Thromboembolic Adverse Drug Reactions in Janus Kinase (JAK) Inhibitors: Does the Inhibitor Specificity Play a Role?

Recent advances in immunology enabled the characterization of several signal transmitting pathways responsible for proper cytokine and chemokine signaling. Among them, Janus kinases (JAKs) are essential components of receptor activation systems. The discovery of JAK kinases enabled the synthesis of JAK kinase inhibitors (JAKi or Jakinibs), which have proven to be efficacious in the treatment of hematologic malignancies and several rheumatological disorders and continue to be investigated in many clinical indications. Blocking multiple cytokines belonging to several cytokine families with a single small molecule may, however, create a potential risk for the patients. Recently, a higher risk of thromboembolic complications, namely, deep vein thrombosis and pulmonary embolism, has been recognized as the main concern during treatment with Jakinibs. At present, it is not entirely clear whether this increased risk is related to direct cytokine blockade, the presence of concomitant diseases in treated patients or other unknown circumstances that work together to increase the risk of this side effect. In this review, we discuss data on the risk of thromboembolic side effects, with special emphasis on the mechanism that may be responsible for this increased risk. Many indirect data indicate that higher thromboembolic risk may be related to the specificity of JAK inhibitor action, such that preferentially blocking one signaling pathway upsets the balance between pro and anti-thrombotic activities.

Hyperferritinaemia: An Iron Sword of Autoimmunity.

BACKGROUND: Ferritin is a molecule that plays many roles being the storage for iron, signalling molecule, and modulator of the immune response. METHODS: Different electronic databases were searched in a non-systematic way to find out the literature of interest. RESULTS: The level of ferritin rises in many inflammatory conditions including autoimmune disorders. However, in four inflammatory diseases (i.e., adult-onset Still's diseases, macrophage activation syndrome, catastrophic antiphospholipid syndrome, and sepsis), high levels of ferritin are observed suggesting it as a remarkable biomarker and pathological involvement in these diseases. Acting as an acute phase reactant, ferritin is also involved in the cytokine-associated modulator of the immune response as well as a regulator of cytokine synthesis and release which are responsible for the inflammatory storm. CONCLUSION: This review article presents updated information on the role of ferritin in inflammatory and autoimmune diseases with an emphasis on hyperferritinaemic syndrome.

Cytometric Characterization of Main Immunocompetent Cells in Patients with Systemic Sclerosis: Relationship with Disease Activity and Type of Immunosuppressive Treatment.

Systemic sclerosis (SSc) is a connective tissue disease that is characterized by widespread skin and internal organ fibrosis vasculopathy and immune response abnormalities, including T, B, natural killer (NK), and natural killer T (NKT) cell involvement. The aim of the study was to investigate the immune cell profile in patients with systemic sclerosis in relation to the disease activity, severity, and antibody presence and their relation to the type of immunosuppressive treatment. Cytometric examination identified following cell lines: B cells (Breg, B memory, B mature) and plasmablasts, T cell, T double positive-Tdp, T double negative-Tdn, NK, and NKT cell and monocytes. The disease severity and activity were assessed based on the Medsger and the EULAR Scleroderma Trials and Research Group (EUSTAR) 2017 scales respectively. In the study, SSc patients were characterized by higher total lymphocyte count parallel to increased frequency of Ts and Th cells. In SSc patients, increment of Tdp and reduction of Tdn as well as NK and NKT cells were observed. Additionally in SSc patients the reduction of B memory was noted. Head to head comparison between cyclophosphamide (CYC) and mycophenolate mofetil (MMF) treatment showed a reduction of CD19+ cells, but increment of plasmablasts in CYC treated patients.