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Background: Since the development of the OMERACT Systemic Lupus Erythematosus (SLE) Core Outcome Set (COS) in 1998, many new SLE domains have been identified and measures developed, creating a need to update the SLE COS. To revisit the 1998 SLE COS and research agenda domains, and generate new candidate domains, we conducted this study of patients with SLE and collaborators., Objective: (1) To evaluate existing candidate SLE domains for inclusion in the SLE COS. (2) To generate additional candidate SLE domains for COS consideration. (3) To engage SLE collaborators, including patients, in developing the updated SLE COS., Methods: The OMERACT SLE Working Group's steering committee developed a survey to assess the importance of candidate SLE domains and generate additional domains for consideration towards the SLE COS. Patients with SLE followed at the University of Toronto Lupus Clinic (patient group) and members of the OMERACT SLE Working Group (collaborator group) were invited to complete the survey between August 2022 and February 2023., Results: A total of 175 patients were invited and 100 completed the survey. Of 178 collaborators invited, 145 completed the survey. Patients tended to prioritize life-impact domains while collaborators prioritized clinical domains. Both patients and collaborators recommended additional domains to those included in the 1998 SLE COS and research agenda., Conclusion: The domain inclusion and importance results demonstrate that patients and collaborators prioritize different domains, so capturing the perspectives of both groups is essential to ensure a holistic assessment of SLE. The results of the study identify domains that already have a high level of agreement for potential inclusion in the SLE COS, domains that require further explanation, and novel domains that warrant consideration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: The Outcome Measures in Rheumatology (OMERACT) Systemic Lupus Erythematosus (SLE) Working Group held a Special Interest Group (SIG) at the OMERACT 2023 conference in Colorado Springs where SLE collaborators reviewed domain sub-themes generated through qualitative research and literature review., Objective: The objective of the SIG and the subsequent meetings of the SLE Working Group was to begin the winnowing and binning of candidate domain sub-themes into a preliminary list of candidate domains that will proceed to the consensus Delphi exercise for the SLE COS., Methods: Four breakout groups at the SLE SIG in Colorado Springs winnowed and binned 132 domain sub-themes into candidate domains, which was continued with a series of virtual meetings by an advisory group of SLE patient research partners (PRPs), members of the OMERACT SLE Working Group Steering Committee, and other collaborators., Results: The 132 domain sub-themes were reduced to a preliminary list of 20 candidate domains based on their clinical and research relevance for clinical trials and research studies., Conclusion: A meaningful and substantial winnowing and binning of candidate domains for the SLE COS was achieved resulting in a preliminary list of 20 candidate domains., Competing Interests: Declaration of competing interest Wils Nielsen, Lee Simon, Maya Desai, Yvonne Enman, Daniel Wallace, Cynthia Aranow, Meggan Mackay, Kimberly Trotter, Ali Duarte Garcia, John A Reynolds, Danaë Papachristos, Sandra Navarra, Amita Aggarwal, Chi Chiu Mok, Keishi Fujio, Rosalind Ramsey-Goldman, Aaron Howe, Behdin Nouwrouzi-Kia, Dennisse Bonilla, Julian Thumboo, Martin Aringer, Sindhu R. Johnson, Zahi Touma: None. Vibeke Strand:All support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges, etc.): I am a founding member of the executive committee of Outcome Measures in Rheumatology (OMERACT) [1992 – present], an international consensus organization that develops and validates outcome measures in rheumatology randomized controlled trials and longitudinal observational studies and has received arms-length funding from as many as 36 sponsors. Grants or Contracts from any entity: I am a founding member of the executive committee of Outcome Measures in Rheumatology (OMERACT) [1992 – present], an international consensus organization that develops and validates outcome measures in rheumatology randomized controlled trials and longitudinal observational studies and has received arms-length funding from as many as 36 sponsors. Ioannis Parodis:All support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges, etc.): I have received research funding from Amgen, I have received research funding from GlaxoSmithKline, I have received research funding from Astra-Zeneca, I have received research funding from Janssen Pharmaceuticals, I have received research funding from Aurinia Pharmaceuticals, I have received research funding from Novartis, I have received research funding from Elly Lilly and Company, I have received research funding from Otsuka Pharmaceutical, I have received research funding from Gilead Sciences, I have received research funding from F. Hoffmann-La Roche AG Payment or Honoraria for lectures, presentations, speakers, bureaus, manuscript writing or educational events: I have received research funding from Amgen, I have received research funding from GlaxoSmithKline, I have received research funding from Astra-Zeneca, I have received research funding from Janssen Pharmaceuticals, I have received research funding from Aurinia Pharmaceuticals, I have received research funding from Novartis, I have received research funding from Elly Lilly and Company, I have received research funding from Otsuka Pharmaceutical, I have received research funding from Gilead Sciences, I have received research funding from F. Hoffmann-La Roche AG Alfred Kim:Grants or Contracts from any entity: Rheumatology Research Foundation – Institution, National Multiple Sclerosis Society – Institution, GlaxoSmithKline – Institution, Novartis – Institution, NIH/NIAMS P30AR073752 – Institution, BMS – Institution Consulting Fees: Alexion Pharmaceuticals – Self, ANI Pharmaceuticals – Self, AstraZeneca – Self, Aurinia Pharmaceuticals – Self, Kypha Inc – Self, Pfizer Inc – Self Payment or Honoraria for lectures, presentations, speakers, bureaus, manuscript writing or educational events: GlaxoSmithKline – Self, Exagen Diagnostics – Self, UpToDate – Self Patents planned, issued, or pending: Kypha US Patent 1102931882 Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: Lupus Foundation of America-Heartland Chapter – Unpaid, St Louis Rheumatology Association – Unpaid, Rheumatology Research Foundation – Unpaid, Lupus Research Alliance – Unpaid Daniel Wallace:Payment or Honoraria for lectures, presentations, speakers, bureaus, manuscript writing or educational events: Speakers bureau GSK, Merck-Serono, Astra Zeneca Yashaar Chaichian:Grants or Contracts from any entity: Lupus Therapeutics, LLC - Payments made to institution, Eli Lilly & Company - Payments made to institution, Amgen Inc. - Payments made to institution, Stanford University, Discovery Innovation Fund in Basic Biomedical Sciences - Payments made to institution Support for attending meetings and/or travel: Lupus Therapeutics, LLC (provided support to attend the 2022 and 2023 LuCIN Community Meeting) -Payments made to institution Oshrat Tayer-Shifman:Consulting Fees: Astra-Zeneca – Payed to me, Abbvie – Payed to me Support for attending meetings and/or travel: Astra-Zeneca – Payment made to institution Lai Shan Tam:Consulting Fees: Janssen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Pfizer, and Sanofi – me Payment or Honoraria for lectures, presentations, speakers, bureaus, manuscript writing or educational events: Pfizer, Abbvie, Janssen – me Support for Attending Meetings and/or travel: abbvie – other institutions Participation on a Data Safety Monitoring Board or Advisory Board: Pfizer, Abbvie, Janssen, AstraZeneca – me Leasdership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: Convenor of the APLAR Academy – unpaid Other financial and non-financial interests: Unrestricted grant from Amgen, Boehringer Ingelheim, GSK, Janssen, Novartis, and Pfizer - To the Chinese University of Hong Kong Manuel F. Ugarte-Gil:Grants or Contracts: Janssen, GSK – Payments were made to my institution Consulting Fees: Astra-Zeneca Payment or Honoraria for lectures, presentations, speakers, bureaus, manuscript writing or educational events: Astra-Zeneca, GSK Guillermo Pons-Estel:Grants of Contracts from any entity: I received grant from Janssen – Payment was made to GLADEL (Latin American Group for the Study of Lupus) Payment or Honoraria for lectures, presentations, speakers, bureaus, manuscript writing or educational events: I received honoraria from GSK for lectures - Payment was made to myself, I received honoraria from Werfen for lectures - Payment was made to myself, I received honoraria from Novartis for lectures - Payment was made to myself, I received honoraria from Pfizer for lectures - Payment was made to myself, I received honoraria from Janssen for lectures - Payment was made to myself. Support for Attending Meetings and/or travel: I received support from ABBVIE to attend to the ACR 2021, I received support from Pfizer to attend to the EULAR 2023 Participation on a Data Safety Monitoring Board or Advisory Board: I received honoraria from Janssen for Advisory Board - Payment was made to myself, I received honoraria from Astra Zeneca for Advisory Board - Payment was made to myself, I received honoraria from GSK for Advisory Board - Payment was made to myself, I received honoraria from Novartis for Advisory Board - Payment was made to myself Mandana Nikpour:Grants of Contracts from any entity: Research grants from Janssen to support the ongoing research of the Australian Scleroderma Cohort Study - Payments made to my institution Consulting Fees: I have consulted for Janssen, Boehringer Ingelheim and Astra Zeneca - Payments made to me Payment or Honoraria for lectures, presentations, speakers, bureaus, manuscript writing or educational events: I have presented for Janssen, Boehringer Ingelheim, Astra Zeneca and GSK - Payments made to me Support for Attending Meetings and/or travel: Support from Boehringer Ingelheim to attend the EULAR Conference in 2023 - No payment made to me or my institution Alberta Hoi:Grants or Contracts from any entity: Arthritis Australia - I was grant recipient, AstraZeneca - Sponsorship of the Australian Lupus Registry and Biobank and Asia Pacific Lupus Collaboration, and also contract research on unmet needs in Australian lupus patients, Perpetual IMPACT - fund I was grant recipient, BMS, Merck Serono, GSK, Eli Lilly, UCB - Sponsored Asia Pacific Lupus Collaboration, for which I contribute data towards, Janssen - Contracted the Asia Pacific Lupus Collaboration to conduct a research study on medication use Consulting Fees: UCB Advisory Board Payment or Honoraria for lectures, presentations, speakers, bureaus, manuscript writing or educational events: Novartis Speaker Fee, Janssen honoraria for chairing Juanita Romero-Diaz:Consulting Fees: Novartis, Biogen Support for Attending Meetings and/or travel: Boehringer Participation on a Data Safety Monitoring Board or Advisory Board: Biogen Marta Mosca:Consulting Fees: Astra Zeneca, GSK, Lilly, UCB, BMS, Idorsia, Otsuka, Abbvie Payment or Honoraria for lectures, presentations, speakers, bureaus, manuscript writing or educational events: Atra Zeneca, GSK, Otsuka, Janssen, UCB, Abbvie Support for Attending Meetings and/or travel: Janssen to attend the European Lupus Meeting in 2022 Participation on a Data Safety Monitoring Board or Advisory Board: Idorsia Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: EMA liaison for EULAR Receipt of equipment, materials, drugs, medical writing, gifts or other services: I have received Anifrolumab as for compassionate use from Astra Zeneca Aaron Drucker:Grants of Contracts from any entity: National Eczema Association, Eczema Society of Canada, Canadian Dermatology Foundation, CIHR, NIH, PSI Foundation Consulting Fees: Canadian Agency for Drugs and Technologies in Health Payment or Honoraria for lectures, presentations, speakers, bureaus, manuscript writing or educational events: British Journal of Dermatology, American Academy of Dermatology, National Eczema Association, Canadian Dermatology Today Eric Morand:Grants of Contracts from any entity: grant/research support from: AbbVie, Amgen, AstraZeneca, Biogen, Bristol Myers Squibb, Eli Lilly and Company, EMD Serono, Genentech, GlaxoSmithKline, Janssen, and UCB Pharma – Research grants to institution Consulting Fees: Consulting fees from AbbVie, AstraZeneca, Biogen, Bristol Myers Squibb, Eli Lilly and Company, EMD Serono, Genentech, GlaxoSmithKline, Janssen, Novartis, Servier, Wolf, Zenas Payment or Honoraria for lectures, presentations, speakers, bureaus, manuscript writing or educational events: Honoraria from AstraZeneca, Biogen, Bristol Myers Squibb, EMD Serono, Gilead Support for Attending Meetings and/or travel: Travel support from AstraZeneca Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: Board Director, Rare Voices Australia – Not for Profit, Board Directory, Exosome Biosciences Ian Bruce:Grants of Contracts from any entity: Janssen Research - Grant to institution, Astra Zeneca - Research Grant to institution, GSK - Research Grant to institution Consulting Fees: GSK - Speaker fees to institution, Astra Zeneca - Speaker fees to institution, Janssen - Speaker fees to institution Participation on a Data Safety Monitoring Board or Advisory Board: AstraZeneca and Merck Serono - INB has served on boards for AstraZeneca and Merck Serono, (Copyright © 2024. Published by Elsevier Inc.)

Objective: SLE and lupus nephritis (LN) have significant impacts on the health-related quality of life of patients living with the condition, which are important to capture from the patient's perspective using patient-reported outcomes (PROs). The objectives of this study were to evaluate the content validity of PROs commonly used in SLE and LN (36-Item Short Form Health Survey (SF-36), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and Lupus Quality of Life (LupusQoL), as well as novel PRO symptom severity items measuring skin rash, joint pain, joint stiffness and swelling of the legs and/or feet, in both populations., Methods: Qualitative, semi-structured, cognitive interviews were conducted with 48 participants (SLE=28, LN=20). Understanding and relevance of symptom and impact PRO concepts from existing PROs were assessed, alongside novel PRO symptom severity items with different recall periods (24 hours vs 7 days) and response scales (Numerical Rating Scale (NRS) vs Verbal Rating Scale). Interviews were conducted in multiple rounds to allow for modifications to the novel PRO items. Analysis of verbatim interview transcripts was performed., Results: Symptom and impact concepts assessed by the SF-36, FACIT-F, and LupusQoL were well understood by both participants with SLE and LN (≥90.0%), with most considered relevant by over half of the participants asked (≥51.9%). All participants asked (100%) understood the novel PRO symptom severity items, and the majority (≥90.0%) considered the symptoms relevant. Minor modifications to the novel PRO items were made between rounds to improve clarity based on participant feedback. The selected 7-day recall period and NRS in the final iteration of the PRO items were understood and relevant. No differences in interview findings between the SLE and LN samples were identified., Conclusions: Findings provide evidence of content validity for concepts assessed by the SF-36, FACIT-F, LupusQoL and the novel PRO symptom severity items, supporting use of these PROs to comprehensively assess disease impact in future SLE and LN clinical trials., Competing Interests: Competing interests: RW-H, NW, MB, AR, AG, CT, HB and AW are employed by Adelphi Values, a health outcomes research company paid for conducting the research reported in this article. PB and PDL work for and own stocks/shares in Janssen Global Services LLC, which funded the research reported. EH and QZ work for and own stocks in Janssen R&D. ZT received funding from Schroeder Arthritis Institute and Lupus Ontario. VS received funding from numerous clients, including Janssen, which funded this research., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Patient-reported outcome measures (PROMs) are evaluated in randomized controlled trials (RCTs) in patients with systemic lupus erythematosus (SLE), but not widely used in clinical practice. However, interest in incorporating PROMs into the management of SLE is increasing as PROMs provide a unique insight into the patient's perception of lupus disease activity. The objective was to assess agreement in PROMs answered using a web app versus an outpatient touchscreen among patients with SLE., Methods: In a crossover RCT, SLE patients answered the following PROMs in a random order using the web app and the outpatient touchscreen: Systemic Lupus Erythematosus Activity Questionnaire (SLAQ) Global Health, SLAQ Symptom, SLAQ Total, SLAQ Worsening, Pain Visual Analog Scale (VAS), Fatigue VAS, Patient Global Health VAS, Health Assessment Questionnaire Disability Index (HAQ-DI), Patient Acceptable Symptom State (PASS), and an Anchoring Question. Equivalence between the two device types was demonstrated if the 95% confidence interval (95% CI) of the difference in PROM scores was within the prespecified equivalence margin. Agreement between the two device types was assessed using mixed linear models., Results: Thirty-four patients with SLE were included. Equivalence was demonstrated between the two device types for SLAQ Global Health with a difference of -0.21 (95% CI: -0.65 to 0.23). Moreover, equivalence was also found for HAQ-DI, Pain VAS, and Fatigue VAS whereas only comparability within the limits of the Minimal Clinically Important Difference (MCID) was demonstrated for VAS Patient Global Health. Statistical comparability was demonstrated for SLAQ Total, SLAQ Worsening, PASS, and Anchoring Question (no predefined MCID/equivalence margins available). However, a statistically significant difference between device types was observed for the SLAQ Symptom of -0.56 (95% CI: -1.10 to -0.01). The difference was, however, very small when considering the scale range of 0-24; thus, it was not judged to be of clinical relevance. Preference for the web app was very high (91.2%)., Conclusion: For the first time ever, equivalence and comparability between two electronic device types for various PROMs were demonstrated among patients with SLE. Implementation of the device is expected to improve the management of SLE.

The interferon (IFN) pathway, especially type I IFN, plays a critical role in the immunopathogenesis of systemic lupus erythematosus (SLE). We have gained significant insights into this pathway over the past two decades, including a better understanding of the key mediators of inflammation upstream and downstream of type I IFN. This has led to the identification of multiple potential targets for the treatment of SLE, for which a significant unmet need remains due to the failure of many patients to adequately respond to standard-of-care medications. Unfortunately, most new therapies in SLE have disappointed in preclinical or clinical trials to date, including a number that target type I IFN. Nevertheless, several IFN-directed therapies aimed at specific steps within this immunologic pathway have recently shown promise, and additional agents are in the treatment pipeline. In this review, we focus on the results of key therapeutic studies targeting the type I IFN pathway and discuss the future state of IFN-blockade in SLE., (© 2021. International League of Associations for Rheumatology (ILAR).)

Objectives: Fatigue is one of the most common symptoms reported in patients living with SLE. We aim to: 1) determine if different trajectories of fatigue associate with specific latent classes of disease activity and 2) define the patient characteristics and associated factors in different latent classes., Methods: Data from an inception cohort of adult patients from the Toronto Lupus Clinic from 1997-2018 were analyzed. Fatigue levels were measured using Fatigue Severity Scale (FSS) and disease activity by the Adjusted Mean Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) (AMS). Dual latent class trajectory analysis, for fatigue and AMS, was performed. Univariable and multivariable logistic regression analyses assessed the association of baseline variables with class membership., Results: Among 280 patients, 4 dual classes (C) of fatigue and disease activity were identified: C1- lowest disease activity and second highest fatigue trajectory (27%); C2- second highest disease activity and highest fatigue trajectory (30%); C3-moderate disease activity and lowest fatigue trajectory (33%); and C4- highest disease activity and moderate fatigue trajectory (10%)., Conclusion: 4 distinct latent classes of dual fatigue and disease activity trajectories were identified. Fatigue and disease activity follow distinct trajectories and disease activity alone cannot fully explain fatigue trajectories. Trajectories with higher FSS scores were associated with more fibromyalgia and trajectories with higher disease activity were associated with higher cumulative glucocorticoid use. Higher baseline glucocorticoid use was more likely associated with more fatigue while older age at SLE diagnosis was associated with less fatigue.

Objective: The heterogeneous multisystem manifestations of SLE include fatigue, pain, depression, sleep disturbance and cognitive dysfunction, and underscore the importance of a multidimensional approach when assessing health-related quality of life. The US Food and Drug Administration has emphasised the importance of patient-reported outcomes (PROs) for approval of new medications and Outcome Measures in Rheumatology has mandated demonstration of appropriate measurement properties of selected PRO instruments., Methods: Published information regarding psychometric properties of the Medical Outcomes Survey Short Form 36 (SF-36), Lupus Quality of Life Questionnaire (LupusQoL) and Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F), and their suitability as end points in randomised controlled trials (RCTs) and longitudinal observational studies (LOS) were assessed. A search of English-language literature using MEDLINE and EMBASE identified studies related to development and validation of these instruments. Evidence addressed content validity, reliability (internal consistency and test-retest reliability), construct validity (convergent and divergent) and longitudinal responsiveness, including thresholds of meaning and discrimination., Results: All instruments demonstrated strong internal consistency, reliability and appropriate face/content validity, indicating items within each instrument that measure the intended concept. SF-36 and LupusQoL demonstrated test-retest reliability; although not published with FACIT-F in SLE supported by evidence from other rheumatic diseases. All instruments demonstrated convergent validity with other comparable PROs and responsivity to treatment., Conclusion: The measurement properties of PRO instruments with published data from RCTs including: SF-36, LupusQoL and FACIT-F indicate their value as secondary end points to support labelling claims in RCTs and LOS evaluating the efficacy of SLE treatments., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To report long-term health-related quality of life (HRQoL) and fatigue outcomes in patients with systemic lupus erythematosus (SLE) receiving belimumab., Methods: Patients with SLE who completed the Study of Belimumab in Subjects with SLE 76-week trial (BLISS-76) were enrolled in this continuation study (BEL112233 [ClinicalTrials.gov identifier: NCT00724867]). The belimumab groups continued to receive the same dose (1 mg/kg or 10 mg/kg) intravenously. After March 2011, all patients received belimumab 10 mg/kg every 28 days plus standard therapy. The placebo group switched to belimumab 10 mg/kg. HRQoL and fatigue assessments included the Short Form 36 (SF-36) health survey and the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue subscale. Post hoc subgroup analyses (BEL206350) assessed clinical characteristics associated with improved HRQoL and fatigue., Results: Of the 268 patients enrolled, 140 completed the study. Patients receiving long-term belimumab treatment reported continued improvements in HRQoL and fatigue. At study year 6, the mean ± SD SF-36 physical component summary (PCS) score and the mental component summary (MCS) score increased from 37.0 ± 9.9 at baseline to 41.7 ± 10.0 (mean ± SD change 4.8 ± 9.4) and from 44.3 ± 11.3 to 47.0 ± 11.6 (mean ± SD change 2.7 ± 11.3) for the PCS and MCS, respectively, exceeding the minimum clinically important difference (MCID) for improvement (2.5 units). The mean ± SD FACIT-Fatigue score exceeded the MCID of 4 at study years 1-5; at study year 6, the mean ± SD change was 3.7 ± 11.8. Statistically significant associations were observed between parent trial treatment groups and change from baseline in PCS, MCS, and FACIT-Fatigue scores (P < 0.01)., Conclusion: Long-term control of SLE disease activity with belimumab plus standard therapy translates into meaningful improvements in patient-reported fatigue and HRQoL., (© 2018, GSK. Arthritis Care & Research published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Objective: To examine correlations between blood levels of complement split product iC3b and serum component C3 with clinically meaningful changes in disease activity in patients with systemic lupus erythematosus (SLE)., Methods: A total of 159 consecutive patients with SLE, diagnosed according to the American College of Rheumatology or Systemic Lupus International Collaborating Clinics classification criteria, were enrolled in CASTLE (Complement Activation Signatures in Systemic Lupus Erythematosus), a prospective observational study. Patients with 1-7 study visits were included in this longitudinal analysis. In addition, 48 healthy volunteers were enrolled to establish a normal reference value for the ratio of blood iC3b to serum C3 concentrations. Serum C3 and C4 levels were measured by nephelometry, and blood iC3b levels were measured by a lateral flow assay. SLE disease activity was monitored with the Responder Index 50 instrument of the SLE Disease Activity Index 2000., Results: Relative changes in the iC3b:C3 ratio, levels of anti-double-stranded DNA (anti-dsDNA) antibodies, and use of a supraphysiologic dose of prednisone (>7.5 mg/day) each independently correlated with SLE disease activity, as determined in multilevel multiple logistic regression analyses. Only the iC3b:C3 ratio was significantly associated with clinically meaningful improvements in disease activity among patients with SLE who were receiving a supraphysiologic dose of prednisone. The iC3b:C3 ratio outperformed C3 and C4 levels with regard to discriminating active SLE from inactive SLE, and major flares from no disease activity. The iC3:C3 ratio, anti-dsDNA antibody levels, erythrocyte sedimentation rate, and use of a supraphysiologic prednisone dose were each independently associated with the presence of lupus nephritis, whereas none of these measures was associated with SLE rash. The association of the iC3b:C3 ratio with lupus nephritis was independent of other observed clinical manifestations., Conclusion: The ratio of blood iC3b to serum C3 concentrations correlates with the extent of SLE disease activity and with clinically meaningful changes in disease activity in patients with SLE. Furthermore, the iC3b:C3 ratio may discriminate between active and inactive SLE, and between major flares and no active disease., (© 2018 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Objective: Trials of new systemic lupus erythematosus (SLE) treatments are hampered by the lack of effective outcome measures. To address this, we developed a novel Lupus Multivariable Outcome Score (LuMOS) and assessed its performance using data from 2 randomized controlled trials of belimumab in patients with SLE., Methods: The LuMOS formula was developed by analyzing raw data from 2 pivotal trials, the Study of Belimumab in Subjects with SLE 52-week (BLISS-52) and 76-week (BLISS-76) trials, which are the basis for approval of belimumab. Using the BLISS-76 trial data as the learning data set, we carried out multivariable logistic regression analyses to optimize discrimination of outcomes between patients treated with 10 mg/kg belimumab and patients receiving placebo over the first 52 weeks of follow-up. In addition, the performance of LuMOS was assessed using an independent validation data set from the BLISS-52 trial., Results: The LuMOS model incorporated the following response criteria: a ≥4-point reduction on the Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index, an increase in C4 levels, a decrease in anti-double-stranded DNA titers, and changes in the British Isles Lupus Assessment Group scores for organ system manifestations (no worsening in renal components, and improvements in mucocutaneous components). A decrease in the prednisone dose and increase in C3 levels had very minor impacts on the total LuMOS score. In all analyses of the BLISS-76 and BLISS-52 trial data sets, the mean LuMOS scores were significantly higher (P < 0.0001) in patients treated with 1 mg or 10 mg belimumab compared to placebo. In contrast to the performance of the SLE Responder Index 4 (SRI-4), the LuMOS revealed significant differences between the active treatment group (1 mg belimumab in the BLISS-76 cohort) and placebo group. The effect sizes were significantly much higher with the LuMOS than with the SRI-4., Conclusion: The evidenced-based LuMOS outcome scoring system, developed with data from the BLISS-76 trial of belimumab in patients with SLE and validated with data from the BLISS-52 trial, exhibits a superior capacity to discriminate responders from nonresponders when compared to the SRI-4. Use of the LuMOS may improve the efficiency and power of analyses in future lupus trials., (© 2018, American College of Rheumatology.)

Objective: The Medical Outcomes Study Short Form 36 (SF-36) and Lupus Quality of Life (LupusQoL) are health-related quality of life questionnaires used in systemic lupus erythematosus (SLE). We first determined the hypothesis-testing construct validity of the SF-36 and LupusQoL against disease activity in patients with active SLE and then compared the sensitivity to change of SF-36 and LupusQoL domains according to different definitions of minimum clinically important differences (MCIDs) for improvement and worsening in the current cohort., Methods: Seventy-eight clinically active SLE patients concurrently completed both questionnaires at their baseline and followup visits. Questionnaire domain scores were correlated with the SLE Disease Activity Index 2000 (SLEDAI-2K) and evaluated for floor/ceiling effects. The sensitivity to change of domains in each questionnaire was analyzed first, according to the various MCID definitions and, second, by clinically meaningful changes in disease activity. The magnitudes of change in each domain score between the baseline and followup visit were evaluated using standardized response means., Results: In the 78 patients, the mean ± SD SLEDAI-2K scores were 9.7 ± 4.8 at baseline and 8.8 ± 5.1 at followup. SF-36/LupusQoL domain scores did not correlate with disease activity. The SF-36 showed floor effects, and ceiling effects were evident in both questionnaires. All domains of both questionnaires showed sensitivity to change over time. Specific domains that reflected worsening or improvement differed according to differing MCID definitions., Conclusion: In SLE patients with active disease, both the SF-36 and LupusQoL are sensitive to change, reflecting both improvement and worsening. More importantly, the LupusQoL SLE-specific domains (planning, burden to others, body image, and intimate relationships) were largely responsive to change., (© 2017, American College of Rheumatology.)

Objectives: This phase II trial evaluated the efficacy and safety of an interleukin (IL) 6 monoclonal antibody for systemic lupus erythematosus (SLE)., Methods: Patients with active disease were randomised to placebo or PF-04236921 10 mg, 50 mg or 200 mg, subcutaneously, every 8 weeks with stable background therapy. SLE Responder Index (SRI-4; primary end point) and British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) were assessed at week 24. Post hoc analysis identified an enriched population based upon planned univariate analyses., Results: 183 patients received treatment (placebo, n=45; 10 mg, n=45; 50 mg, n=47; 200 mg, n=46). The 200 mg dose was discontinued due to safety findings and not included in the primary efficacy analysis. The SRI-4 response rates were not significant for any dose compared with placebo; however, the BICLA response rate was significant for 10 mg (p=0.026). The incidence of severe flares was significantly reduced with 10 mg (n=0) and 50 mg (n=2) combined versus placebo (n=8; p<0.01). In patients with greater baseline disease activity (enriched population), the SRI-4 (p=0.004) and BICLA (p=0.012) response rates were significantly different with 10 mg versus placebo. Four deaths (200 mg, n=3; 10 mg, n=1) occurred. The most frequently reported adverse events included headache, nausea and diarrhoea., Conclusions: PF-04236921 was not significantly different from placebo for the primary efficacy end point in patients with SLE. Evidence of an effect with 10 mg was seen in a post hoc analysis. Safety was acceptable for doses up to 50 mg as the 200 mg dose was discontinued due to safety findings., Trial Registration Number: NCT01405196; Pre-results., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Purpose of Review: Systemic lupus erythematosus (SLE) is a disabling and deadly disease. Development of novel therapies for SLE has historically been limited by incomplete understanding of immune dysregulation. Recent advances in lupus pathogenesis, however, have led to the adoption or development of new therapeutics, including the first Food and Drug Administration-approved drug in 50 years., Recent Findings: Multiple cytokines (interferon, B lymphocyte stimulator, IL-6, and IL-17), signaling pathways (Bruton's Tyrosine Kinase, Janus kinase/signal transducer and activator of transcription), and immune cells are dysregulated in SLE. In this review, we cover seminal discoveries that demonstrate how this dysregulation is integral to SLE pathogenesis and the novel therapeutics currently under development or in clinical trials. In addition, early work suggests metabolic derangements are another target for disease modification. Finally, molecular profiling has led to improved patient stratification in the heterogeneous SLE population, which may improve clinical trial outcomes and therapeutic selection., Summary: Recent advances in the treatment of SLE have directly resulted from improved understanding of this complicated disease. Rheumatologists may have a variety of novel agents and more precise targeting of select lupus populations in the coming years.

One challenge in caring for patients with systemic lupus erythematosus (SLE) is a paucity of approved therapeutics for treatment of the diverse disease manifestations. In the last 60 years, only one drug, belimumab, has been approved for SLE treatment. Critical evaluation of investigator initiated and pharma-sponsored randomized controlled trials (RCTs) highlights barriers to successful drug development in SLE, including disease heterogeneity, inadequate trial size or duration, insufficient dose finding before initiation of large trials, handling of background medications, and choice of primary endpoint. Herein we examine lessons learned from landmark SLE RCTs and subsequent advances in trial design, as well as discuss efforts to address limitations in current SLE outcome measures that will improve detection of true therapeutic responses in future RCTs., (© The Author(s) 2016.)

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., (© 2016, American College of Rheumatology.)

Objective: To derive and validate a brief patient-completed instrument, the Lupus Impact Tracker (LIT), to assess and monitor the impact of systemic lupus erythematosus (SLE)., Methods: Items for the LIT were selected from the LupusPRO, a validated patient-reported outcomes measure, using 3 approaches: confirmatory factor analysis (CFA), stepwise regression, and patient focus groups. CFA was conducted to find items from the LupusPRO that fit a unidimensional structure to allow scoring as a single index. Stepwise regression methods identified items with the strongest relationship (convergent validity) with disease activity measures and patient health rating. Focus groups (n = 26 patients) identified the most important items describing SLE impact. Selected items were evaluated for reliability and validity., Results: CFA found 21 items that fit a unidimensional structure. Stepwise regressions identified 15 of 21 items having good convergent validity with clinical measures. Patient focus groups identified 9 of 15 items as best capturing the impact of SLE. Overall, 7 items were selected across all 3 approaches (CFA, stepwise regression, and focus groups). Another 15 items were selected across 2 approaches. Through consensus with rheumatology clinician experts, a final set of 10 items was selected for the LIT. The LIT items showed good internal consistency (0.89) and test-retest reliabilities (0.87). Mean LIT scores differed significantly (P < 0.05) across criterion groups in the hypothesized direction, providing evidence of discriminant validity and responsiveness., Conclusion: The LIT is reliable and valid in SLE patients and offers a practical way for physicians and patients to assess and monitor the impact of SLE., (Copyright © 2014 by the American College of Rheumatology.)

Objective: Assess the effects of belimumab treatment plus standard systemic lupus erythematosus (SLE) therapy on health-related quality of life (HRQOL) in patients with active, autoantibody-positive SLE., Methods: Patients received standard therapy plus placebo or belimumab 1 or 10 mg/kg in two multicentre, randomised controlled trials of 52 (BLISS-52; N=865) and 76 (BLISS-76; N=819) weeks' duration. Responders were evaluated by SLE Responder Index at week 52. Patient-reported outcome assessments included SF-36, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue, and EQ-5D., Results: Mean SF-36 Physical Component Summary (PCS) scores at week 24 was a major secondary endpoint. Baseline SF-36 scores were 1.5 SDs below age-/sex-matched US norms with similar improvement at week 24 across treatment groups. Mean changes from baseline in PCS scores were significantly (p<0.05) greater with belimumab 1 mg/kg (4.20) and 10 mg/kg (4.18) versus placebo (2.96) in BLISS-52, week 52. In BLISS-76, significantly (p<0.05) greater improvements were seen with belimumab 1 mg/kg in PCS (belimumab 1 mg/kg=4.37, 10 mg/kg=3.41 vs placebo=2.85) and Mental Component Summary (MCS) scores (belimumab 1 mg/kg=3.14, 10 mg/kg=2.70 vs placebo=1.40) at week 52, and in MCS score at week 76 (belimumab 1 mg/kg=3.05, 10 mg/kg=2.28 vs placebo=1.36). In pooled analysis, significantly greater improvements in PCS, SF-36 vitality domain, and FACIT-Fatigue scores at week 52 were evident with both belimumab doses., Conclusions: The clinically meaningful improvements in HRQOL in autoantibody-positive patients with active SLE treated with belimumab and standard therapy are consistent with the reductions in disease activity observed in these trials., Clinicaltrialsgov Number: NCT00424476, NCT00410384.

Objective: To evaluate health-related quality of life (HRQOL) and corticosteroid use in patients with moderate to severely active SLE enrolled in two international, multicentre, randomized controlled trials of epratuzumab (ALLEVIATE-1 and -2) and a long-term extension study (SL0006)., Methods: Ninety ALLEVIATE patients (43% BILAG A, mean BILAG score 13.2) were randomized to receive 360 mg/m(2) (n = 42) or 720 mg/m(2) (n = 11) epratuzumab or placebo (n = 37), plus standard of care, in 12-week cycles. Corticosteroid use, patient and physician global assessments of disease activity (PtGA and PGA) and 36-item Medical Outcomes Survey Short Form (SF-36) results were recorded at baseline and every 4 weeks. Both trials were prematurely discontinued due to a drug supply interruption; patients followed for ≥6 months were analysed. Twenty-nine patients continued in SL0006, with interim analysis at a median exposure of 120 (range 13-184) weeks., Results: At week 12, proportions of patients with a PGA ≥20% above baseline or with a PtGA improvement greater than or equal to the minimum clinically important difference were higher in the epratuzumab arms than the placebo arm. PGA and PtGA improvements were sustained but did not reach statistical significance. At week 24, mean cumulative corticosteroid doses with epratuzumab 360 and 720 mg/m(2) were 1051 and 1973 mg less than placebo (P = 0.034 and 0.081, respectively). At week 48, SF-36 scores approached or exceeded US age- and gender-matched norms in five domains with the 360 mg/m(2) treatment. Improvements were maintained in SL0006 over ∼2 years., Conclusion: Epratuzumab treatment produced clinically meaningful and sustained improvements in PGA, PtGA and HRQOL and reductions in corticosteroid doses.

Objective: To identify a suitable dosing regimen of the CD22-targeted monoclonal antibody epratuzumab in adults with moderately to severely active systemic lupus erythematosus (SLE)., Methods: A phase IIb, multicentre, randomised controlled study (NCT00624351) was conducted with 227 patients (37-39 per arm) receiving either: placebo, epratuzumab 200 mg cumulative dose (cd) (100 mg every other week (EOW)), 800 mg cd (400 mg EOW), 2400 mg cd (600 mg weekly), 2400 mg cd (1200 mg EOW), or 3600 mg cd (1800 mg EOW). The primary endpoint (not powered for significance) was the week 12 responder rate measured using a novel composite endpoint, the British Isles Lupus Assessment Group (BILAG)-based Combined Lupus Assessment (BICLA)., Results: Proportion of responders was higher in all epratuzumab groups than with placebo (overall treatment effect test p=0.148). Exploratory pairwise analysis demonstrated clinical improvement in patients receiving a cd of 2400 mg epratuzumab (OR for 600 mg weekly vs placebo: 3.2 (95% CI 1.1 to 8.8), nominal p=0.03; OR for 1200 mg EOW vs placebo: 2.6 (0.9 to 7.1), nominal p=0.07). Post-hoc comparison of all 2400 mg cd patients versus placebo found an overall treatment effect (OR=2.9 (1.2 to 7.1), nominal p=0.02). Incidence of adverse events (AEs), serious AEs and infusion reactions was similar between epratuzumab and placebo groups, without decreases in immunoglobulin levels and only partial reduction in B-cell levels., Conclusions: Treatment with epratuzumab 2400 mg cd was well tolerated in patients with moderately to severely active SLE, and associated with improvements in disease activity. Phase III studies are ongoing.

Objective: The Medical Outcomes Short Form-36 Survey (SF-36) has been widely used as a measure of health-related quality of life (HRQOL) in different populations. SLE patients have consistently reported lower scores compared with the general population. The objective of our study was to identify predictors of HRQOL using SF-36 among patients with SLE enrolled in a 2-year randomized controlled trial (RCT)., Methods: We analysed 200 SLE patients enrolled in the Lupus Atherosclerosis Prevention Study (LAPS), an RCT of atorvastatin vs placebo, who completed SF-36 at qualifying, 12- and 24-month (final) visits., Results: At baseline, mean SF-36 domain scores were lower than those of age- and gender-matched population norms. There was no statistical difference reported between Physical Component Summary (PCS), Mental Component Summary and eight domain scores in the atorvastatin vs placebo group at 2 years. In multiple regression analyses, African American patients reported significantly lower scores in Physical Functioning compared with Caucasians. The presence of FM was significantly associated with lower scores in physical functioning, role physical, bodily pain, general health, vitality, social functioning and lower overall mean PCS scores. The Physician's Global Assessment of disease activity was associated with multiple SF-36 domains in univariate analysis., Conclusion: This longitudinal study confirmed lower scores reported across all SF-36 domains. No one explanatory variable was independently associated with all domain scores. FM was independently associated with poorer HRQOL in most domains, underscoring the need for effective treatments for FM in SLE.

Objective: To evaluate epratuzumab treatment in patients with moderately-to-severely active SLE in two international, randomized, controlled trials (ALLEVIATE-1 and -2) and an open-label extension study (SL0006)., Methods: Ninety ALLEVIATE patients (43% BILAG A, median BILAG score 12.0) received standard of care plus 10 total doses of placebo (n = 37) or 360 mg/m(2) (n = 42) or 720 mg/m(2) (n = 11) epratuzumab, administered across 12-week cycles for up to 48 weeks, with BILAG assessments every 4 weeks. Patients were followed for ≥ 6 months and their data combined for analysis. The primary endpoint was BILAG response at week 12 (all BILAG A scores reduced to B/C/D and B scores to C/D, no new A and <2 new B scores). Twenty-nine patients continued in SL0006, receiving 12-week cycles of 360 mg/m(2) epratuzumab; this interim analysis was performed at median 120 weeks (range 13-184) of exposure., Results: Both ALLEVIATE trials were discontinued prematurely because of interruption in drug supply. Exploratory pooled analyses found that responses at week 12 were 15/34 (44.1%) and 2/10 (20.0%) for epratuzumab 360 and 720 mg/m(2), respectively, vs 9/30 (30.0%) for placebo. Total BILAG scores were lower in both epratuzumab arms vs placebo at week 48 and at all but two time points. The incidence of adverse events was similar between groups. In SL0006, median total BILAG score was 8.0 (n = 29) at study entry and 7.0 (n = 19) at week 100, with no additional safety signals., Conclusion: This initial efficacy and safety profile of epratuzumab supports its continued development for SLE treatment.

An independent cross-sectional survey assessed systemic lupus erythematosus (SLE) disease and treatment burden. Variables included medication classes prescribed, disease activity, flare occurrences, treatment satisfaction, and validated measures of health-related quality of life (HRQoL), fatigue and work productivity. Of 886 eligible patients (mean age 41.3 years, 89% female), 515 completed the survey. One-third reported moderate-to-severe disease activity, and 31% had flared in the last 12 months. Higher severity of disease activity (moderate-to-severe) was associated with ≥ 2 medication classes prescribed and treatment regimens that included corticosteroids (CS) (both p<0.0001). Patients receiving CS reported lower EQ-5D scores (p=0.0019) and higher fatigue levels (p<0.001), and both patients (p=0.0019) and physicians (p=0.0001) were less likely to report satisfaction with treatment regimens including CS. Among responders eligible for work (n=456), severity of disease activity (moderate-to-severe vs. mild) was associated with unemployment (52.9% vs. 40.8%; p=0.0189), greater impairment in work productivity (36% vs. 21%; p=0.0003) and participation in daily activities (41% vs. 21%; p<0.0001). This survey confirms that SLE and current treatment options substantially impair patients' health status and work productivity. Physician- and patient-reported satisfaction with current treatment regimens, despite poorly controlled disease activity, indicate they are resigned to the limitations of available SLE treatment regimens.

The recent approval of the biologic therapy, belimumab, for treatment of systemic lupus erythematosus (SLE) by the US FDA has shifted the developmental landscape of therapeutics for this autoimmune disease. Promising therapies are currently in development for the treatment of SLE, with trials designed to emphasize clinically relevant end points. This article will discuss outcome measures that have been utilized including disease activity indices, definitions of flare, measures of damage, global assessments of disease activity and measures of health-related quality of life. Application of these outcome measures in recent trials are highlighted as illustrative examples. Contributions to the recent success of randomized controlled trials in SLE have included use of evidence-based responder indices, clear definitions of treatment failure, predefined management strategies for use of immunosuppressive agents and corticosteroids, sufficient sample sizes and efforts to identify responsive patient populations. Each completed study in SLE promises to better inform trial design and offer further opportunities for success in a field with a continuing unmet therapeutic need.

The Lupus Foundation of America (LFA) convened an international working group to obtain a consensus definition of disease flare in lupus. With help from the Paediatric Rheumatology International Trials Organization (PRINTO), two web-based Delphi surveys of physicians were conducted. Subsequently, the LFA held a second consensus conference followed by a third Delphi survey to reach a community-wide agreement for flare definition. Sixty-nine of the 120 (57.5%) polled physicians responded to the first survey. Fifty-nine of the responses were available to draft 12 preliminary statements, which were circulated in the second survey. Eighty-seven of 118 (74%) physicians completed the second survey, with an agreement of 70% for 9/12 (75%) statements. During the second conference, three alternative flare definitions were consolidated and sent back to the international community. One hundred and sixteen of 146 (79.5%) responded, with agreement by 71/116 (61%) for the following definition: "A flare is a measurable increase in disease activity in one or more organ systems involving new or worse clinical signs and symptoms and/or laboratory measurements. It must be considered clinically significant by the assessor and usually there would be at least consideration of a change or an increase in treatment." The LFA proposes this definition for lupus flare on the basis of its high face validity.

Objective: To describe a new systemic lupus erythematosus (SLE) responder index (SRI) based on a belimumab phase II SLE trial and demonstrate its potential utility in SLE clinical trials., Methods: Data from a randomized, double-blind, placebo-controlled study in 449 patients of 3 doses of belimumab (1, 4, 10 mg/kg) or placebo plus standard of care therapy (SOC) over a 56-week period were analyzed. The Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and British Isles Lupus Assessment Group (BILAG) SLE disease activity instruments, the Short Form 36 health survey, and biomarker analyses were used to create a novel SRI. Response to treatment in a subset of 321 serologically active SLE patients (antinuclear antibodies >/=1:80 and/or anti-double-stranded DNA antibodies >/=30 IU/ml) at baseline was retrospectively evaluated using the SRI., Results: SRI response is defined as 1) a >/=4-point reduction in SELENA-SLEDAI score, 2) no new BILAG A or no more than 1 new BILAG B domain score, and 3) no deterioration from baseline in the physician's global assessment by >/=0.3 points. In serologically active patients, the addition of belimumab to SOC resulted in a response in 46% of patients at week 52 compared with 29% of the placebo patients (P = 0.006). SRI responses were independent of baseline autoantibody subtype., Conclusion: This evidence-based evaluation of a large randomized, placebo-controlled trial in SLE resulted in the ability to define a robust responder index based on improvement in disease activity without worsening the overall condition or the development of significant disease activity in new organ systems.

It is difficult to assess outcomes in randomized controlled trials in SLE. Its cyclic nature and multiorgan involvement complicate the identification and reproducibility of outcome measures. Disease activity indices do not necessarily reflect disease outcome in the generally short timeframes of protocol treatment. Patient and physician assessments of disease may not correlate well. Responder analyses do not function well if they are proposed in the absence of data from RCTs. Changes in medical practice may affect patient selection and make it difficult to replicate findings in a subsequent protocol. Background therapy even if stable during protocol participation may confound treatment effects. While objective outcome measures are well defined in renal and hematologic disease, few SLE patients have isolated organ system involvement at any one time. Protocol designs must anticipate changes in disease activity and need for treatment of emergent disease manifestations. Despite these difficulties, a body of evidence derived from RCTs has developed. Although limited and yet to result in an approved therapy, early markers of treatment response have been defined and shown to correlate with longer term clinical outcomes. Biomarkers are an appealing idea to assess biologic effects of study treatment and hopefully predict clinical outcome.

With improvements in mortality in systemic lupus erythematosus (SLE), the functional status of these patients, assessed using health-related quality of life (HRQoL) instruments, is increasingly being recognised as an important outcome measure in clinical research. Domains of HRQoL of particular importance to SLE patients include fatigue, ability to work, good health, independence, social and family life, learned helplessness (reflecting the unpredictability of lupus), pain and the home environment. The SF-36 currently appears to be the best available generic instrument for the assessment of HRQoL in SLE, and is likely to be complemented by several newly-developed disease-specific HRQoL instruments. It has been shown that SLE patients have poorer functional status than the general population, and that specific manifestations of SLE (disease activity, previous renal involvement and fibromyalgia) may influence HRQoL. HRQoL in SLE patients has been improved by (1) psycho-educational interventions including telephone counselling, a self-help course, group psychotherapy; (2) therapies including Riquent, belimumab, mycophenolate mofetil, dehydroepiandrosterone, oestrogen therapy and a cholesterol- lowering diet. Additional research is needed to identify strategies which can improve HRQoL in SLE patients.

Objective: To determine whether prasterone administration results in improvement or stabilization of systemic lupus erythematosus (SLE) disease activity and its symptoms., Methods: Women with active SLE were treated with prasterone 200 mg/day plus standard SLE treatments or with placebo plus standard SLE treatments for up to 12 months in this randomized, double-blind investigation conducted at 27 centers. Standard SLE treatments included prednisone (/=6 weeks prior to enrollment and remain unchanged during protocol treatment. Responders were patients who experienced no clinical deterioration and had improvement or stabilization over the duration of the study in 2 disease activity measures (the SLE Disease Activity Index [SLEDAI] and the Systemic Lupus Activity Measure) and 2 quality of life measures (patient's global assessment and the Krupp Fatigue Severity Scale)., Results: A total of 381 women with SLE were enrolled. Among patients with clinically active disease at baseline (SLEDAI score >2), 86 of 147 in the prasterone group (58.5%) demonstrated improvement or stabilization without clinical deterioration, as compared with 65 of 146 in the placebo group (44.5%) (P = 0.017). Acne and hirsutism were reported in 33% and 16%, respectively, of the prasterone group and in 14% and 2%, respectively, of the placebo group (P < 0.05 for both comparisons). However, most cases of acne and hirsutism were mild and did not require withdrawal from therapy. Myalgias and oral stomatitis were reported less frequently in the prasterone group (22% and 15%, respectively) than in the placebo group (36% and 23%, respectively) (P < 0.05 for both comparisons). Serum levels of high-density lipoprotein cholesterol, triglycerides, and C3 complement significantly decreased, while levels of testosterone and, to a lesser extent, estradiol increased in the prasterone group., Conclusion: In adult women with active SLE, administration of prasterone at a dosage of 200 mg/day improved or stabilized signs and symptoms of disease and was generally well tolerated.

Designing successful randomized controlled trials (RCTs) in systemic lupus erythematosus (SLE) poses many challenges. It remains difficult to correlate alterations in biologic markers with clinical outcome, especially when signs and symptoms are intermittent and broadly variable between patients. Disease activity indices were not designed specifically as outcome measures in RCTs, as they were developed in the context of longitudinal observational studies. Although all disease activity indices have been validated against each other and demonstrated to show change, organ system manifestations are variably weighted; fatigue and autoantibody titers are scored in some and not in others. Due to the variability of the underlying disease course an assessment of disease activity may most accurately be portrayed as change over time, such as an area under the curve analysis. Another lesson learned is that 'responder indices' proposed in the absence of prospective validation in RCTs do not function well. The argument can always be made that any response criteria will work if the treatment is effective; but without the precedent of a product specifically approved for use in SLE, this is hard to prove. The ACR/Systemic Lupus International Cooperating Clinics (SLICC) damage index was designed to score irreversible manifestations of disease or consequences of its treatment, provided they had been present for at least six months. The damage index may best be utilized to stratify patients or balance randomization at baseline. It may also be incorporated into an endpoint analysis, to ensure that treatment or disease associated deterioration in organ system function (that may be overlooked in scoring disease activity alone) has not occurred. Patient cohort data have demonstrated that the medical outcomes survey short form-36 (SF-36) reflected the effects of SLE better than other patient reported measures. Worsening SF-36 domain scores best correlate with higher disease activity, increased glucocorticoid doses and use of cytotoxic agents. It has been shown sensitive to change in RCTs and observational cohorts, and reflects the impact of treatment with high dose glucocorticoids and immunosuppressive agents, as well as end stage renal disease. There is now a body of data derived from RCTs in SLE. Albeit limited, yet to result in an approved therapy, evidence is accumulating that indicate 'early markers' of response can be defined which may correlate with longer term clinical outcomes. This should inform us in our ongoing efforts to clinically test a broad variety of promising interventions.

In a 76-week, randomized controlled trial, patients received 100 mg LJP 394 or placebo weekly for 16 weeks followed by three 12-week treatment cycles of 50 mg LJP 394 or placebo weekly each separated by eight-week periods when no therapy was administered. Health-related quality of life (HRQOL) was assessed using SF-36 at baseline, 16 weeks and every 12 weeks thereafter. Analyses populations included intent to treat (ITT) (n = 179) and patients with high-affinity anti-dsDNA antibody binding (HA): 157/179; 85% active, 90% placebo. In the ITT population, there were improvements in role emotional (RE) (+7.3 versus -8.2), social functioning (SF) (+4.3 versus +0.7), and role physical (RP) (+11.3 versus +6.0) domains in the active treatment group when compared with placebo, with similar changes observed in the HA population. In 37 patients with data pre- and post-renal flares, those receiving LJP 394 reported stabilization or improvement in all but one domain compared with deterioration in all domains with placebo. Changes in RE domain scores following a flare differed by 22.7 points between the two treatment groups, favouring LJP 394 treatment. Patients receiving LJP 394 reported stable or improved HRQOL with active treatment following renal flares compared with deterioration in placebo. Differences between treatment groups in RE and SF domains are clinically important and were replicated irrespective of the protocol population analysed.

Objective: To evaluate whether treatment with prasterone (dehydroepiandrosterone [DHEA]) would allow the dosage of prednisone (or an equivalent corticosteroid) to be reduced to < or = 7.5 mg/day for 2 months or longer while maintaining stable or reduced disease activity in steroid-dependent women with systemic lupus erythematosus (SLE)., Methods: In a double-blind, randomized trial, 191 female SLE patients receiving prednisone (10-30 mg/day) were treated daily with either placebo, 100 mg of oral prasterone (an adrenal androgen), or 200 mg of oral prasterone for 7-9-months. At monthly intervals, corticosteroid dosages were reduced by algorithm in patients whose SLE Disease Activity Index (SLEDAI) score was stable or improved. Patients for whom a sustained reduction in the dosage of prednisone (< or = 7.5 mg/day) was achieved for at least the last 2 months of the 7-9-month treatment period were classified as responders., Results: Response rates were 41% in the placebo group, 44% in the 100-mg prasterone group, and 55% in the 200-mg group (P = 0.110, 200 mg versus placebo). Among the 137 subjects (45 in the placebo group, 47 in the 100-mg group, and 45 in the 200-mg group) who had active disease at baseline (defined as SLEDAI score >2), 29%, 38%, and 51%, respectively, were responders (P = 0.031 for 200 mg prasterone versus placebo). Acne was the most common adverse event but was generally mild. Clinical and laboratory changes primarily reflected androgenic effects of prasterone., Conclusion: Among women with lupus disease activity, reducing the dosage of prednisone to < or = 7.5 mg/day for a sustained period of time while maintaining stabilization or a reduction of disease activity was possible in a significantly greater proportion of patients treated with oral prasterone, 200 mg once daily, compared with patients treated with placebo.

The treatment of systemic lupus erythematosus (SLE) presents a significant therapeutic challenge: multi-organ involvement and a variable disease course characterized by clinical exacerbations and remissions make it difficult to predict outcome. Few products have been specifically developed in this clinical indication and most accepted therapies have not been tested in randomized controlled trials in SLE. A variety of biologic agents under investigation as potential treatments for SLE are designed to interfere with specific immunologic responses, hopefully avoiding generalized immunosuppression. These include therapies to downregulate IL-10 and/or upregulate TGFb production. Agents which interfere with T cell activation and T cell-B cell collaboration, such as CTLA4-Ig and anti-CD40 ligand monoclonal antibodies, may result in long term therapeutic benefit; alone or in combination, even following brief treatment courses. Products designed to decrease production of anti-dsDNA antibodies or inhibit complement activation may prevent immune complex deposition and amerliorate organ-specific manifestations such as renal disease. More aggressive interventions include gene therapy and stem cell transplantation. As these agents enter clinical trials, efforts to develop international consensus regarding trial methodology and outcome measures will be crucial to their successful development.

New therapies for the treatment of SLE have gained increased attention, as demonstrated by a growing number of new modalities being studied. These modalities include novel biologic agents that target specific immunologic responses and more traditional pharmaceutical agents. This article summarizes these new therapies and briefly discusses their mechanisms of action and the most recent research performed to characterize their safety and efficacy.

The goal of the 'Outcome Measures in Rheumatology' (OMERACT) process is to select domains and/or outcome measures for clinical trials in each defined disease category according to truth, discrimination and feasibility. OMERACT IV, held in Cancun, Mexico, April 1998, included the module 'Systemic Lupus Erythematosus (SLE)', designed to define a preliminary core set of outcome domains for randomized controlled trials and longitudinal observational studies (LOS). Although specific measures to be used in clinical trials of SLE have yet to be determined, both randomized controlled trials and longitudinal observation studies groups recommended that outcome be assessed in terms of disease activity and damage in all organ systems involved, as well as by health related quality of life, meaningful to patients, and adverse events. These recommendations were ratified by the majority of participants. In a heterogeneous patient population such as SLE, it is recognized that any individual measure of clinical response may reflect only a portion of what might be termed the 'true outcome'. A responder index could integrate such relatively independent measures of outcome into a single assessment, potentially increasing statistical power and decreasing sample size. Results from randomized controlled trials currently underway assessing these outcome domains are eagerly awaited, and are expected to rapidly advance the field.

Systemic lupus erythematosus (SLE) is a difficult disease to study, having a variable disease course characterized by exacerbations and remissions. A variety of biologic agents are under investigation as potential treatments for SLE. These products are designed to specifically interfere with the following immunologic processes: T cell activation/T cell-B cell collaboration, production of anti-double-stranded DNA antibodies, deposition of anti-double-stranded DNA antibody complexes, complement activation, and immune complex deposition and cytokine activation and modulation. More aggressive interventions include gene therapy and stem cell transplantation. Immunomodulatory agents recently examined in patients with SLE include: thalidomide, AS101, 2' chlordeoxyadenosine, mycophenolate mofetil, and bindarit. Additional innovative pharmaceutical treatments include the mild androgen dehydroepiandrosterone, selective estrogen receptor modulators, and the prolactin inhibitor, bromocriptine. A variety of these biologic and pharmaceutical agents offer promise as potential therapies. Active participation in clinical trial efforts to develop international consensus regarding trial methodology and outcome measures are crucial to the development of these innovative therapies.

The OMERACT module on systemic lupus erythematosus (SLE) dealt with the definition of preliminary core sets of outcome domains for randomized clinical trials (RCT) and longitudinal observational studies (LOS). After lectures introducing the problems and addressing the key issues, 6 discussion groups, 3 each for LOS and RCT, discussed and weighted more than a dozen possible items for use as outcome domains. The means of the respective 3 groups were calculated. For both RCT and LOS the same outcome domains received more than 10 of a total maximum of 100 points: disease activity, health related quality of life (HRQOL), damage, and toxicity/adverse events. However, the weights for HRQOL and damage were different for LOS and RCT. A final vote led to the acceptance of these 4 variables as a preliminary core set for outcome in SLE by more than 80% of the participants. This core set will allow for improved design, performance, and evaluation of future studies in SLE. However, a number of domains not included in the core set were regarded as important for further analysis and research.

The optimal outcome measures to be employed in clinical trials of systemic lupus erythematosus (SLE) have yet to be determined. Useful instruments should assess disease outcome in terms of all organ system involvement, as well as measures important to the patient. This article reviews those outcome measures that have been utilized in cohort studies in SLE, as well as their limited use in randomized clinical trials (RCT). Six disease activity measures have been developed: British Isles Lupus Assessment Group Scale (BILAG), European Consensus Lupus Activity Measure (ECLAM), Lupus Activity Index (LAI), National Institutes of Health SLE Index Score (SIS), Systemic Lupus Activity Measure (SLAM), and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). They have been validated in cohort studies as reflecting change in disease activity, and against each other. RCT utilizing SLAM, SLEDAI, BILAG, ECLAM, SIS, SLAM, SLEDAI are ongoing. It is recommended that the disease activity index of choice be selected; but simultaneous computer generation of multiple indices will facilitate comparisons across therapeutic interventions. A damage index has been developed and validated as the Systemic Lupus International Cooperating Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index or SDI. In several cohort studies it has been shown sensitive to change over time, and to reflect cumulative disease activity. There is no health status or disability instrument specific to SLE. The Medical Outcomes Survey (SF-20) captures health status/health related quality of life (HRQOL) better than the Health Assessment Questionnaire (HAQ) in patients with SLE, but does not adequately reflect fatigue. The SF-36 does assess fatigue, and correlates closely with the SF-20. These data indicate that any individual measure of clinical response to a therapeutic intervention in SLE may reflect only a portion of what might be termed the "true outcome." Based on this work, the way is now paved to attempt to develop consensus on the important domains to be measured in clinical trials in SLE, the most appropriate instruments to use and the minimal clinically important differences in their results.

Systemic lupus erythematosus is a difficult disease to study with a variable disease course characterized by exacerbations and remissions. A variety of biologic agents are under investigation as potential treatments for systemic lupus erythematosus, either in murine disease models or in clinical trials. These products are designed to specifically interfere with the following immunologic processes: T-cell activation and T-cell-B-cell collaboration, production of anti-dsDNA antibodies, deposition of anti-dsDNA antibody complexes, complement activation, and deposition, and cytokine activation and modulation. More aggressive interventions include gene therapy and stem-cell transplantation. Recently developed immunomodulators have been studied in patients with systemic lupus erythematosus 2'-Chlorodeoxyadenosine, mycophenolate mofetil, and leflunomide. Additional innovative pharmaceutical treatments include the mild androgen dehydroepiandrosterone, estrogen antagonists, including tamoxifen and selective estrogen receptor modulators, and the prolactin inhibitor bromocriptine. Other promising pharmaceutical interventions include products designed to inhibit synthesis of the proinflammatory mediators: prostaglandins, leukotrienes, and nitric oxide. Although previously regarded as an indication to be avoided in the development of new therapeutics, enthusiasm for studying systemic lupus erythematosus in clinical trials now exists. A variety of biologic and pharmaceutical agents offer promise as potential therapies. As with rheumatoid arthritis, development of these products will benefit from active involvement of rheumatologists and efforts to develop international consensus regarding trial methodology and outcome measures.