Patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) are at a significantly higher risk of developing severe infection(s), which is the leading cause of death during the first year following diagnosis.
The introduction of rituximab has revolutionized AAV patient care; it has been proven to be an excellent candidate for inducing remission in microscopic polyangiitis and granulomatosis with polyangiitis. When the merits of rituximab were examined in light of cyclophosphamide, researchers found that they were both roughly equal in their effectiveness in inducing remission in patients with AAV.
However, studies have also discovered that the risk of serious infections remain in the months following remission. This is true in studies that follow up patients up to 18 months. The number of individuals who have undergone at least 1 episode of severe infection remains balanced between both rituximab and cyclophosphamide users.
“Infections are a major contributor to morbidity and mortality of patients with AAV,” Odler and colleagues wrote in the Annals of the Rheumatic Disease. “In the first year of diagnosis, infections are the main cause of death, while infectious complications remain the leading contributing factor to mortality thereafter.”
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Note that infections are a “major” contributor to morbidity and mortality. In light of evidence that suggests that patients on rituximab or cyclophosphamide are still likely to experience at least an episode of severe infection in the months postremission, we can conclude that infection remains a severe risk factor for poorer clinical outcomes among individuals with AAV, and that commonly used therapeutics confer little to no benefit in preventing them from occurring.
Researching Tools to Reduce Infection Risk
Odler and colleagues conducted a study in which they aimed to identify risk factors associated with severe infection in patients with AAV who received either rituximab or cyclophosphamide. They conducted a post hoc analysis using data from the RAVE trial, which randomized patients with AAV to receive either medication. All patients received the necessary therapies during remission periods, such as daily prophylaxis against Pneumocystis jirovecii. The median follow-up period was 531 days.
The research team then noted any cases of infection that occurred during the study period; infections graded 3 and above were considered severe. Infection sites were grouped into 4 categories: respiratory, gastrointestinal, urinary tract, and other areas.
The data of 197 patients from the RAVE trial were analyzed. Twenty-two severe infections were recorded, 8 of which occurred during the first 6 months. Patients with lower absolute numbers of CD19+ were most vulnerable to experiencing severe infections, regardless of the drug randomized to them.
The research team found 2 factors were associated with a depressed risk of severe infection: prophylaxis against P. jirovecii using the therapeutic combination of trimethoprim-sulfamethoxazole, as well as higher baseline total of CD19+ B cells.
“These data further suggest that certain B cell subpopulations may serve as a useful tool to determine general immunocompetence of AAV patients, and to identify individuals at higher risk of infectious complications,” Odler et al concluded.
A Brief Look at COVID-19 Infection
The study by Older and colleagues establishes 2 things: first, severe infection is a threat to the quality of life of patients with AAV, reducing clinical outcomes and contributing to a poorer prognosis. Second, certain therapeutic agents can depress the likelihood of such severe infections from occurring. It then becomes the job of the physician to diligently assess the suitability of all patients with AAV under their care to see if the therapies proposed are beneficial.
On the topic of severe infection, we venture briefly to consider the concurrent infection of COVID-19. Latief and colleagues wrote about their experience in managing patients with AAV who contracted COVID-19, and how they administered care during that most trying of times.
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From the onset, physicians were in a conundrum regarding the type of medications they were able to prescribe to reduce infection symptoms. Physicians had to balance carefully the benefits of immunosuppressants against the risk that they might make patients more vulnerable to COVID-19 infections. Latief and coauthors concluded that immunosuppressants are safe to be resumed once COVID-19 infection subsides.
“We suggest that in patients on AAV induction contracting COVID-19, withholding cytotoxic agent and close monitoring till infection settles is a pragmatic course to take,” they wrote.
In other words, with the specific example of COVID-19, Latief and colleagues found that a more conservative approach worked best: withholding cytotoxic medication, closely monitoring a patient’s condition, and continuing steroids until active infection subsides.
Both the studies by Older et al and Latief et al highlight the incredibly delicate balancing act that is moving patients back to health while taking pains not to inadvertently contribute to increased vulnerability to active infection. Their work shines a light on the difficult decisions physicians have to make all the time regarding the administration of powerful drugs, without those same drugs in some way contributing to the problem at hand.
As always, the best approach to contributing to better clinical decision-making is to carry out more high-quality clinical studies that specifically look at the prevention and resolution of infection in patients with a background of AAV.
References
Odler B, Riedl R, Gauckler P, et al. Risk factors for serious infections in ANCA-associated vasculitis. Ann Rheum Dis. 2023;82(5):681-687. doi:10.1136/ard-2022-223401
Latief M, Mir TH, Wani ML. Management of antineutrophil cytoplasmic antibody-associated vasculitis with COVID-19: a single center experience. Indian J Nephrol. 2023;33(1):50-53. doi:10.4103/ijn.ijn_423_21
