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Dilemma of immunosuppression and infection risk in systemic lupus erythematosus


Patients with SLE are at high risk of various infections as evidenced by a number of studies. The main determinants of infection in SLE are disease activity, organ damage, and often inevitable medication. The molecular and cellular mechanisms underlying infection remain unclear. Impaired immunity, immunosuppressants and corticosteroids clearly increase the risk of infection, whereas some medications, such as low-dose IL-2, hydroxychloroquine and IVIG are safe in SLE patients with substantial evidence. It is important to balance the immunosuppression and infection risks in practice. This article focuses on medication-related infections in SLE and discusses the therapeutic options for the disease in clinical practice.


Infection in SLE is an important cause of hospitalizations and mortality. Previous studies showed that infection is the leading cause of death in SLE patients. Infection accounts for ∼29.2–43.9% of the morbidity of SLE patients. Other factors, including atherosclerosis and nephritis, can also increase morbidity. Opportunistic infections are very common clinically and are related to impaired cellular and humoral immune functions in patients with SLE.

The underlying mechanisms for susceptibility to infection remain unclear, but various explanations have been proposed, including immunosuppressive therapies and immunological changes responsible for infections. On the other hand, pathogens are thought to induce autoimmunity via molecular mimicry and have been shown to stimulate the production of IFN and anti-dsDNA antibodies in SLE patients.

It has been suggested that dysfunction in T cells, B cells, and NK cells, might play a role in the development of infection in SLE. Defective phenotypes and functioning of neutrophils, monocytes, macrophages, and dendritic cells (DCs) have been identified in SLE patients. These defects are important in the pathogenesis of SLE, including ineffective apoptotic debris clearance, self-antigen presentation, and inflammatory cytokine production.


Moreover, immunosuppressive treatments and corticosteroids (CSs) can impair protective immunity, which increases the risk of infections in these patients. Of note, certain medications such as low-dose IL-2 (Ld-IL2), HCQ and IVIG, emerge as promising therapies for treating autoimmune disorders, including SLE, without interfering with anti-infective immune responses.


Diverse therapy associated with the susceptibility to infection in SLE

Treatment options in SLE that are now commonly applied are antimalarial drugs, glucocorticoids, immunosuppressive drugs, and biologics. These medications can interfere with cell-mediated and humoral immunity to achieve control of the disease by suppressing inappropriately activated T cells, B cells, and other immune cells. Meanwhile, suppression of immunity by medications greatly increases the risk of infection in patients with SLE, including the most common viral infections.

Glucocorticoids (GCs) exert powerful anti-inflammatory effects and therefore have been a mainstay in the treatment of SLE, especially in moderate and severe SLE presenting with organ damage. In a cohort study involving 3030 SLE patients and followed for 4 years, GC administration was shown to significantly increase the incidence of infection. It was clearly suggested that prednisone dose was a potent risk factor for increased infection in a multiracial, multiethnic cohort study involving 1243 patients. In addition, GCs also increase the risk of atherosclerotic death, and they should not be used at doses above 5 mg of prednisone q.d. in the long term.

Immunosuppressive drugs such as MMF and AZA inhibit cell proliferation, increasing the risk of infection while reducing the disease activity. In an open-label randomized controlled clinical study, patients being treated with MMF and AZA had a significantly higher incidence of infection, up to 48.7%. CYC, an alkylating drug still commonly used in severe SLE patients, is also generally associated with infectious complications. CSA and tacrolimus have been found to increase the risk of infection in SLE patients. The calcineurin-mediated signalling pathways have been shown to contribute significantly to fungal virulence, and inhibiting calcineurin is a possible antifungal strategy. In a randomized, double-blind, phase II study of 314 patients with SLE, patients being treated with baricitinib were found to have a higher infection incidence than the placebo control group. In patients being treated with a combination of rituximab and belimumab, up to 73.3% increase in infection was found. A randomized, placebo-controlled phase IIb clinical study reported a higher incidence of infection in patients being treated with high-dose atacicept. Treatment with anifrolumab has a good response in SLE, but an increased rate of infection. In a randomized controlled trial, herpes zoster and bronchitis occurred in 7.2% and 12.2% of patients, respectively, who received anifrolumab. In addition, the clinical trial of ocrelizumab was terminated prematurely owing to increased infection in patients when used in combination with MMF. As for targeted T cell therapy, ustekinumab was shown to enhance infection in a clinical study among active SLE patients.


Reference

Jing He, Zhanguo Li, Dilemma of immunosuppression and infection risk in systemic lupus erythematosus, Rheumatology, Volume 62, Issue Supplement_1, April 2023, Pages i22–i29, https://doi.org/10.1093/rheumatology/keac678

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