Clinical outcomes and predictors of difficult-to-treat lupus nephritis: observations from a single center retrospective cohort

Background/Aims Lupus nephritis (LN) is a serious manifestation of systemic lupus erythematosus (SLE). About 14-33% of LN patients fail to respond to standard treatment. In this study we evaluated the treatment outcomes of LN patients who failed to respond to standard first-line immunosuppressives and attempted to define the clinical characteristics of 'difficult-to-treat' (DTT) LN. Methods Records of all SLE patients from the lupus clinic in our center who underwent renal biopsy were reviewed. Those with class III, IV, and V LN were included. Demographic, clinical, laboratory and histopathological features were recorded. Any patient with inadequate response to first-line induction which, according to the ACR, is disease worsening at three months or treatment failure by six months or who did not have partial or complete response as per EULAR/ERA-EDTA definition, were classified as DTT LN. Those who achieved complete response but developed flares within 24 months of therapy warranting second induction were also considered DTT. All of these patients received a second induction therapy. The outcome of interest was a composite outcome of worsening creatinine, end-stage renal disease (ESRD) or death. Secondary outcomes included response rates, time to achieve response, progression to ESRD, mortality, and adverse events. Results We identified 181 SLE patients (91.7% female) with biopsy-proven LN with complete records who had at least 2-year follow-up from 2004 to 2022. Their age (median, IQR) was 29 (24-32) years, median duration of disease 48 (24-84) months, median SLEDAI-2K was 12 (8-16). Among the initial kidney biopsies, 71 (39.2%) were class III, 74 (40.8%) class IV, 23 (12.7%) pure class V and 13 (7.1%) class III/IV + V. Fifty-seven of 181 (31.4%) were identified as DTT. Among these, 28/57 (49.1%) received second induction treatment, 22/57 (38.6%) received three induction, and 7/57 (12.3%) received >3 induction. Being of male sex, presence of constitutional symptoms, serositis, hypertension, leucopenia, active sediments in the initial urinalysis, anti-Ro-60, anti-U1RNP, any antiphospholipid antibodies (aPLs), low C3, wire loop lesions, interstitial inflammation, fibrinoid necrosis, cellular or fibrocellular crescents, and glomerulosclerosis were significantly associated with DTT LN (Table 1). On multivariate logistic regression, only the presence of aPLs and active urinary sediments remained as independent predictors of DTT LN(table 1). A Kaplan-Meier plot showed the cumulative incidence of the composite outcome to be significantly high in the DTT group. After follow up of 250 months, 24/57 (42.1%) DTT patients were in complete remission and 11/57 (19.3%) in partial remission, while 22/57 (38.6%) remained non-responsive to treatment. Conclusion The burden of DTT LN was 30% in our cohort, of whom 65% responded completely to second or third inductions, while a significant proportion failed to achieve remission even with repeat induction. Presence of active sediments at initial diagnosis and co-existence of aPLs were independent predictors of DTT LN.