An Opportunistic Infection Associated With Ruxolitinib, a Novel Janus Kinase 1,2 Inhibitor

Wysham, Nicholas G.; Sullivan, Donald R.; Allada, Gopal

doi:10.1378/chest.12-1604

Cited by 109 publications

(76 citation statements)

References 6 publications

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“…Even though recent clinical trials have not shown markedly increased infection rates, viral reactivation (eg, herpes zoster), urinary tract, and opportunistic infections may be more frequently observed. 33 Thus, potential effects of the drug on infectious prevalence in patients during longterm JAK-inhibitor therapy have to be closely monitored in the future. This assumption is further supported by our second in vivo model, showing that clearance of a hepatic adenoviral infection is delayed by systemic ruxolitinib therapy.…”

Section: Discussionmentioning

confidence: 99%

The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo

Heine

Held

Daecke

et al. 2013

Blood

312

233

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Key Points• The JAK-inhibitor ruxolitinib affects dendritic cell differentiation, phenotype, and function leading to impaired T-cell activation.The Janus kinase (JAK)-inhibitor ruxolitinib decreases constitutional symptoms and spleen size of myelofibrosis (MF) patients by mechanisms distinct from its anticlonal activity. Here we investigated whether ruxolitinib affects dendritic cell (DC) biology. The in vitro development of monocyte-derived DCs was almost completely blocked when the compound was added throughout the differentiation period. Furthermore, when applied solely during the final lipopolysaccharide-induced maturation step, ruxolitinib reduced DC activation as demonstrated by decreased interleukin-12 production and attenuated expression of activation markers. Ruxolitinib also impaired both in vitro and in vivo DC migration. Dysfunction of ruxolitinib-exposed DCs was further underlined by their impaired induction of allogeneic and antigen-specific T-cell responses. Ruxolitinib-treated mice immunized with ovalbumin (OVA)/CpG induced markedly reduced in vivo activation and proliferation of OVA-specific CD81 T cells compared with vehicle-treated controls. Finally, using an adenoviral infection model, we show that ruxolitinib-exposed mice exhibit delayed adenoviral clearance. Our results demonstrate that ruxolitinib significantly affects DC differentiation and function leading to impaired T-cell activation. DC dysfunction may result in increased infection rates in ruxolitinib-treated patients. However, our findings may also explain the outstanding anti-inflammatory and immunomodulating activity of JAK inhibitors currently used in the treatment of MF and autoimmune diseases. (Blood. 2013; 122(7):1192-1202)

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Section: Discussionmentioning

confidence: 99%

The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo

Heine

Held

Daecke

et al. 2013

Blood

312

233

View full text Add to dashboard Cite

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“…1,2 Next-generation sequencing can be a powerful tool to identify novel genetic etiologies in patients with unclassified IBMFS, especially in the setting of consanguinity where the causal mutation usually resides within the easily tractable autozygome. 3,4 This phenomenon narrows the candidacy of the large number of variants that are generated by next-generation sequencing, which makes it possible to identify the causal mutation even in simplex cases. 5,6 Thus, the study of unclassified IBMFSs in Saudi Arabia where the consanguinity rate is high represents an opportunity to identify novel disease genes, and these may similarly contribute to the causation of IBMFSs in outbred populations.…”

Section: And Cd8mentioning

confidence: 99%

Ruxolitinib is a potent immunosuppressive compound: is it time for anti-infective prophylaxis?

Heine

Brossart

Wolf

2013

Blood

144

109

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“…48,49 The DC impairments might result in increased infection rates, while the NK cell dysfunction may impair the GVL effect. 50 Conversely, JAK inhibitors appear to reduce acute GVHD in murine models by increasing T-regulatory cells, which has led to the successful treatment of six patients with ruxolitinib for steroidrefractory acute GVHD. 51 Another JAK inhibitor, tofacitinib, a selective JAK3 inhibitor, has been found to reverse CD8 + T-cellmediated mucocutaneous GVHD-like disease in a murine model.…”

Section: Impact Of Targeting the Jak/signal Transducers And Activatormentioning

confidence: 99%

Allo-SCT for myelofibrosis: reversing the chronic phase in the JAK inhibitor era?

Tamari

Mughal

Rondelli

et al. 2015

Bone Marrow Transplant

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At present, allogeneic hematopoietic stem cell transplantation (allo-SCT) is the only curative treatment for patients with myelofibrosis (MF). Unfortunately a significant proportion of candidate patients are considered transplant ineligible due to their poor general condition and advanced age at time of diagnosis. The approval of the first JAK inhibitor, Ruxolitinib, for patients with advanced MF in 2011 has had a qualified impact on the treatment algorithm. The drug affords substantial improvement in MF-associated symptoms and splenomegaly but no major effect on the natural history. There has, therefore, been considerable support to assess the drug’s candidacy in the peri-transplant period. The drug’s precise impact on clinical outcome following allo-SCT is currently not known; nor is the drug’s long term efficacy and safety known. Considering the rarity of MF and the small proportion of patients who are undergoing allo-SCT, well designed collaborative efforts are required. In order to address some of the principal challenges, an expert panel of laboratory and clinical experts in this field was established, and an independent workshop held during the 54th American Society of Hematology’s meeting in New Orleans, USA, on 6th December 2013 and the European Hematology Association meeting in Milan, Italy on 13th June 2014. This document summarizes the results of these efforts.

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An Opportunistic Infection Associated With Ruxolitinib, a Novel Janus Kinase 1,2 Inhibitor

Cited by 109 publications

References 6 publications

The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo

The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo

Ruxolitinib is a potent immunosuppressive compound: is it time for anti-infective prophylaxis?

Allo-SCT for myelofibrosis: reversing the chronic phase in the JAK inhibitor era?

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