HBV reactivation in patients with rheumatoid arthritis treated with anti-interleukin-6:a systematic review and meta-analysis

OBJECTIVE: The objective of this study was to assess the possibility of HBV reactivation (HBVr) in patients with RA under anti-IL-6 treatment.METHODS: Using PubMed, Scopus and EMBASE, we performed a systematic literature search for articles related to HBVr in RA patients under anti-IL-6 treatment. The search was performed with no date limits and was last updated 28 January 2023. The results from all the databases were combined and duplicates were excluded, as were non-English articles, case reports, position articles, comments, and paediatric studies.RESULTS: Our initial search led to 427 articles; 28 were duplicates, 46 non-English, 169 reviews, 31 books/letters, 25 case reports, and 88 irrelevant to the meta-analysis aim; 21 were excluded due to inadequate information, leaving 19 articles, with a sum of 372 RA patients with chronic HBV (CHB) or resolved HBV infection, for further analysis. The overall risk for HBVr in RA patients with CHB was 6.7%, increasing to 37% when only RA patients with CHB and no antiviral prophylaxis were included. On the contrary, HBVr was close to 0% in RA patients with resolved HBV infection, irrespective of antiviral prophylaxis. All RA patients experiencing HBVr in these studies were successfully managed with antiviral treatment and/or drug withdrawal.CONCLUSION: Overall, anti-IL-6 treatment comes with a significant risk of HBVr in RA patients with CHB; risk is diminished when antiviral prophylaxis is used. In contrast, in RA patients with resolved HBV infection, the risk of HBVr seems to be extremely low. Large, well-designed studies (either controlled trials or multicentre/international observational studies) are warranted to further validate these results.</p

SGLT-2 Inhibitors in NAFLD: Expanding Their Role beyond Diabetes and Cardioprotection?

Non-alcoholic fatty liver disease (NAFLD) is an ‘umbrella’ term, comprising a spectrum ranging from benign, liver steatosis to non-alcoholic steatohepatitis, liver fibrosis and eventually cirrhosis and hepatocellular carcinoma. NAFLD has evolved as a major health problem in recent years. Discovering ways to prevent or delay the progression of NAFLD has become a global focus. Lifestyle modifications remain the cornerstone of NAFLD treatment, even though various pharmaceutical interventions are currently under clinical trial. Among them, sodium-glucose co-transporter type-2 inhibitors (SGLT-2i) are emerging as promising agents. Processes regulated by SGLT-2i, such as endoplasmic reticulum (ER) and oxidative stress, low-grade inflammation, autophagy and apoptosis are all implicated in NAFLD pathogenesis. In this review, we summarize the current understanding of the NAFLD pathophysiology, and specifically focus on the potential impact of SGLT-2i in NAFLD development and progression, providing current evidence from in vitro, animal and human studies. Given this evidence, further mechanistic studies would advance our understanding of the exact mechanisms underlying the pathogenesis of NAFLD and the potential beneficial actions of SGLT-2i in the context of NAFLD treatment

Liver Fibrosis during Antiretroviral Treatment in HIV-Infected Individuals. Truth or Tale?

After the introduction of antiretroviral treatment (ART) back in 1996, the lifespan of people living with HIV (PLWH) has been substantially increased, while the major causes of morbidity and mortality have switched from opportunistic infections and AIDS-related neoplasms to cardiovascular and liver diseases. HIV itself may lead to liver damage and subsequent liver fibrosis (LF) through multiple pathways. Apart from HIV, viral hepatitis, alcoholic and especially non-alcoholic liver diseases have been implicated in liver involvement among PLWH. Another well known cause of hepatotoxicity is ART, raising clinically significant concerns about LF in long-term treatment. In this review we present the existing data and analyze the association of LF with all ART drug classes. Published data derived from many studies are to some extent controversial and therefore remain inconclusive. Among all the antiretroviral drugs, nucleoside reverse transcriptase inhibitors, especially didanosine and zidovudine, seem to carry the greatest risk for LF, with integrase strand transfer inhibitors and entry inhibitors having minimal risk. Surprisingly, even though protease inhibitors often lead to insulin resistance, they do not seem to be associated with a significant risk of LF. In conclusion, most ART drugs are safe in long-term treatment and seldom lead to severe LF when no liver-related co-morbidities exist

Μελέτη του σηματοδοτικού μονοπατιού PI3K/AKT στο μυελό των ασθενών με μυελοδυσπλαστικά σύνδρομα υψηλού και χαμηλού κινδύνου

Εισαγωγή: Η οδός PI3K/ΑΚΤ/mTOR κατέχει ρόλο κλειδί στη ρύθμιση της κυτταρικής ανάπτυξης, της διαφοροποίησης και του πολλαπλασιασμού των κυττάρων σε πληθώρα νοσημάτων και νεοπλασιών, συμπεριλαμβανομένων και των αιματολογικών κακοηθειών. Ο M Nyakern και οι συνεργάτες έδειξαν ότι τα επίπεδα φωσφορυλίωσης (ενεργοποίησης) της Akt στη Ser473 (pAkts) είναι υψηλότερα σε PBMCs ή BMMCs ασθενών MDS υψηλού κινδύνου, ενώ BMMCs από μη νοσούντα MO ή από ασθενείς με MDS χαμηλού κινδύνου παρουσιάζουν απουσία ή περιορισμένη χρώση για pAkts. Τα ευρήματα αυτά μας ώθησαν στο ερευνητικό και κλινικό ερώτημα εάν η παρατηρούμενη διαφορά στην ενεργοποίηση (φωσφορυλίωση) της ΑΚΤ θα ήταν εξίσου εμφανής και παρούσα κατά την ημιποσοτική μικροσκοπική εκτίμηση οστεομυελικών βιοψιών (ΒΜΒ) από αντίστοιχους ασθενείς με MDS. Υλικά και Μέθοδοι: Το μόριο ΑΚΤ καθώς και τα φωσφορυλιωμένα (p) Akt στη threonine-308 και στη serine-473 καθώς και PRAS40 μελετήθηκαν με τη μέθοδο της ανοσοϊστοχημείας σε δείγματα BMB από 10 περιστατικά MDS και 4 μάρτυρες. Επίσης, έγινε προσπάθεια συσχέτισης με τα κλινικο-παθολογοανατομικά χαρακτηριστικά των ασθενών. Αποτελέσματα: Όλα τα περιστατικά, ασθενείς και μάρτυρες, ήταν θετικά για την ΑΚΤ, pAktT, pAktS και pPRAS40. Αναλυτικότερα, η έκφραση της ολικής ΑΚΤ αλλά και των pAktT, pAktS αφορούσε πρωτίστως την κοκκιώδη σειρά όχι μόνο στους ασθενείς αλλά και στους μάρτυρες, και ήταν κυρίως κυτταροπλασματική με εν μέρει λίγες περιπτώσεις πυρηνικής έκφρασης. Δεν παρατηρήθηκε διαφορά στην ένταση των επιμέρους χρώσεων αφενός μεταξύ ασθενών και μαρτύρων και αφετέρου μεταξύ διακριτών υποομάδων ασθενών, όπως ασθενείς με MDS-SLD και MDS-MLD με χαμηλό ποσοστό βλαστών (ν=5) έναντι ασθενών με περίσσεια βλαστών (ΕΒ 1 ή/και 2) (ν=5) αλλά και ασθενείς χαμηλού κινδύνου (ν=5) έναντι μέτριου ή υψηλού κινδύνου βάση το IPSS-R (ν=5) για κανένα από τα μελετώμενα μόρια. Τέλος, η ανοσοϊστοχημική έκφραση την ενεργοποιημένης (φωσφορυλιωμένης) μορφής του PRAS40, προσδέτη της AKT, ήταν εντόνως θετική σε όλα τα μελετώμενα δείγματα BM, ασθενών (ν=10) και μαρτύρων (ν=4), αφορούσε όλες τις κυτταρικές σειρές και ήταν κυρίως πυρηνική χρώση και εν μέρη κυτταροπλασματική. Συμπεράσματα: H αδυναμία ανάδειξης διαφοράς στην ενεργοποίηση-φωσφορυλίωση των μελετώμενων μορίων σε BMB μεταξύ ασθενών με MDS υψηλού κινδύνου και ασθενών με MDS χαμηλού κινδύνου ή μάρτυρες δίχως MDS στην παρούσα εργασία επιτάσσει την περαιτέρω μελέτη της ανοσοϊστοχημικής έκφρασης των μελετώμενων μορίων σε μεγαλύτερο αριθμό ασθενών με ακριβείς μεθόδους ποσοτικοποίησης των αποτελεσμάτων καθώς και παράλληλες επιβεβαιωτικές τεχνικές.Introduction: The PI3K/Akt/mTOR pathway plays a key role in regulating cell growth, differentiation and proliferation in a variety of diseases and neoplasms, including hematological malignancies. It has been known in the available literature from the studies by M Nyakern at al. since 2006 that the phosphorylation (activation) levels of Akt in Ser473 (pAKTs) is higher in BMMCs of high-risk myelodysplastic syndrome (MDS) patients, while BMMCs from non-neoplastic ΒΜ or patients with low-risk MDS present absence or low intensity staining for pAKTs. These findings prompted us to study whether the observed difference in the activation-phosphorylation of Akt between BMMCs from patients with high-risk MDS compared to those with low risk MDS would be also detectable in a semi-quantitative manner during microscopic assessment of bone marrow biopsies (BMB) from MDS patients. Material and Methods: The Akt molecule, as well as the phosphorylated (p) Akt in threonine-308 and serine-473 and PRAS40 were studied immunohistochemically in BMB samples from 10 cases of MDS patients and 4 controls and assessment of any associations between the staining intensity and the clinicopathological-anatomical characteristics of patients was attempted. Results: All cases, both patients and controls, were positive for Akt, pAKTT, pAKTS and pPRAS40. Specifically, the expression of total Akt but also that of pAKTT and pAKTS primarily concerned the granulocytic lineage in both patient and control groups and was mainly cytoplasmic with only a few cases of partial nuclear expression. No differences were observed in any of the molecules studied between patients and controls, but also among distinct subgroups of patients, such as patients with SLD and MLD with a low percentage of blasts (n=5) versus patients with excess blasts (EB 1 and/or 2) (n=5) but also low-risk patients (n=5) versus moderate or high-risk IPSS-R (n=5). Finally, the immunohistochemical expression of the activated (phosphorylated) form of PRAS40, a substrate of AKT, was strongly positive in all studied specimens, the 10 patients (n=10) and 4 controls, concerned all cell lineages and displayed primarily a nuclear staining pattern and partly cytoplasmic one. Conclusions: Our findings did not detect differences in the activation-phosphorylation pattern of the studied molecules in BMB specimens between patients with high-risk MDS and low-risk MDS patients or controls without MDS in the current study. Nevertheless, considering the importance of PI3K/AKT pathway in human oncogenesis, further studies on the immunohistochemical expression of these molecules in a larger study group with more precise quantification methods and concomitant confirmatory techniques are warranted

Antibody Responses after SARS-CoV-2 Vaccination in Patients with Liver Diseases

The novel mRNA-based vaccines against SARS-CoV-2 display encouraging safety and efficacy profiles. However, there is a paucity of data regarding their immunogenicity and safety in patients with liver diseases (PWLD), especially in those with cirrhosis. We prospectively assessed anti-SARS-CoV-2 S-spike IgG antibodies and neutralizing activity in fully vaccinated PWLD (n = 87) and controls (n = 40). Seroconversion rates were 97.4% (37/38) in cirrhotic PWLD, 87.8% (43/49) in non-cirrhotic PWLD and 100% (40/40) in controls. Adequate neutralizing activity was detected in 92.1% (35/38), 87.8% (43/49) and 100% (40/40) of cirrhotics, non-cirrhotics and controls, respectively. On multivariable analysis, immunosuppressive treatment was negatively correlated with anti-SARS-CoV-2 antibody titers (coefficient (SE): &minus;2.716 (0.634), p &lt; 0.001) and neutralizing activity (coefficient (SE): &minus;24.379 (4.582), p &lt; 0.001), while age was negatively correlated only with neutralizing activity (coefficient (SE): &minus;0.31(0.14), p = 0.028). A total of 52 responder PWLD were reassessed approximately 3 months post-vaccination and no differences were detected in humoral responses between cirrhotic and non-cirrhotic PWLD. No significant side effects were noted post vaccination, while no symptomatic breakthrough infections were reported during a 6-month follow up. Overall, our study shows that m-RNA-based SARS-CoV-2 vaccines are safe and efficacious in PWLD. However, PWLD under immunosuppressive treatment and those of advanced age should probably be more closely monitored after vaccination

Single Nucleotide Polymorphisms of Toll-like Receptor 4 in Hepatocellular Carcinoma&mdash;A Single-Center Study

Hepatocellular carcinoma (HCC) is the most common primary liver tumor leading to significant morbidity and mortality; its exact genetic background is largely unrecognized. Toll-like receptor-4 (TLR4) reacts with lipopolysaccharides, molecules found in the outer membrane of Gram-negative bacteria. In damaged liver, TLR4 expression is upregulated, leading to hepatic inflammation and injury. We tried to investigate the role of the two most common single-nucleotide polymorphisms (SNPs) of TLR4 in HCC-genesis. Aged &gt; 18 years old, cirrhotic patients were included in this study. Exclusion criteria were non-HCC tumors and HIV co-infection. TLR4 SNPs association with HCC occurrence was the primary endpoint, and associations with all-cause and liver-related mortality, as well as time durations between diagnosis of cirrhosis and HCC development or death and diagnosis of HCC and death were secondary endpoints. A total of 52 out of 260 included patients had or developed HCC. TLR4 SNPs showed no correlation with primary or secondary endpoints, except for the shorter duration between HCC development and death in patients with TLR4 mutations. Overall, TLR4 SNPs showed no correlation with carcinogenesis or deaths in patients with liver cirrhosis; patients with TLR4 SNPs that developed HCC had lower survival rates, a finding that should be further evaluated

Scleroderma specific autoantibodies in rheumatoid arthritis and Sjögren's syndrome patients with interstitial lung disease: Prevalence and associations

Systemic sclerosis (SSc) has been classically linked to interstitial lung disease (ILD) development, often in association with specific SSc autoantibodies. In the present report, we aimed to estimate the prevalence of SSc autoantibodies in 60 seropositive RA and 41 primary SS patients complicated or not by ILD. SSc autoantibodies were determined in patients’ sera by a commercial immunoblot assay. RA ILD patients displayed higher frequency of SSc-specific antibodies at strong titers compared to RA-with no lung involvement (25% vs 3.1%, p = 0.01)[OR 95% CI:10.9 (1.2–94.5)], with no differences detected between primary SS groups. These data indicate that many seropositive RA ILD patients probably represent an overlap RA/SSc entity, requiring tailored diagnostic and therapeutic approach

A rare case of duodenal-type follicular lymphoma in rectum appearing as hyperplastic polyp with metachronous appearance in duodenum and stomach

Hyperplastic polyps consist a very frequent finding in colonoscopy having a very low potential to malignancy. According to the international guidelines, it is recommended that all polyps should be resected except for diminutive (&lt;= 5 mm) rectal and rectosigmoid polyps which are predicted with confidence to be hyperplastic. Therefore, in departments where optical diagnosis can be ensured, a “resect and discard” strategy may be implemented for diminutive polyps. In our case, a duodenal-type follicular lymphoma was detected in a 5 mm rectum polyp with hyperplastic appearance. After 4 months, the lymphoma was detected also in stomach and duodenum. Under therapy with Rituximab, she is in remission. To our knowledge, there has never been reported such a case in the literature. Furthermore, it alerts us that we should be very cautious with the optical diagnosis and the “resect and discard strategy”