TMP-SMX reduces serious infections ‘by about half’ in patients with GPA using rituximab
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SAN DIEGO — Trimethoprim sulfamethoxazole prophylaxis halves serious infection risk in patients with granulomatosis with polyangiitis receiving B-cell depletion with rituximab, according to data presented at ACR Convergence 2023.
“Infections are the major unintended consequence of immunosuppression across all rheumatic diseases,” Arielle Mendel, MD, MSc, assistant professor in the division of rheumatology at the McGill University Health Center, told Healio.
Mendel noted that rituximab (Rituxan, Genentech) is a standard therapy for patients with GPA, a form of ANCA-associated vasculitis. Infections such as pneumocystis jirovecii pneumonia in this population are often managed using trimethoprim sulfamethoxazole (TMP-SMX).
“A few prior studies observed that this drug was associated with reduced serious infections, meaning those that are severe enough to require hospitalization,” Mendel said.
To determine whether that same association was present in a larger population-based cohort, as well as examine the impact of preventative antibiotics on non-serious infections, Mendel and colleagues analyzed data from the Merative Marketscan Research Database. Specifically, they included patients with GPA who initiated treatment with rituximab between 2011 and 2020.
The outcome of interest was serious infections. Outpatient infections and pneumocystis jirovecii pneumonia served as secondary endpoints. Among the 919 patients included in the analysis, 53% were women and the mean age was 52 years (standard deviation, 16).
At the time of index rituximab treatment, 281 patients received prophylactic TMP-SMX. Of these patients, 40% received a daily dose of prednisone of 20 mg or greater. The median follow-up duration was 496 days (interquartile range, 138-979). During this period, serious infections occurred in 6.1 patients (95% CI, 5-7) per 100 person-years. Outpatient infections were reported in 28.7 (95% CI, 26-32), while pneumocystis jirovecii pneumonia occurred in 0.7 (95% CI, 0.4-1.2) patients per 100 person-years.
In the serious infection group, 36% were pulmonary, while 45% reported general sepsis.
Multivariate analysis results demonstrated a negative association between TMP-SMX and serious infections when baseline exposure (adjusted HR = 0.5; 95% CI, 0.3-0.8) and time-varying exposure (aHR = 0.5; 95% CI 0.3-0.9) were factors.
“We found that the incidence of serious infections was reduced by about half in patients with GPA who take trimethoprim sulfamethoxazole prophylaxis during treatment with rituximab,” Mendel said. “Not only that, but the use of this antibiotic was also associated with reduced non-serious infections. This was after taking into account differences in age, sex, health conditions, prednisone use, and prior hospitalizations/infections between groups.”
A negative association was also observed between TMP-SMX prophylaxis and outpatient infections (aHR = 0.7; 95% CI, 0.5-0.9), according to the researchers.
Among the 13 pneumocystis jirovecii pneumonia infections reported, none occurred in patients exposed to TMP-SMX. However, TMP-SMX failed to reduce herpes zoster (aHR = 1.6; 95% CI, 0.6-3.2), according to the findings.
Meanwhile, adverse event rates potentially attributable to TMP-SMX were 29.6 (95% CI, 22-39) per 100 person-years during treatment and 13.4 (95% CI, 11-16) per 100 person-years during periods without TMP-SMX exposure.
“This drug also seemed to increase the risk of adverse drug events,” Mendel said.
According to Mendel, it is important to understand that while this study confirmed the findings of smaller observational studies, a randomized controlled trial will be necessary to be fully confident there is no additional confounding leading to the primary result.
“TMP-SMX is already viewed as the standard of care to use antibiotic prophylaxis at the start of GPA treatment in the absence of allergies,” she said. “What is less clear is how long the antibiotics should be continued, as GPA treatment with rituximab can continue for years. Furthermore, we need to understand how long-term antibiotics could be affecting people — from adverse drug events, drug interactions, antibiotic resistance, and effects on the microbiome — as well as patient preferences.”
These data will be useful when discussing the rationale for antibiotic prophylaxis with patients at the start of their AAV treatment, as it may prevent the occurrence of more common infections, rather than only a rare form of pneumonia, according to Mendel.
“Of course, prophylaxis will not protect against viral infections, and patients still need to get vaccinated for all vaccine-preventable infections,” she said. “Although we don't yet know for certain how long prophylaxis should be continued among long-term rituximab users, I think it is reasonable to discuss the potential risks and benefits of continuing longer-term prophylaxis with individual patients, taking into account their preferences.”
Perspective
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David A. McLain, MD, MACR, FACP, FRCP
Sulfamethoxazole-trimethoprim (SMX/TMP) is a standard drug for prophylaxis in immunocompromised patients against pneumocystis pneumonia (PJP), a potentially life-threatening opportunistic infection caused by pneumocystis jirovecii. Comprising two components, SMX and TMP, both inhibit different enzymes in the folate synthetic pathway of pneumocystis. In HIV-positive patients, the prevention rate is reported to be 89% to 100% if taken correctly.
With a predilection for immunocompromised patients, the incidence of PJP exceeds 50% in patients who are HIV-positive, 22% to 45% in those with hematological malignancies, and 5% to 10% in post-organ transplant patients. In rheumatic diseases, the overall incidence is approximately 2%, but this risk is heightened by the use of moderate (40 mg) to high doses of corticosteroids, concomitant immunosuppressive drugs, patient comorbidities and demographic characteristics.
Morbidity rates also vary among different rheumatic diseases, ranging from 8% to 12% in granulomatosis with polyangiitis (GPA), 6.5% in polyarteritis nodosa, 2.7% in polymyositis/dermatomyositis, 2% in systemic lupus erythematosus, and 0.1% to 0.3% in rheumatoid arthritis.
For patients initiating corticosteroids, conventional immunosuppressants, or biologics for active rheumatic diseases, PJP ranks as the second most frequent pulmonary infection after bacterial pneumonia. Despite the high efficacy of SMX/TMP, providers often face the need to halt or reduce its dose due to adverse events, including gastrointestinal symptoms, increased serum creatinine, rash, renal tubular acidosis, elevated liver enzymes, hypoglycemia, hyperkalemia and hyponatremia.
The present article reveals that SMX/TMP was associated with a reduction in serious and overall infections in patients with GPA treated with rituximab (Rituxan, Genentech). We need to be alert and remember PJP prophylaxis in our seriously immunosuppressed patients.
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Mendel A. Abstract 1584. Presented at: ACR Convergence 2023; Nov. 10-15, 2023; San Diego.
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