Antimalarials and their association with remission, damage and glucocorticoid use in Systemic Lupus Erythematosus

Introduction: Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease with a protean clinical phenotype. Antimalarials (AMs) are a cornerstone in SLE treatment, and over the years have been associated with many benefits. Nevertheless, clinicians and patients not infrequently discontinue AMs therapy, due to remission, AM-induced retinopathy, and non-adherence. Objective: to assess the prevalence and use patterns of AMs and to examine whether different patterns perform differently in disease activity, attainment of remission and low disease activity, glucocorticoid (GC) use, and damage accumulation. Methods: We performed a retrospective analysis of 455 SLE patients referring to Padua Clinic between 1980 and 2020. Disease activity was assessed by SLE Disease Activity Index 2000 (SLEDAI-2K) and damage accumulation by Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). Remission on GCs was defined as clinical SLEDAI-2K=0, stable background therapy, and prednisone (PDN) ≤ 5 mg/day. Low disease activity status (LLDAS) was defined according to Franklyn et al., modified by excluding PGA. Cumulative SDI, SLEDAI-2K, achievement of remission, and PDN therapy at the end of follow-up were examined. AM therapy status was defined as: AMs never prescribed, prescribed and never stopped, prescribed and stopped. Among the latter, we identified patients who discontinued AMs due to retinopathy or due to other reasons. Retinopathy was defined according to a certified ophthalmologist evaluation contraindicating further AM therapy. Time without AMs (difference between SLE duration and AM therapy duration) and fraction of time off AMs (time without AMs divided by SLE duration) were also calculated. The Cox regression model was used to explore predictors of retinopathy. The association between AM therapy status and SDI was evaluated in a multivariable logistic regression model. Results: Less than 5% of the enrolled patients never assumed AMs. In this group, neurological manifestations, vasculitis, the use of immunosuppressants and SDI ≥2 were more frequent. Patients who had stopped AMs were less likely to be off GCs (44.9% vs. 68%, p=0.0001) and more likely to have an active SLE (20% vs. 9%, p=0.0003). SDI ≥2 was also highly discordant (47.9% vs. 27.89%, p<0.0001). Moreover, patients who stopped AMs were less likely to be free of chronic kidney disease (CKD) (81.6% vs. 91.1%, p=0.002). The prevalence of discontinuation of AM therapy due to confirmed retinopathy was 6.4% with a median duration of therapy of 9 years (IQR: 4-19). At Cox regression analysis, older age in years (per unit change: HR 1.04, 95% CI 1.01-1.07 p=0.04) and anti-U1RNP positivity (HR 3.2, 95% CI 1.38-7.46, p=0.006) were predictors of retinopathy. Furthermore, patients with eGFR <30 ml/min or history of renal transplantation showed a HR of 10.1 (95% CI 1.24-82.4) towards retinopathy vs. patients with no eGFR reduction. Patients with damage at the end of follow-up had an incrementally higher mean fraction of SLE duration spent without AM exposure (0.18 vs. 0.24 vs. 0.35 for SDI=0, SDI =1, and SDI ≥2, respectively, p=0.0034). A similar pattern emerged regarding GC dose (p=0.0013) and disease activity status (p=0.0009). Conclusions: Time spent without AMs during SLE is associated with increased disease activity, damage accumulation, and GC use. The development of retinopathy is infrequent below the threshold of 5 mg/kg/day of HCQ.