Background: Sjögren disease (SD) is a B cell driven systemic auto-immune disease in which there is a need for identification of biomarkers to better assess disease activity, risk of lymphoma and finding new therapeutic targets. Chronically activated B cells and antibody-secreting cells (e.g., plasmablasts; plasma cells) are pivotal in SD pathogenesis. Association between systemic complications including lymphoma in SD and BAFF/BlyS, a B cell survival activation and growth cytokine involved in precoce steps of B cell ontogeny, has been previously shown [1]. Conversely, only limited data are available regarding a proliferation-inducing ligand (APRIL), which is a cytokine of B cell survival and activation playing a role in late stages of B cell ontogeny, on plasmablasts and plasma cells upon BCMA and TACI receptor engagement. Thus, APRIL may contribute in antibodies hyperproduction participating in immune-complexes formation that are important in systemic complications and risk of lymphoma in SD. A role for APRIL in SD activity and risk of lymphoma has been suggested in previous studies, but existing data are scarce.

Objectives: This study aimed to investigate associations between APRIL, B cell biomarkers, disease activity and risk of lymphoma.

Methods: APRIL serum levels were measured by ELISA (Invitrogen) in 40 healthy donors (HD) and 337 patients with SD at enrolment in the French prospective ASSESS cohort (with a current 17-year follow-up). All patients enrolled in the ASSESS cohort fulfilled the ACR/EULAR 2016 criteria for SD. Patients with available APRIL dosage were stratified depending on their disease activity/severity and their risk of lymphoma based on the previously validated clustering of the ASSESS cohort [2]. APRIL levels in patients with incident (n=9) and prevalent (n=16) lymphoma were compared to patients with moderate to severe disease activity - systemic complications (cluster 2, n=114), those with B cell activation markers - no systemic manifestations (cluster 1, n=154), low disease activity - low-risk of lymphoma - high symptom burden (cluster 3, n=44) and HD. The association between SD-related lymphoma and APRIL serum concentrations, the values of lymphoma predictors at enrolment (clinESSDAI, ESSDAI, parotidomegaly, adenopathy, lymphocytopenia <0.5 G/L, CD4/CD8 T cell ratio≤0.8, RF positivity, cryoglobulinemia, monoclonal component, and low C4) and other potential biomarkers (IgG levels, total gammaglobulins, immune-complexes, beta2microglobulin, kappa and lambda free light chains, quantitative [q] anti-SSA/SSB autoantibodies, digital interferon [IFN] alpha, s-FLT3, CXCL10, CCL19, CXCL13, BAFF), were analyzed in univariate and multivariate models. Multivariate analyses took into account APRIL and variables significantly associated with lymphoma (incident and prevalent) in univariate analyses selected by a stepwise procedure. Estimation of incident lymphoma risk was assessed in a separate multivariate model.

Results: A gradual increase in APRIL cytokine serum levels across healthy donors (median [range] 0.36 ng/ml [6.45], p<0.0001), SD patients with low disease activity - low-risk of lymphoma - high symptom burden (cluster 3) (0.34 ng/ml [9.2] p<0.0001), patients with B cell activation markers (cluster 1) (0.97 ng/ml [21.85], p<0.0001), patients with systemic manifestations (cluster 2) (1.2 ng/ml [21.2], p=0.007), and those with SD-associated lymphoma (2.33 ng/ml [41.1]), was observed. Interestingly, APRIL levels were higher in patients with incident lymphoma (2.8 ng/ml [41.1]) compared to all subgroups (HD, p<0.0001; cluster 3, p= 0.0004, cluster 1, p=0.0004; cluster 2, p= 0.02). In multivariate analysis, including only markers significantly associated with lymphoma (prevalent and incident) in univariate analyses, APRIL expression at enrolment remained significantly associated with lymphoma (OR 1.1; 95% CI [1-1.17] p=0.045), along with BAFF levels (mean [SD]: 1085.1 pg/ml [742.4]; per 1000 BAFF units, OR 1.75; 95% CI [1.11-2.71]; p=0.0012), CD4/CD8 ratio ≤ 0.8 (OR 4.7 95% CI [1.13-18.03]; p=0.027), low C4 (OR 5.38 95% CI [1.89-16.04]; p=0.002), lymphopenia <0.5 G/L (OR 51.02 95% CI [4.65-611.01]; p=0.001), glandular (OR 4.95 95% CI [1.49-15.97]; p=0.007), and adenopathy (OR 6.43 95% CI [1.1-31.8]; p=0.027) domains of the ESSDAI. In a separate multivariate model, APRIL (OR 1.1 95% CI [1.01-1.21]; p=0.02) and CXCL13 (OR 1.0 95% CI [1.0-1.0]; p=0.01) were found independently associated with the risk of developing incident lymphoma. APRIL serum levels were also significantly associated with disease activity clinESSDAI (p=0.017), glandular (p=0.026), hematological (p=0.003) and biological domains of the ESSDAI score (p<0.001), IFN alpha (p<0.001), and B cell activation markers such as total gammaglobulins (p<0.001), IgG levels (p<0.001), immune complexes (p<0.001), kappa and lambda free light chains (p<0.001), beta2microglobulin (p<0.001), qSSA (p=0.001) and qSSB (p<0.001), RF positivity (p<0.001), cryoglobulinemia (p=0.009), low C4 (p= 0.02), BAFF levels (p=0.015), CXCL10 (p<0.001), CCL19 (p<0.001) and CXCL13 (p<0.001).

Conclusion: This study confirms at the protein level the result previously observed in the transcriptomic analysis of the ASSESS cohort [3]: serum APRIL is associated with the risk of developing lymphoma in SD. Moreover, APRIL serum levels are associated with B cell biomarkers, cryoglobulinemia, and systemic disease activity. These results confirm the interest of APRIL, a B-cell cytokine easily measurable in patients’ sera, as a predictor of SD-related lymphoma, and as a potentially relevant therapeutic target in SD.

REFERENCES: [1] Gottenberg JE, et al. PLoS ONE. 2013.

[2] Nguyen Y, et al. Lancet Rheumatol. 2024.

[3] Duret PM, et al. Arthritis Rheumatol. 2023.

Acknowledgements: To the patients participating to the “Assessment of Systemic Signs and Evolution in Sjögren’s syndrome” ASSESS cohort and co-investigators; this work was supported by the Innovative Medicines Initiative 2 Joint Undertaking NECESSITY (grant 806975); Novartis° (Grant DREAMER 2023); Association Française du Syndrome de Gougerot-Sjögren et des syndromes secs (AFGS); The ASSESS cohort was supported by two research grants from the French Society of Rheumatology.

Disclosure of Interests: Pierre-Marie DURET NOVARTIS (Grant: DREAMER 2023), Pascal Schneider: None declared, Ludivine Robin: None declared, Marine Vierling: None declared, Nicolas Meyer: None declared, Valerie Devauchelle-Pensec: None declared, Divi Cornec: None declared, Alain Saraux: None declared, Jean SIBILIA: None declared, Raphaèle Seror: None declared, Yann Nguyen: None declared, Gaetane Nocturne: None declared, Laurent Mauvieux: None declared, Laurent Miguet: None declared, Xavier Mariette: None declared, Jacques-Eric Gottenberg: None declared.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.