Large-Scale Meta-Analysis Finds Higher Influenza and Shingles Risk with JAK-STAT Inhibitors

Overview

Janus kinase-signal transducer and activator of transcription inhibitors, commonly known as JAK-STAT inhibitors or simply JAK inhibitors, have changed the treatment landscape for several immune-mediated inflammatory skin diseases. These include atopic dermatitis, alopecia areata, and vitiligo, conditions in which the immune system contributes to persistent inflammation or autoimmune injury.

At the same time, the JAK-STAT pathway is also important for normal immune defense. That has raised an important clinical question: do these treatments increase the risk of infections, and if so, which infections are most relevant in daily practice? Previous meta-analyses have helped answer parts of this question, but many focused only on a few predefined infection outcomes. The present large-scale meta-analysis took a broader approach by evaluating all reported infection types in randomized controlled trials and by comparing systemic and topical JAK-STAT inhibitors.

Why infection risk matters

The immune system relies on JAK-STAT signaling to transmit messages from many cytokines and growth factors. These signals help the body recognize and fight viruses, bacteria, and other pathogens. Because JAK-STAT inhibitors interrupt this signaling, they may reduce inflammation in skin disease, but they can also weaken some protective immune responses.

This does not mean that these medicines are unsafe overall. Rather, their use requires a careful balance between disease control and potential adverse effects. For clinicians, the key issue is not just whether infection risk exists, but which infections occur more often, in which patients, and whether the risk differs between oral/systemic and topical therapies.

How the study was done

The investigators conducted a systematic review and meta-analysis of randomized controlled trials involving patients with immune-mediated inflammatory skin diseases who were treated with either systemic or topical JAK-STAT inhibitors. The analysis followed PRISMA 2020 and Cochrane methodology and was registered in PROSPERO, which increases transparency and reduces the risk of selective reporting.

In total, 74 randomized controlled trials were included, representing more than 29,000 patients. Infection-related adverse events were extracted and pooled using a random-effects model, which is appropriate when studies differ in patient populations, drug types, and follow-up durations. The main outcome was risk ratio, or RR. An RR above 1 indicates a higher risk in the treatment group than in the control group.

Main findings

Compared with placebo, JAK-STAT inhibitors were associated with a significantly increased risk of several common infections:

Influenza: RR 2.12, 95% CI 1.03-4.36
Bronchitis: RR 2.03, 95% CI 1.43-2.88
Herpes zoster: RR 1.67, 95% CI 1.29-2.15

These results suggest that patients receiving JAK-STAT inhibitors had about twice the risk of influenza and bronchitis, and a clearly increased risk of shingles, compared with those receiving placebo.

The risk appeared especially elevated in patients with atopic dermatitis. In this subgroup, the risk of influenza was substantially higher (RR 3.22, 95% CI 2.03-5.10), and the risk of herpes zoster was also increased (RR 2.00, 95% CI 1.34-2.99). This finding is clinically important because atopic dermatitis is one of the most common indications for JAK-STAT inhibitors in dermatology.

What was not found

Importantly, the meta-analysis did not identify a significant increase in the risk of serious infections. It also did not show clear evidence of higher rates of fungal infections or opportunistic infections.

This distinction matters. Serious infections are those that lead to hospitalization, are life-threatening, or require intensive treatment. Opportunistic infections are unusual infections that tend to occur when immune defenses are severely weakened. The absence of a significant signal for these outcomes is reassuring, although it does not eliminate the need for monitoring, especially in patients with additional risk factors.

Systemic versus topical treatment

The analysis also compared topical JAK-STAT inhibitors with vehicle controls. Topical agents showed a favorable safety profile and were generally comparable to vehicle, meaning that infection risk was not meaningfully increased in the available trial data.

This difference is biologically plausible. Topical therapies usually lead to lower systemic exposure than oral or injectable treatments, so they are less likely to affect immune defense throughout the body. For patients and clinicians, this supports the idea that topical JAK-STAT inhibitors may be a safer option when appropriate for the disease and the body site involved.

Clinical interpretation

The findings help refine how clinicians should counsel patients before starting JAK-STAT inhibitors. The overall safety profile remains acceptable, but the data support heightened attention to influenza and herpes zoster, particularly in patients with atopic dermatitis.

Practical prevention steps may include:

Reviewing vaccination status before treatment begins
Considering influenza vaccination when appropriate
Considering herpes zoster vaccination in eligible adults, following local guidelines
Assessing individual infection risk, including age, prior infections, and comorbidities
Educating patients to report fever, cough, skin lesions, or other signs of infection promptly

For patients with recurrent infections or multiple risk factors, clinicians may also want to review concurrent immunosuppressive medications, recent exposure history, and other conditions that could further increase susceptibility.

How this fits into current dermatology practice

JAK-STAT inhibitors are now an important part of dermatologic care because they can offer rapid and meaningful symptom relief, especially in diseases where conventional therapies may be inadequate or poorly tolerated. Their benefits are often substantial, but this study reinforces the need for individualized prescribing rather than a one-size-fits-all approach.

For many patients, the increased relative risk of common infections may still be outweighed by the clinical benefits of disease control. However, relative risk does not always tell the full story. The absolute risk of infection may still be modest in selected patients, especially in short-term trials. That is why shared decision-making, vaccination planning, and follow-up remain essential.

Strengths of the study

This meta-analysis has several important strengths. It included a large number of randomized trials and more than 29,000 patients, which increases statistical power. It also evaluated a broad range of infection outcomes rather than restricting the analysis to only a few predefined categories. In addition, it distinguished between systemic and topical therapy, which improves clinical usefulness.

The use of established systematic review methods and trial registration further strengthens confidence in the approach. Together, these features make the findings more comprehensive than earlier summaries of the literature.

Limitations to keep in mind

The main limitation is that the trial populations were highly selected. Patients in randomized trials often have fewer comorbidities, lower baseline infection risk, and closer monitoring than patients seen in routine practice. Follow-up was also relatively short in many studies, so rare or delayed adverse events may have been missed.

In addition, trial reports may vary in how infections are defined and recorded. Mild upper respiratory infections, for example, may be captured differently across studies. These issues can influence the precision of pooled estimates.

Because of these limitations, real-world safety data will remain important, especially for older adults, patients with prior herpes zoster, those with chronic lung disease, and individuals receiving combination immunosuppressive therapy.

Bottom line

This large meta-analysis suggests that JAK-STAT inhibitors used for skin-related immune-mediated inflammatory diseases are associated with a higher risk of influenza, bronchitis, and herpes zoster, especially in patients with atopic dermatitis. No significant increase was seen for serious, fungal, or opportunistic infections, and topical JAK-STAT inhibitors appeared to have a reassuring safety profile.

The overall message is one of balanced optimism: these therapies are effective and generally safe, but clinicians should proactively manage infection prevention, especially through vaccination and patient education in higher-risk groups.

Reference

Krebs M, Gulyás L, Fazekas KK, Nagy B, Kolonics MV, Meznerics FA, Kiss N, Bánvölgyi A, Hegyi P, Holló P, Kemény LV. Large-scale meta-analysis of infection risk with JAK-STAT inhibitors in 29,000 patients. J Eur Acad Dermatol Venereol. 2026 May 26. doi: 10.1111/jdv.70508. Epub ahead of print. PMID: 42187316.