Lupus patients at high risk for adverse reactions to PCP antibiotic prophylaxis


Patients with systemic lupus erythematosus (SLE) who take trimethoprim-sulfamethoxazole (TMP-SMX) prophylactically to ward against the life-threatening fungal infection pneumocystis carinii pneumonia (PCP), seen in patients who are on high-dose glucocorticoids or immunosuppressants, had more than double the likelihood for adverse drug reactions (ADRs) when compared with patients with other connective tissue diseases, according to findings from a study presented at the virtual annual meeting of the American College of Rheumatology.

Risk for ADRs to TMP-SMX was especially higher in patients with anti-Smith (anti-Sm) autoantibodies, in whom the odds climbed to fivefold higher.

“When we administer [TMP-SMX] to lupus patients, especially patients with anti-Sm antibodies, we should monitor them carefully for adverse events,” first author Shinji Izuka, MD, a clinical fellow in rheumatology at the National Center for Global Health and Medicine in Tokyo, said at a press conference during the meeting.

Against a background of a higher overall rate of ADRs in patients with SLE, Dr. Izuka and colleagues sought to determine the prevalence of ADRs and find risk factors for ADRs in patients taking TMP-SMX at a single center in Japan during January 2009–April 2020.

Of 164 SLE patients, 13.4% experienced ADRs, compared with 6.9% of 263 patients with other connective tissue diseases (polymyositis or dermatomyositis, Sjögren’s syndrome, systemic sclerosis, mixed connective tissue disease, eosinophilic granulomatosis with polyangiitis, granulomatosis with polyangiitis, microscopic polyangiitis, polyarteritis nodosa, Takayasu’s arteritis, and giant cell arteritis). The ADRs among SLE patients in the study included thrombocytopenia in six, skin rash in five, fever in five, liver function test abnormality in five, elevation of creatinine in four, leukopenia in three, and elevated potassium in one.

Dr. Shinji Izuka
In a multivariate analysis, anti-Sm positivity was the only significant independent predictor for having an ADR among SLE patients, with an odds ratio of 5.08 (95% confidence interval, 1.74-14.80; P = .002)

This study may help to reduce and anticipate ADRs to TMP-SMX in lupus patients, but the mechanisms behind increased ADRs to TMP-SMX are unclear. ADRs could be associated with disease activity, which was not assessed in the study, Dr. Izuka said.

When it’s necessary to give TMP-SMX, “we can consider desensitization, starting TMP-SMX at a very low dose and increasing it gradually,” or administering another agent, such as atovaquone, he said.

For SLE patients at lower risk for PCP, such as younger patients or those not on high-dose glucocorticoids, treatment without prophylaxis for PCP may be an option, he said.

When asked whether more frequent monitoring of patients’ laboratory markers is necessary, Dr. Izuka said that he and his associates do more frequent blood monitoring when starting TMP-SMX, particularly for patients with lupus nephritis or neuropsychiatric SLE, in whom ADRs appear more common.

In commenting on the study, S. Sam Lim, MD, professor of medicine and epidemiology at Emory University, Atlanta, said that he and others at his institution stay away from TMP-SMX in SLE patients because of higher ADRs and potential exacerbation of photosensitivity. He called for more research and validation of the results in other populations.

David Karp, MD, PhD, chief of the division of rheumatology at the University of Texas Southwestern Medical Center, Dallas, called the study “very interesting” and wondered if SLE patients who have an ADR to TMP-SMX “have higher overall autoantibody levels, and are ‘better’ at generating anti-SMX-protein responses.”

Dr. Izuka noted that five patients had a skin rash, and some of them might have developed a rash immediately after taking TMP-SMX. “It may be a type 1 allergic reaction.”

Credit top image: Will & Deni McIntyre / Science Source
Credit background image: Scott Camazine / Science Source

Marina Macedo, MSc, of the University of São Paulo, wondered whether the type of immunosuppressive drug patients were taking could have influenced the rate of ADRs. Ms. Macedo noted that “TMP-SMX can interact with several DMARDs, such as methotrexate, such that the coadministration of those drugs could potentiate the occurrence of ADR.”

Dr. Izuka said that, while data on medications that the patients used was not available, he believed that most patients taking TMP-SMX were on high-dose glucocorticoids, and some might have been taking mycophenolate mofetil, tacrolimus, or hydroxychloroquine; a few patients might have been on methotrexate.

Dr. Izuka and colleagues had no relevant disclosures.