Patients with overt or occult hepatitis B virus (HBV) infection receiving immunosuppressive treatments have a wide risk of HBV reactivation (HBVr). We performed meta-analysis with decision curve analyses (DCA) to estimate the risk of HBVr in HBsAg-negative anti-HBc-positive patients naïve to nucleos(t)ide analogues (NAs) receiving immunosuppressive treatments.

Studies were identified through literature search until October 2022. Pooled estimates were obtained using random-effects model. Subgroup analyses were performed according to underlying disease and immunosuppressive treatments. DCA was used to identify the threshold probability associated with the net benefit of antiviral prophylaxis in HBsAg-negative anti-HBc-positive patients. We selected 68 studies (40 retrospective and 28 prospective), including 8034 patients with HBsAg negative anti-HBc positive. HBVr was 4% (95% CI 3%-6%) in HBsAg-negative anti-HBc-positive patients, with a significantly high heterogeneity (I2 69%; p < .01). The number-needed-to-treat (NNT) by DCA ranged from 8 to 24 for chemotherapy plus rituximab, from 12 to 24 for targeted therapies in cancer patients and from 13 to 39 for immune-mediated diseases. Net benefit was small for monoclonal antibodies.

Our DCA in HBsAg-negative anti-HBc-positive patients provided evidence that NA prophylaxis is strongly recommended in patients treated with chemotherapy combined with rituximab and could be appropriate in patients with cancer treated with targeted therapies and in patients with immune-mediated diseases. Finally, in patients with cancer treated with monoclonal antibodies or with chemotherapy without rituximab, the net benefit is even lower.

The risk of infections associated with biological drugs (BD) and Janus kinase inhibitors (JAKi) has been extensively explored in the literature. However, there is a dearth of studies that evaluate both pharmacological groups together and, furthermore, compare them. Here, we review the risk of infections associated with BD and JAKi used in dermatology.

A narrative review was performed. All relevant articles evaluating the risk of infection and opportunistic infections with BD and JAKi between January 2010 and February 2024 were selected.

Overall, the incidence of infections, serious infections, and opportunistic infections associated with BD and JAKi is low, but higher than in the general population. JAKi approved for dermatological disorders (abrocitinib, baricitinib, deucravacitinib, upadacitinib, ritlecitinib, and topical ruxolitinib) have been shown to be safe, and present a low rate of infections. We found an elevated risk, especially with anti-tumor necrosis factor (anti-TNF) agents, rituximab, and JAKi (particularly tofacitinib at high doses). Specific associations with infections include tuberculosis and tuberculosis reactivation with anti-TNF agents and tocilizumab; candidiasis with anti-interleukin (IL) 17 agents; hepatitis B virus reactivation with rituximab, anti-TNF, and JAKi; and herpes simplex and herpes zoster infections with JAKi (especially tofacitinib and upadacitinib at high doses). The incidence of infections with ustekinumab and anti-IL-23 was very low. Anti-IL-1, nemolizumab, tralokinumab, and omalizumab were not associated with an increased risk of infections. Dupilumab could decrease the incidence of cutaneous infections.

Anti-TNF agents, rituximab, and JAKi (particularly tofacitinib) can increase the risk of infections. Close monitoring of patients undergoing these therapies is recommended. Prospective studies with long-term follow-up are needed to comparatively evaluate the risks of infection deriving from treatment with BD and JAKi.

Myeloproliferative neoplasms (MPN) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized clinically by the proliferation of one or more hematopoietic lineage(s). The classical Philadelphia-chromosome (Ph)-negative MPNs include polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). The Asian Myeloid Working Group (AMWG) comprises representatives from fifteen Asian centers experienced in the management of MPN. This consensus from the AMWG aims to review the current evidence in the risk stratification and treatment of Ph-negative MPN, to identify management gaps for future improvement, and to offer pragmatic approaches for treatment commensurate with different levels of resources, drug availabilities and reimbursement policies in its constituent regions. The management of MPN should be patient-specific and based on accurate diagnostic and prognostic tools. In patients with PV, ET and early/prefibrotic PMF, symptoms and risk stratification will guide the need for early cytoreduction. In younger patients requiring cytoreduction and in those experiencing resistance or intolerance to hydroxyurea, recombinant interferon-α preparations (pegylated interferon-α 2A or ropeginterferon-α 2b) should be considered. In myelofibrosis, continuous risk assessment and symptom burden assessment are essential in guiding treatment selection. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in MF should always be based on accurate risk stratification for disease-risk and post-HSCT outcome. Management of classical Ph-negative MPN entails accurate diagnosis, cytogenetic and molecular evaluation, risk stratification, and treatment strategies that are outcome-oriented (curative, disease modification, improvement of quality-of-life).

Classical Philadelphia-negative myeloproliferative neoplasms (MPNs), i.e., polycythemia vera, essential thrombocythemia, and primary/secondary myelofibrosis, are clonal disorders of the hematopoietic stem cell in which an uncontrolled proliferation of terminally differentiated myeloid cells occurs. MPNs are characterized by mutations in driver genes, the JAK2V617F point mutation being the most commonly detected genetic alteration in these hematological malignancies. Thus, JAK inhibition has emerged as a potential therapeutic strategy in MPNs, with ruxolitinib being the first JAK inhibitor developed, approved, and prescribed in the management of these blood cancers. However, the use of ruxolitinib has been associated with a potential risk of infection, including opportunistic infections and reactivation of hepatitis B. Here, we briefly describe the association between ruxolitinib treatment in MPNs and hepatitis B reactivation.

Recently, there have been clinical reports of hepatitis B virus reactivation (HBVr) related with Janus kinase (JAK) inhibitors. However, there were no studies to investigate the association between HBVr and different JAK inhibitors.

This study was a retrospective review utilizing the FAERS pharmacovigilance database and a systematic literature search for all cases of HBVr reported with JAK inhibitors. Disproportionality analysis and Bayesian analysis were used in data detection to screen the suspected HBVr after the administration of different JAK inhibitors, based on the FDA Adverse Event Reporting System (FAERS) pharmacovigilance database from Q4 2011 to Q1 2022.

There were a total number of 2097 (0.02%) reports of HBVr in FAERS, of which 41 (1.96%) were associated with JAK inhibitors. Baricitinib appeared to have the strongest signal among four JAK inhibitors, based on the highest reporting odds ratio (ROR = 4.45, 95% confidence interval [CI] 1.67-11.89). Ruxolitinib also showed signals, whereas no signals were detected among Tofacitinib and Upadacitinib.

While there may be an association between JAK inhibitors and HBVr, it appears to be a numerically uncommon occurrence. Further studies are needed to optimize the safety profiles of JAK inhibitors.

Since the first description of gain of function (GOF) mutations in signal transducer and activator of transcription (STAT) 1, more than 300 patients have been described with a broad clinical phenotype including infections and severe immune dysregulation. Whilst Jak inhibitors (JAKinibs) have demonstrated benefits in several reported cases, their indications, dosing, and monitoring remain to be established.

A retrospective, multicenter study recruiting pediatric patients with STAT1 GOF under JAKinib treatment was performed and, when applicable, compared with the available reports from the literature.

Ten children (median age 8.5 years (3-18), receiving JAKinibs (ruxolitinib (n = 9) and baricitinib (n = 1)) with a median follow-up of 18 months (2-42) from 6 inborn errors of immunity (IEI) reference centers were included. Clinical profile and JAKinib indications in our series were similar to the previously published 14 pediatric patients. 9/10 (our cohort) and 14/14 patients (previous reports) showed partial or complete responses. The median immune deficiency and dysregulation activity scores were 15.99 (5.2-40) pre and 7.55 (3-14.1) under therapy (p = 0.0078). Infection, considered a likely adverse event of JAKinib therapy, was observed in 1/10 patients; JAKinibs were stopped in 3/10 children, due to hepatotoxicity, pre-HSCT, and absence of response.

Our study supports the potentially beneficial use of JAKinibs in patients with STAT1 GOF, in line with previously published data. However, consensus regarding their indications and timing, dosing, treatment duration, and monitoring, as well as defining biomarkers to monitor clinical and immunological responses, remains to be determined, in form of international prospective multicenter studies using established IEI registries.

Objectives The aim of this retrospective analysis was to assess the incidence of hepatitis B virus (HBV) reactivation among patients with myeloproliferative neoplasms (MPN) during and after ruxolitinib treatment. Methods Between February 2013 and February 2020, 224 patients with MPN were treated using ruxolitinib at Peking Union Medical College Hospital. Of these, 6 had chronic, and 56 had resolved HBV infection, including 43 patients who received combination treatment with thalidomide, prednisone, and stanozolol (TSP) during ruxolitinib treatment. Results Two patients with chronic HBV infection who did not take any antiviral prophylaxis developed HBV reactivation and hepatitis flare. The other four patients with chronic HBV infection, who took antiviral prophylaxis before ruxolitinib treatment, did not develop HBV reactivation. Also, no patients with resolved HBV infection received antiviral prophylaxis and developed HBV reactivation. Conclusion This study demonstrated that HBV reactivation and hepatitis flare might commonly occur a few months after initiating ruxolitinib treatment in patients with chronic HBV infection who did not take antiviral prophylaxis, especially in combination with TSP. Still, it was extremely rare in patients with resolved HBV infection.

The recognition of the role of complement and Janus kinase (JAK)-dependent cytokines in the pathogenesis of inflammatory and immune-mediated disorders has revolutionized the treatment of a myriad of rheumatological and inflammatory diseases. C5 inhibitors and Janus kinase inhibitors have emerged as attractive therapeutic options. Because of the blockage of immune pathways, these targeted therapies carry an increased risk of infection. This article reviews the mechanism of action and the approved and off-label indications of the agents with most clinical experience within this drug classes. It discusses the associated risks of infection, proposing screening, prevention, and risk mitigation strategies.

Introduction: Real-world data of responses, quality-of-life (QOL) changes and adverse events in patients with myeloproliferative neoplasms (MPN) on conventional therapy (hydroxyurea ± anagrelide), pegylated interferon alpha-2A (PEG-IFNα-2A) or ruxolitinib are limited. Methods: We prospectively studied MPN patients receiving conventional therapy, PEG-IFNα-2A or ruxolitinib. Next-generation sequencing of 69 myeloid-related genes was performed. Clinicohematologic responses, adverse events, and QOL (determined by the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score, MPN-SAF TSS) were evaluated. Results: Seventy men and fifty-five women with polycythemia vera (PV) (N = 23), essential thrombocythemia (ET) (N = 56) and myelofibrosis (MF) (N = 46) were studied for a median of 36 (range: 19-42) months. In PV, responses were comparable for different modalities. CREBBP mutations were associated with inferior responses. In ET, PEG-IFNα-2A resulted in superior clinicohematologic complete responses (CHCR) (P = 0.045). In MF, superior overall response rates (ORR) were associated with ruxolintib (P = 0.018) and JAK2V617F mutation (P = 0.04). For the whole cohort, ruxolitinib led to rapid and sustained reduction in spleen size within the first 6 months, and significant improvement of QOL as reflected by reduction in MPN-SAF TSS (P < 0.001). Adverse events of grades 1-2 were observed in 44%, 62% and 20% of patients receiving conventional therapy, PEG-IFNα-2A and ruxolitinib respectively; and of grade 3-4 in 7% and 9% of patients receiving PEG-IFNα-2A and ruxolitinib. Conclusions: Conventional therapy, PEG-IFNα-2A and ruxolitinib induced responses in all MPN subtypes. PEG-IFNα-2A led to superior CHCR in ET; whereas ruxolitinib resulted in superior ORR in MF, and significant reduction in spleen size and improvement in QOL.

Hepatitis B virus (HBV) reactivation can be a serious complication for patients with chronic or resolved HBV infection when treated with biologics. For HBsAg-positive patients receiving biologics, the risk of HBV reactivation is moderate to high. HBsAg-negative/anti-HBc positive patients are at lower risk of HBV reactivation than HBsAg-positive patients. However, patients taking anti-CD20 agents, such as rituximab, have high risk of HBV reactivation (>10%), so antiviral prophylactic therapies are required. This review provides the different classes of biologics associated with HBV reactivation, stratifies the various reactivation risk levels by HBV status and biologic agent, and discusses management strategies.

Occult hepatitis B virus (HBV) infection, so-called occult B infection (OBI), is defined by the recognition of HBV-DNA in the absence of serum hepatitis B surface antigen (HBsAg). The HBV-DNA genome in OBI is fully replication competent and produced in the liver, characteristically with low-level HBV-DNA fluctuations in the bloodstream. The OBI status remains between chronic (HBsAg +) and resolved (anti-HBs +) phases in the natural history of HBV infection.

The clinical interest in OBI has increased because of its potential for overt HBV reactivation under immunosuppression as well as for HBV transmission, well established in recipients of blood transfusions and/or organ transplants.

Given the shared transmission routes for HIV and HBV, earlier reports claimed that OBI was more frequent in AIDS patients. By contrast, the current scenario shows that OBI is negligible in the HIV population. One explanation is that HBV immunization and recall vaccination campaigns have been very active in this group. A second and most important reason points to the wide use of antiretroviral regimens that include anti-HBV active agents, that is, tenofovir, lamivudine, and/or emtricitabine. They are recommended either as treatment for all HIV carriers or as pre-exposure prophylaxis for uninfected individuals at risk. The consequences are that HBV reactivations associated with HIV-related immunodeficiency have become very rare. Furthermore, HBV suppression with these antivirals has markedly reduced the likelihood of transmission from OBI carriers and/or acquisition by uninfected exposed individuals.

Enthusiasm unabated, however, new tenofovir-sparing antiretroviral regimens are becoming popular and might account for a resurgence of OBI in the HIV setting.

Ruxolitinib has proved to be effective for the treatment of patients with myelofibrosis (either primary or secondary) and polycythaemia vera, and its approval led to a significant change in the current treatment algorithm. Despite its efficacy and beyond its well described haematological toxicity, a peculiar immunosuppressive effect emerged as our clinical experience grew, both within and outside of a clinical trial setting. Definite and negative interactions with multiple pathways of the immune system of patients have been reported so far, involving both adaptive and innate immune responses. These pathophysiological mechanisms may contribute to the increased risk of reactivation of silent infections (e.g., tuberculosis, hepatitis B virus and varicella zoster virus) that have been associated with the drug. Even though such infectious events may be fatal or may lead to significant impairment of organ function, compromising the eligibility of patients for an allotransplant procedure, there are no dedicated guidelines that may help us in assessing and managing the risk of developing serious infections. On this basis, our aim for the present work was to review the current knowledge on the pathophysiological mechanisms through which ruxolitinib may exert its immunosuppressive effect, and to illustrate our personal approach to the management of three peculiar clinical scenarios, for which a risk-based algorithm is suggested.

Treatment options for hematologic malignancies have been rapidly expanding in the past decade, resulting in better survival outcomes for many patients. Infection is an important cause of morbidity and mortality in this patient population. Cytotoxic chemotherapy has well-studied infectious risks related to the degree and duration of myelosuppression. Targeted therapies and immunotherapies have less clearly predictable infectious risk and diverse effects on immune function. This review discusses contemporary management of hematologic malignancies, followed by special discussion of novel agents, including signaling/small molecule inhibitors, monoclonal antibodies, immunomodulators, and immunotherapies, for treatment of hematologic malignancies with focus on infectious risk.

Hepatitis B virus (HBV) is an important public health problem that poses a serious threat to human health. HBV reactivation generally occurs in overt or occult HBV infection patients who suffered DDAs, chemotherapy, or immunosuppressive therapy, especially when some solid tumors and leukemia patients are using hormones such as prednisolone and imatinib. The approximate incidence of HBV reactivation ranged from about 10% to 40%. Scientists often explore the molecular mechanisms from both the virus and the host. But some studies have reported that some drugs (cisplatin, rituximab, imatinib, and glucocorticoid) could induce HBV reactivation directly. However, the specific molecular mechanisms were unclear. With the emergence of new antiviral drugs and molecular targeted drugs, the risk of HBV reactivation will increase significantly. Therefore this review was expected to be used to provide recommendations for future research in HBV reactivation.

To describe and quantify the incidence and morbidity of hepatitis B reactivation (HBVr) secondary to pharmaceutical agents (eg, rituximab, tumor necrosis factor inhibitors, direct-acting antivirals [DAAs] for hepatitis C) among patients with previously resolved hepatitis B infection.

The MEDLINE database was searched from inception through July 2018 using the terms hepatitis B + ( reactivation OR [drug or drug class linked to HBVr]).

Relevant English-language cohort studies or randomized trials quantifying the incidence of HBVr secondary to pharmacotherapy among patients negative for hepatitis B surface antigen and DNA and positive for hepatitis B core antibody were included.

Among 2045 articles, 102 met inclusion criteria. Receipt of rituximab was associated with the highest risk of HBVr (for oncological indication: 6.2% rate [225/3601 patients]) and subsequent hepatitis (up to 52.4% of all HBVr cases). Biologic agents for autoimmune disease were uncommonly associated with HBVr (2.4%, 56/2338), with only 4 cases of hepatitis, all attributable to rituximab. Reactivation caused by DAAs was rare (0.3%, 28/8398), with no cases of hepatitis. Relevance to Patient Care/Clinical Practice: This review compares and contrasts the incidence and clinical relevance of HBVr for various pharmacotherapies among patients with functionally cured hepatitis B, with discussion of appropriate risk mitigation strategies.

Among patients with prior functional cure of hepatitis B, prophylactic antiviral therapy is recommended with rituximab administration irrespective of indication because of a high risk for HBVr-associated morbidity. Enhanced monitoring alone is reasonable for patients receiving nonrituximab biologics or DAAs.