In a new review, a group of infectious disease experts have summarized and made recommendations about recent findings regarding infections that can occur during treatment with an evolving set of targeted and biologic therapies for rheumatoid arthritis and psoriatic arthritis.
“We claim for the need for multicenter registries and multidisciplinary approaches, for new vaccines trials in RA and PsA, and for better defining when and how biologics can be restarted after severe infections,” lead author Olivier Lortholary, MD, of the Institut Pasteur in Paris, and his coauthors wrote in Annals of the Rheumatic Diseases.
Dr. Kevin L. Winthrop
“The take-home message is that different DMARDs [disease-modifying antirheumatic drugs], in many ways, are very similar,” said coauthor Kevin L. Winthrop, MD, MPH, professor of public health and ophthalmology at Oregon Health & Science University, Portland, in an interview. “They all have fairly similar risks when it comes to ‘classical’ or routine bacterial infections. But when you talk about opportunistic infections, you start seeing the differences between these drugs.”
The experts began by addressing the current view of the infectious risk of biologic therapies, citing a recent meta-analysis in which standard (odds ratio, 1.31; 95% confidence interval, 1.09-1.58) and high (OR, 1.90; 95% CI, 1.50-2.39) doses of biologics were associated with increased risk of serious infection. They also noted that the ‘healthy drug survivor effect’ tends to confound long-term extensions of randomized clinical trials involving biologics.
“That is largely because people who are more likely to do well or have proven themselves to do well with that infection, they tend to stay in [trials] and stay on drugs,” Dr. Winthrop said. “The ones who develop infections are more likely to drop out. You see this survival of the fittest-type situation, where healthy users dominate a cohort over time. That’s why you see incidence rates decreasing.”
In response, Arthur Kavanaugh, MD, professor of medicine in the division of rheumatology, allergy, and immunology at the University of California, San Diego, and the director of the Center for Innovative Therapy there, backed the idea of a general ‘depletion of the susceptibles’ but warned doctors to evaluate each patient and situation accordingly. “Providers need to be vigilant throughout for common infections, rarer infections, and infections at greatest risk for the individual patient based on factors like comorbidities and concomitant medications,” he said in an interview.
When considering restarting a biologic in a patient who recently suffered a serious infection, the experts prescribed no general rule and noted that it will “depend on the type of infection, on the mechanism of action of the drug, on the other available drugs for the considered disease and, of course, on the willingness of the patients to restart a drug possibly having [given] him/her a side effect.”
Assessing infection risk related to various inhibitors
Regarding infections caused by TNF-alpha inhibitors (TNFIs), the experts acknowledged a broad increase in risk for mycobacterial and fungal infections, especially tuberculosis and histoplasmosis. They added that patients on TNFIs are more prone to developing pneumonia and soft tissue infections, while smaller studies have indicated a higher risk of listeriosis, legionellosis, herpes zoster (HZ), and reactivation of chronic hepatitis B virus infection.
As for recommendations, they endorsed discontinuing TNFIs when a serious infection occurs and not restarting until after treatment and clinical response. Patients should be screened for latent tuberculosis infection (LTBI) before starting the drug, and anti-TB drugs should be presented to patients with LTBI so they do not progress to active TB.
Regarding other biologics, they cited several studies indicating that IL-6 inhibitors can increase infection risks in RA patients at a rate similar to TNFIs. Among the most common infections were pneumonia and cellulitis. In addition, although PsA patients on IL-17 inhibitors have a dose-dependent risk of mild to moderate mucocutaneous candidiasis, there was no increased risk of serious opportunistic infections like TB.
In assessing JAK inhibitors, they cited a pooled analysis that indicated pneumonia and skin and soft-tissue infections as the most common and noted the high incidence of HZ, compared with other infections. They added that abatacept (Orencia) did not appear to increase risk of infections in RA patients, such as HZ, dermatomycosis, candidiasis, or endemic mycoses. Those same patients did not see an increased overall infection risk after treatment with rituximab (Rituxan), and clinical trials containing treatment with apremilast (Otezla) reported a rare occurrence of serious infections.
Recommendation-wise, they endorsed screening for LTBI before starting IL-6 inhibitors and antiviral prophylaxis with acyclovir in particularly at-risk patients on JAK inhibitors. Age-appropriate influenza vaccinations were also recommended for rituximab, because of the development of rituximab-induced hypogammaglobulinemia.
Prediction and prevention
When it comes to predicting infections in patients on biologics, the experts wrote that it “remains a challenge.” The potential effects of pretreatment underlying disease, the lack of validated biomarkers, and the relatively low rate of infections all combine to stymie prediction. That said, they acknowledged ongoing efforts in monitoring lymphocyte subpopulation counts and immunoglobin levels, as well as a clinical score called the RABBIT Risk Score for Infections, which was validated in two separate cohorts.
Dr. Arthur Kavanaugh
“As Yogi Berra said, predictions are hard, especially about the future,” Dr. Kavanaugh said. “Discussions with your patient are always important.”
In regard to overall prevention, they acknowledged that most of their recommendations are of low evidence, except for antiviral prophylaxis for hepatitis B patients on rituximab and the aforementioned LTBI therapy in patients on TNFIs. Broadly, they advocated for all RA and PsA patients to receive a full infectious disease evaluation before the start of targeted and biologic therapies.
They also addressed vaccinations, recommending an evaluation of the patient’s immunization history and potentially planning a catch-up schedule for those in need of the influenza vaccine, a diphtheria-tetanus-pertussis booster, or the pneumococcal vaccine. More broadly, they stated that “a better response is expected if [non-live] vaccination is performed before the introduction of immunosuppressive drugs.” They added that live vaccines should be administered as soon as possible.
What rheumatologists can do
“So how do you mitigate risk?” Dr. Winthrop asked. “You have to be able to predict the risk, see what’s modifiable, and try to act on it. A lot of the risk of infection has more to do with the patient than the therapy.
“You try to minimize what you’re doing to the patient, particularly around steroids,” he said. “And then you think about screening and vaccinations. Rheumatologists need to be involved in those conversations because they’re the ones who know how these drugs interact with vaccines. A lot of the drugs might dumb down vaccine responses. Be sure to consider that and give the vaccines at times that will optimize their immunogenicity and likely efficacy.”
“Thankfully, infections are not that common,” Dr. Kavanaugh said. “Rheumatologists depend on data from trials, but more safety data comes from registry data and personal and shared experience.”
The authors declared no potential conflicts of interest.
SOURCE: Lortholary O et al. Ann Rheum Dis. 2020 Sep 22. doi: 10.1136/annrheumdis-2020-217092.