort within 15 months of diagnosis. The association between anti-DFS70 and multiple parameters in 1137 patients was assessed using univariate and multivariate logistic regression. The frequency of anti-DFS70 was 7.1% (95% CI: 5.7-8.8%), while only 1.1% (95% CI: 0.6-1.9%) were monospecific for anti-DFS70. In multivariate analysis, patients with musculoskeletal activity (Odds Ratio (OR) 1.24 [95% CI: 1.10, 1.41]) or with anti-ß2 glycoprotein 1 (OR 2.17 [95% CI: 1.22, 3.87]) were more likely and patients with anti-dsDNA (OR 0.53 [95% CI: 0.31, 0.92]) or anti-SSB/La (OR 0.25 [95% CI: 0.08, 0.81]) were less likely to have anti-DFS70. In this study, the prevalence of anti-DFS70 was higher than the range previously published for adult SLE (7.1 versus 0-2.8%) and was associated with musculoskeletal activity and anti-ß2 glycoprotein 1 autoantibodies. However, 'monospecific' anti-DFS70 autoantibodies were rare (1.1%) and therefore may be helpful to discriminate between ANA-positive healthy individuals and SLE.

The psychometric properties of the Perceived Stress Scale-10 among patients with systemic lupus erythematosus.

Objective Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease characterized by periods of remission and recurrent flares, which have been associated with stress. Despite the significance of stress in this disease, the Perceived Stress Scale-10 has yet to be psychometrically evaluated in patients with SLE. Methods Exploratory factor analysis was used to examine the structural validity of the Perceived Stress Scale-10 among patients with SLE ( N = 138) receiving medical care at Cedars Sinai Medical Center. Cronbach's coefficient alpha was used to examine internal consistency reliability, and Pearson product-moment correlations were used to examine convergent validity with measures of anxiety, depression, helplessness, and disease activity. Results Exploratory factor analysis provided support for a two-factor structure (comparative fit index = .95; standardized root mean residual = .04; root mean square error of approximation = .08). Internal consistency reliability was good for both factors (α = .84 and .86). Convergent validity was evidenced via significant correlations with measures of anxiety, depression, and helplessness. There were no significant correlations with the measure of disease activity. Conclusion The Perceived Stress Scale-10 can be used to examine perceived stress among patients with SLE.

Failure of a systemic lupus erythematosus response index developed from clinical trial data: lessons examined and learned.

Background Our primary goal was to create an outcome change score index similar to a standard rheumatoid arthritis (RA) model utilizing real-world data in systemic lupus erythematosus (SLE) patients that occurred during their phase 3 trials with a Food and Drug Administration-approved drug. Methods We utilized raw data from trials of belimumab for the treatment of SLE. Data were split 80/20 into training/validation sets. Index variables present in a majority of patients and with face validity were selected. Variables were scored for each patient as percentage improvement from baseline after one year. The percentage of placebo- and drug-treated patients considered improved after the application of various criteria was ascertained. Logistic regression was employed to determine the ability of the new index to predict treatment assignment. Results A total of 1693 subjects had data for analyses. Eight variables were chosen: arthritis, rash, physician global assessment, fatigue, anti-double stranded DNA antibodies, C3, C4 and C-reactive protein. In the training dataset, ≥20% improvement in ≥4 of eight variables produced the largest difference between placebo- and drug-treated patients (22.1%) with an acceptable rate of improved placebo-treated patients (25%). This resulted in an odds ratio for belimumab (10 mg/kg) vs placebo of 2.7 (95% CI: 2.0-3.6; p < 0.001). However, in the validate dataset the odds ratio was not significant at 1.3 (95% CI: 0.8-2.2; p = 0.863). Conclusions The index created from training data did not achieve statistical significance when tested in the validation set. We have speculated why this happened. Is the lack of success of therapeutics for SLE caused by ineffective medications, study design and outcome instruments that fail to inform us, or is the heterogeneity of the disease too daunting? The lessons learned here can help direct future endeavors intended to improve SLE outcome instruments.

Improved strategies for designing lupus trials with targeted therapies: learning from 65 years of experience.

The development of new agents to manage lupus erythematosus has lagged behind other autoimmune rheumatic diseases. This is in large part because lupus is a heterogeneous disorder affecting nine principal domains (organ systems) that are difficult to measure and quantify and can be at variance with each other. Over the last two decades, a variety of guidelines, definitions, candidate surrogate or biomarkers, metrics and composite indices have been presented as benchmarks that can be utilized to assess lupus in clinical trials. Despite this, over 20 agents have failed to achieve their primary outcome measure, some of which are generally believed to be clinically effective. This article presents constructive suggestions and improved strategies in trial design that will hopefully lead to the introduction of new agents for the disease.

Cardiovascular events prior to or early after diagnosis of systemic lupus erythematosus in the systemic lupus international collaborating clinics cohort.

OBJECTIVE: To describe the frequency of myocardial infarction (MI) prior to the diagnosis of systemic lupus erythematosus (SLE) and within the first 2 years of follow-up. METHODS: The systemic lupus international collaborating clinics (SLICC) atherosclerosis inception cohort enters patients within 15 months of SLE diagnosis. MIs were reported and attributed on a specialised vascular event form. MIs were confirmed by one or more of the following: abnormal ECG, typical or atypical symptoms with ECG abnormalities and elevated enzymes (≥2 times upper limit of normal), or abnormal stress test, echocardiogram, nuclear scan or angiogram. Descriptive statistics were used. RESULTS: 31 of 1848 patients who entered the cohort had an MI. Of those, 23 patients had an MI prior to SLE diagnosis or within the first 2 years of disease. Of the 23 patients studied, 60.9% were female, 78.3% were Caucasian, 8.7% black, 8.7% Hispanic and 4.3% other. The mean age at SLE diagnosis was 52.5±15.0 years. Of the 23 MIs that occurred, 16 MIs occurred at a mean of 6.1±7.0 years prior to diagnosis and 7 occurred within the first 2 years of follow-up. Risk factors associated with early MI in univariate analysis are male sex, Caucasian, older age at diagnosis, hypertension, hypercholesterolaemia, family history of MI and smoking. In multivariate analysis only age (OR=1.06 95% CI 1.03 to 1.09), hypertension (OR=5.01, 95% CI 1.38 to 18.23), hypercholesterolaemia (OR=4.43, 95% CI 1.51 to 12.99) and smoking (OR=7.50, 95% CI 2.38 to 23.57) remained significant risk factors. CONCLUSIONS: In some patients with lupus, MI may develop even before the diagnosis of SLE or shortly thereafter, suggesting that there may be a link between autoimmune inflammation and atherosclerosis.

Long-Term Safety and Efficacy of Epratuzumab in the Treatment of Moderate-to- Severe Systemic Lupus Erythematosus: Results From an Open-Label Extension Study.

OBJECTIVE: The primary objective was to assess the long-term safety of repeated courses of epratuzumab therapy in patients with moderate-to-severe systemic lupus erythematosus. Secondary objectives were to assess long-term efficacy and health-related quality of life (HRQOL). METHODS: Eligible patients from the 12-week, phase IIb, randomized, placebo-controlled EMBLEM study enrolled into the open-label extension (OLE) study, SL0008. In the SL0008 study, patients received 1,200 mg epratuzumab infusions at weeks 0 and 2 of repeating 12-week cycles, plus standard of care. Safety measures included treatment-emergent adverse events (TEAEs) and serious TEAEs. Efficacy measures included combined treatment response, the British Isles Lupus Assessment Group score, the Systemic Lupus Erythematosus Disease Activity Index score, and the physician's and patient's global assessment of disease activity. Total daily corticosteroid dose and HRQOL (by the Short Form 36 health survey) were also assessed. RESULTS: A total of 113 of the 203 patients (55.7%) who entered the SL0008 study continued epratuzumab therapy until study closure (total cumulative exposure: 381.3 patient-years, median exposure: 845 days, and maximum exposure: 1,185 days/approximately 3.2 years). TEAEs were reported in 192 patients (94.6%); most common were infections and infestations (68.0%, 138 patients). Serious TEAEs were reported in 51 patients (25.1%), and 14 patients (6.9%) had serious infections. In patients treated for 108 weeks (n = 116), the median corticosteroid dose was reduced from 10.0 mg/day at OLE screening to 5.0 mg/day at week 108. Improvements in efficacy and HRQOL measures in EMBLEM were maintained in the OLE, while placebo patients exhibited similar improvements in disease activity upon a switch to epratuzumab. CONCLUSION: Open-label epratuzumab treatment was well tolerated for up to 3.2 years, and associated with sustained improvements in disease activity and HRQOL, while steroids were reduced.

Efficacy and safety of subcutaneous tabalumab in patients with systemic lupus erythematosus: results from ILLUMINATE-1, a 52-week, phase III, multicentre, randomised, double-blind, placebo-controlled study.

OBJECTIVES: Evaluate efficacy and safety of tabalumab, a human IgG4 monoclonal antibody that binds and neutralises membrane and soluble B-cell activating factor (BAFF) versus placebo plus standard of care (SoC) in patients with systemic lupus erythematosus (SLE). METHODS: This phase III, 52-week study randomised 1164 patients with moderate-to-severe SLE (Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index ≥6 at baseline). Patients received SoC plus subcutaneous injections of tabalumab or placebo, starting with a loading dose (240 mg) at week 0 and followed by 120 mg every two weeks (120 Q2W, n=387), 120 mg every four weeks (120 Q4W, n=389) or placebo Q2W (n=388). PRIMARY ENDPOINT: proportion of patients achieving SLE Responder Index 5 (SRI-5) response at week 52. RESULTS: Similar proportions of patients in each group achieved SRI-5 response at week 52 (120 Q2W: 31.8%; 120 Q4W: 35.2% and placebo: 29.3%). Key secondary endpoints were not met. In a sensitivity analysis not excluding patients who decreased antimalarials or immunosuppressants, SRI-5 response was achieved with 120 Q4W (37.0% vs 29.8% placebo; p=0.021), but not 120 Q2W (34.1%; p=0.171). Significant reductions in anti-dsDNA antibodies, increases in C3 and C4, and reductions in total B cells and immunoglobulins were observed with tabalumab. No differences were observed between treatment groups in percentage of deaths (120 Q2W: 0.8%; 120 Q4W: 0.5%; placebo: 0.5%), serious adverse events (AEs) (range 11.1-14.4%) or treatment-emergent AEs (range 81.1-82.3%). CONCLUSIONS: Tabalumab had biological activity-changes in anti-dsDNA, complement, B cells and immunoglobulins-consistent with BAFF pathway inhibition. Key clinical efficacy endpoints did not achieve statistical significance. Safety profiles were similar with tabalumab and placebo. TRIAL REGISTRATION NUMBER: NCT01196091.

Anti-C1q antibodies in systemic lupus erythematosus.

OBJECTIVE: Anti-C1q has been associated with systemic lupus erythematosus (SLE) and lupus nephritis in previous studies. We studied anti-C1q specificity for SLE (vs rheumatic disease controls) and the association with SLE manifestations in an international multicenter study. METHODS: Information and blood samples were obtained in a cross-sectional study from patients with SLE (n = 308) and other rheumatologic diseases (n = 389) from 25 clinical sites (84% female, 68% Caucasian, 17% African descent, 8% Asian, 7% other). IgG anti-C1q against the collagen-like region was measured by ELISA. RESULTS: Prevalence of anti-C1q was 28% (86/308) in patients with SLE and 13% (49/389) in controls (OR = 2.7, 95% CI: 1.8-4, p < 0.001). Anti-C1q was associated with proteinuria (OR = 3.0, 95% CI: 1.7-5.1, p < 0.001), red cell casts (OR = 2.6, 95% CI: 1.2-5.4, p = 0.015), anti-dsDNA (OR = 3.4, 95% CI: 1.9-6.1, p < 0.001) and anti-Smith (OR = 2.8, 95% CI: 1.5-5.0, p = 0.01). Anti-C1q was independently associated with renal involvement after adjustment for demographics, ANA, anti-dsDNA and low complement (OR = 2.3, 95% CI: 1.3-4.2, p < 0.01). Simultaneously positive anti-C1q, anti-dsDNA and low complement was strongly associated with renal involvement (OR = 14.9, 95% CI: 5.8-38.4, p < 0.01). CONCLUSIONS: Anti-C1q was more common in patients with SLE and those of Asian race/ethnicity. We confirmed a significant association of anti-C1q with renal involvement, independent of demographics and other serologies. Anti-C1q in combination with anti-dsDNA and low complement was the strongest serological association with renal involvement. These data support the usefulness of anti-C1q in SLE, especially in lupus nephritis.

The importance of implementing proper selection of excipients in lupus clinical trials.

Peptide therapeutics hold attractive potential. However, the proper stabilization of such therapeutics remains a major challenge. Some peptides are marginally stable and are prone to degradation. Therefore, in addition to chemical modifications that can be introduced in their sequence, a wide variety of excipients are added in the formulation to stabilize them, as is also done routinely for protein therapeutics. These substances are supposed to suppress peptide/protein aggregation and surface adsorption, facilitate their dispersion and additionally to provide physiological osmolality. Particular attention has to be paid to the choice of such excipients. Here we highlight the observation that in certain clinical situations, an excipient that is not totally inert can play a highly damaging role and mask (or even reverse) the beneficial effect of a molecule in clinical evaluation. This is the case, for instance, of trehalose, a normally safe excipient, which notably has proven to act as an activator of autophagy. This excipient, although used efficiently in several therapeutics, adversely impacted a phase IIb clinical trial for human and murine lupus, a systemic autoimmune disease in which it has been recently discovered that at the base line, autophagy is already abnormally enhanced in lymphocytes. Thus, in this particular pathology, while the peptide that was tested was active in lupus patients when formulated in mannitol, it was not efficient when formulated in trehalose. This observation is important, since autophagy is enhanced in a variety of pathological situations, such as obesity, diabetes, certain neurological diseases, and cancer.