Background: Non-corticosteroid immunosuppressants such as azathioprine (AZA), mycophenolate mofetil (MMF), cyclophosphamide (CYC), calcineurin inhibitors (CNIs) and methotrexate (MTX) are widely used in the treatment of SLE. However, their effectiveness in preventing organ damage remains unclear as observational studies are subject to confounding by indication (where patients with more severe disease are more likely to receive these medications). While corticosteroid use is associated with accrual of organ damage, the precise relationship between dose level and the risk of damage is not fully defined.

Objectives: This study aimed to identify the relationship between the use of these immunosuppressive medications and the development of organ damage in a real-world SLE cohort.

Methods: All SLE patients fulfilled the 1997 ACR Updated Classification Criteria for SLE. At each medical consultation, the disease activity was assessed using the classic BILAG index (or BILAG-2004 from 2013 onwards), and damage was evaluated using the SLICC/ACR damage index (SDI). In addition, serological test results, and treatment plans, including any change in the management plan, were recorded. Propensity scores (PS) were estimated for the likelihood of receiving each immunosuppressant based on covariates including age, gender, ethnicity, year of diagnosis, disease duration, smoking, antimalarial use, immunosuppressive use, and baseline SDI. For the treatment group, the baseline was the first exposure to the index medication, while for the control group, baseline was the first date with a disease activity score of A or B in any domain of the BILAG index. Multivariable Cox Proportional Hazard (PH) models were developed to study the effect of each immunosuppressive medication on organ damage over 10 years of follow-up, adjusted for PS, disease activity, and corticosteroid use. Immunosuppressants used by less than 10% of the study populations were excluded from the analysis. In models of steroids, cumulative, average daily oral doses, and the use of pulse corticosteroid were calculated and their association with organ damage was estimated using separate multivariable Cox HR models that adjusted for age, gender, ethnicity, year of diagnosis, disease duration, smoking, antimalarial use, immunosuppressive use, disease activity, and baseline SDI. Steroid models did not include PS adjustment, as 88% of patients were receiving steroids at some point of their follow-up.

Results: We included 361 SLE patients of whom 334 (92.5%) were female. There were 214 (59.2%) White, 66 (18.2%) African or Caribbean, 69 (19.1%) South Asian, 8 (2.2%) East Asian patients, and 16 (4.4%) from other ethnic backgrounds. The median (IQR) age at enrolment was 34 (26-45) years. The frequencies of patients who were ever treated with immunosuppressive drugs were as follows: AZA (49.8%), MMF (30.7%), CNI (16.3%), MTX (22.9%), and CYC (25%). After 10 years of follow-up, a total of 166 (45.9%) patients had 1 or more new items of organ damage. In separate multivariable Cox PH models adjusting for PS, use of corticosteroids, and disease activity, there was an inverse association between the development of new organ damage and the use of AZA (hazard ratio [HR] 0.59 [95% CI: 0.44, 0.79]), MMF (HR 0.41 [95% CI: 0.27, 0.62]), CNI (HR 0.34 [95% CI: 0.19, 0.60]), and MTX (HR 0.49 [95% CI: 0.30, 0.78]), suggesting a protective effect. However, there was no association between use of CYC (HR 1.12 [95% CI: 0.62, 2.04]) and damage (Table 1). There was a significant association between the development of new organ damage and corticosteroid use. Each 1gm increase in the cumulative dose was associated with a 2% higher risk (HR 1.02 [95% CI: 1.01, 1.30]), and every 1 mg increase in the average daily dose was associated with a 5% higher risk (HR 1.05 [95% CI: 1.03, 1.06]). In addition, the use of pulse steroids was associated with more than 3 times increase in the risk of organ damage (HR 3.07 [95% CI: 2.04, 4.61]) (when daily oral steroid was also included in the model, pulse steroid remained significantly associated with higher risk of new organ damage (HR 2.94 [95% CI: 1.96, 4.42]).

Conclusion: AZA, MMF, CNI, and MTX may have protective effect against the development of organ damage. In contrast to previous studies, after PS adjustment, treatment with CYC was not associated with new organ damage. Corticosteroid use was independently associated with the development of new items of organ damage.

REFERENCES: NIL.

Acknowledgements: NIL.

Disclosure of Interests: Ahmed Saleh: None declared, Caroline Gordon received consultancy fees over the last 36 months from Alumis, Amgen, Astra-Zeneca and UCB for advice on design and analysis of SLE clinical trials and/or adjudication of blinded SLE clinical trial data, John Reynolds received research grants from Otsuka and MSD.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.