SLE is a complex autoimmune disease with diverse clinical features. SLE pathophysiology is characterized by the production of multiple autoantibodies, leading to immune complex formation, deposition, and other manifestations of immune dysregulation [17]. The global incidence of SLE is estimated to be 5.14 (range, 1.4–15.13) per 100,000 person-years, and the disease predominantly affects women. In the Asia–Pacific region, the crude incidence ranges from 0.9 to 3.1 per 100,000 person-years, and the mean age of onset ranges from 25.7 to 34.5 years. Previous studies have shown that SLE is associated with high annual hospitalization costs, particularly during periods of disease activity [18,19,20].

The treatment of SLE consistently relies on immunosuppressive agents. More aggressive treatment is necessary during active disease, whereas less intensive maintenance therapy can be considered when the disease is controlled. Drugs commonly prescribed during maintenance therapy include prednisolone, rituximab, mycophenolic acid, tacrolimus, and azathioprine. However, these immunosuppressive regimens can impair humoral and cell-mediated immune responses, increasing susceptibility to OIs. Impaired humoral immune responses predispose patients to bacterial infections, whereas impaired cell-mediated immune response increases susceptibility to intracellular pathogens (e.g., Candida spp., Cryptococcus spp., P. jirovecii, and T. gondii). Due to the heightened risk of infection, preventative measures such as influenza vaccination and screening and prophylaxis for chronic and opportunistic infections are recommended. The 2022 European Alliance of Associations for Rheumatology (EULAR) recommends PCP prophylaxis for adults with autoimmune inflammatory rheumatic diseases receiving high-dose glucocorticoids (15–30 mg prednisolone or equivalent) for more than 2–4 weeks. The suggested TMP/SMX dose is one single-strength (80/400 mg) tablet daily or one double-strength (160/800 mg) tablet three times weekly [21, 22]. A large retrospective cohort study by Park et al., involving 28,292 treatment episodes with non-high-dose steroids, evaluated the use of TMP/SMX as primary prophylaxis for PCP in patients with rheumatic diseases. The findings indicated that the incidence of PCP was relatively low in patients receiving low to medium corticosteroid doses (prednisolone equivalent < 15 mg/day) compared with patients in the high-dose corticosteroid group (prednisolone equivalent ≥ 15 mg/day) and patients with additional risk factors receiving moderate doses. Moreover, Qian et al. identified renal dysfunction and lymphopenia as independent risk factors for PCP infection in children with SLE receiving prolonged high-dose steroid therapy [5, 23].

Although TMP/SMX prophylaxis is recommended for HIV-negative immunocompromised patients receiving high-dose corticosteroids, there is no consensus regarding its use in patients receiving lower-intensity immunosuppressive regimens or a combination of low-level immunosuppressive agents, including other specific non-corticosteroid immunosuppressive drugs. Furthermore, there is no evidence-based guidance concerning the appropriate timing for prophylaxis discontinuation [7].

In the present study, most patients were women and had low SLEDAI-2 K scores. All patients received low-level immunosuppressive regimens; half received combination immunosuppressive therapy, and the median prednisolone dose was 5 mg/day. Notably, no TMP/SMX-sensitive OIs occurred during the 12-month follow-up period. However, the intervention group experienced a relatively high rate of ADRs, mostly mild to moderate skin and gastrointestinal manifestations. One patient developed a serious ADR, which fully resolved after treatment. Therefore, in the previous study that was performed before the HIV infection epidemic, reported reactions associated with sulfa prescriptions among hospitalized patients from 1966 to 1980 were 8% [24].

However, the relatively high rate of ADRs, including one serious but resolved ADR, raises concerns about the risks of unnecessary prophylaxis. Notably, ADR rates in our study are consistent with findings from Watanabe et al., who reported an incidence of drug hypersensitivity reactions ranging from 20 to 38% in SLE patients, particularly with sulfa antibiotics. These hypersensitivity reactions may result from shared pathogenic pathways between SLE and drug-induced eruptions, including mechanisms involving neutrophil extracellular traps (NETs) and T-cell activation. Imbalances in NET production and degradation, particularly in active SLE, have been associated with reduced NET clearance and enhanced necrotic skin reactions. Izuka et al. reported that specific antibodies, such as anti-Sm, anti-ribonucleoprotein (RNP), and anti-Ro/SS-A, were significantly associated with drug hypersensitivity in SLE. However, this finding requires confirmation because of the small sample size [25,26,27,28,29].

From an antibiotic stewardship and safety perspective, TMP/SMX prophylaxis might not be required for patients receiving low-level immunosuppressive therapy and may lead to ADRs. A previous study showed that unnecessary TMP/SMX use could disrupt the vaginal microbiota, potentially increasing the risk of urinary tract infections in SLE patients [30]. Thus far, there have been no reports of increased resistance to TMP/SMX among previously susceptible pathogens. However, although no resistance has been reported so far, the frequent and unnecessary use of antibiotics can contribute to the global problem of antimicrobial resistance. Overusing broad-spectrum antibiotics like TMP/SMX can promote resistance in targeted pathogens and the commensal microbiota, which serves as a reservoir for resistance genes. This raises concerns that, even in the absence of immediate resistance in TMP/SMX-sensitive organisms, the selective pressure exerted by unnecessary prophylaxis could contribute to the emergence of resistant strains over time [31, 32].

A notable strength of this randomized controlled study was that it highlighted the potential risk of prescribing unnecessary TMP/SMX prophylaxis to SLE patients receiving low-level immunosuppressive treatment in a real-world setting that this knowledge gap has never been addressed before in any clinical practice guidelines to our knowledge. The clinical relevance is enhanced by the absence of TMP/SMX-sensitive OIs during the 12-month follow-up period and the use of diverse immunosuppressive regimens beyond prednisolone alone. Patients with SLE can remain in a good state of health by consuming a well-balanced diet and regular exercise. Stress reduction, avoiding direct sunlight exposure, receiving regular comprehensive cardiovascular assessments to detect left ventricular diastolic dysfunction early, receiving necessary vaccinations per healthcare providers, and avoiding unnecessary antibiotic use [33,34,35]. However, this study had some significant limitations that should be considered when interpreting the results:

1.

Small sample size: The study was prematurely terminated due to high ADR rates, reducing its statistical power. This limited our ability to detect rare OIs, and future studies should aim for larger sample sizes to provide more robust conclusions.

2.

Single-center design: Conducting the trial at a single institution limits the generalizability of the findings, as patient demographics and clinical practices may differ in other settings. Multicenter trials would improve the external validity of such research.

3.

Short follow-up duration: A 12-month follow-up may not capture long-term OI development, as some opportunistic infections can take longer to manifest. Longer follow-up periods in future studies beyond 12 months would provide a more comprehensive evaluation of TMP/SMX prophylaxis and a better assessment of long-term infection rates and ADRs.

4.

Homogeneous study population: Most of our patients were in disease remission, which may not reflect the broader SLE population, particularly those with higher disease activity and non-Asian population. Future studies on a more diverse population would provide a more comprehensive understanding of TMP/SMX prophylaxis in SLE patients.

5.

Lack of pharmacogenomic and comprehensive immune status evaluation: Including pharmacogenomics testing and monitoring of immune function, particularly lymphocyte subset or immunoglobulin levels, could have provided more profound insights into patient susceptibility to OIs or ADRs. This personalized approach could optimize prophylactic strategies.

6.

The lack of a placebo group for comparison may have affected the study’s ability to assess subtle prophylactic effects and ADRs.

7.

Definitions of low-level immunosuppressive therapy: Clinical practices and treatment regimens may differ. Therefore, a careful interpretation of the study results should be considered.

In conclusion, our findings indicate that TMP/SMX-sensitive OIs are not a significant concern for SLE patients on low-level immunosuppressive therapy, and the relatively high rate of ADRs suggests that routine prophylaxis may not be necessary in this population. Future research should explore the long-term safety of TMP/SMX, particularly in populations with higher disease activity, and consider incorporating pharmacogenomic and immunological assessments to personalize prophylactic strategies.