Targeted biologic and targeted synthetic therapies have revolutionized the management of inflammatory and autoimmune diseases, including rheumatoid arthritis, psoriasis, spondyloarthritis, inflammatory bowel disease, and hidradenitis suppurativa. These therapies have achieved unprecedented efficacy and substantially improved patients’ quality of life. However, by modulating key immune pathways, they can cause secondary immunodeficiency, increasing the risk for a broad range of infections.

A narrative review published in Microorganisms presented an interdisciplinary risk stratification framework to optimize clinical safety.

Treatment Risks

International researchers reviewed the literature published through March 2026 in PubMed, Embase, and the Cochrane Library, prioritizing evidence from large international registries, including the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis, DANBIO, and RABBIT, and guidelines from the American College of Rheumatology (ACR), the European Alliance of Associations for Rheumatology, and the Infectious Diseases Society of America.

The review found that the risk for infection varied according to the molecular target of the treatment.

• TNF inhibitors and rituximab were associated with the highest rates of serious infections, including bacterial pneumonia, sepsis, and reactivation of granulomatous infections, such as tuberculosis.
• Interleukin-6 inhibitors, including tocilizumab, increased the risk for serious bacterial and opportunistic infections, requiring close monitoring of neutrophil and platelet counts and lipid profiles.
• JAK inhibitors substantially increased the risk for varicella-zoster virus reactivation (herpes zoster) in a dose-dependent manner.
• Interleukin-17 and interleukin-23 inhibitors had a more favorable safety profile, with lower rates of serious infections, although interleukin-17 inhibitors increased the risk for mucocutaneous candidiasis.

Risk Factors

The authors identified older age, particularly 60 years or older, female sex, comorbidities such as chronic lung disease, diabetes, chronic kidney disease, and cardiovascular disease, and most importantly, a history of serious infections as the most consistent risk modifiers. Patients aged 60 years or older who initiated biologic therapy had a 2.28-fold higher risk for infection than younger patients.

Among treatment-related factors, glucocorticoids emerged as the most important modifiable risk factor, with a dose-dependent effect evident at doses of 7.5 mg/d or higher. Combining biologics with glucocorticoids or other immunosuppressive agents further increases the risk for infection.

Prevention Strategies

One of the main findings of the review was the gap between the clinical guidelines and routine practice. Data from the ACR Rheumatology Informatics System for Effectiveness registry showed that only 15.5% of the patients underwent the recommended comprehensive screening before starting biologic therapy. This finding highlighted a substantial gap between guideline recommendations and their implementation in clinical practice.

To address this patient safety issue, researchers have proposed a prevention strategy on the basis of three key components.

• Universal baseline screening should include tuberculosis testing using an interferon-gamma release assay, hepatitis B and C screening, HIV testing, and complete blood count. In endemic regions, screening should also include parasites such as Strongyloides stercoralis and Trypanosoma cruzi.
• Routine vaccination before treatment should include inactivated vaccines against pneumococcus, seasonal influenza, and hepatitis B for at-risk patients, together with the recombinant herpes zoster vaccine, which is safe for immunocompromised individuals, and the human papillomavirus vaccine, according to population-based recommendations. Live vaccines remain contraindicated during periods of significant immunosuppression.
• Monitoring during treatment should include complete blood counts and liver function tests every 4-8 weeks after treatment initiation and every 3 months thereafter, together with a clinical assessment at each follow-up visit.

The authors also recommended selective antimicrobial prophylaxis, such as trimethoprim-sulfamethoxazole, to prevent Pneumocystis jirovecii pneumonia in patients receiving long-term high-dose corticosteroids, defined as prednisone at a dose ≥ 20 mg/d for at least 4 weeks.

Speaking with Univadis Spain, part of the Medscape Professional Network, Cristiana Sieiro Santos, MD, PhD, postdoctoral researcher at the Centre for Musculoskeletal Research, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, England, said “The priority should not be choosing between controlling the disease and preventing infections but integrating both strategies as safely as possible. Whenever clinically feasible, guidelines recommend reviewing vaccination status and administering vaccines before the onset of immunosuppression, ideally 2-6 weeks in advance. However, when disease activity is high or there is a risk of irreversible organ damage, evidence and major consensus statements agree that effective biologic therapy should not be delayed solely to complete the vaccination schedule. In summary, the goal is not to postpone treatment to allow vaccination but to take every opportunity to optimize protection against infections without compromising disease control.”

Tailored Screening

“Probably not. We now know that infection risk depends not only on whether a patient receives a biologic but also on the immune pathway it targets, the underlying disease, concomitant treatments, the patient’s comorbidities, and the epidemiologic context. The most appropriate approach is, therefore, to maintain a standard baseline screening protocol, including vaccination status, infection history, and assessment of the risk for tuberculosis, hepatitis B and C, and, when indicated, HIV, while adding specific measures according to the therapeutic target,” Sieiro Santos said.

“With interleukin-17 inhibitors, the evidence shows an increased risk for mucocutaneous candidiasis, but this does not currently justify universal screening for Candida colonization. It is more useful to identify predisposing factors, educate patients about symptoms, and maintain appropriate clinical surveillance during follow-up. We shifted from asking whether a patient will receive a biologic to asking which biologic they will receive and what their individual risk profile is. This change allowed us to develop preventive strategies that were much more efficient and tailored to each patient. In my opinion, that is the key message from the available evidence: Infection prevention must become increasingly personalized, just as treatment for immune-mediated diseases already has,” she concluded.

Benefit Profile

Despite these risks, the benefit-risk profile of targeted biologic and targeted synthetic therapies remains highly favorable because effective control of autoimmune disease reduces the need for rescue corticosteroids. From a clinical perspective, the goal is not to avoid these therapies but to systematically implement evidence-based prevention, vaccination, and monitoring strategies. Such measures can substantially reduce infectious complications without compromising therapeutic efficacy.

The researchers also emphasized the importance of close collaboration among rheumatologists, infectious disease specialists, and tropical medicine specialists in managing complex patients. They further highlighted the need to develop individualized risk prediction tools, including RABBIT, DANBIO, and the recently developed RAISE model, to support the more personalized use of these transformative therapies.

The authors of the study reported having no relevant conflicts of interest. Sieiro Santos reported having no relevant conflicts of interest.

This story was translated from Univadis Spain.