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Long-Term Glucocorticoid Therapy in SLE and Infective Sequelae: A Faustian Pact

In SLE, higher doses of prednisolone and the use of immunosuppressive agents, such as cyclophosphamide, have been associated with higher rates of infective sequelae.

Steroids remain an unwelcome but frequently necessary tool in the management of systemic lupus erythematosus (SLE). The long-term sequelae of oral steroid therapy are well documented and, in general, clinicians are well versed in tapering doses to the minimum levels required for effective disease control. Nevertheless, osteoporotic fractures, avascular necrosis, weight gain, diabetes mellitus, and infective sequelae remain a reality for many lupus patients.There is growing sentiment that long-term steroid therapy in SLE should be avoided and may even be unnecessary in non-renal lupus. Therefore, further information which clarifies this area is of clear interest to jobbing rheumatologists and researchers alike.

In SLE, higher doses of prednisolone (>7.5mg OD) and the use of immunosuppressive agents, such as cyclophosphamide, have been associated with higher rates of infective sequelae.2 However, the effects of lower dose prednisolone on infection rates are less clear. This paper by Kazuya Abe et al examines the impact of lower dose oral prednisolone on infection prevalence in 509 SLE patients from a Japanese multicenter registry.3

Data was collected from 8 university hospitals and 1 district general hospital. Oral prednisolone use was split into 3 categories, 0-2.5mg, 2.6- 5mg, 5.1-7.5mg, and 7.6-15mg daily dose. The primary outcome was infective episodes requiring hospital admission. Total follow-up time was 946.2 patient years during which 52 infective episodes requiring hospitalization were identified in 50 patients. Of these infective episodes, just under half were respiratory, followed by urinary and then intrabdominal sources. A comparison of baseline characteristics between the infection and non-infection groups demonstrated a higher mean age in the infection group (52.3 vs 46.1 years, p=0.009) and a higher rate of administered methylprednisolone pulse therapy (54% vs 37%, p =0.02).

The rate of infection in the 2 higher prednisolone dose groups (5.1-7.5mg and 7.6-15mg daily) was compared to incidence within the 0-2.5mg daily group. Age, sex, and concurrent immunosuppression were used as covariates. The adjusted hazard ratio was shown to be significantly higher in the higher dosage groups (Adjusted HR 6.80 and 7.68, 95% CI 2.15-21.27 and 2.37-24.85 respectively). Non statistically significant increases in infection rates were observed in the lower (2.6-5mg daily) prednisolone dose group.

This study addressed some of the methodological weaknesses of previous work by adjusting for key covariates within the analysis. However, it does suffer from a lack of ethnic diversity within the cohort which may limit its global generalisability. Additionally, the authors note that they were unable to adjust for hydroxychloroquine (HCQ) treatment within their analysis. This was due to the generally low rates of hydroxychloroquine prescription within this cohort (17.1%), significantly lower than equivalent cohorts in the US/Europe. The authors noted the association between HCQ treatment and lower infection rates in previous work.4 They, therefore, performed a sensitivity analysis comparing HCQ and non-HCQ treated patients, which yielded comparable results to their primary analysis.

Despite these weaknesses, this study provides much-needed clarity on the effects of low-dose steroid therapy on a key adverse event in SLE, infections requiring hospitalization. The Lupus Low Disease Activity State (LLDAS) requires a daily dose of prednisolone ≤7.5mg. This represents an achievable goal for clinicians but perhaps should not represent an end goal. These data suggest that infection remains a serious concern in these lower steroid burden patients. Previous work by Professor Petri has shown the association between corticosteroid use and solid organ damage accrual in SLE which persists even after adjustment for disease activity.5 Therefore, we should perhaps consider any degree of long-term steroid therapy in non-renal SLE an unhappy union from which we should try to extricate our patients wherever feasible. This will not however be an easy divorce, and in the future, we may have to utilize our expanding therapeutic complement to make this possible.

References:

1. Sawah S Al, Zhang X, Zhu B, Magder LS, Foster SA, Iikuni N, et al. Effect of corticosteroid use by dose on the risk of developing organ damage over time in systemic lupus erythematosus—the Hopkins Lupus Cohort. Lupus Sci Med [Internet]. 2015 Jun 1 [cited 2022 Sep 11];2(1):66. Available from: /pmc/articles/PMC4378372/

2. Banerjee S, Biehl A, Ghaderi-Yeganeh M, Manna Z, Hasni S. Low incidence of opportunistic Infections in Lupus Patients treated with Cyclophosphamide and Steroids in a Tertiary care setting. Med Res Arch [Internet]. 2017 [cited 2022 Sep 11];5(3). Available from: /pmc/articles/PMC5737929/

3. Abe K, Ishikawa Y, Kita Y, Yajima N, Inoue E, Sada K, et al. Association of low-dose glucocorticoid use and infection occurrence in systemic lupus erythematosus patients: a prospective cohort study. Arthritis Res Ther [Internet]. 2022 Dec 28 [cited 2022 Aug 12];24(1):179. Available from: https://pubmed.ncbi.nlm.nih.gov/35902976/

4. Dima A, Jurcut C, Chasset F, Felten R, Arnaud L. Hydroxychloroquine in systemic lupus erythematosus: overview of current knowledge. Ther Adv Musculoskelet Dis [Internet]. 2022 Feb 1 [cited 2022 Sep 11];14. Available from: /pmc/articles/PMC8848057/

5. Petri M, Purvey S, Fang H, Magder LS. Predictors of organ damage in systemic lupus erythematosus: The Hopkins Lupus Cohort. Arthritis Rheum. 2012 Dec;64(12):4021–8.