Systemic sclerosis and systemic lupus erythematosus represent two distinct autoimmune diseases belonging to the group of connective tissue disorders. Despite the great progress in the basic science, this progress has not been translated to the development of novel therapeutic approaches that can radically change the face of these diseases. The discovery of JAK kinases, which are tyrosine kinases coupled with cytokine receptors, may open a new chapter in the treatment of so far untreatable diseases. Small synthetic compounds that can block Janus kinases and interact directly with cytokine signalling may provide therapeutic potential in these diseases. In this review, we discuss the therapeutic potential of Jak kinases in light of the cytokine network that JAK kinases are able to interact with. We also provide the theoretical background for the rationale of blocking cytokines with specific JAK inhibitors.

Systemic sclerosis is a connective tissue disease of unknown origin and with an unpredictable course, with both cutaneous and internal organ manifestations. Despite the enormous progress in rheumatology and clinical immunology, the background of this disease is largely unknown, and no specific therapy exists. The therapeutic approach aims to treat and preserve the function of internal organs, and this approach is commonly referred to as organ-based treatment. However, in modern times, data from other branches of medicine may offer insight into how to treat disease-related complications, making it possible to find new drugs to treat this disease. In this review, we present therapeutic options aiming to stop the progression of fibrotic processes, restore the aberrant immune response, stop improper signalling from proinflammatory cytokines, and halt the production of disease-related autoantibodies.

Systemic sclerosis (SSc) is a rare autoimmune connective tissue disorder characterized by massive fibrosis, vascular damage, and immune imbalance. Advances in rheumatology and immunology over the past two decades have led to a redefinition of systemic sclerosis, shifting from its initial perception as primarily a “hyperfibrotic” state towards a recognition of systemic sclerosis as an immune-mediated disease. Consequently, the search for genetic markers has transitioned from focusing on fibrotic mechanisms to exploring immune regulatory pathways. Immunogenetics, an emerging field at the intersection of immunology, molecular biology, and genetics has provided valuable insights into inherited factors that influence immunity. Data from genetic studies conducted thus far indicate that alterations in genetic messages can significantly impact disease risk and progression. While certain genetic variations may confer protective effects, others may exacerbate disease susceptibility. This paper presents a comprehensive review of the most relevant genetic changes that influence both the risk and course of systemic sclerosis. Special emphasis is placed on factors regulating the immune response, recognizing their pivotal role in the pathogenesis of the disease.

Systemic sclerosis, a connective tissue disease of unknown etiology and unpredictable outcomes, is characterized by the fibrosis of the skin and internal organs, vasculopathy, and immune system dysregulation. The disease is classified into two main subtypes, which differ in clinical presentation, complications, and prognosis. While several biomarkers have been proposed to distinguish between these subtypes, none have achieved high sensitivity and specificity. The search for dependable markers that can differentiate between the two primary subtypes of systemic sclerosis continues. To address this gap, our study evaluated the utility of novel cardiac biomarkers, including growth differentiation factor 15 (GDF15), galectin-3, mid-regional pro-atrial natriuretic peptide (MR-proANP), glutathione S-transferase π, mid-regional adrenomedullin, and soluble urokinase plasminogen activator receptor (suPAR), in a cohort of 79 patients with both lcSSc and dSSc subtypes. The results demonstrated a significant elevation of GDF15 (medians: 2.07 vs. 1.10 ng/L; p < 0.001) and MR-proANP (92.55 vs. 65.60 pmol/L; p < 0.05) levels in SSc patients compared to healthy controls. Moreover, GDF15 (1.65 vs. 2.34 ng/mL; p < 0.05), MR-proANP (80.87 vs. 109.27 pmol/L; p < 0.05), and suPAR (1.83 vs. 2.44 ng/mL; p < 0.05) levels were notably higher in patients with dSSc compared to those with lcSSc. In the ROC analysis, only GDF-15, MR-proANP, and suPAR proved to have a statistically significant area under the curve (AUC). Patients with the GDF-15 ≥ 2182 ng/mL, MR-prANP ≥ 85.808 pmol/L, and suPAR ≥ 2.315 ng/mL have more than six-, eight-, and seven-times-higher odds for dcSSc, respectively. These findings highlight the potential of GDF15, suPAR, and MR-proANP as biomarkers for differentiating between the two main subtypes of systemic sclerosis.

Citation: Lastname, F.; Lastname, F.; Last-name, F. Title. Phar-maceuticals 2022, 15, x. https://doi.org/10.3390/xxxxx Academic Editor: Firstname Lastname Received: date Accepted: date Published: date Publisher’s Note: MDPI stays neutral with regard to jurisdic-tional claims in pub-lished maps and insti-tutional affiliations. Copyright: © 2023 by the authors. Submitted for possible open access publication under the terms and conditions of the Creative Commons 1Olga Gumkowska-Sroka, 2Kacper Kotyla, 3Ewa Mojs, 2Klaudia Palka, 1,2*Przemysław Kotyla 1. Department of Rheumatology and Clinical Immunology Voivodeship Hospital No5 in Sosnowiec Medical University of Silesia Katowice, Poland 2. Department of Internal Medicine Rheumatology and Clinical Immunology Medical University of Silesia Katowice , Poland 3. 3. Department of Clinical Psychology, Poznan University of Medical Sciences Poznan, Poland *Correspondence: Prof Przemysław Kotyla Department of Internal Medicine Rheumatology and Clinical Immunology Medical University of Silesia, Katowice, Poland- Summary Systemic sclerosis is a connective tissue disease of unknown origin and unpredictable course, with both cutaneous and internal organ manifestations. In spite of enormous progress in rheumatology and clinical immunology, the background of diseases is largely unknown and no specific therapy exists. The therapeutic approach to the disease is aimed to treat and preserve the function of internal organs, and this approach is commonly referred to as an organ-based treatment. However, in modern times data from the other branches of medicine may help to treat disease-related complications, making it possible to find a group of drugs to be utilized in the treatment of the disease. In this review, we present possible therapeutic options aiming to stop the progression of fibrotic processes, restore aberrant immune response, stop improper signalling from proinflammatory cytokines, and halt the production of disease-related autoantibodies.

Objectives: This study aimed to investigate the associations among cytokines of the IL-12 family in patients with systemic sclerosis (SSc) and to evaluate their relationships with the pro-inflammatory cytokines TNF-α and IL-6, the latent form of TGF-β1 (LAP-bound, without prior sample activation), clinical parameters, and disease subtypes. Methods: Concentrations of IL-12p70, IL-12p40, IL-23, IL-27, IL-35, IL-39, TNF-α, and IL-6 were measured in serum, whereas latent TGF-β1 concentrations were determined in plasma obtained from 60 patients with systemic sclerosis (SSc) and 21 age- and sex-matched healthy controls. Results: Compared with healthy controls, patients with SSc exhibited significantly elevated levels of IL-12p40, IL-23, and IL-35, whereas IL-27, TNF-α, and TGF-β concentrations were significantly reduced. Correlation analysis revealed significant negative associations between latent TGF-β1 and IL-6, IL-27, and IL-35. Significant positive correlations were observed between TNF-α and IL-6, TNF-α and IL-12p40, IL-35 and IL-12p40, IL-23 and IL-12p40, and IL-12p40 with both IL-6 and IL-12p70. No significant associations were identified between the investigated cytokines and the Medsger severity score, patient age, anti-centromere antibody (ACA) status, anti-topoisomerase I antibody (Scl-70) status, the presence of pulmonary fibrosis, or diffusing capacity of the lungs for carbon monoxide (DLCO). In contrast, IL-35 levels demonstrated significant moderate negative correlations with both the modified Rodnan Skin Score (mRSS) (ρ = −0.35, p < 0.01) and disease duration (ρ = −0.30, p < 0.05). Conclusions: These findings may indicate the presence of a complex network of associations among IL-12 family cytokines in systemic sclerosis.