Uncovering the hidden drivers of autoinflammation of unknown origin
Some patients with systemic autoinflammatory diseases (SAID) remain particularly difficult to diagnose because of the wide variability of symptoms, which are often nonspecific and shared across multiple disorders. For years, they may experience recurrent fever episodes, persistent inflammation, joint pain, and profound fatigue, without any identifiable cause to explain their condition. These patients are therefore classified as having autoinflammation of unknown origin.
When the clinical approach reaches its limits, it becomes essential to explore other avenues. The identification of specific immune signatures is now emerging as a promising path forward, as demonstrated by this international study published in Nature Communications.
This work is based on a collaboration between the team of Prof. Adrian Liston (University of Cambridge), KU Leuven, and the Laboratory of Rheumatology at GIGA (University of Liège, Liège University Hospital), whose expertise in plasma proteomics played a key role.
The researchers analyzed blood samples from 36 patients with autoinflammation of unknown origin, comparing their immune profiles with those of 58 healthy controls and 92 patients with established SAID diagnoses, including Adult-onset Still’s disease (AOSD), familial Mediterranean fever (FMF), and Behçet’s disease. These samples were collected by more than 30 European medical centers through the ImmunAID consortium.
A biological signature finally demonstrated
One of the major questions was whether these patients truly formed a homogeneous group or simply represented a collection of atypical clinical presentations.
The study’s answer is clear: these patients share a common and coherent immune signature.
By analyzing samples from the 36 patients, the researchers identified marked activation of specific T-cell subsets, together with increased levels of circulating acute-phase inflammatory proteins.
These findings demonstrate that this is not merely a “diagnosis of exclusion,” but rather a distinct immunological entity with its own biomarkers.
“The key message of this study is that these patients display a measurable and reproducible biological signal. We are moving from clinical uncertainty toward an objective characterization of the disease,” says Christophe Poulet, researcher at the Laboratory of Rheumatology (GIGA and Liège University Hospital) and co-first author of the study.
GIGA’s proteomics expertise at the heart of the discovery
In Liège, the teams from the GIGA Laboratory of Rheumatology and the GIGA Proteomics Facility performed an in-depth plasma analysis using mass spectrometry.
This approach identified a panel of characteristic inflammatory proteins, independently confirming the immunological observations obtained through deep flow cytometry immunophenotyping. The convergence of these two technologies is one of the study’s major strengths.
“The fact that cytometry and proteomics converge on the same conclusions considerably strengthens the robustness of the findings. It provides us with solid biomarkers to better understand and ultimately better classify these patients,” adds Christophe Poulet.
An unexpected overlap with Adult-onset Still’s disease
Another major finding is that patients with autoinflammation of unknown origin share important immunological features with Adult-onset Still’s disease (AOSD), another SAID frequently diagnosed by rheumatologists.
The researchers observed several immune alterations common to AOSD, notably the upregulation of CD38 and HLA-DR across T-cell subsets.
This overlap suggests the existence of shared immunological mechanisms and opens particularly promising therapeutic perspectives.
“This overlap with Adult-onset Still’s disease is an extremely exciting lead. If confirmed, it could help us more rapidly evaluate treatments already proven effective in that condition for these patients as well,” explains Dominique de Seny, head of the Laboratory of Rheumatology and co-senior author of the study.
Reducing the diagnostic odyssey
Today, for many patients with autoinflammation of unknown origin, the diagnosis still relies on a diagnosis-by-exclusion approach, often reached only after months or even years of investigations.
The identification of specific biomarkers opens the way to future tools capable of shortening this diagnostic journey, better distinguishing or linking these patients to other SAID entities such as AOSD, and guiding clinicians more rapidly toward the most appropriate treatment strategy.
Beyond the publication itself, the implications are highly tangible: improving the lives of patients who often face prolonged medical uncertainty.
International visibility for GIGA
This publication in Nature Communications also highlights the international impact of the University of Liège, Liège University Hospital, and GIGA.
The close collaboration with the University of Cambridge and Adrian Liston’s team, a world-leading reference in immunology, underscores GIGA’s ability to contribute to top-tier European projects on rare and systemic autoinflammatory diseases.
For patients, this breakthrough is above all a sign of hope: a condition that has long remained difficult to define may now become better understood, better diagnosed, and ultimately better treated.
