Background: Aminaphtone (3-Methyl-1,4-dioxo-1,4-dihydro-naphthalen-2-y4-amino-benzoate) is a chemical vasoactive compound licensed to treat microvascular disorders [1]. The drug has been proved to play a role in the management of both primary and secondary Raynaud’s phenomenon (RP), with a good safety profile, being able to reduce RP clinical symptoms and increase peripheral blood perfusion [1,2]. In-vitro clinical studies reported the downregulation by aminaphtone of adhesion molecules, vasoconstrictor peptides and pro-inflammatory cytokine expression, including transforming growth factor beta (TGF-beta) [3]. This latter is a growth factor playing a crucial role in fibrotic processes.

Objectives: The aim of the study was to investigate the effect of aminaphtone short-term treatment (3 months) on TGF-beta plasma levels in systemic sclerosis (SSc) patients with secondary RP.

Methods: 26 patients affected by SSc according to the EULAR/ACR 2013 criteria (4 males and 22 females, mean age 63±17 years; mean disease duration 11±5 years), who complained of secondary RP, started treatment with aminaphtone (75 mg BID) in addition to their stable therapies. All patients provided written informed consent to enter the study and for the management of their clinical data. Blood samples were collected at baseline (W0), after 3 (W3) and 12 weeks (W12), and were frozen (-80 °C) until assayed by ELISA (Ella automated immunoassay system) in triplicate to measure the endogenous level of the active form of TGF-beta. Median values were reported as pg/ml. Laser speckle contrast analysis (LASCA) was also performed at week 0, 3 and 12 to measure digital blood perfusion (2). Statistical analysis was carried out by non-parametric tests.

Results: TGF-beta plasma levels progressively decreased from W0 to W12 in aminaphtone treated patients (Freedman test p=0.05; median 7942 [IQR 13411], 7050 [7655], 5154 [3985] pg/ml, respectively at W0, W3 and W12). In particular, the Wilcoxon signed rank test confirmed a strong statistical significance (p=0.007) comparing TGF-beta levels between W3 and W12. Interestingly, at all times, TGF-beta levels were found lower in SSc patients with better clinical response to aminaphtone treatment, as assessed by LASCA (increase of peripheral blood perfusion) than in those with poorer response, even if this difference was not statistically significant (median and [IQR] respectively at W0, W3 and W12 for higher vs poorer-responders: 6137 [14253] vs 10491 [29400], 5940 [13632] vs 10430 [25054], 4861 [7353] vs 5447 [3185] pg/ml). Results are limited by large biological variability of TGF-beta levels since evaluated in a small cohort of patients. No serious side effects were observed during the follow-up, and one patients had to discontinue the treatment due to head ache.

Conclusion: Aminaphtone seems to reduce TGF-beta plasma levels in SSc patients when added to their ongoing standard treatment. The reduction of TGF-beta levels as profibrotic mediator might explain, at least partially, the beneficial clinical effects observed in SSc patients treated with aminaphtone. Indeed, TGF-beta might be considered a serum biomarker to assess aminaphtone clinical response in SSc patients in presence of secondary RP, at least within 12 weeks.

REFERENCES: [1] Gotelli E et al. Pharmaceuticals (Basel) 2023;16(4):569.

[2] Ruaro B et al. Front Pharmacol 2019;10:293.

[3] Salazar Get al. Eur. J. Pharmacol. 2016;782:59–69.

Acknowledgements: NIL.

Disclosure of Interests: Alberto Sulli Laboratori Baldacci, Stefano Soldano: None declared, Emanuele Gotelli: None declared, Andrea Cere: None declared, Rosanna Campitiello: None declared, Elvis Hysa: None declared, Tamara Vojinovic: None declared, Sabrina Paolino: None declared, Maurizio Cutolo Laboratori Baldacci.