Steroid, rituximab use can lead to secondary immunodeficiencies

Key takeaways:

• Systemic corticosteroids can lead to CD4 lymphopenia and lower IgG levels.
• Rituximab therapy can lead to hypogammaglobinemia and delayed neutropenia.
• Prophylaxis is recommended.

ANAHEIM, Calif. — Use of steroids and B-cell depleting therapies may lead to secondary immunodeficiencies, according to a presentation at the American College of Allergy, Asthma & Immunology Annual Scientific Meeting.

“Everyone in this room probably prescribes systemic steroids,” S. Shahzad Mustafa, MD, chief of allergy, immunology and rheumatology at Rochester Regional Health and clinical professor of medicine at University of Rochester School of Medicine & Dentistry, said during his presentation.

Systemic corticosteroids, which often are prescribed for many atopic conditions, represent the 30th most common class of drug prescribed in the United States, Mustafa said, with 21 million people receiving more than 30 million doses.

“It’s not right or wrong,” Mustafa said. “I just want you to be thoughtful about when you’re doing this, you are having impacts on the immune system.”

Monoclonal antibodies and other biologics have enabled physicians to prescribe fewer prescriptions over the past few years, he continued, but some indications remain.

Also, side effects from systemic steroids including increased risks for infection may persist even months after the treatment has ended, Mustafa said, with greater side effects accompanying higher doses with longer durations.

“We want to be thoughtful about that,” Mustafa said.

Common effects

CD4 lymphocytopenia is the most common immune defect with corticosteroids, appearing even with short 5-day or 7-day courses, Mustafa said. Depending on the dose and duration, he continued, steroids may affect B cells as well.

“Of all the immunoglobulin classes, the most likely to be driven down by systemic steroids is IgG, maybe IgM and IgA, but much less so IgA,” he said.

Risks for opportunistic infections such as Pneumocystis jirovecii and other fungal infections, cytomegalovirus, and herpes zoster increase, with the greatest risks among hosts who have had bone marrow transplants, Mustafa said. Mortality risks increase as well.

“The host matters,” Mustafa said. “Treating someone with systemic steroids with rheumatoid arthritis is very different than [a patient’s] status post bone marrow transplant. Infectious risk is very different.”

Mustafa encouraged physicians to stratify these risks based on underlying disease states and consider prophylaxis such as Bactrim (trimethoprim and sulfamethoxazole; Roche), especially for patients with CD4 lymphocytopenia.

“This is more than an academic discussion,” he said. “There’s an opportunity for us to intervene.”

Oral corticosteroids impact hypogammaglobinemia as well, Mustafa continued, with down-regulation of genes contributing to immunoglobulin synthesis, which decreases because of the increased apoptosis of B-cell subsets. Immunoglobulin catabolism also increases.

“That’s important,” Mustafa said. “You’re kind of having two hits there.”

IgG levels drop by approximately 20% with systemic steroids, Mustafa said, and these impaired immune effects continue even after therapy is discontinued. The same pattern emerges with rituximab and B-cell depletion, he continued.

“So be thoughtful,” Mustafa said.

Mustafa also noted the importance of distinguishing between primary and secondary immunodeficiencies, even if treatment for either gets to the same endpoint of immunoglobulin replacement.

“Whether it’s primary or secondary has a huge impact on prognosis and how you’re going to monitor these individuals,” he said.

For example, Mustafa said, patients with hypogammaglobinemia may have lower or even undetectable IgA levels with a primary immunodeficiency, but higher IgA levels with a secondary immunodeficiency.

“There’s a lot of nuance to it. There are ways to try to figure it out. But I think a very simple, crude way to start is by looking at the IgA,” Mustafa said.

Rituximab therapy

It is important to consider anti-CD20 immune effects with B-cell depleting therapies, Mustafa said, as rituximab may lead to hypogammaglobinemia and late-onset neutropenia, with viral, bacterial, fungal and protozoan infections to follow.

Risk factors due to rituximab for hypogammaglobinemia include low baseline serum IgG, IgM and IgA, the number of treatment cycles, younger age in children, older age in adults, and the use of glucocorticoids, mycophenolate mofetil, cyclophosphamide, purine analogs and fludarabine.

Risk factors due to rituximab for neutropenia include low baseline serum IgG, number of treatment cycles, low serum IgG or IgM post-therapy, glucocorticoids and prednisone, older age and clinical comorbidities such as cardiac insufficiency and chronic lung disease.

“Very interestingly, it often doesn’t happen while you’re on it or even during your courses or cycles,” he said.

Neutropenia happens later with a mean time between 30 and 180 days after treatment with rituximab has ended.

Mustafa called baseline IgG the best predictor for these conditions.

“There’s often a conversation of ‘Why do I need to check these levels beforehand?’ Right? Well, I think establishing a baseline is nice, but it also helps with prognosis,” Mustafa said.

Mustafa also noted a series published in Clinical Lymphoma, Myeloma & Leukemia of 15 patients with non-Hodgkin lymphoma who had completed treatment with rituximab between a month and 20 months before. Their immunoglobulin levels were a little low but not bad, he said.

“Nothing that catches your eye,” Mustafa said. “But look at their function.”

These patients did not respond to polysaccharide or peptide vaccines, he said.

“Tetanus is the most immunogenic antigen that you’re going to have. If you don’t respond to tetanus, you definitely have some B-cell defects,” he said. “These individuals, despite having relatively low numbers, didn’t have much function at all.”

Hypogammaglobinemia increased in prevalence among children using rituximab as well, as a study by LaBrosse and colleagues showed 42.6% with lower IgG, 20.4% with lower IgA and 62% with lower IgM.

It is important to screen the pediatric population as a small percentage of those with hypogammaglobinemia receiving rituximab actually have a primary immunodeficiency, which Mustafa called a “branch point” in determining how these patients will be treated.

Risk factors included lower IgG and IgA before treatment, Mustafa said, with increased risks for severe infection and lower IgG persistent among 26.7% of those children with lower IgG levels after treatment.

Next steps

“So, what the heck can we do?” Mustafa asked. “Because I’m certainly not going to stop prescribing steroids, and there is more and more B-cell depletion being prescribed.”

Mustafa encouraged physicians to minimize the use of these drugs to the best of their ability, use steroid-sparing agents instead in addition to prophylaxis for opportunistic infections, and consider long-term effects as they strive to minimize immunosuppression, potentially with immunoglobulin replacement.

Because infections remain the most common cause of morbidity and mortality for these patients, Mustafa continued, such cases present opportunities for physicians to collaborate with other providers.

“When you’re taking care of sick people with complicated medical conditions, they do better with a multidisciplinary approach,” he said. “It’s fun to work with your colleagues, your rheumatology colleagues, your oncology colleagues. As immunologists, we have a lot to offer.”

References:

• LaBrosse R, et al. J Allergy Clin Immunol. 2021;doi:10.1016/j.jaci.2021.03.041.
• Mustafa SS, et al. Clin Lymph Myel Leuk. 2020;doi:10.1016/j.clml.2020.04.006.