JAK1 Inhibition With Upadacitinib Reduces Systemic Inflammation in AD, With Potential Cardiovascular Implications

Systemic inflammation is a common discussion associated with atopic dermatitis (AD), especially related to disease morbidity beyond the skin. Recent evidence highlights elevations in biomarkers such as high-sensitivity C-reactive protein (hs-CRP) and absolute eosinophil count (AEC) correlating with disease severity and systemic immune activation. The Janus kinase (JAK)/STAT pathway plays an important role in mediating inflammatory cytokines in AD, offering a therapeutic target.¹

A poster from the 2026 Winter Clinical Dermatology Conference evaluated the effect of upadacitinib (Rinvoq; AbbVie), a selective JAK1 inhibitor approved for multiple immune-mediated inflammatory disorders, on systemic inflammatory biomarkers in moderate to severe AD. Data were analyzed from 3 phase 3 trials—Heads Up (NCT03738397), Measure Up 1 (NCT03569293), and Measure Up 2 (NCT03607422)—totaling more than 600 patients treated with upadacitinib at 15-mg or 30-mg doses compared with placebo or dupilumab (Dupixent; Sanofi and Regeneron).¹

Upadacitinib treatment resulted in rapid, statistically significant reductions in hs-CRP and AEC from baseline as early as week 2, sustained through week 16, outperforming placebo and dupilumab in some measures. Additionally, exploratory serum proteomics using the Olink cardiovascular panel identified significant decreases in multiple proteins associated with cardiovascular inflammation and immune regulation, including IL2RA, CEACAM8, LGALS3, MMP3, TNFRSF1A, and XCL, after treatment with upadacitinib.¹

Key results:

• In the combined Heads Up and Measure Up studies, patients treated with upadacitinib demonstrated a significant reduction of hs-CRP from baseline to week 16.
• In the Measure Up studies, the upadacitinib 15 mg and 30 mg groups showed statistically significant reductions in mean hs-CRP and AEC vs placebo, with reductions evident as early as week 2 and sustained through week 16.
• In the Heads Up study, upadacitinib 30 mg showed greater reductions in mean hs-CRP and AEC than dupilumab; these differences were statistically significant at most visits, including week 16.
• In the Heads Up study, serum proteins measured with the Olink cardiovascular panel were significantly decreased from baseline in patients treated with upadacitinib 30 mg.

According to the poster authors, these findings suggest that upadacitinib not only improves cutaneous disease but also mitigates systemic inflammatory burden in moderate to severe AD. Reductions in cardiovascular-related inflammatory proteins may have clinical relevance, given the increased cardiovascular risk observed in this population. Limitations include short follow-up and exploratory biomarker subgroups; thus, further research is warranted to define the long-term clinical implications of upadacitinib’s systemic anti-inflammatory effects.¹

Why This Matters

A recent paper published in the European Heart Journal reviewed CRP and cardiovascular risk in the general population. As the authors noted, cardiovascular disease remains the leading cause of morbidity and mortality worldwide, and despite decades of progress in identifying and managing traditional risk factors, a substantial proportion of cardiovascular events occur in individuals whose risk is inadequately captured by conventional tools. Inflammation has emerged as a fundamental driver of residual cardiovascular risk, and hs-CRP—a widely available, inexpensive marker of systemic inflammation—has long been studied as a potential tool for refining risk stratification. The published large-scale analysis by Kurt et al provides compelling population-level evidence supporting the routine clinical use of hs-CRP in primary prevention.²

The study drew on data from 448,653 UK Biobank participants without known atherosclerotic cardiovascular disease (ASCVD), making it among the largest analyses of its kind. Participants had a median age of 57 years and median hs-CRP levels of 1.32 mg/L. Over a median follow-up of nearly 14 years, the investigators assessed the association between hs-CRP levels and 3 key outcomes: major adverse cardiovascular events (MACEs; a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke), cardiovascular death, and all-cause death.²

After adjusting for a comprehensive panel of established cardiovascular risk factors, including age, sex, body mass index, diabetes, smoking, systolic blood pressure, low-density lipoprotein (LDL) cholesterol, and creatinine, individuals with hs-CRP levels above 3 mg/L faced a 34% higher risk of MACEs, a 61% higher risk of cardiovascular death, and a 54% higher risk of all-cause death vs those with levels below 1 mg/L. Even at a lower threshold, participants with hs-CRP at or above 2 mg/L had a 22% higher risk of MACEs and a 37% higher risk of cardiovascular death relative to those below this level. These associations held across all prespecified subgroups, including individuals without any conventional modifiable risk factors, highlighting the independent prognostic contribution of low-grade systemic inflammation.²

"Moderate to severe [AD] is increasingly recognized as a systemic inflammatory disease, and hs-CRP is one of the clearest windows into that systemic biology. The recent UK Biobank analysis published in the European Heart Journal, including nearly 450,000 individuals followed for more than 13 years, confirmed that hs-CRP independently predicts cardiovascular events, with levels above 3 mg/L associated with a 34% higher risk of MACEs and levels [of] 2 mg/L [or greater] also associated with increased risk,” Christopher Bunick, MD, PhD, associate professor of dermatology at Yale School of Medicine, editor in chief of Dermatology Times, and poster author, said in an exclusive statement.

The predictive performance of hs-CRP was not only additive but also ranked above several traditional risk markers, including LDL cholesterol, in head-to-head comparisons. When hs-CRP was incorporated into the SCORE2 risk model, the standard European tool for cardiovascular risk estimation, model fit improved significantly, yielding a net reclassification improvement of 14.1%. According to the authors, this enhancement was primarily driven by more accurate downward reclassification of individuals who remained event-free, reflecting improved specificity.²

The study also confirmed that hs-CRP levels are stable over time, with the majority of participants retaining their baseline risk category across a median interval of over 4 years, supporting its reliability as a clinically actionable biomarker from a single measurement.²

Together, these data provide large-scale validation of hs-CRP as an independent predictor of cardiovascular events in the general population and suggest its routine incorporation into primary prevention guidelines.

“Routine hs-CRP assessment should be considered for inclusion in future guidelines to refine cardiovascular risk assessment and to improve prevention strategies in patients without a history of ASCVD,” Kurt et al concluded.

Connecting to AD

The findings from the upadacitinib poster analysis, compared with the large-scale evidence from Kurt et al, demonstrate why reducing systemic inflammation in patients with moderate to severe AD may matter beyond skin clearance. Patients with AD carry an elevated baseline cardiovascular risk, and hs-CRP—now validated as an independent predictor of MACEs, cardiovascular death, and all-cause mortality—is increasingly recognized as a clinically relevant marker of that risk.^1,2

“What we observed with upadacitinib is biologically consistent with that framework: Patients started with hs-CRP levels in the higher-risk inflammatory range and were reduced below the clinically relevant 2-mg/L threshold within weeks, with reductions sustained through week 16,” Bunick said.

The demonstration that upadacitinib reduces hs-CRP, eosinophils, and a broad panel of cardiovascular inflammatory proteins suggests that JAK1 inhibition may address not only the cutaneous and quality-of-life burden of AD but also the residual inflammatory risk that standard cardiovascular risk tools may not catch.

“Although exploratory, these findings suggest that effective control of systemic inflammation in [AD] may have implications beyond the skin, including the potential to reduce residual inflammatory cardiovascular risk. That hypothesis deserves further study,” Bunick concluded.

For more atopic dermatitis news and research, register to attend the 2026 Revolutionizing Atopic Dermatitis (RAD) conference in Nashville, Tennessee, held June 17-19. Use code DT40 for 40% off registration.

References

1. Bunick CG, Kwatra SG, Grada A, et al. Effect of upadacitinib on biomarkers of systemic inflammation in patients with moderate to severe atopic dermatitis. Poster presented at: 2026 Winter Clinical Hawaii; January 16-21, 2026; Maui, HI.
2. Kurt B, Reugels M, Schneider KM, et al. C-reactive protein and cardiovascular risk in the general population. Eur Heart J. Published online December 11, 2025. doi:10.1093/eurheartj/ehaf937