Catestatin and adropin bioactive peptides levels in patients with rheumatoid arthritis

Uvod: Katestatin je biokativni peptid uključen u patofiziologiju brojnih upalnih bolesti. Adropin je sekretorni protein koji prvenstveno modulira metaboličku homeostazu i funkciju endotela. Postoji sve više dokaza koji upućuju na povezanost adropina s različitim upalnim stanjima. No, kontrolirani su podatci o njegovoj razini i mogućoj povezanosti s metaboličkim procesima u reumatoidnom artritisu (RA) nedostatni. Unatoč nedvojbenoj uključenosti katestatina u upalne procese nema studija koje su istraživale povezanost njegove razine s RA-om. Poznato je da se mediteranski način prehrane smatra optimalnim za bolesnike s RA-om zbog blagotvornoga učinka na zglobove i kardiometaboličke poremećaje te protuupalnoga učinka. Ciljevi istraživanja: Ciljevi su ove studije bili utvrditi postoji li razlika u serumskim razinama katestatina i adropina te MDSS zbira u ispitanika s RA-om u odnosu na zdrave ispitanike kontrolne skupine odgovarajuće dobi i spola. Nadalje, istraživana je povezanost serumskih razina katestatina i adropina s pokazateljima kronične upale, aktivnošću i trajanjem RA-a, funkcionalnom onesposobljenošću bolesnika, parametrima metabolizma glukoze te ostalim kliničkim, biokemijskim i laboratorijskim značajkama. Dodatni je cilj nam bio utvrditi povezanost MDSS zbira sa serumskim razinama katestatina i adropina, kao i s aktivnošću RA-a i funkcionalnošću ispitanika s RA-om. Ispitanici i metode: U ovo presječno istraživanje ukupno je bilo uključeno 160 ispitanika, odnosno 80 ispitanika s RA-om i 80 odgovarajućih ispitanika kontrolne skupine za studiju s katestatinom te 70 bolesnika s RA-om i 70 zdravih ispitanika podudarnih dobnih i spolnih značajki za studiju s adropinom. Bolesnicima uključenim u istraživanje s katestatinom dodatno je bio izračunat MDSS zbir. Svim ispitanicima s RA-om određeni su DAS28 i HAQ zbir. Svim je sudionicima u istraživanju, uz uzimanje anamnestičkih podataka, obavljen i detaljan fizikalni pregled, antropometrijska mjerenja te uzorkovanje krvi za laboratorijsku analizu. Serumske razine katestatina i adropina određene su ELISA metodom, dok su ostali laboratorijski parametri određivani standardnim laboratorijskim procedurama. Istraživanje je provedeno u Zavodu za reumatologiju, alergologiju i kliničku imunologiju Kliničkog bolničkog centra Split u periodu od 30. listopada 2020. do 30. lipnja 2021. godine. Rezultati: Serumska razina katestatina bila je značajno viša u bolesnika s RA-om u odnosu na kontrolnu skupinu ispitanika (10,53 ± 3,90 vs. 5,24 ± 2,37 ng/mL, P < 0,001). Nadalje, u skupini ispitanika s RA-om utvrđena je statistički značajna pozitivna korelacija između katestatina i dobi (r = 0,418, P < 0,001) te DAS28 (r = 0,469, P < 0,001) i HAQ zbira (r = 0,483, P < 0,001)). Također, pokazana je značajna korelacija između serumske razine katestatina i trajanja RA-a (r = 0,583, P < 0,001). Multiplom linearnom regresijskom analizom, prilagođenom za zbunjujuće varijable (dob, spol, ITM i HAQ zbroj), pokazano je da je razina katestatina zadržala statistički značajnu i pozitivnu korelaciju s trajanjem RA-a (β ± SE, 0,13 ± 0,04, P = 0,002) i DAS28 zbirom (0,94 ± 0,45, P = 0,039), sa serumskom razinom katestatina kao ovisnom varijablom. Serumska razina adropina bila je značajno niža u bolesnika s RA-om u odnosu na kontrolnu skupinu ispitanika (2,85 ± 0,91 vs. 4,02 ± 0,99 ng/mL, P < 0,001). U skupini bolesnika s RA-om, serumske razine adropina bile su u značajnoj negativnoj korelaciji s ukupnim kolesterolom (r = -0,172, P = 0,043), HbA1c (r = -0,406, P < 0,001), glukozom natašte (r = -0,377, P < 0,001) i HOMA-IR (r = -0,315, P = 0,008). Multipla linearna regresijska analiza, nakon prilagodbe zbunjujućih čimbenika, pokazala je da su serumske razine adropina zadržale značajnu povezanost s razinama glukoze natašte (β ± SE, -0,450 ± 0,140, P = 0,002) i vrijednošću HbA1c (-0,528 ± 0,223, P = 0,021). Nije pronađena statistički značajna razlika između ukupnoga MDSS zbira između 80 bolesnika s RA-om i kontrolne skupine ispitanika (7,57 ± 4,11 vs. 7,29 ± 3,61, P = 0,661). Također, u skupini bolesnika s RA-om nije utvrđena značajna korelacija MDSS zbira sa serumskim razinama katestatina (r = -0,059, P = 0, 621) i adropina (r = 0,012, P = 0,917), kao ni s DAS28 (r = 0,031, P = 0,993) i HAQ zbrojem (r = 0,222, P = 0,062). Zaključak: Rezultati dobiveni ovim istraživanjima impliciraju moguću povezanost katestatina sa složenom patofiziologijom RA-a i aktivnošću bolesti te potencijalni utjecaj adropina na metaboličku homeostazu u RA-u. Nadalje, pokazano je kako nepridržavanje mediteranske prehrane može imati negativan sveukupni učinak na aktivnost RA-a, funkcionalnost bolesnika, ali i smanjenu kvalitetu života. Za konačnu evaluaciju i integraciju dobivenih rezultata potrebne su daljnje veće multicentrične longitudinalne studije praćenja.Background: Catestatin (CST) is an important peptide that influences various inflammatory diseases. Adropin is a secretory protein that mainly modulates metabolic homeostasis and endothelial function. There is growing evidence supporting association of adropin with various inflammatory diseases. However, controlled data of possible connection among serum adropin levels and metabolic processes in rheumatoid arthritis (RA) are insufficient. Regardless the incontestable involvement of CST in inflammatory disorders, there have been no published studies that explored the association of serum CST levels with RA. The Mediterranean diet (MD) is considered optimal for patients with RA due to its beneficial effect on joints and cardiometabolic disorders and anti-inflammatory effect. Aims of the study: The aims of this study were to determine difference in serum CST and adropin levels, as well as difference in MDSS score between patients with RA and healthy control subjects matched by age and sex. Furthermore, we assessed the relationship between serum CST and adropin levels and chronic inflammation, duration and activity of RA, functional disability of patients with RA and parameters of glucose metabolism, as well as other clinical, biochemical and anthropometric parameters. An additional goal was to determine the association of the MDSS score with CST and adropin levels and RA activity and functionality of RA patients. Participants and Methods: A total of 160 subjects were included in this cross-sectional study. Study of serum CST levels was conducted on 80 patients with RA and 80 healthy control subjects matched by age and sex. 70 RA patients and 70 healthy controls, matched by age and sex, were included in the study of serum adropin levels. Additionally, the MDSS score was determined to participants involved in the study of serum CST levels. Measurement of disease activity, using DAS28 and functional disability, using HAQ, were measured only in the patient group. Detailed medical history, a physical examination, anthropometric measurements and laboratory analysis of all the participants were obtained and performed. Serum CST and adropin levels were determined by ELISA, while other biochemical analyses were performed using standard laboratory procedures. The study was conducted at the Department of Rheumatology, Allergology and Clinical Immunology, University Hospital of Split, over a period from October 30, 2020 to June 30, 2021. Results: Serum CST levels were significantly higher in RA patients than in the control group (10.53 ± 3.90 vs. 5.24 ± 2.37 ng/mL, P < 0.001). In RA patients, there was a statistically significant correlation between CST and patient age (r = 0.418, P < 0.001) and both DAS28 (r = 0.469, P < 0.001) and HAQ scores (r = 0.483, P < 0.001). There was a statistically significant correlation between serum CST levels and RA duration (r = 0.583, P < 0.001). Multiple linear regression analysis showed that serum CST levels retained a significant association with RA duration (β ± SE, 0.13 ± 0.04, P = 0.002) and DAS28 score (0.94 ± 0.45, P = 0.039) after model adjustment for age, body mass index (BMI) and HAQ score, with serum CST levels as a dependent variable. Serum adropin levels were significantly lower in RA patients than in the control group (2.85 ± 0,91 vs. 4.02 ± 0.99 ng/mL, P < 0.001). In the RA group, serum adropin levels had a significant negative correlation with total cholesterol (r = -0.172, P = 0.043), HbA1c (r = -0.406, P < 0.001), fasting glucose (r = -0.377, P < 0.001) and HOMA-IR (r = -0.315, P = 0.008). Multiple linear regression analysis showed that serum adropin levels retained a significant association with levels of fasting glucose (β ± SE, -0.450 ± 0.140, P = 0.002) and HbA1c (-0.528 ± 0.223, P = 0.021) after model adjustments. There were no statistically significant difference in MDSS score between the RA group and the control group (7.57 ± 4.11 vs.7.29 ± 3.61, P = 0.661). We did not find a significant correlation of MDSS score with serum CST (r = -0.059, P = 0.621) and adropin levels (r = 0.012, P = 0.917) and neither with DAS28 (r = 0.031, P = 0.993) and HAQ score (r = 0.222, P = 0.062). Conclusions: These findings imply that CST is possibly associated with RA complex pathophysiology and disease activity, while adropin could have an impact on metabolic homeostasis in RA. Furthermore, it was shown that non-adherence to the MD can have a negative overall impact on RA activity, patient functionality, and reduced quality of life. Future larger multicentric longitudinal follow-up studies are necessary in order to establish and integrate our results