BACKGROUND: Interleukin 40 (IL-40) is a cytokine implicated in malignancies and rheumatic disorders. Its association with fibrotic mediators has been previously described. Since inflammation and fibrosis are hallmarks of systemic sclerosis (SSc), we aimed to analyze the role of IL-40 in SSc. METHODS: IL-40 levels were analyzed in the serum of 90 SSc patients and 75 healthy controls (HCs). IL-40 expression in dermal biopsies from 5 SSc patients and 5 HCs was assessed via immunohistochemistry. IL-40 was analyzed in 39 SSc patients with interstitial lung disease treated with cyclophosphamide (CPA) and in 24 SSc patients with active progressive disease treated with rituximab (RTX). SSc activity was assessed by the European Scleroderma Study Group (ESSG) index. The effect of recombinant IL-40 on peripheral blood mononuclear cells (PBMCs) from 10 SSc patients was determined in vitro. IL-40 was analyzed in 24 individuals at risk of developing SSc (VEDOSS), who were categorized as progressors (n = 11) and nonprogressors (n = 13). RESULTS: IL-40 expression was elevated in the skin of SSc patients compared to HCs, particularly in fibroblasts and immune infiltrates. Serum IL-40 was increased in SSc compared to HCs (p < 0.0001) and was associated with ESSG (r = 0.372, p = 0.0005) and gastrointestinal involvement (p < 0.05). IL-40 correlated with serum IL-8 (r = 0.270, p = 0.019) and TGF-β1 (r = 0.301, p = 0.024) levels. In the CPA and RTX cohort, no significant changes in the serum IL-40 were observed upon treatment. Baseline and changes in IL-40 levels were associated with changes in several clinical parameters. IL-40 was elevated in patients at risk of SSc compared to HCs (p = 0.0003). No significant changes were observed in progressors vs. nonprogressors; however, IL-40 was associated with capillaroscopy findings (p < 0.05). IL-40 induced the upregulation of IL-6 (p = 0.002), MCP-1 (p = 0.002) and IL-10 (p = 0.002) in PBMCs from SSc patients in vitro. CONCLUSIONS: IL-40 was upregulated in the skin and serum of SSc patients and was associated with disease activity, gastrointestinal involvement and fibrotic mediators. Our in vitro findings indicate that IL-40 might be involved in the immune response and fibrotic processes in SSc.

Department of Dermatovenerology University General Hospital Prague and 1st Faculty of Medicine Charles University Prague Czech Republic

Department of Rheumatology 1st Faculty of Medicine Charles University Prague Czech Republic

Faculty of Mathematics and Physics Charles University Prague Czech Republic

Institute of Anatomy 1st Faculty of Medicine Charles University Prague Czech Republic

Institute of Rheumatology Na Slupi 4 Prague 128 00 Czech Republic

Zobrazit více v PubMed

mith V, Scirè CA, Talarico R, Airo P, Alexander T, Allanore Y, Bruni C, Codullo V, Dalm V, De Vries-Bouwstra J, Della Rossa A, Distler O, Galetti I, Launay D, Lepri G, Mathian A, Mouthon L, Ruaro B, Sulli A, Tincani A, Vandecasteele E, Vanhaecke A, Vanthuyne M, Van den Hoogen F, Van Vollenhoven R, Voskuyl AE, Zanatta E, Bombardieri S, Burmester G, Eurico FJ, Frank C, Hachulla E, Houssiau F, Mueller-Ladner U, Schneider M, van Laar JM, Vieira A, Cutolo M, Mosca M, Matucci-Cerinic M. Systemic sclerosis: state of the Art on clinical practice guidelines. RMD Open. 2018;4(Suppl 1):e000782. 10.1136/rmdopen-2018-000782. PMID: 30402270; PMCID: PMC6203100. PubMed PMC

Carnevale A, Silva M, Maietti E, Milanese G, Saracco M, Parisi S, Bravi E, De Gennaro F, Arrigoni E, Bodini FC, Fusaro E, Scirè CA, Sverzellati N, Ariani A. Longitudinal change during follow-up of systemic sclerosis: correlation between high-resolution computed tomography and pulmonary function tests. Clin Rheumatol. 2021;40(1):213–219. 10.1007/s10067-020-05375-y. Epub 2020 Sep 3. PMID: 32880053. PubMed

Smith V, Pizzorni C, Riccieri V, Decuman S, Brusselle G, DE Pauw M, Deschepper E, Piette Y, Ruaro B, Sulli A, Vandecasteele E, Melsens K, DE Keyser F, Cutolo M. Stabilization of Microcirculation in Patients with Early Systemic Sclerosis with Diffuse Skin Involvement following Rituximab Treatment: An Open-label Study. J Rheumatol. 2016;43(5):995-6. 10.3899/jrheum.151018. PMID: 27134280. PubMed

Shima Y. Cytokines involved in the pathogenesis of SSc and problems in the development of Anti-Cytokine therapy. Cells. 2021;10(5):1104. 10.3390/cells10051104. PMID: 34064515; PMCID: PMC8147957. PubMed PMC

Bellando-Randone S, Matucci-Cerinic M. Very early systemic sclerosis and pre-systemic sclerosis: definition, recognition, clinical relevance and future directions. Curr Rheumatol Rep. 2017;19:65. PubMed

Avouac J, Fransen J, Walker UA, Riccieri V, Smith V, Muller C, Miniati I, Tarner IH, Randone SB, Cutolo M, Allanore Y, Distler O, Valentini G, Czirjak L, Müller-Ladner U, Furst DE, Tyndall A, Matucci-Cerinic M, EUSTAR Group. Preliminary criteria for the very early diagnosis of systemic sclerosis: results of a Delphi consensus study from EULAR scleroderma trials and research group. Ann Rheum Dis. 2011;70(3):476–81. Epub 2010 Nov 15. PMID: 21081523. PubMed

Bellando-Randone S, Matucci-Cerinic M. From Raynaud’s phenomenon to very early diagnosis of systemic sclerosis- the VEDOSS approach. Curr Rheumatol Rev. 2013;9(4):245–8. PubMed

Catalan-Dibene J, Vazquez MI, Luu VP, Nuccio SP, Karimzadeh A, Kastenschmidt JM, Villalta SA, Ushach I, Pone EJ, Casali P, Raffatellu M, Burkhardt AM, Hernandez-Ruiz M, Heller G, Hevezi PA, Zlotnik A. Identification of IL-40, a novel B Cell-Associated cytokine. J Immunol. 2017;199(9):3326–35. 10.4049/jimmunol.1700534. Epub 2017 Oct 4. PMID: 28978694; PMCID: PMC5667921. PubMed PMC

Navrátilová A, Andrés Cerezo L, Hulejová H, Bečvář V, Tomčík M, Komarc M, Veigl D, Tegzová D, Závada J, Olejárová M, Pavelka K, Vencovský J, Šenolt L. IL-40: A new B Cell-Associated cytokine Up-Regulated in rheumatoid arthritis decreases following the rituximab therapy and correlates with disease activity, autoantibodies, and NETosis. Front Immunol. 2021;12:745523. 10.3389/fimmu.2021.745523. PMID: 34745117; PMCID: PMC8566875. PubMed PMC

Navrátilová A, Bečvář V, Hulejová H, Tomčík M, Štolová L, Mann H, Růžičková O, Šléglová O, Závada J, Pavelka K, Vencovský J, Šenolt L. Andrés cerezo L. New pro-inflammatory cytokine IL-40 is produced by activated neutrophils and plays a role in the early stages of seropositive rheumatoid arthritis. RMD Open. 2023;9(2):e002894. 10.1136/rmdopen-2022-002894. PMID: 37208028; PMCID: PMC10201233. PubMed PMC

Guggino G, Rizzo C, Mohammadnezhad L, Lo Pizzo M, Lentini VL, Di Liberto D, La Barbera L, Raimondo S, Shekarkar Azgomi M, Urzì O, Berardicurti O, Campisi G, Alessandro R, Giacomelli R, Dieli F, Ciccia F. Possible role for IL-40 and IL-40-producing cells in the lymphocytic infiltrated salivary glands of patients with primary Sjögren’s syndrome. RMD Open. 2023;9(2):e002738. 10.1136/rmdopen-2022-002738. PMID: 37137540; PMCID: PMC10163598. PubMed PMC

Cerezo LA, Navrátilová A, Kuklová M, Prokopcová A, Baloun J, Kropáčková T, Veigl D, Popelka S, Fulín P, Ballay R, Pavelka K, Vencovský J, Šenolt L. IL-40 is up-regulated in the synovial fluid and cartilage of osteoarthritis patients and contributes to the alteration of chondrocytes phenotype in vitro. Arthritis Res Ther. 2024;26(1):146. 10.1186/s13075-024-03372-z. PMID: 39080724; PMCID: PMC11289996. PubMed PMC

Rubaye AM, Sharquie IK, Gorial FI. Serum Interleukin 40: an innovative diagnostic biomarker for patients with systemic lupus erythematosus. Med J Malaysia. 2023;78:609–15. PubMed

van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, Matucci-Cerinic M, Naden RP, Medsger TA Jr, Carreira PE, Riemekasten G, Clements PJ, Denton CP, Distler O, Allanore Y, Furst DE, Gabrielli A, Mayes MD, van Laar JM, Seibold JR, Czirjak L, Steen VD, Inanc M, Kowal-Bielecka O, Müller-Ladner U, Valentini G, Veale DJ, Vonk MC, Walker UA, Chung L, Collier DH, Csuka ME, Fessler BJ, Guiducci S, Herrick A, Hsu VM, Jimenez S, Kahaleh B, Merkel PA, Sierakowski S, Silver RM, Simms RW, Varga J, Pope JE. 2013 Classification criteria for systemic sclerosis: an American college of rheumatology/european league against rheumatism collaborative initiative. Arthritis Rheum. 2013;65(11):2737–47. 10.1002/art.38098. Epub 2013 Oct 3. PMID: 24122180; PMCID: PMC3930146. PubMed PMC

Bellando-Randone S, Del Galdo F, Lepri G, Minier T, Huscher D, Furst DE, Allanore Y, Distler O, Czirják L, Bruni C, Guiducci S, Avouac J, Cutolo M, Smith V, Matucci-Cerinic M. Very Early Diagnosis of Systemic Sclerosis collaborators. Progression of patients with Raynaud’s phenomenon to systemic sclerosis: a five-year analysis of the European Scleroderma Trial and Research group multicenter, longitudinal registry study for Very Early Diagnosis of Systemic Sclerosis (VEDOSS). Lancet Rheumatol. 2021;3(12):e834-e843. 10.1016/S2665-9913(21)00244-7. PMID: 38287630. PubMed

Silver RM, Miller KS, Kinsella MB, Smith EA, Schabel SI. Evaluation and management of scleroderma lung disease using bronchoalveolar lavage. Am J Med. 1990;88(5):470-6. 10.1016/0002-9343(90)90425-d. PMID: 2337105. PubMed

Valentini G, Bencivelli W, Bombardieri S, D’Angelo S, Della Rossa A, Silman AJ, Black CM, Czirjak L, Nielsen H, Vlachoyiannopoulos PG. European scleroderma study group to define disease activity criteria for systemic sclerosis. III. Assessment of the construct validity of the preliminary activity criteria. Ann Rheum Dis. 2003;62:901–3. 10.1136/ard.62.9.901. PubMed PMC

Clements PJ, Lachenbruch PA, Seibold JR, Zee B, Steen VD, Brennan P, Silman AJ, Allegar N, Varga J, Massa M, et al. Skin thickness score in systemic sclerosis: an assessment of interobserver variability in 3 independent studies. J Rheumatol. 1993;20(11):1892–6. PMID: 8308774. PubMed

Standardization of Spirometry. 1994 Update. American Thoracic Society. Am J Respir Crit Care Med. 1995;152(3):1107-36. 10.1164/ajrccm.152.3.7663792. PMID: 7663792. PubMed

Bombardieri S, Medsger TA Jr, Silman AJ, Valentini G. The assessment of the patient with systemic sclerosis. Introduction. Clin Exp Rheumatol. 2003;21(3 Suppl 29):S2-4. PMID: 12889213. PubMed

Medsger TA Jr, Silman AJ, Steen VD, Black CM, Akesson A, Bacon PA, Harris CA, Jablonska S, Jayson MI, Jimenez SA, Krieg T, Leroy EC, Maddison PJ, Russell ML, Schachter RK, Wollheim FA, Zacharaie H. A disease severity scale for systemic sclerosis: development and testing. J Rheumatol. 1999;26(10):2159–67. PMID: 10529133. PubMed

Fries JF, Spitz P, Kraines RG, Holman HR. Measurement of patient outcome in arthritis. Arthritis Rheum. 1980;23(2):137–45. 10.1002/art.1780230202. PubMed

Ware JE Jr, Gandek B. Overview of the SF-36 Health Survey and the International Quality of Life Assessment (IQOLA) Project. J Clin Epidemiol. 1998;51(11):903– 12. 10.1016/s0895-4356(98)00081-x. PMID: 9817107. PubMed

Fisk JD, Ritvo PG, Ross L, Haase DA, Marrie TJ, Schlech WF. Measuring the functional impact of fatigue: initial validation of the fatigue impact scale. Clin Infect Dis. 1994;18(Supplement1):S79–83. PubMed

Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of health status for chronic airflow limitation. The St. George’s Respiratory Questionnaire. Am Rev Respir Dis. 1992;145(6):1321-7. 10.1164/ajrccm/145.6.1321. PMID: 1595997. PubMed

Zampatti N, Garaiman A, Jordan S, Dobrota R, Becker MO, Maurer B, Distler O, Mihai C. Performance of the UCLA scleroderma clinical trials consortium Gastrointestinal tract 2.0 instrument as a clinical decision aid in the routine clinical care of patients with systemic sclerosis. Arthritis Res Ther. 2021;23(1):125. 10.1186/s13075-021-02506-x. PMID: 33888149; PMCID: PMC8061014. PubMed PMC

Heřmánková B, Oreská S, Šmucrová H, Mikulášová M, Špiritović M, Štorkánová H, Bečvář R, Vencovský J, Mann H, Tomčík M. Validation of Czech versions of questionnaires assessing functional impairment in patients with systemic sclerosis: scleroderma health assessment questionnaire (SHAQ), Cochin hand functional scale (CHFS), mouth handicap in systemic sclerosis (MHISS), UCLA scleroderma clinical trial consortium Gastrointestinal tract 2.0 (UCLA SCTC GIT 2.0. Ceska Revmatol. 2020;28:216–30.

Heřmánková B, Štorkánová H, Mikulášová M, Oreská S, Špiritović M, Štorkánová H, Tomčík M. Validation of Czech versions of questionnaires assessing fatigue and physical activity in patients with rheumatic diseases: fatigue impact scale (FIS), multidimensional assessment of fatigue scale (MAF), human activity profile (HAP). Ceska Revmatol. 2020;28:132–51.

Sobotík Z. Zkušenosti s použitím Předběžné České Verze Amerického Dotazníku O Zdraví (SF-36) Zdravotnictví V České Republice. 1998;1:50–4.

Šléglová O, Dušek L, Olejárová M, Tegzová D, Vencovský J, Pavelka K. Posuzování Funkční Schopnosti U Pacientů s revmatoidní artritidou; validace České Verze Stanfordského Dotazníku health assessment questionnaire (HAQ) Čes. Revmatol. 2010;18:73–83.

Chlumský J, Štěrbová L, Smolíková L, Matouš M, Salajka F. Vztah ventilačních Plicních Parametrů, tolerance Fyzické Zátěže a Kvality Života U Pacientů s chronickou obstrukční plicní nemocí. Vnitř Lék. 2002;48:320–4. PubMed

Jaber AS, Ad’hiah AH. A novel signature of interleukins 36α, 37, 38, 39 and 40 in ankylosing spondylitis. Cytokine. 2023;162:156117. 10.1016/j.cyto.2022.156117. Epub 2022 Dec 29. Erratum in: Cytokine. 2023;166:156195. doi: 10.1016/j.cyto.2023.156195. PMID: 36586188.

Volkmann ER, Hoffmann-Vold AM. Gastrointestinal tract microbiota modifications in systemic sclerosis. Eur J Rheumatol. 2020;7(Suppl 3):S228–36. 10.5152/eurjrheum.2019.19103. Epub 2019 Dec 19. PMID: 31922474; PMCID: PMC7647687. PubMed PMC

Nassar M, Ghernautan V, Nso N, Nyabera A, Castillo FC, Tu W, Medina L, Ciobanu C, Alfishawy M, Rizzo V, Eskaros S, Mahdi M, Khalifa M, El-Kassas M. Gastrointestinal involvement in systemic sclerosis: an updated review. Med (Baltim). 2022;101(45):e31780. 10.1097/MD.0000000000031780. PMID: 36397401; PMCID: PMC9666124. PubMed PMC

McMahan ZH, Kulkarni S, Chen J, Chen JZ, Xavier RJ, Pasricha PJ, Khanna D. Systemic sclerosis gastrointestinal dysmotility: risk factors, pathophysiology, diagnosis and management. Nat Rev Rheumatol. 2023;19(3):166–181. 10.1038/s41584-022-00900-6. Epub 2023 Feb 6. Erratum in: Nat Rev Rheumatol. 2023;19(3):191. doi: 10.1038/s41584-023-00929-1. PMID: 36747090. PubMed

Ondrejčáková L, Navrátilová A, Gregová M, Bubová K, Grega T, Šenolt L, Pavelka K, Andrés Cerezo L. AB0927 serum Interleukin-40 levels in patients with inflammatory bowel diseases-associated spondyloarthritis: A preliminary study. Ann Rheum Dis June 2024 83(Suppl 1):1772–3. 10.1136/annrheumdis-2024-eular.5225. EULAR 2024 European Congress of Rheumatology, 12–15 June. Vienna, Austria.

Chighizola C, Ong VH, Denton CP. Cyclophosphamide as disease-modifying therapy for scleroderma: pros and cons. Int J Clin Rheumatol. 2011;6(2):219–30. 10.2217/ijr.10.112.

Oreska S, Jirankova A, Bobrova A, Bobrova K, Heřmánková B, Štorkánová H, Ciferská H, Pavelka K, Šenolt L, Vencovský J, Bečvář R, Tomčík M. AB1207 rituximab in patients with systemic sclerosis non-responsive to csDMARDs– preliminary results of a prospective, observational, monocentric study. Ann Rheum Dis June 2024. 1941;83(Suppl 1). 10.1136/annrheumdis-2024-eular.3939. EULAR 2024 European Congress of Rheumatology, 12–15 June. Vienna, Austria.

Burbelo PD, Gordon SM, Waldman M, Edison JD, Little DJ, Stitt RS, Bailey WT, Hughes JB, Olson SW. Autoantibodies are present before the clinical diagnosis of systemic sclerosis. PLoS ONE. 2019;14(3):e0214202. 10.1371/journal.pone.0214202. PMID: 30913258; PMCID: PMC6435159. PubMed PMC

Dooms H, Volfson-Sedletsky V, Belkina AC, Bujor A. T cell subsets in systemic sclerosis patients show features of exhaustion and reduced anti-fibrotic activities. J Immunol 1 May. 2023;210(1Supplement):155. 10.4049/jimmunol.210.Supp.155.08.

Ko J, Noviani M, Chellamuthu VR, Albani S, Low AHL. The pathogenesis of systemic sclerosis: the origin of fibrosis and interlink with vasculopathy and autoimmunity. Int J Mol Sci. 2023;24(18):14287. 10.3390/ijms241814287. PMID: 37762589; PMCID: PMC10532389. PubMed PMC

Song JY, Chan WC, Warden C, Wu X, Weisenburger DD, Chen R, Herrera AF. PO17(0120) Immunologic biomarkers of response and resistance to bretuximab vedotin in patients with relapsed or refractory classical hodkin lymphoma. Abstract Book for the 11th International Symposium on Hodgkin Lymphoma., October, 27–29, 2018 Cologne, Germany.

Bashi MA, Ad’hiah AH. Molecular landscape of the interleukin-40 encoding gene, C17orf99, in patients with acute myeloid leukemia. PMID: 38286266 10.1016/j.gene.2024.148214 Epub 2024 Jan 28. PubMed

Sagmeister P, Daza P, Ofner A, Ziesch A, Ye L, Khaled NB, Ebert M, Mayerle J, Teufel A, De Toni EN, Munker S. Comparative response of HCC cells to TKIs: modified in vitro testing and descriptive expression analysis. J Hepatocellular Carcinoma. 2022;595–607. 10.2147/ JHC.S356333. PubMed PMC

Pellicano C, Vantaggio L, Colalillo A, Pocino K, Basile V, Marino M, Basile U, Rosato E. Type 2 cytokines and scleroderma interstitial lung disease. Clin Exp Med. 2023;23(7):3517–25. 10.1007/s10238-023-01125-x. Epub 2023 Jul 1. PMID: 37392249; PMCID: PMC10618297. PubMed PMC

Wu M, Baron M, Pedroza C, Salazar GA, Ying J, Charles J, Agarwal SK, Hudson M, Pope J, Zhou X, Reveille JD, Fritzler MJ, Mayes MD, Assassi S. Arthritis Rheumatol. 2017;69(9):1871–8. Epub 2017 Aug 8. PMID: 28575534; PMCID: PMC5575955. CCL2 in the Circulation Predicts Long-Term Progression of Interstitial Lung Disease in Patients With Early Systemic Sclerosis: Data From Two Independent Cohorts. PubMed PMC

Shu Y, Yue X, Wax J, Kasper B, Yin J, Wang X, Zhang L, Ahmadi M, Heidecke H, Müller A, Lamprecht P, Yu X, Riemekasten G, Petersen F. Both T and B cells are indispensable for the development of a PBMC transfer-induced humanized mouse model for SSc. Arthritis Res Ther. 2022;24(1):209. 10.1186/s13075-022-02896-6. PMID: 36008863; PMCID: PMC9404611. PubMed PMC

Pellicano C, Oliva A, Colalillo A, Gigante A, D’Aliesio E, Al Ismail D, Miele MC, Cianci R, Mastroianni CM, Rosato E. Serum markers of microbial translocation and intestinal damage in assessment of Gastrointestinal tract involvement in systemic sclerosis. Clin Exp Med. 2024;24(1):225. 10.1007/s10238-024-01466-1. PMID: 39294494; PMCID: PMC11410972. PubMed PMC