Inflammation contributes centrally to cardiovascular diseases, and anti-inflammatory treatments can reduce cardiovascular events. The JAK-STAT pathway is an emerging target in inflammation, mainly in rheumatoid arthritis (RA) and chronic myeloproliferative neoplasms (MPNs), disorders that heighten cardiovascular risk. The aim of this study was to review the international literature on the relationship between dysregulation of the JAK-STAT pathway in RA/MPNs and cardiovascular risk and on the potential cardiovascular effects of JAK-STAT inhibitors. The JAK-STAT pathway sustains inflammatory and thrombotic events in autoimmune disorders such as RA and MPNs. Here, an imbalance exists between pro- and anti-inflammatory cytokines [increased levels of interleukin (IL)-6, IL-1-β, tumour necrosis factor-α, decreased levels of IL-10] and the over-expression of some prothrombotic proteins, such as protein kinase Ce, on the surface of activated platelets. This pathway also operates in atherosclerotic cardiovascular disease. JAK-STAT inhibitors may reduce cardiovascular events and related deaths in such conditions, but the potential of these agents requires more studies, especially with regard to cardiovascular safety, and particularly for potential prothrombotic effects. JAK-STAT inhibitors merit consideration to curb heightened cardiovascular risk in patients with RA and MPNs, with rigorous assessment of the potential benefits and risks.

The JAK–STAT pathway: an emerging target for cardiovascular disease in rheumatoid arthritis and myeloproliferative neoplasms

We retrospectively investigated a cohort of 176 myelofibrosis patients (128 primary-PMF; 48 secondary-SMF) from five hematology centers. The presence of chronic kidney disease (CKD) was determined in addition to other clinical characteristics. CKD was present in 26.1% of MF patients and was significantly associated with older age (P   0.05 for all analyses). The presence of CKD was significantly associated with shorter time to arterial (HR = 3.49; P = 0.041) and venous thrombosis (HR = 7.08; P = 0.030) as well as with shorter overall survival (HR 2.08; P = 0.009). In multivariate analyses, CKD (HR = 1.8; P = 0.014) was associated with shorter survival independently of the DIPSS (HR = 2.7; P < 0.001); its effect being more pronounced in lower (HR = 3.56; P = 0.036) than higher DIPSS categories (HR = 2.07; P = 0.023). MF patients with CKD should be candidates for active management aimed at the improvement of renal function. Prospective studies defining the optimal therapeutic approach are highly needed.

Reduced renal function strongly affects survival and thrombosis in patients with myelofibrosis.

C‑reactive protein (CRP) and albumin are inflammation sensitive parameters that are regulated by interleukin‑6 inflammatory pathways. The CRP to albumin ratio (CAR) integrates these two into a potent clinical parameter whose clinical and prognostic association in the context of coronavirus disease 2019 (COVID-19) have not been well defined. We aimed to investigate the clinical and prognostic significance of CAR in the context of COVID-19 infection.We retrospectively analyzed 2309 consecutive COVID-19 patients hospitalized at a tertiary level hospital in the period from March 2020 to March 2021 who had baseline data for a CAR assessment. Findings were validated in an independent cohort of 1155 patients hospitalized from March 2021 to June 2021.The majority of patients (85.8%) had severe or critical COVID-19 on admission. Median CRP, albumin and CAR levels were 91 mg/L, 32 g/L and 2.92, respectively. Higher CAR was associated with a tendency for respiratory deterioration during hospitalization, increased requirement of high-flow oxygen treatment and mechanical ventilation, higher occurrence of bacteriemia, higher occurrence of deep venous thrombosis, lower occurrence of myocardial infarction, higher 30-day mortality and higher postdischarge mortality rates. We defined and validated four CAR prognostic categories (< 1.0, 1.0-2.9, 3.0-5.9 and ≥ 6.0) with distinct 30-day survival. In the series of multivariate Cox regression models we could demonstrate robust prognostic properties of CAR that was associated with inferior 30-day survival independently of COVID-19 severity, age and comorbidities and additionally independently of COVID-19 severity, CURB-65 and VACO index in both development and validation cohorts.The CAR seems to have a good potential to improve prognostication of hospitalized COVID-19 patients. 

/pdf/clinical-and-prognostic-significance-of-c-reactive-protein-8l9y2mco.pdf

Clinical and prognostic significance of C-reactive protein to albumin ratio in hospitalized coronavirus disease 2019 (COVID-19) patients

New Perspectives of Interferon-alpha2 and Inflammation in Treating Philadelphia-negative Chronic Myeloproliferative Neoplasms.

Patients with BCR-ABL negative chronic myeloproliferative neoplasms (MPNs) present with chronic kidney disease (CKD) in up to one third of cases. These patients are known to have increased cardiovascular risk and usually present with features of stronger myeloproliferation. In recent years CKD has gained attention in MPN patients as a potential renal manifestation of the disease termed MPN-related glomerulopathy. This view has been supported mainly by evidence from kidney biopsies and renal post-mortem autopsy findings of MPN patients, as well as by clinical observations of improvement/slower deterioration of renal function after institution of specific therapies in some MPN cohorts. All current evidence is based only on retrospective datasets which are known to be susceptible to different types of bias. Prospectively designed interventional studies are needed to properly understand true effects of CKD and its control by differently targeted (CKD and MPN directed) therapies.

Renal disease associated with chronic myeloproliferative neoplasms

Chronic kidney disease (CKD) is a well-known risk factor for venous thromboembolism and cardiovascular (CV) disease development in the general population, but its role in thrombotic risk in essential thrombocythemia (ET) and polycythemia vera (PV) remains poorly understood. This retrospective multicenter study analyzed clinical correlations and the potential impact of CKD on thrombosis development in ET and PV patients. We included 167 patients (76 ET and 91 PV); 25.7% had CKD at diagnosis, defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 for ≥ 3 months. Lower eGFR correlated with advanced age, female sex, higher granulocytes, higher serum C-reactive protein, history of thrombosis, CV risk factors, and the presence of palpable splenomegaly. CKD was univariately associated with inferior thrombosis-free survival in the entire cohort, as well as in both ET and PV patients. These results remained significant in the multivariate Cox regression models when adjusted to disease-specific risk models. Therefore, CKD could be a risk factor for thrombosis in ET and PV patients. Additional studies on a larger number of patients are needed to confirm our findings and to elucidate whether the addition of CKD to the current risk stratification models might improve prognostication in ET and PV patients.

Chronic kidney disease could be a risk factor for thrombosis in essential thrombocythemia and polycythemia vera.

Patients with post polycythemia vera myelofibrosis might experience increased thrombotic risk in comparison to primary and post essential thrombocythemia myelofibrosis.

/pdf/no-impact-of-the-increased-number-of-cardiovascular-risk-1cx62krxbk.pdf

No Impact of the Increased Number of Cardiovascular Risk Factors on Thrombosis and Survival in Polycythemia Vera.

Estimating plasma volume using the Strauss-derived formula may improve prognostication in polycythemia vera.

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