Anti-inflammatory cytokine IL-38 rises with rheumatoid arthritis severity in Iraqi cohort

Serum levels of interleukin-38, an anti-inflammatory member of the interleukin-1 cytokine family, are markedly higher in people with rheumatoid arthritis than in healthy controls, and the degree of elevation tracks closely with clinical disease activity, according to a cross-sectional study conducted at rheumatology centers in Babylon, Iraq. The finding adds a puzzling twist to the biology of a cytokine that is supposed to dampen inflammation: in this cohort, the more active the disease, the more of this braking molecule was circulating in the blood.

The study, published in Egyptian Rheumatology and Rehabilitation, enrolled 140 participants: 70 patients with rheumatoid arthritis diagnosed by specialist rheumatologists under the 2010 ACR/EULAR classification criteria, and 70 apparently healthy controls matched for age and sex. The patients, 52 women and 18 men with a mean age of about 48 years, were recruited between October 2025 and April 2026 from Marjan Medical City, Al-Hilla Teaching Hospital, Imam Al-Sadiq Teaching Hospital, and the Central Blood Bank in Babylon. Molecular analyses were carried out at the Institute of Genetic Engineering and Biotechnology at the University of Baghdad.

The numbers behind the headline finding are striking. Serum interleukin-38 averaged 104.47 plus or minus 37.82 picograms per milliliter in the patients, compared with 58.60 plus or minus 16.73 picograms per milliliter in controls, a difference of roughly 78 percent above the control mean that was highly statistically significant. Interleukin-6 showed the largest relative increase, about 407 percent above the control mean, while interleukin-17A and tumor necrosis factor alpha were also significantly elevated. All four cytokines were measured by sandwich enzyme-linked immunosorbent assay on duplicate samples.

The correlation analysis was the core of the study. It also correlated with C-reactive protein (0.661), interleukin-6 (0.587), interleukin-17A (0.543), and the erythrocyte sedimentation rate (0.543). The correlation with tumor necrosis factor alpha did not reach statistical significance. Disease duration showed a negative correlation with interleukin-38, an association the authors flag as descriptive only, since a cross-sectional snapshot cannot speak to change over time.

The researchers went a step further by measuring, at the transcript level, the expression of two well-established rheumatoid arthritis risk-factor genes, PTPN22 and HLA-DRB1, using quantitative real-time PCR on whole blood RNA. By contrast, its association with HLA-DRB1 expression was essentially zero. The authors are careful to note that these were expression measurements, not genotyping, so the null HLA-DRB1 result says nothing about shared-epitope genetic background.

That inverse PTPN22 link, however, largely dissolved under statistical control. When the researchers computed a partial correlation adjusting for DAS28-ESR, the coefficient fell from minus 0.664 to minus 0.054, effectively nothing. PTPN22 expression itself correlated with disease activity at minus 0.897, even more strongly than with interleukin-38. The most parsimonious reading, which the authors endorse, is that interleukin-38 and PTPN22 behave as co-regulated readouts of the same disease-activity axis rather than being linked by a disease-activity-independent molecular mechanism. The authors had hypothesized a compensatory response to PTPN22 suppression, but their own adjustment analysis shows the cross-sectional data cannot establish that pathway.

Treatment intensity told a parallel story. Patients were sorted into six mutually exclusive therapeutic tiers, from newly diagnosed and untreated through NSAIDs, corticosteroids, methotrexate, other conventional DMARDs, and biologic therapy. Serum interleukin-38 differed significantly across these subgroups, highest in newly diagnosed untreated patients at 142.98 plus or minus 38.73 picograms per milliliter and lowest in the biologic-treated group at 67.84 plus or minus 19.36, a 52.5 percent difference. Interleukin-17A followed the same pattern. Because different patients were compared across subgroups rather than the same patients followed over time, these differences cannot establish that any treatment reduced interleukin-38; disease activity, disease duration, or both could account for the gradient.

In a multivariable linear regression model of DAS28-ESR that included PTPN22, interleukin-38, interleukin-6, interleukin-17A, tumor necrosis factor alpha, and HLA-DRB1 together, interleukin-38 retained independent statistical significance with an adjusted coefficient of 0.005, as did PTPN22, while the other predictors fell to non-significance. The model explained 81.8 percent of the variance in disease activity scores, though the authors caution that with 70 patients and six predictors, overfitting is a real risk and the unstandardized coefficients are on different scales and not directly comparable.

The interpretive puzzle the study set out to address is why an anti-inflammatory cytokine would be elevated in an inflammatory disease. Two hypotheses frame the field: either interleukin-38 acquires pro-inflammatory properties in the rheumatoid joint environment, or it rises as a compensatory counter-regulatory response proportional to the inflammatory drive. The pattern observed here, activity-proportional elevation, parallel behavior with interleukin-17A, and lower levels in more intensively treated patients, is consistent with the compensatory model, but the authors repeatedly stress that a cross-sectional design cannot confirm it. Preclinical work cited in the paper, showing that interleukin-38 deficiency worsens Th17-driven inflammation in experimental arthritis models, provides biological plausibility, not human proof.

The limitations are laid out plainly. No causality or temporal ordering can be inferred from a single time point. The newly diagnosed subgroup had a mean of nearly two years of symptoms before starting therapy, a diagnostic delay that may itself have contributed to their high disease activity. Genotyping for the PTPN22 risk variant was not available. Serum measurements may not reflect interleukin-38 concentrations in the synovial compartment where much of the relevant biology occurs, and complement components C3 and C4 were measured as concentrations rather than activation fragments, so no conclusion about complement activation is possible. The authors position interleukin-38 as a candidate disease-activity-associated biomarker, potentially useful for pharmacodynamic monitoring pending prospective longitudinal validation in independent cohorts, rather than as an established clinical tool.

Subject of Research: Serum interleukin-38 levels in rheumatoid arthritis and their association with disease activity and treatment intensity

Article Title: Serum interleukin-38 is paradoxically elevated in rheumatoid arthritis and associated with disease activity and treatment intensity: a cross-sectional study

Article References: Chnani, Y., & Abdulkarrem, R. (2026). Serum interleukin-38 is paradoxically elevated in rheumatoid arthritis and associated with disease activity and treatment intensity: a cross-sectional study. Egyptian Rheumatology and Rehabilitation, 53(1), Article 82. https://doi.org/10.1186/s43166-026-00449-2

Image Credits: AI Generated

DOI: 10.1186/s43166-026-00449-2

Keywords: rheumatoid arthritis, interleukin-38, cytokines, DAS28-ESR, PTPN22, biomarkers, cross-sectional study, Th17, ELISA, Iraq, autoimmunity, Serum