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Efficacy and Safety of Upadacitinib or Elsubrutinib Alone or in Combination for Patients With Systemic Lupus Erythematosus: A Phase 2 Randomized Controlled Trial

Merrill, Joan T; Tanaka, Yoshiya; D'Cruz, David; Vila-Rivera, Karina; Siri, Daniel; Zeng, Xiaofeng; Saxena, Amit; Aringer, Martin; D'Silva, Kristin M; Cheng, Ling; Mohamed, Mohamed-Eslam F; Siovitz, Lucia; Bhatnagar, Sumit; Gaudreau, Marie-Claude; Doan, Thao T; Friedman, Alan
OBJECTIVE:The 48-week, phase 2 SLEek study (NCT03978520) evaluated the efficacy and safety of upadacitinib (JAK inhibitor) and elsubrutinib (BTK inhibitor) alone or in combination (ABBV-599) in adults with moderately to severely active systemic lupus erythematosus (SLE). METHODS:Patients were randomized 1:1:1:1:1 to elsubrutinib 60 mg and upadacitinib 30 mg once daily (ABBV-599 high dose), elsubrutinib 60 mg and upadacitinib 15 mg once daily (ABBV-599 low dose), elsubrutinib 60 mg once daily (QD), upadacitinib 30 mg QD, or placebo QD. The primary endpoint was the proportion of patients achieving both Systemic Lupus Erythematosus Responder Index 4 (SRI-4) and glucocorticoid dose ≤10 mg QD at week 24. Additional assessments through week 48 included British Isles Lupus Assessment Group-Based Composite Lupus Assessment (BICLA) and Lupus Low Disease Activity State (LLDAS) responses, number of flares, time to first flare, and adverse events. RESULTS:The study enrolled 341 patients. The ABBV-599 low dose and elsubrutinib arms were discontinued after a planned interim analysis showed lack of efficacy (no safety concerns). More patients achieved the primary endpoint with upadacitinib (54.8%; P = 0.028) and ABBV-599 high dose (48.5%; P = 0.081) versus placebo (37.3%). SRI-4, BICLA, and LLDAS response rates were higher for both upadacitinib and ABBV-599 high dose versus placebo at weeks 24 and 48. Flares were reduced, and time to first flare through week 48 was substantially delayed with both upadacitinib and ABBV-599 high dose versus placebo. No new safety signals were observed beyond those previously reported for upadacitinib or elsubrutinib. CONCLUSION/CONCLUSIONS:Upadacitinib 30 mg alone or in combination with elsubrutinib (ABBV-599 high dose) demonstrated significant improvements in SLE disease activity and reduced flares and were well tolerated through 48 weeks.
PMID: 38923871
ISSN: 2326-5205
CID: 5695672

Anti-KIF20B autoantibodies are associated with cranial neuropathy in systemic lupus erythematosus

Krustev, Eugene; Hanly, John G; Chin, Ricky; Buhler, Katherine A; Urowitz, Murray B; Gordon, Caroline; Bae, Sang-Cheol; Romero-Diaz, Juanita; Sánchez-Guerrero, Jorge; Bernatsky, Sasha; Wallace, Daniel J; Isenberg, David; Rahman, Anisur; Merrill, Joan T; Fortin, Paul R; Gladman, Dafna D; Bruce, Ian N; Petri, Michelle A; Ginzler, Ellen M; Dooley, Mary Anne; Ramsey-Goldman, Rosalind; Manzi, Susan; Jönsen, Andreas; Alarcón, Graciela S; van Vollenhoven, Ronald F; Aranow, Cynthia; Mackay, Meggan; Ruiz-Irastorza, Guillermo; Lim, Sam; Inanc, Murat; Kalunian, Kenneth C; Jacobsen, Søren; Peschken, Christine A; Kamen, Diane L; Askenase, Anca; Buyon, Jill; Fritzler, Marvin J; Clarke, Ann E; Choi, May Y
BACKGROUND:Cranial neuropathies (CN) are a rare neuropsychiatric SLE (NPSLE) manifestation. Previous studies reported that antibodies to the kinesin family member 20B (KIF20B) (anti-KIF20B) protein were associated with idiopathic ataxia and CN. We assessed anti-KIF20B as a potential biomarker for NPSLE in an international SLE inception cohort. METHODS:Individuals fulfilling the revised 1997 American College of Rheumatology (ACR) SLE classification criteria were enrolled from 31 centres from 1999 to 2011 and followed annually in the Systemic Lupus Erythematosus International Collaborating Clinics inception cohort. Anti-KIF20B testing was performed on baseline (within 15 months of diagnosis or first annual visit) samples using an addressable laser bead immunoassay. Logistic regression (penalised maximum likelihood and adjusting for confounding variables) examined the association between anti-KIF20B and NPSLE manifestations (1999 ACR case definitions), including CN, occurring over the first 5 years of follow-up. RESULTS:Of the 1827 enrolled cohort members, baseline serum and 5 years of follow-up data were available on 795 patients who were included in this study: 29.8% were anti-KIF20B-positive, 88.7% female, and 52.1% White. The frequency of anti-KIF20B positivity differed only for those with CN (n=10) versus without CN (n=785) (70.0% vs 29.3%; OR 5.2, 95% CI 1.4, 18.5). Compared with patients without CN, patients with CN were more likely to fulfil the ACR haematological (90.0% vs 66.1%; difference 23.9%, 95% CI 5.0%, 42.8%) and ANA (100% vs 95.7%; difference 4.3%, 95% CI 2.9%, 5.8%) criteria. In the multivariate analysis adjusting for age at baseline, female, White race and ethnicity, and ACR haematological and ANA criteria, anti-KIF20B positivity remained associated with CN (OR 5.2, 95% CI 1.4, 19.1). CONCLUSION/CONCLUSIONS:Anti-KIF20B is a potential biomarker for SLE-related CN. Further studies are needed to examine how autoantibodies against KIF20B, which is variably expressed in a variety of neurological cells, contribute to disease pathogenesis.
PMCID:11015279
PMID: 38599670
ISSN: 2053-8790
CID: 5669862

Association between severe non-adherence to hydroxychloroquine and SLE flares, damage, and mortality in 660 patients from the SLICC Inception Cohort

Nguyen, Yann; Blanchet, Benoît; Urowitz, Murray B; Hanly, John G; Gordon, Caroline; Bae, Sang-Cheol; Romero-Diaz, Juanita; Sanchez-Guerrero, Jorge; Clarke, Ann E; Bernatsky, Sasha; Wallace, Daniel J; Isenberg, David A; Rahman, Anisur; Merrill, Joan T; Fortin, Paul R; Gladman, Dafna D; Bruce, Ian N; Petri, Michelle; Ginzler, Ellen M; Dooley, Mary Anne; Ramsey-Goldman, Rosalind; Manzi, Susan; Jönsen, Andreas; Alarcón, Graciela S; van Vollenhoven, Ronald F; Aranow, Cynthia; Le Guern, Véronique; Mackay, Meggan; Ruiz-Irastorza, Guillermo; Lim, S Sam; Inanc, Murat; Kalunian, Kenneth C; Jacobsen, Søren; Peschken, Christine A; Kamen, Diane L; Askanase, Anca; Buyon, Jill; Costedoat-Chalumeau, Nathalie
OBJECTIVES/OBJECTIVE:To assess the associations of severe non-adherence to HCQ, objectively assessed by HCQ serum levels, and risks of SLE flares, damage, and mortality over 5 years of follow-up. METHODS:The SLICC Inception Cohort is an international multicenter initiative (33 centers; 11 countries). Serum of patients prescribed HCQ for at least 3 months at enrollment were analyzed. Severe non-adherence was defined by a serum HCQ level <106 ng/ml or <53 ng/ml, for HCQ doses of 400 or 200 mg/d, respectively. Associations with the risk of a flare (defined as a SLEDAI-2K increase ≥4 points, initiation of prednisone or immunosuppressive drugs, or new renal involvement) were studied with logistic regression, and associations with damage (first SLICC/ACR Damage Index (SDI) increase ≥1 point) and mortality with separate Cox proportional hazard models. RESULTS:Of 1849 cohort subjects, 660 patients (88% women) were included. Median (interquartile range) serum HCQ was 388 ng/ml (244-566); 48 patients (7.3%) had severe HCQ non-adherence. No covariates were clearly associated with severe non-adherence, which was however independently associated with both flare (OR 3.38; 95% CI 1.80-6.42) and an increase in the SDI within each of the first 3 years (HR 1.92 at 3 years; 95% CI 1.05-3.50). Eleven patients died within 5 years, including 3 with severe non-adherence (crude HR 5.41; 95% CI 1.43-20.39). CONCLUSION/CONCLUSIONS:Severe non-adherence was independently associated with the risks of an SLE flare in the following year, early damage, and 5-year mortality.
PMID: 37459273
ISSN: 2326-5205
CID: 5535452

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

Clarke, Ann E; Hanly, John G; Urowitz, Murray B; St Pierre, Yvan; Gordon, Caroline; Bae, Sang-Cheol; Romero-Diaz, Juanita; Sanchez-Guerrero, Jorge; Bernatsky, Sasha; Wallace, Daniel J; Isenberg, David A; Rahman, Anisur; Merrill, Joan T; Fortin, Paul R; Gladman, Dafna D; Bruce, Ian N; Petri, Michelle; Ginzler, Ellen M; Dooley, Mary Anne; Ramsey-Goldman, Rosalind; Manzi, Susan; Jönsen, Andreas; Alarcón, Graciela S; Van Vollenhoven, Ronald F; Aranow, Cynthia; Mackay, Meggan; Ruiz-Irastorza, Guillermo; Lim, S Sam; Inanc, Murat; Kalunian, Kenneth C; Jacobsen, Soren; Peschken, Christine A; Kamen, Diane L; Askanase, Anca; Farewell, Vernon
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/CONCLUSIONS:Patients with new/ongoing SLE or non-SLE NP events incurred higher direct and indirect costs.
PMID: 36691838
ISSN: 2151-4658
CID: 5419522

Machine learning identifies clusters of longitudinal autoantibody profiles predictive of systemic lupus erythematosus disease outcomes

Choi, May Yee; Chen, Irene; Clarke, Ann Elaine; Fritzler, Marvin J; Buhler, Katherine A; Urowitz, Murray; Hanly, John; St-Pierre, Yvan; Gordon, Caroline; Bae, Sang-Cheol; Romero-Diaz, Juanita; Sanchez-Guerrero, Jorge; Bernatsky, Sasha; Wallace, Daniel J; Isenberg, David Alan; Rahman, Anisur; Merrill, Joan T; Fortin, Paul R; Gladman, Dafna D; Bruce, Ian N; Petri, Michelle; Ginzler, Ellen M; Dooley, Mary Anne; Ramsey-Goldman, Rosalind; Manzi, Susan; Jönsen, Andreas; Alarcón, Graciela S; van Vollenhoven, Ronald F; Aranow, Cynthia; Mackay, Meggan; Ruiz-Irastorza, Guillermo; Lim, Sam; Inanc, Murat; Kalunian, Kenneth; Jacobsen, Søren; Peschken, Christine; Kamen, Diane L; Askanase, Anca; Buyon, Jill P; Sontag, David; Costenbader, Karen H
OBJECTIVES/OBJECTIVE:A novel longitudinal clustering technique was applied to comprehensive autoantibody data from a large, well-characterised, multinational inception systemic lupus erythematosus (SLE) cohort to determine profiles predictive of clinical outcomes. METHODS:Demographic, clinical and serological data from 805 patients with SLE obtained within 15 months of diagnosis and at 3-year and 5-year follow-up were included. For each visit, sera were assessed for 29 antinuclear antibodies (ANA) immunofluorescence patterns and 20 autoantibodies. K-means clustering on principal component analysis-transformed longitudinal autoantibody profiles identified discrete phenotypic clusters. One-way analysis of variance compared cluster enrolment demographics and clinical outcomes at 10-year follow-up. Cox proportional hazards model estimated the HR for survival adjusting for age of disease onset. RESULTS:Cluster 1 (n=137, high frequency of anti-Smith, anti-U1RNP, AC-5 (large nuclear speckled pattern) and high ANA titres) had the highest cumulative disease activity and immunosuppressants/biologics use at year 10. Cluster 2 (n=376, low anti-double stranded DNA (dsDNA) and ANA titres) had the lowest disease activity, frequency of lupus nephritis and immunosuppressants/biologics use. Cluster 3 (n=80, highest frequency of all five antiphospholipid antibodies) had the highest frequency of seizures and hypocomplementaemia. Cluster 4 (n=212) also had high disease activity and was characterised by multiple autoantibody reactivity including to antihistone, anti-dsDNA, antiribosomal P, anti-Sjögren syndrome antigen A or Ro60, anti-Sjögren syndrome antigen B or La, anti-Ro52/Tripartite Motif Protein 21, antiproliferating cell nuclear antigen and anticentromere B). Clusters 1 (adjusted HR 2.60 (95% CI 1.12 to 6.05), p=0.03) and 3 (adjusted HR 2.87 (95% CI 1.22 to 6.74), p=0.02) had lower survival compared with cluster 2. CONCLUSION/CONCLUSIONS:Four discrete SLE patient longitudinal autoantibody clusters were predictive of long-term disease activity, organ involvement, treatment requirements and mortality risk.
PMID: 37085289
ISSN: 1468-2060
CID: 5466422

Longitudinal analysis of ANA in the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort

Choi, May Yee; Clarke, Ann Elaine; Urowitz, Murray; Hanly, John; St-Pierre, Yvan; Gordon, Caroline; Bae, Sang-Cheol; Romero-Diaz, Juanita; Sanchez-Guerrero, Jorge; Bernatsky, Sasha; Wallace, Daniel J; Isenberg, David; Rahman, Anisur; Merrill, Joan T; Fortin, Paul R; Gladman, Dafna D; Bruce, Ian N; Petri, Michelle; Ginzler, Ellen M; Dooley, Mary Anne; Ramsey-Goldman, Rosalind; Manzi, Susan; Jönsen, Andreas; Alarcón, Graciela S; van Vollenhoven, Ronald F; Aranow, Cynthia; Mackay, Meggan; Ruiz-Irastorza, Guillermo; Lim, Sam; Inanc, Murat; Kalunian, Ken; Jacobsen, Søren; Peschken, Christine; Kamen, Diane L; Askanase, Anca; Buyon, Jill P; Costenbader, Karen H; Fritzler, Marvin J
OBJECTIVES/OBJECTIVE:A perception derived from cross-sectional studies of small systemic lupus erythematosus (SLE) cohorts is that there is a marked discrepancy between antinuclear antibody (ANA) assays, which impacts on clinicians' approach to diagnosis and follow-up. We compared three ANA assays in a longitudinal analysis of a large international incident SLE cohort retested regularly and followed for 5 years. METHODS:Demographic, clinical and serological data was from 805 SLE patients at enrolment, year 3 and 5. Two HEp-2 indirect immunofluorescence assays (IFA1, IFA2), an ANA ELISA, and SLE-related autoantibodies were performed in one laboratory. Frequencies of positivity, titres or absorbance units (AU), and IFA patterns were compared using McNemar, Wilcoxon and kappa statistics, respectively. RESULTS:At enrolment, ANA positivity (≥1:80) was 96.1% by IFA1 (median titre 1:1280 (IQR 1:640-1:5120)), 98.3% by IFA2 (1:2560 (IQR 1:640-1:5120)) and 96.6% by ELISA (176.3 AU (IQR 106.4 AU-203.5 AU)). At least one ANA assay was positive for 99.6% of patients at enrolment. At year 5, ANA positivity by IFAs (IFA1 95.2%; IFA2 98.9%) remained high, while there was a decrease in ELISA positivity (91.3%, p<0.001). Overall, there was >91% agreement in ANA positivity at all time points and ≥71% agreement in IFA patterns between IFA1 and IFA2. CONCLUSION/CONCLUSIONS:In recent-onset SLE, three ANA assays demonstrated commutability with a high proportion of positivity and titres or AU. However, over 5 years follow-up, there was modest variation in ANA assay performance. In clinical situations where the SLE diagnosis is being considered, a negative test by either the ELISA or HEp-2 IFA may require reflex testing.
PMID: 35338033
ISSN: 1468-2060
CID: 5205902

Prediction of hospitalizations in systemic lupus erythematosus using the Systemic Lupus International Collaborating Clinics Frailty Index (SLICC-FI)

Legge, Alexandra; Kirkland, Susan; Rockwood, Kenneth; Andreou, Pantelis; Bae, Sang-Cheol; Gordon, Caroline; Romero-Diaz, Juanita; Sanchez-Guerrero, Jorge; Wallace, Daniel J; Bernatsky, Sasha; Clarke, Ann E; Merrill, Joan T; Ginzler, Ellen M; Fortin, Paul R; Gladman, Dafna D; Urowitz, Murray B; Bruce, Ian N; Isenberg, David A; Rahman, Anisur; Alarcón, Graciela S; Petri, Michelle; Khamashta, Munther A; Dooley, M A; Ramsey-Goldman, Rosalind; Manzi, Susan; Zoma, Asad A; Aranow, Cynthia; Mackay, Meggan; Ruiz-Irastorza, Guillermo; Lim, S Sam; Inanc, Murat; van Vollenhoven, Ronald F; Jonsen, Andreas; Nived, Ola; Ramos-Casals, Manuel; Kamen, Diane L; Kalunian, Kenneth C; Jacobsen, Soren; Peschken, Christine A; Askanase, Anca; Hanly, John G
OBJECTIVE:The Systemic Lupus International Collaborating Clinics (SLICC) frailty index (FI) predicts mortality and damage accrual in SLE, but its association with hospitalizations has not been described. We estimated the association of baseline SLICC-FI values with future hospitalizations in the SLICC inception cohort. METHODS:Baseline SLICC-FI scores were calculated. The number and duration of inpatient hospitalizations during follow-up were recorded. Negative binomial regression was used to estimate the association between baseline SLICC-FI values and the rate of hospitalizations per patient-year of follow-up. Linear regression was used to estimate the association of baseline SLICC-FI scores with the proportion of follow-up time spent in hospital. Multivariable models were adjusted for relevant baseline characteristics. RESULTS:The 1549 SLE patients eligible for this analysis were mostly female (88.7%) with mean (SD) age 35.7 (13.3) years and median (IQR) disease duration 1.2 (0.9-1.5) years at baseline. Mean (SD) baseline SLICC-FI was 0.17 (0.08). During mean (SD) follow-up of 7.2 (3.7) years, 614 patients (39.6%) experienced 1570 hospitalizations. Higher baseline SLICC-FI values (per 0.05 increment) were associated with more frequent hospitalizations during follow-up (Incidence Rate Ratio 1.21; 95%CI 1.13-1.30), adjusting for baseline age, sex, corticosteroid use, immunosuppressive use, ethnicity/location, SLE disease activity index 2000 (SLEDAI-2K), SLICC/ACR damage index (SDI), and disease duration. Among patients with ≥1 hospitalization, higher baseline SLICC-FI values predicted a greater proportion of follow-up time spent hospitalized (Relative Rate 1.09; 95%CI 1.02-1.16). CONCLUSION/CONCLUSIONS:The SLICC-FI predicts future hospitalizations among incident SLE patients, further supporting the SLICC-FI as a valid health measure in SLE.
PMCID:8096857
PMID: 33152181
ISSN: 2151-4658
CID: 4874932

Increasing Ancestral Diversity in Systemic Lupus Erythematosus Clinical Studies

Williams, Jessica N; Dall'Era, Maria; Lim, S Sam; Feldman, Candace H; Arntsen, Kathleen A; Blazer, Ashira D; Goode, Tawara; Merrill, Joan T; Sheikh, Saira; Stevens, Anne M; Lipsky, Peter E; Costenbader, Karen H
Non-white people are more likely to develop systemic lupus erythematosus (SLE), yet are underrepresented in SLE clinical trials. The efficacy and safety of drugs may be influenced by ancestry, and ancestrally diverse study populations are necessary to optimize treatments across the full spectrum of patients. However, barriers to entry into clinical trials are amplified in non-white populations. To address these issues, a conference was held in Bethesda, Maryland from October 15th -16th , 2019 entitled "Increasing Ancestral Diversity in Systemic Lupus Erythematosus Clinical Studies: Overcoming the Barriers." Participants included people with lupus, lupus physicians, lupus clinical trialists, treatment developers from biotechnology, social scientists, patient advocacy groups, and United States government representatives (the Office of Minority Health, Centers for Disease Control and Prevention, National Institutes of Health, and the Food and Drug Administration). For all of these groups, the organizers purposefully included people of non-white ancestry. Decreased participation of non-white SLE patients in clinical research was evaluated through historical, societal, experiential, and pragmatic perspectives, and several interventional programs to increase non-white patient participation in SLE and non-SLE research were described and discussed. The presentations and discussions highlighted the need for changes at the societal, institutional, research team, referring physician, and patient education levels to achieve equitable ancestral representation in SLE clinical studies.
PMID: 33026693
ISSN: 2151-4658
CID: 4626922

EXPLORATORY SEGREGATION OF PATIENTS UPON THEIR LEVELS OF ANTI-MITOCHONDRIAL ANTIBODIES (AMAS) REVEALS ASSOCIATIONS BETWEEN AMAS AND DISEASE MANIFESTATIONS [Meeting Abstract]

Becker, Y L C; Boilard, E; Rollet-Labelle, E; Lood, C; Julien, A -S; Leclerc, J; Levesque, T; Urowitz, M; Hanly, J; Gordon, C; Bae, S -C; Romero-Diaz, J; Sanchez-Guerrero, J; Clarke, A E; Bernatsky, S; Wallace, D; Isenberg, D; Rahman, A; Merrill, J; Gladman, D; Bruce, I N; Petri, M; Ginzler, E; Dooley, M A; Ramsey-Goldman, R; Manzi, S; Jonsen, A; Alarcon, G; Van, Vollenhoven R; Aranow, C; Ruiz-Irastorza, G; Lim, S; Inanc, M; Kalunian, K; Jacobsen, S; Peschken, C; Kamen, D; Askanase, A; Buyon, J; Fortin, P R
Background Mitochondria are intracellular organelles derived from the endosymbiosis between an a-proteobacterium and a primitive eukaryotic cell. Mitochondria thus display proinflammatory and antigenic properties, when released into the extracellular milieu. Several cross-sectional studies reported increased levels of anti-mitochondrial antibodies (AMAs) in patients with systemic lupus erythematosus (SLE) and the antiphospholipid syndrome (APS). These autoantibodies also displayed correlations with the SLE disease activity index 2000 (SLEDAI-2K) and associations with various clinical manifestations (e.g. lupus nephritis, thromboses, carotid plaque). In the present study, we aim to detect AMAs against either whole organelles (AwMA), mitochondrial DNA (mtDNA) or RNA (mtRNA) through time in samples from patients included in the SLICC cohort. Methods Clinically relevant variables (e.g., sociodemographic variables, disease-specific outcomes including death and arterial vascular events (AVE)) were documented and biosamples were harvested upon patient enrolment in the SLICC cohort, as well as at each follow-up visit. AMA levels were measured by in-house direct ELISAs whereas SLE autoantibodies were detected by clinical laboratories. Healthy individuals, defined as having no known illnesses and infectious symptoms at the time of the blood draw, were recruited. 90% confidence intervals were calculated for both limits of the 95% nonparametric two-sided reference intervals for values measured in healthy donors. AMA values were segregated into 3 categories: Normal values were determined as within the inner limits of the range while values outside this range were characterized as abnormal, either lower or higher than the reference interval. (figure 1). Marginal Cox models with AMAs in 3 categories were adjusted for covariables and are presented as [hazard ratio (95% CI)]. Interactions with sex were tested in models with the AMAs as continuous variables. Results Sera from healthy individuals (n=126) or SLE patients included in the SLICC cohort, from their inclusion, up to 7 years of follow-up (n=1114 patients at baseline, 3577 samples in total). AwMA displayed lower correlations with antibodies to mitochondrial nucleic acids (versus AmtDNA: rs=0.37, and vs AmtRNA: rs=0.38), while antibodies to mitochondrial DNA or RNA shown higher correlations (rs=0.59). During our preliminary analyses on the distribution of the variables, We made intriguing observations regarding patients with AMA levels that were either lower or higher than those of healthy individuals. This information led us to categorize SLE patients as described in the methods and in figure 1. For each of the three antibodies assessed, SLE patients displayed more abnormal AMA levels at baseline than controls. The percentage of patients with higher levels of AwMA and AmtRNA increased at subsequent follow-up visits, while a slight decrease was observed for AmtDNA (figure 2). SLE patients with higher levels of AwMA showed higher risks of death [2.12 (1.18-3.83)]. It is of interest that an inverse relationship was found between AmtRNA and AVEs, with a small subset of patients with low levels of AmtRNA (n = 4), this autoantibody was associated with increased risks of this manifestation [4.46 (1.71-11.66)]. Additionally, patients with higher levels of AmtDNA and AmtRNA displayed increased risks of lupus nephritis [respectively: 3.05(2.05-4.54), and 1.56(1.12-2.18)]. Interestingly, there was an interaction with sex for AmtRNA levels effect on AVEs [males: 0.32 (0.11-0.99). Females: 1.56 (1.11-2.19)], and AmtDNA association with nephritis was only significant in female patients [4.00 (2.51-6.36)] (table 1). Conclusion These results show that AMAs display different associations with disease manifestations in various clusters of patients. These results prompt for further analyses by machine-learning in order to delineate clusters of clinical interests by adding AMAs in the routine serological assessment of SLE autoantibodies. Acknowledgements We acknowledge the contribution of the study participants, individual center support staff as well as investigators of the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort project who for the past 20 years have made this study possible. LAY ABSTRACT The mitochondrion is a part of the cell that controls various biological mechanisms (e.g., energy supply, whether the cell should live or die, control, or produce various cellular components). They are derived, through evolution, from a microbe. Mitochondria may sometimes be jettisoned out of their host cell and subsequently elicit immune reactions - including the production of antibodies. Previous studies indicated that patients with autoimmune conditions such as systemic lupus erythematosus (SLE) and the antiphospholipid syndrome (APS) have antibodies against mitochondria in their blood stream. Presence of these antibodies was associated with increased disease activity and clinical manifestations of these diseases (e.g. kidney disease, arterial vessel disease). In this study, we studied blood samples harvested by an international group dedicated to the study of SLE [i.e., the SLE International Collaborating Clinics (SLICC) cohort] and observed that patients may be clustered into groups, upon their levels of antibodies and/or sex, allowing to have a better appreciation of their risks of death, vascular events, and kidney disease. These results might lead to improved diagnosis and/or prognosis in SLE and thus, in improved care and quality of life for the people living with lupus
EMBASE:640016011
ISSN: 2053-8790
CID: 5513992

M-PHASE PHOSPHOPROTEIN 1 (MPP-1) AUTOANTIBODIES AS A POTENTIAL BIOMARKER FOR CRANIAL NEUROPATHIES IN AN INTERNATIONAL SLE INCEPTION COHORT [Meeting Abstract]

Krustev, E; Hanly, J G; Chin, R; Buhler, K; Cardwell, F; Urowitz, M B; Gordon, C; Bae, S -C; Romero-Diaz, J; Sanchez-Guerrero, J; Bernatsky, S; Wallace, D J; Isenberg, D A; Rahman, A; Merrill, J T; Fortin, P R; Gladman, D D; Bruce, I N; Petri, M; Ginzler, E M; Dooley, M A; Ramsey-Goldman, R; Manzi, S; Jonsen, A; Alarcon, G S; Van, Vollenhoven R F; Aranow, C; Mackay, M; Ruiz-Irastorza, G; Lim, S; Inanc, M; Kalunian, K C; Jacobsen, S; Peschken, C A; Kamen, D L; Askanase, A; Buyon, J; Fritzler, M J; Clarke, A E; Choi, M Y
Objectives We previously reported in a single centre prevalent SLE cohort that antibodies against the cytokinesis-associated protein M-Phase Phosphoprotein 1 (anti-MPP-1) were associated with SLE-related cranial neuropathy (CN), a rare manifestation of neuropsychiatric SLE (NPSLE). The purpose of this study was to assess whether anti-MPP-1 is a biomarker for CN or other NPSLE manifestations using an international SLE inception cohort. Methods SLE patients fulfilling the updated 1997 ACR classification criteria for SLE were included. Anti-MPP-1 antibody testing was performed on baseline samples (within 15 months of diagnosis) or first annual assessment using an addressable laser bead immunoassay (ALBIA) with purified recombinant human protein with results expressed as median florescence units (MFU). Based on healthy controls, a dilution of >=1:500 MFU was considered positive. NPSLE manifestations occurring over the first 5 years of follow up were documented annually based on ACR case definitions using published NPSLE attribution rules1). The frequency of anti-MPP-1 positivity between patients with versus without each of the 19 NPSLE manifestations was compared using univariate logistic regression. For any NPSLE manifestations where anti-MPP-1 positivity differed between patients with versus without the manifestation, baseline demographic and clinical characteristics were compared using t-tests and twosample tests of proportions. For NPSLE manifestations associated with anti-MPP-1 positivity in the univariate analysis, multivariable logistic regression analysis using penalized maximum likelihood estimates was then performed to assess the relationship between anti-MPP-1 and the NPSLE manifestation, adjusting for age at anti-MPP-1 testing, female, White race/ethnicity, and significantly different baseline clinical characteristics. Results Seven hundred and ninety-five SLE patients were assessed; 29.8% were anti-MPP-1 positive, 88.7% female, and 52.1% White. The frequency of anti-MPP-1 positivity differed only for those with versus without CN (70.0% vs. 29.3%; odds ratio [OR] 5.16, 95%CI 1.44, 18.54) (table 1). Compared to patients without CN (n=785), patients with CN (n=10) were more likely to fulfill the ACR hematologic (difference: 23.9%, 95%CI 5.0%, 42.8%) and antinuclear antibody criteria (difference: 4.3%, 95%CI 2.9%, 5.8%) (table 2). (Table Presanted)In the multivariate analysis, anti-MPP-1 remained associated with CN (OR 5.24, 95%CI 1.44, 19.09) after adjusting for age at anti-MPP-1 testing, female, White race/ethnicity, hematologic disorder, and antinuclear antibody (table 3). Conclusion Anti-MPP-1 is a potential biomarker for CN. Although anti-MPP-1 is differentially expressed in a variety of neurological cells and tissues, the link to a pathogenic role requires further study
EMBASE:640015976
ISSN: 2053-8790
CID: 5513552