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People with inflammatory rheumatic diseases face a higher risk for infection. As Christian Kneitz, MD, rheumatologist, emphasized at Rheuma Update 2026 Mainz, Germany, this is especially the case when organs are involved, such as in lupus nephritis or interstitial lung disease (ILD). The main factor is disease activity, although the degree to which medications weaken the immune system also plays an important role.

Andrea Rubbert-Roth, MD, an active member of the German Society of Rheumatology and Clinical Immunology, made it clear that methotrexate (MTX) is generally not a cause for concern in this context; in fact, it may even help prevent infections overall. She also stressed the importance of keeping vaccinations up to date to protect against vaccine-preventable infectious diseases.

“In rheumatological diseases, infections increase mortality and thus also determine our therapeutic options,” Kneitz noted. “Of course, we ensure that our treatment does not cause unnecessary infections. They occur particularly at the start of therapy and when switching therapies — the critical phases — and are both a cause and consequence of increased disease activity.”

Patients with systemic lupus erythematosus (SLE) already have a high risk for infection; this risk increases further with lupus nephritis. In a retrospective French cohort study, nearly half of 168 patients experienced infections within 15 years of a first nephritis flare-up. Overall, 59 individuals had severe infections, and three of the four deaths that occurred during the average follow-up of 9.6 years were due to an infection.

“This shows that we have a patient population here that requires special attention, and of course, it is best if we can prevent severe lupus nephritis from occurring,” said the rheumatologist.

Disease Activity Promotes Infections and Vice Versa

What matters most, therefore, is controlling the underlying disease — especially since there is an interplay between infections and disease activity: Inadequately treated SLE promotes infections, and infections, in turn, can trigger SLE flares. “That’s probably not the case with milder infections,” said Kneitz, referring to a Dutch observational study involving 203 participants. The incidence rates were 5.3 per 100 patient-years for severe infections and 63.9 per 100 patient-years for mild infections. Severe flares occurred at a rate of 3.6 per 100 patient-years, while mild flares occurred at a rate of 15.1 per 100 patient-years.

The risk for a severe SLE flare following a severe infection was 7.4 times higher. The implication is clear to Kneitz: “If you have a patient with lupus who is going through a severe infection, then afterward you can expect to have to monitor them closely to see if it leads to a lupus flare-up that will then further impair the patient.”

Comparatively Few Infections With Belimumab

Treatment also influences the risk for infection. Among biologics, belimumab is a suitable option. “It’s really a quite safe therapy,” said the rheumatologist. In a retrospective comparison, anifrolumab had a higher cumulative 3-year infection rate of 38.3% compared to belimumab’s 21.3% and a 40% higher risk for infection.

“The difference stems primarily from herpes zoster and COVID-19 infections,” explained Kneitz. The zoster issue with anifrolumab is well-known. In the study, endogenous reinfection occurred four times as frequently during therapy with the interferon receptor antibody — a preventable risk. Kneitz: “We should try to vaccinate anifrolumab patients against shingles.” For those who absolutely refuse to be vaccinated, there is also the option of valacyclovir prophylaxis.

The anti-CD20 antibody obinutuzumab is “the next new agent to be used for lupus;” it has been approved since late 2025 for active lupus nephritis in combination with mycophenolate mofetil. Obinutuzumab appears to pose a particular challenge in the context of SARS-CoV-2 infections due to its strong B-cell depletion. In the regulatory phase 3 trial, COVID pneumonia occurred frequently at a rate of 5.1%. “Other severe infections are also more common with this drug,” said Kneitz. Risks and benefits must be carefully weighed. “We have a better drug for treatment, but we also have a relatively high risk of infection.”

MTX: No Cause for Concern

According to Rubbert-Roth, the main risk factors for severe infections in rheumatoid arthritis (RA) include older age, current or former smoking habit, comorbidities such as diabetes and hypertension, seropositivity, and high disease activity at baseline. This was demonstrated by a cohort study from England and Wales involving 17,472 newly diagnosed individuals with RA. While glucocorticoids were associated with an increased risk only before adjustment, the study clearly gave the all-clear regarding MTX. The gold standard for RA basic therapy reduced the risk for severe infections by 24% after adjustment compared to non-MTX-based initial therapies.

“The fact that MTX has a protective effect in this regard is a new finding and can certainly be used as an argument in individual patient consultations to support the initiation of MTX therapy,” said the rheumatologist.

The study found that the greatest risk stemmed from concomitant lung diseases, which nearly doubled the risk. RA is frequently associated with RA-ILD or bronchiectasis. As Kneitz reported, scientists found a significant 60% increase in severe infections among 221 RA patients with lung disease and 980 RA patients without lung disease when lung disease was present. RA-ILD increased the risk by 79%.

Although most infections in this context affected the lungs themselves — yet another argument for vaccination, primarily against influenza and respiratory syncytial virus, which the researchers observed frequently — skin, soft tissue, and ear, nose, and throat infections were also more common in this group.

New Score for Individual Risk Assessment in RA

A new tool for estimating the individual risk for infection in RA prior to treatment with biologics or targeted synthetic therapeutics is the RAISE score, which includes a free online risk calculator. “The score is relatively comprehensive, more so than the RABBIT infection risk score, which raises the question of whether it can really be used,” Kneitz acknowledged. “But it might be of interest to individual patients.”

Despite the focus on severe infections, it should not be forgotten that milder infections also have consequences. According to recent analyses from a US rheumatology practice network, these occurred at a rate of 3.3 per person per year, leading to work absences in 37% of cases and treatment interruptions in 26%. “All of this definitely affects the resilience of those affected,” emphasized Kneitz, but he also pointed to a higher relapse rate of 66.4% following treatment breaks compared to 53.3% with continued treatment.

“We should certainly pay attention to these milder infections as well. When patients have infections, we should make the effort to assess what we can do with the basic therapy?” the rheumatologist emphasized. However, this remains difficult and, as a survey of rheumatologists in the US shows, is handled variably. What, when, and for how long should treatment be paused? “That will always be an individual decision in each case.”

This story was translated from Medscape's German edition.