Hydroxychloroquine in Systemic Lupus Erythematosus
Hydroxychloroquine in Systemic Lupus Erythematosus
A Systemic lupus erythematosus, SLE is disease in which immune system is over-active causing
 inflammation in joints skin or any organ system. There are many areas where better approaches
 in SLE could improve outcomes. One example relates to hydroxychloroquine (HCQ) key drug which
 can reduce risk of serious disease flares. There are increasing concerns about eye damage
 main side effect with long-term use of HCQ. At present investigators cannot precisely predict
 which SLE patient is most likely to flare once HCQ is tapered. It is not clear what drives
 risk of eye damage. Investigators' study will fill these knowledge gaps. Investigators'
 hypothesis is that baseline demographic and clinical factors are associated with risk of SLE
 flare after HCQ taper/discontinuation and with risk of retinal toxicity in all HCQ exposed
 patients. Research will link and analyze data on 3700 SLE patients across Canada.
B OBJECTIVES B1 To evaluate in SLE patients who lower but do not discontinue HCQ factors
 associated with flare (significant increase in disease activity, augmentation of therapy or
 hospitalization for SLE).

 B2 To determine in SLE patients who discontinue HCQ factors associated with flare
 (significant increase in disease activity, therapy augmentation or hospitalization for SLE).

 B3 To evaluate temporal relationship between HCQ use and retinal toxicity in SLE patients and
 how this may be associated with demographic and clinical factors.

 B4 To assess SLE patient preferences for HCQ therapy and how preferences are associated with
 demographic and clinical factors.

 B5 To evaluate temporal relationship between antimalarial use and other forms of toxicity in
 SLE patients and how this may be associated with demographic and clinical factors.

 Team members have prospectively followed cohorts > 3700 adult SLE patients (90% HCQ exposed)
 with collected and harmonized data on demographics and clinical factors. Team members
 (Bernatsky Abrahamowicz Fortin Hazlewood) are founding members of CAN-AIM CIHR-funded Drug
 Safety and Effectiveness Network team.

 Members have history of working with patients as research partners (Bartlett Li Bernatsky
 Fortin Hazlewood). Investigators' ties to stakeholders including patient research partners
 and Lupus Canada facilitates knowledge translation.

 METHODS C1 Cohorts: Investigators will use existing data on adult SLE patients enrolled into
 study cohorts in Montreal Quebec Halifax Winnipeg Calgary and Toronto.

 Investigators are members of national (Canadian Network for Improved Outcomes in SLE CaNIOS)
 and/or international (Systemic Lupus International Collaborating Clinics SLICC) research
 networks. CaNIOS and SLICC have worked decades on harmonized approach to
 prospectively-collected. Cohorts enroll unselected patients when they present to clinic. At
 annual assessments data are collected on drugs disease activity organ damage etc C2.1 Patient
 selection for Objective 1: At baseline and follow up visits records are made of patient HCQ
 doses. Starting with first visit with HCQ exposure investigators will determine how many
 patients are recorded as receiving lower dose or discontinuing HCQ at follow-up visit.
 Patients identified as having lowered HCQ dose will form sub-cohort for time-to-event
 (survival) analyses. Investigators will evaluate only first-ever lowering of HCQ. Analysis
 will evaluate patients from time zero (annual visit at which lower HCQ dose was recorded) to
 assess combined outcome of earliest of a) increase in SLEDAI-2K of at least 4 points and/or
 b) hospitalization for SLE and/or c) augmented SLE therapy defined as increase in HCQ or new
 start or increase in corticosteroids or other immunosuppressant. In addition to accepted
 minimal clinically significant SLEDAI-2K change investigators include drug changes and
 SLE-related hospitalizations.

 Patients studied in Objective 1 will be right censored if HCQ is discontinued completely;
 these will enter into analyses for Objective 2. Otherwise patients will be followed until
 outcome of interest or end of study.

 C2.3 Subject selection for Objective 2 Analyses will be similarly conducted but time zero
 will begin when individual discontinues HCQ. Objective 1 and 2 analyses conducted separately;
 patients who have HCQ dose lowered but then discontinued will be in analyses for Objective 1
 up to point of discontinuation then patients will be right censored for Objective 1. Subjects
 are able to contribute data (from the point of HCQ discontinuation) to analyses for Objective
 2. Patient can contribute to analyses for one or both objectives and contributing to
 Objective 3. If not right-censored patients will be followed until outcome of interest or end
 of study.

 C2.3 Subject selection for Objective 3 Outcome is retinal toxicity assessed in HCQ-exposed
 patients from time of first visit with HCQ exposure up to time of retinal toxicity
 documentation or end of study for patients without outcome. Exposure to CQ (relatively
 uncommon drug exposure) is also risk factor for retinal toxicity but essentially patients
 exposed to CQ will have prior exposure to HCQ.

 C3 Demographic and clinical factors C3.1 Variables assessed include sex age at SLE onset and
 race/ethnicity. Analyses adjusted for education as education can alter adherence.

 C3.2 Clinical factors for multivariable analyses include smoking BMI baseline disease
 activity malignancy data and renal damage. Baseline refers to time zero. Renal damage is
 captured with SLICC Damage Index measuring accumulated damage. Baseline disease activity
 measured by internationally used SLEDAI-2K reliable validated widely used global score
 index.Investigators will model time-varying drug exposures with step-up approach initially
 with baseline use ie current, recent, ever or total past dose. Investigators use
 sophisticated and novel weighted cumulative dose modelling to flexibly represent exposures
 accumulated by individual subjects up to given time-point corresponding to each risk set for
 time-to-event analyses. In multivariable analyses approach will allow investigators to
 explore how risk of retinal toxicity may depend on details of past HCQ exposure including not
 only total cumulative dose but temporal pattern of doses at various time in past with
 differential weights for early versus later exposures.

 C4 Outcome assessment: SLEDAI-2K and drugs are recorded. SLICC Damage Index has item for
 retinal damage and updated yearly.

 C5 Model development: Investigators will perform multivariable time-to-event analyses in
 patients who lower or discontinue HCQ. Data for outcomes are available longitudinally at
 annual visit with actual dates only available for addition/increase in corticosteroid or SLE
 hospitalization. For other outcomes investigators will deal with interval-censored data
 familiar issue in pharmacoepidemiology.

 Models include baseline demographics education BMI SLE duration SLEDAI-2K renal damage and
 medications. Simplistic survival analyses often assume linear effects of continuous
 covariates and impose conventional proportional hazards (PH) assumptions; investigators know
 that prognostic factors may have time-dependent and/or nonlinear effects that violate
 assumptions. Investigators will account for this. Methods account for possible changes in
 hazard ratio over time (violation of the PH) and allow estimation of relative risks (hazard
 ratios) and actual probabilities of event of interest occurring.

 Similar approach will be used for Objective 3 in time-to-event analyses of retinal toxicity
 in patients exposed to HCQ.

 Competing risks occur when subjects can experience one or more events that may compete with
 outcome of interest and hinder observation of event of interest or modify chances for event
 to occur. In sensitivity analyses investigators use competing risks models to simultaneously
 estimate associations between HCQ exposures and hazards of competing event.

 D POWER/SAMPLE CALCULATIONS D1 Power calculations for multivariate models Combined cohorts
 include over 3300 patients have exposed to HCQ. Patients have had lowering of dose 45% or
 discontinuation of HCQ during their follow-up. Power calculations are based on available data
 suggesting that 45%-60% of SLE patients may flare over ten years of follow-up.

 For baseline SLEDAI-2K assuming 35% of patients score less than 3 investigators would have
 90% power to detect unadjusted HR of 1.30 and adjusted HR of 1.37 for variable. Assuming 20%
 of patients have renal damage investigators will have 90% power to detect an unadjusted HR of
 1.37 and an adjusted HR of 1.45 for variable.

 E KNOWLEDGE TRANSLATION activities are informed by history of partnerships between
 investigators and knowledge-users directed by Dr. Linda Li Canada Research Chair in
 Patient-Oriented KT and Director of Knowledge Translation Research Program at UBC's Arthritis
 Research Centre of Canada.

 E1 Integrated KT Proposal developed in consultation patients from Lupus Canada patients
 Canadian Alliance of Patients with Arthritis (CAPA) and Singer Family Fund for Lupus
 Research. Wendy Singer (providing expertise health information dissemination and provides
 insight of SLE patient who has been affected by HCQ-induced retinal toxicity) will assist
 with educational tool developments. Co-PI Dr. Bartlett has over decade of work with patient
 partners through OMERACT (Outcome Measures in Rheumatology) and other organizations to help
 disseminate findings patient communities.

 E2 Dissemination via MyLupusGuide: Data on HCQ from current study will be incorporated into
 MyLupusGuide web-based patient-centred health-management tool developed by Dr. Fortin in
 partnership with Jack Digital Productions CaNIOS Lupus Canada. Development
 validation/dissemination of current version funded by CIHR operating and dissemination
 grants.

 E3 Clinicians and professional groups: Dr. Bernatsky is member of CRA Therapeutics Committee
 which advises CRA on policies related to drug use for rheumatic diseases. Group monitors
 information about adverse events related to drugs used in rheumatology including HCQ.
 Investigators submit abstracts to scientific meetings (American College of Rheumatology,
 European League Against Rheumatism, CRA meeting). Investigators will seek feedback on
 feasibility/approaches to integrate MyLupusGuide as gold standard for patient education tool
 concerning HCQ.

 E4 Informing future guidelines: Team member Dr. S. Keeling has already produced Canadian SLE
 care guidelines (funded by the CIHR and endorsed by the CRA and CaNIOS) . In 2019, again
 mandated by these groups, Dr. Keeling will spearhead guidelines for SLE therapies.

 E5 Health agency stakeholders: Investigators have connections Drug Safety and Effectiveness
 Network (DSEN) Health Canada's Marketed Health Product Directorate and Canadian Agency for
 Drugs and Technologies in Health (CADTH). Drs. Abrahamowicz and Bernatsky are co-leads
 DSEN-funded team.
Inclusion Criteria:

 -  Must be 18 years of age or over

 -  Must be diagnosed with Systemic Lupus Erythematosus (SLE)

 -  Must be exposed to hydroxychloroquine

 -  Must be enrolled at participating sites

 Exclusion Criteria:

 -  Under 18 years of age

 -  Not diagnosed with SLE

 -  Not exposed to hydroxychloroquine

 -  Not enrolled at participating sites