Ruxolitinib (RUX), a Janus kinase 2 (JAK2) inhibitor, and lenalidomide (LEN), an immunomodulatory agent, have recently been proposed as a combined treatment for myelofibrosis (MF). This combination has demonstrated improved efficacy, safety, and tolerability compared to monotherapy. To further refine these findings, an efficient analytical tool is needed to simultaneously determine RUX and LEN concentrations in blood plasma. This tool would enable the study of their pharmacokinetics, drug-drug interactions, and therapeutic monitoring during MF therapy. Unfortunately, such a method has not been existed in the literature. This study presents the first HPLC method with UV detection for the simultaneous quantitation of RUX and LEN in plasma. The method was validated according to the ICH guidelines for bioanalytical method validation. It exhibited linearity in the concentration ranges of 10 to 3150 ng mL- 1 for RUX and 80 to 5200 ng mL- 1 for LEN. The limits of quantitation were determined to be 25 and 90 ng mL- 1 for RUX and LEN, respectively. All other validation parameters were satisfactory. The HPLC-UV method was successfully employed to study the pharmacokinetics and drug-drug interactions of RUX and LEN in rats following oral administration of single doses. The results demonstrated that the pharmacokinetics of both drugs were changed substantially by their coadministration. LEN exhibited synergistic effects on the maximum plasma concentration (Cmax) and total bioavailability of RUX, meanwhile it exhibited diminishing effect on the values of volume of distribution (Vd) and clearance (CL). Additionally, RUX decreased the Cmax and total bioavailability of LEN, meanwhile it increased its Vd and CL. These data suggest that the use of RUX, as a combination with LEN, is a better therapeutic approach for MF, compared with RUX as a monotherapy. The effects of LEN on the pharmacokinetics of RUX should be considered and can be useful in determining the appropriate RUX dosage and dosing regimen to achieve the desired therapeutic effect when used as a combination therapy with LEN. The method\'s environmental friendliness was confirmed through three comprehensive tools. This method represents a valuable tool for determining the appropriate dosage and dosing regimen of RUX in combination therapy with LEN to achieve the desired therapeutic effect. Furthermore, it can aid in predicting drug distribution in different patients and assessing the drug accumulation or insufficient drug levels in specific body compartments.

UNASSIGNED: The signal transducer and activator of transcription 3 (STAT3) gain-of-function (GOF) syndrome (STAT3-GOF) is an inborn error of immunity (IEI) characterized by diverse manifestations of immune dysregulation that necessitate systemic immunomodulatory treatment. The blockade of the interleukin-6 receptor and/or the inhibition of the Janus kinases has been commonly employed to treat diverse STAT3-GOF-associated manifestations. However, evidence on long-term treatment outcome, especially in the case of adult patients, is scarce.
UNASSIGNED: Clinical data, including laboratory findings and medical imaging, were collected from all seven patients, diagnosed with STAT3-GOF, who have been treated at the Hannover University School, focusing on those who received a Janus kinase (JAK) inhibitor (JAKi). Previously published cases of STAT3-GOF patients who received a JAKi were evaluated, focusing on reported treatment efficacy with respect to diverse STAT3-GOF-associated manifestations of immune dysregulation and safety.
UNASSIGNED: Five out of seven patients diagnosed with STAT3-GOF were treated with a JAKi, each for a different indication. Including these patients, outcomes of JAKi treatment have been reported for a total of 41 patients. Treatment with a JAKi led to improvement of diverse autoimmune, inflammatory, or lymphoproliferative manifestations of STAT3-GOF and a therapeutic benefit could be documented for all except two patients. Considering all reported manifestations of immune dysregulation in each patient, complete remission was achieved in 10/41 (24.4%) treated patients.
UNASSIGNED: JAKi treatment improved diverse manifestations of immune dysregulation in the majority of STAT3-GOF patients, representing a promising therapeutic approach. Long-term follow-up data are needed to evaluate possible risks of prolonged treatment with a JAKi.

Myelofibrosis should be diagnosed according to the WHO classification (2022, 5th Ed.) and International Consensus Conference 2022 criteria. Testing for driver mutations in the three genes JAK2, CALR, and MPL is recommended to ensure a definitive diagnosis. Ruxolitinib is the only JAK inhibitor currently approved in Japan, but momelotinib is under regulatory review. The MOMENTUM study showed similar spleen volume reduction at 24 weeks and MFSAF-TSS reduction as the COMFORT study of ruxolitinib. Momelotinib acts on ACVR1 and, therefore, improves anemia through suppression of hepcidin. Anemia and/or transfusion dependency are known to be associated with overall survival duration. Consequently, supportive care measures such as ESA and danazol in lieu of transfusion should be considered in addition to JAK inhibitor selection. Mean survival after discontinuation of JAK inhibitors is 11 to 14 months. Pacritinib (not approved in Japan) is suitable for MF patients with thrombocytopenia. JAK inhibitor selection and supportive care by ESA or danazol in lieu of transfusion should be considered. Many classes of drugs other than JAK inhibitors for myelofibrosis are under investigation.

We report the case of a 54-year-old healthy Han Chinese male presenting with fever, pallor, erythematous subcutaneous nodules on the limbs, and significant anemia as indicated by routine blood tests, with no response to antimicrobial therapy. Initial skin biopsy was inconclusive. The erythematous subcutaneous nodules on the limbs rapidly progressed to widespread subcutaneous nodules across the body, with worsening anemia. Bone marrow biopsy revealed multifocal fibroblastic proliferation with focal fibrosis, classified as MF-2, and positive for the JAK2V617F mutation alongside SRSF2 positivity. Whole-body PET-CT scans did not reveal any lymph nodes or suspect lesions with high SUV uptake. A subsequent skin biopsy identified the condition as nodular panniculitis (NP), leading to a final diagnosis of primary myelofibrosis(PMF)with NP. The patient initially received treatment with oral ruxolitinib and prednisone acetate, resulting in normalization of body temperature, resolution of erythematous nodules, and normalization of blood parameters.

JAK-STAT signaling cascade has emerged as an ideal target for the treatment of myeloproliferative diseases, autoimmune diseases, and neurological disorders. Ruxolitinib (Rux), is an orally bioavailable, potent and selective Janus-associated kinase (JAK) inhibitor, proven to be effective to target activated JAK-STAT pathway in the diseases previously described. Unfortunately, limited studies have investigated the potential cytotoxic profile of Rux on other cell populations within the heterogenous CNS microenvironment. Two stem and progenitor cell populations, namely the oligodendrocyte precursor cells (OPCs) and neural stem/progenitor cells (NSPCs), are important for long-term maintenance and post-injury recovery response of the CNS. In light of the limited evidence, this study sought to investigate further the effect of Rux on proliferating and differentiating OPCs and NSPCs populations. In the present study, cultured rat OPCs and NSPCs were treated with various concentrations of Rux, ranging from 2 μM to 20 μM. The effect of Rux on proliferating OPCs (PDGF-R-α+) and proliferating NSPCs (nestin+) was assessed via a 3-day Rux treatment, whereas its effect on differentiating OPCs (MBP+/PDGF-R-α+) and differentiating NSPCs (neurofilament+) was assessed after a 7-day treatment. Cytotoxicity of Rux was also assessed on OPC populations by examining its influence on cell death and DNA synthesis via YO-PRO-1/PI dual-staining and BrdU assay, respectively. The results suggest that Rux at a dosage above 10 μM reduces the number proliferating OPCs, likely via the induction of apoptosis. On the other hand, Rux treatment from 2.5 μM to 20 μM significantly reduces the number of differentiating OPCs by inducing necrosis. Meanwhile, Rux treatment has no observable untoward impact on NSPC cultures within the dosage range tested. Taken together, OPCs appears to be more vulnerable to the dosage effect of Rux, whereas NSPCs are not significantly impacted by Rux, suggesting a differential mechanism of actions of Rux on the cell types.

Although pulmonary complications are frequent in patients suffering from hematological diseases, secondary pulmonary alveolar proteinosis is a very rare complication of myelofibrosis. We describe the case of a 65-year-old male patient treated by Ruxolitinib for myelofibrosis who developed a secondary pulmonary alveolar proteinosis complicated by a Mycobacterium avium infection. We believe that this respiratory complication might be related to the myelofibrosis and to the initiation of the Ruxolitinib according to its temporal relationship. Pulmonologists should be aware that respiratory symptoms in myelofibrosis patients taking Ruxolitinib may be related to pulmonary alveolar proteinosis.

Janus Kinase (JAK) inhibitors have emerged as a novel category of medications to treat a variety of immune-mediated conditions. However, limited insight exists regarding the impact of safety concerns on their usage and prescribing practices. Therefore, the objective of this study was to describe the utilization of JAK-inhibitors in Canada, both nationally and within individual provinces. We used data from IQVIA\'s Compuscript database. We conducted a repeated cross-sectional study of all JAK-inhibitor units dispensed in retail pharmacies (tofacitinib, ruxolitinib, baricitinib, and upadacitinib) within the ten Canadian provinces from July 1, 2016, to June 30, 2022. Throughout Canada, outpatient pharmacies dispensed an estimated total of 26,126,409 JAK-inhibitor units between 2016 and 2022, averaging 9,431 units dispensed per 100,000 population. All provinces had increasing rates of JAK-inhibitor units dispensed over time, whereby between July 2021 to June 2022, New Brunswick exhibited the highest rates (27,696 units per 100,000), and Prince Edward Island demonstrated the lowest rates (10,065 units per 100,000). In this study, utilization of JAK-inhibitors increased in Canada over the study period, evident at both provincial and national levels. Variability in JAK-inhibitor utilization between provinces underscores the necessity for further investigations to ascertain appropriate usage practices. Key Points • From 2016 to 2022, an estimated total of 26,126,409 JAK-inhibitor units were dispensed in retail pharmacies across Canada, with an average rate of 9,431 units dispensed for every 100,000 people in the population. • Tofacitinib was the most dispensed JAK-inhibitor during the entire study period, making up 76% of all units dispensed. Ruxolitinib, upadacitinib, and baricitinib made up 16%, 7.9%, and 1.1% of the JAK-inhibitor units dispensed, respectively. • The variance in provincial adoption of JAK-inhibitors across Canada might be influenced by several factors, including drug coverage availability, disease prevalence, and physician prescribing patterns.

UNASSIGNED: The Janus kinase (JAK) family includes four cytoplasmic tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) constitutively bound to several cytokine receptors. JAKs phosphorylate downstream signal transducers and activators of transcription (STAT). JAK-STAT5 pathways play a critical role in basophil and mast cell activation. Previous studies have demonstrated that inhibitors of JAK-STAT pathway blocked the activation of mast cells and basophils.
UNASSIGNED: In this study, we investigated the in vitro effects of ruxolitinib, a JAK1/2 inhibitor, on IgE- and IL-3-mediated release of mediators from human basophils, as well as substance P-induced mediator release from skin mast cells (HSMCs).
UNASSIGNED: Ruxolitinib concentration-dependently inhibited IgE-mediated release of preformed (histamine) and de novo synthesized mediators (leukotriene C4) from human basophils. Ruxolitinib also inhibited anti-IgE- and IL-3-mediated cytokine (IL-4 and IL-13) release from basophils, as well as the secretion of preformed mediators (histamine, tryptase, and chymase) from substance P-activated HSMCs.
UNASSIGNED: These results indicate that ruxolitinib, inhibiting the release of several mediators from human basophils and mast cells, is a potential candidate for the treatment of inflammatory disorders.

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Hydroxyurea is the preferred first-line cytoreductive treatment for high-risk essential thrombocythaemia (ET), but many patients are intolerant or refractory to hydroxyurea. Ruxolitinib has been shown to improve symptoms in patients with ET. This post hoc analysis compared the clinical outcomes of patients with ET who received hydroxyurea only with those who switched from hydroxyurea to ruxolitinib due to intolerance/resistance to hydroxyurea. Patients with ET refractory/intolerant to hydroxyurea treated with ruxolitinib in a completed phase 2 study (HU-RUX) were propensity score matched with patients who received hydroxyurea only in an observational study (HU). Changes in leukocyte and platelet counts were reported at 6-month intervals during the 48-month follow-up. Following propensity score matching, 37 patients were included for analysis in each cohort. Mean (standard deviation [SD]) leukocyte and platelet counts at index were higher for HU-RUX versus HU (leukocyte: 9.3 [5.1] vs. 6.8 [3.1] × 109/L; platelet: 1027.4 [497.8] vs. 513.9 [154.7] × 109/L), both of which decreased significantly from index to 6 months through to 48 months in HU-RUX (mean [SD] change from index at 6 months-leukocyte: -1.8 [4.6] × 109/L; platelet: -391.7 [472.9] × 109/L; at 48 months-leukocyte: -3.8 [5.3] × 109/L; platelet: -539.0 [521.8] × 109/L), but remained relatively stable in HU (mean [SD] change from index at 6 months-leukocyte: 0 [1.8] × 109/L; platelet: -5.7 [175.3] × 109/L; at 48 months-leukocyte: -0.1 [2.7] × 109/L; platelet: -6.9 [105.1] × 109/L). In conclusion, these results demonstrate that switching from hydroxyurea to ruxolitinib in patients with ET who are intolerant or refractory to hydroxyurea could improve abnormal haematologic values similar to those who receive first-line hydroxyurea.