Dipeptidyl-Peptidase 4 (Cd26): a Possible Therapeutic Target in Covid-19

ARS-COV-2, a novel β-coronavirus, is the cause of a severe inflammatory infectious disease of the respiratory tract (COVID-19). The spread has already taken on pandemic proportions, affecting over 2,5 million people and causing more than 170,000 deaths. The mechanisms and strategies underlying the virus power of penetrating human cells and causing the well-known spectrum of diseases induced by SARS-COV-2 have been explored worldwide. Two host receptors able to specifically inducing virus-host linkage, entry and, consequently, productive infection, have been suggested to interact with the outer membrane spike viral glycoprotein: the angiotensin converting enzyme 2 (ACE2) and the dipeptidyl-peptidase 4 (DPP4), also known as CD26. Both these receptors are highly expressed on several human tissues (i.e. kidney, pancreas, gut, lung, endothelium, pleura, myocardium, connective tissue) accounting for the variable clinical manifestations of COVID-19. CD26 is also over-expressed in stimulated T, B, and NK cells, thus representing an activation marker of the immune system. However, CD26 is not only the functional host receptor for SARS- CoV-2. Indeed, published data available from the previous SARS-CoV and MERS-CoV outbreaks showed that CD26 is also utilized for sustaining inflammation and counteracting the host immune response. Specifically, through CD26, coronavirus may increase inflammatory cytokine production, down- modulate the autophagy, and increase levels of adenosine, hence further deactivating the host immune response. Thus, compounds able to inhibit the DPP4/CD26 pathway might be useful against COVID-19. In this respect, promising therapeutic approaches could include: 1) DPP4 inhibitors, such as sitagliptin, already used for treating diabetic patients; 2) Begelomab, the anti-CD26 monoclonal antibody already successfully employed in the treatment of graft-versus-host disease, and 3) adenosine deaminase agonists, already used in the immunodeficiencies sustained by the adenosine deaminase gene mutations. The article will review some pathogenic landscapes and will hypothesize some promising drugs to face the COVID-19 emergency

Myeloproliferative and lymphoproliferative disorders: State of the art.

Myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are clonal disorders complicated mainly by vascular events and transformation to myelofibrosis (for PV and ET) or leukemia. Although secondary malignancies, in particular, lymphoproliferative disorders (LPNs), are rare, they occur at a higher frequency than found in the general population, and there has been recent scientific discussion regarding a hypothetical relationship between treatment with JAK inhibitors in MPN and the risk of development of LPN. This has prompted increased interest regarding the coexistence of MPN and LPN. This review focuses on the role of JAK2 and the JAK/STAT pathway in MPN and LPN, whether there is a role for the genetic background in the occurrence of both MPN and LPN and whether there is a role for cytoreductive drugs in the occurrence of both MPN and LPN. Furthermore, whether an increased risk of lymphoma development is limited to patients who receive the JAK inhibitor ruxolitinib, is a more general phenomenon that occurs following JAK1/2 inhibition or is associated with preferential JAK1 or JAK2 targeting is discussed

High-dose (40,000 IU twice/week) alpha recombinant human erythropoietin as single agent in low/intermediate risk myelodysplastic syndromes: a retrospective investigation on 133 patients treated in a single institution.

We investigated the efficacy of alpha recombinant human erythropoietin (α-rHuEPO) administered as single agent to 133 patients affected by myelodysplastic syndromes referring to our Institution in the last 10 years. WPSS score was "very low" in 67%, "low" in 19%, "intermediate" in 14%. The starting schedule was: 40,000 IU bi-weekly, with reduction or suspension, when necessary, in responsive patients. According to new IWG criteria, response rate (RR) was 75%, 66%, 59% after 8, 16, 24 weeks, respectively. Comparing "very low" and "low/intermediate" risk, RR was 81% vs. 43% (P < 0.001); 70% vs. 45% (P = 0.040); 63% vs. 42% (P = NS) after 8, 16, 24 weeks. RR was significantly influenced by transfusion dependence (P = 0.039) and basal serum EPO level (P < 0.001). Mean Hb value was 94 ± 11 g/l before therapy; 114 ± 19 after 8 weeks (P < 0.001); 116 ± 18 after 16 weeks (P < 0.001); 114 ± 17 after 24 weeks (P < 0.001). Reduction or suspension of therapy significantly affected Hb level after 4 (P < 0.001) and 8 weeks (P < 0.01). Conversely, restart of full dosage significantly enhanced again Hb level after 4 (P < 0.01) and 8 weeks (P < 0.001). 65% patients are alive (mean survival: 74 weeks). Seventy percent are alive in the "very low risk" group and 38% in "low/intermediate risk" group (P < 0.001). Overall mean follow-up was 69 weeks (range, 8-376): it was 80 weeks in responsive patients (max 376) and 38 weeks in patients who progressively became unresponsive (max 168) (P < 0.01). Median response was 36 weeks, with 33% of patients still responding after one year. Treatment was well tolerated. 0.001). 65% patients are alive (mean survival: 74 weeks). Seventy percent are alive in th

THU0264 MYELOID MALIGNANCIES, SYSTEMIC AUTOIMMUNE DISEASES AND CARDIOVASCULAR RISK: AN UNDER-REPORTED ASSOCIATION?

Background: The association between systemic autoimmune diseases (ADs) and lymphoproliferative malignancies is well established; nonetheless, few stud- ies have investigated the prevalence and prognostic impact of myeloid malignan- cies on systemic autoimmune conditions. Objectives: To investigate the frequency of myeloid malignancies (i.e myelo- dysplastic syndrome (MDS) and chronic, either Philadelphia-positive or Phila- delphia-negative, myeloproliferative disorders (MPNs)) in patients with ADs and their influence on the ADs clinical course and vice-versa. Methods: A retrospective systematic search through the electronic health records of the patients admitted at our Rheumatology University Hospital from 2009 and 2019 was performed to select those presenting with ADs and MDS or MPNs. To refine the search the ICD-9-CM diagnosis codes for MDS/MPNs were utilized. Medical charts of eligible patients were retrieved and data were collected with regard to demo- graphics, type of AD, AD duration, prior treatments, serum laboratory indices, bone marrow aspiration and biopsy data. Categorical variables were compared using chi square test and Fisher’s test; continuous variables were compared using Student’s t-test. A 2-tailed value of p &lt;0.05 was taken to indicate statistical significance. Results: Out of the medical records of 5040 patients, we identified 51 patients (31 F: 20 M, mean age: 61 years (15)) with AD and myeloid malignancies: 17/51 with AD and MDS and 34/51 with AD and MPNs. No demographic differences were observed in the two subgroups. Regarding MDS, anaemia was the most common haematologic presenting finding (15/17, 88%), while the most common diagnosis was refractory anemia with excess of blasts (RAEB I/II) (5/17, 29%) followed by sideroblastic anemia (2/17, 12%). In the MPNs subgroup, 12/34 patients (35%) had a diagnosis of chronic myeloid leukemia (CML), 9/34 (26%) had a myelofibrosis (MF), 7/34 (21%) had an essential thrombocythemia (ET) and 6/34 (18%) had a polycythemia vera (PV). The JAK2 V617F mutation was detected in 100%, 57%, and 66% of PV, ET, and MF patients. Regarding the temporal appearance of myeloid malignancy, MDS occurred concurrently (9/17) or followed (7/17) the diagnosis of ADs in the vast majority of the cases whereas MPNs generally preceded the diagnosis of ADs (19/34). In MDS the most com- monly diagnosed ADs were seronegative arthritis (5/17, 29 %), large and small vessel vasculitis (4/17, 23%) and Systemic Lupus Erythematosus (3/17, 17%). In patients with MPNs the diagnosis of rheumatoid arthritis (2/9, 22%), and antiphospholipid syndrome (3/9, 33%) were often associated with MF, whereas anti-Ro52 (TRIM21) positive systemic connective tissue disorders (4/7, 57%) were more frequently detected in ET. Cardiovascular events were observed in 14/51 (27%): 4/17 (23%) in MDS, 3/12 (25%) in CML and 7/22 (32%) in Philadel- phia-negative MPNs. The latter seven cardiovascular events were all observed in patients presenting JAK2 V617F mutation (p=0.05). Conclusion: Our study is limited by its retrospective design. However, our results documented that the frequency of MDS and MPNs in ADs is not negligible and might be considered in the assessment of cardiovascular risk in systemic auto- immunity. Moreover, it has been reported that, under viral infection, TRIM21 is up-regulated by activation of the IFN/JAK/STAT pathway; interestingly, anti-Ro52 (TRIM21) were over-represented in MPN, where the JAK/STAT signal is hyper activated. This could explain also our observation that frequently the onset of ADs follows the diagnosis of MPN

CLINICAL AND BIOLOGICAL FEATURES DISTINGUISH MYELOID DISEASES FROM MYELOID DISORDERS ASSOCIATED WITH AUTOIMMUNE DISEASES.

In a series of 11000 patients withmyeloproliferative neoplasms (MPN) and 43,000 matched controls, a Swedish group reported that a prior history of autoimmune diseases (ADs) was significantly associated with a higher risk of MPN. More recently, our group showed that in chronic myeloid leukemia (CML) some genes correlated with AD (GLYPR1, PCARD, S100) were highly expressed at diagnosis and that the treatment with Imatinib impacted on the “inflammatory” profile of CML patients. Aims To investigate the frequency of myeloid malignancies (i.e myelodysplastic syndrome (MDS) and chronic, either Philadelphia-positive or Philadelphia-negative, myeloproliferative disorders (MPNs)) in patients with ADs, their influence on the ADs clinical course and vice-versa, and to identify several distinctive clinical and biological features. Methods A retrospective systematic search through the electronic health records of the patients admitted at Rheumatology from 2009 and 2019 was performed to select those presenting with ADs and MDS or MPNs. Categorical variables were compared using chi square test and Fisher’s test; continuous variables were compared using Student’s t-test. A 2-tailed value of p &lt;0.05 was taken to indicate statistical significance. Results Out of the medical records of 5040 patients, we identified 55 patients (33 F: 22 M, mean age: 61 years) with ADs and myeloid malignancies (1%): 20/55 with AD and MDS and 35/55 with AD and MPNs. No demographic differences were observed in the two subgroups. Regarding MDS, anemia was the most common hematologic presenting finding (16/20, 80%), with diagnosis of refractory anemia with excess of blasts (RAEB I/II) done in 25% of cases, followed by syderoblastic anemia in 12%. In the MPNs, 12/35 patients (34%) had a diagnosis of chronic myeloid leukemia (CML), 9/35 (26%) had MF 8/35 (23%) had an ET and 6/35 (17%) a PV. The JAK2 V617F mutation was detected in 100%, 57%, and 66% of PV, ET, and MF patients respectively. Regarding the temporal appearance of myeloid malignancy, MDS occurred concurrently (10/20) or followed (10/20) the diagnosis of Ads, whereas MPNs generally preceded the diagnosis of ADs (19/35). In MDS, the most commonly diagnosed ADs were seronegative arthritis (5/20, 25%), large and small vessel vasculitis (4/20, 20%), Systemic Lupus Erythematosus (3/20, 15%) and other ones in the remaining 8 cases. In patients with MPNs, the diagnosis of rheumatoid arthritis (2/9, 22%), and anti-phospholipid syndrome (3/9, 33%) were often associated with MF, whereas anti-Ro52 (TRIM21) positive systemic connective tissue disorders (4/8, 50%) were more frequently detected in ET. Cardiovascular events were observed in 14/55 (26%): 4/20 (20%) in MDS, 3/12 (25%) in CML and 7/23 (30%) in Philadelphia-negative MPNs. In this cohort, as expected, cardiovascular events were all observed in patients presenting JAK2V617F mutation. Conclusion Our study shows that the frequency of MDS and MPNs in ADs is not negligible and might be considered in the assessment of cardiovascular risk in systemic autoimmunity. It has been reported that, under viral infection, TRIM21 is up-regulated by activation of the IFN/JAK/STAT pathway; interestingly, anti-Ro52 (TRIM21) were over-represented in MPN, where the JAK/STAT signal is hyper activated. This could explain also our observation that frequently the onset of ADs follows the diagnosis of MPN. Ackowledges: this study received support from university of Pisa PRA 2018 PI Prof. Petrin