Impact of Different JAK Inhibitors and Methotrexate on Lymphocyte Proliferation and DNA Damage

Reddig, Annika; Voss, Linda D; Guttek, Karina; Roggenbuck, Dirk; Feist, Eugen; Reinhold, Dirk

doi:10.3390/jcm10071431

Cited by 14 publications

(13 citation statements)

References 75 publications

(123 reference statements)

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“… 133 It exhibits sub nM IC50 for JAK1 (0.76 nM), 2 nM for JAK2 and >100 nM for JAK3 and TYK2. 130 Its in vitro pharmacology was determined in primary peripheral mononuclear cells from healthy subjects in comparison with baricitinib and tofacitinib. 134 In primary cells upadacitinib also inhibited JAK2 downstream IL3 type cytokines, not only JAK1 downstream inflammatory cytokines like IL6.…”

Section: Introductionmentioning

confidence: 99%

JAK inhibitors and COVID-19

Levy

Guglielmelli

Langmuir

et al. 2022

J Immunother Cancer

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During SARS-CoV-2 infection, the innate immune response can be inhibited or delayed, and the subsequent persistent viral replication can induce emergency signals that may culminate in a cytokine storm contributing to the severe evolution of COVID-19. Cytokines are key regulators of the immune response and virus clearance, and, as such, are linked to the—possibly altered—response to the SARS-CoV-2. They act via a family of more than 40 transmembrane receptors that are coupled to one or several of the 4 Janus kinases (JAKs) coded by the human genome, namely JAK1, JAK2, JAK3, and TYK2. Once activated, JAKs act on pathways for either survival, proliferation, differentiation, immune regulation or, in the case of type I interferons, antiviral and antiproliferative effects. Studies of graft-versus-host and systemic rheumatic diseases indicated that JAK inhibitors (JAKi) exert immunosuppressive effects that are non-redundant with those of corticotherapy. Therefore, they hold the potential to cut-off pathological reactions in COVID-19. Significant clinical experience already exists with several JAKi in COVID-19, such as baricitinib, ruxolitinib, tofacitinib, and nezulcitinib, which were suggested by a meta-analysis (Patoulias et al.) to exert a benefit in terms of risk reduction concerning major outcomes when added to standard of care in patients with COVID-19. Yet, only baricitinib is recommended in first line for severe COVID-19 treatment by the WHO, as it is the only JAKi that has proven efficient to reduce mortality in individual randomized clinical trials (RCT), especially the Adaptive COVID-19 Treatment Trial (ACTT-2) and COV-BARRIER phase 3 trials. As for secondary effects of JAKi treatment, the main caution with baricitinib consists in the induced immunosuppression as long-term side effects should not be an issue in patients treated for COVID-19.We discuss whether a class effect of JAKi may be emerging in COVID-19 treatment, although at the moment the convincing data are for baricitinib only. Given the key role of JAK1 in both type I IFN action and signaling by cytokines involved in pathogenic effects, establishing the precise timing of treatment will be very important in future trials, along with the control of viral replication by associating antiviral molecules.

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Section: Introductionmentioning

confidence: 99%

JAK inhibitors and COVID-19

Levy

Guglielmelli

Langmuir

et al. 2022

J Immunother Cancer

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“…This is related to inhibition of the interferon-γ pathway 14 . It has been shown before that human T-lymphocyte proliferation is inhibited by tofacitinib, however antiproliferative effects are strongly attenuated, when tofacitinib is given to preactivated PBMCs, which suggests that the surrounding conditions play a pivotal role 15 . Moreover, and again in humans, during phase III studies in patients with rheumatoid arthritis with more than 7000 patients, tofacitinib treatment resulted in an initial increase in lymphocyte counts within the rst 3 months versus pretreatment baseline, which gradually declined to steady state by ~ 48 months 16 .…”

Section: Discussionmentioning

confidence: 99%

Tofacitinib fails to prevent T cell transfer colitis in mice but ameliorates disease activity

Subramanyam

Hrcziko

Pappas

et al. 2022

Preprint

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Introduction: Tofactinib is a JAK inhibitor approved for ulcerative colitis in humans. Despite of its’ proven effectiveness in humans, mechanistic data are scarce on the effectiveness of Tofactinib in experimental colitis in mice. Methods: We induced experimental colitis by transfer of CD4 + CD25- isolated T cells into lymphopenic RAG2-/- mice and treated these mice with tofacitinib for 5–6 weeks either with a dosage of 10 or 40 mg/kg body weight immediately after CD4 + transfer or started treatment after first symptoms of disease for several weeks. Results: While treatment with tofacitinib immediately after transfer resulted in an enhanced expansion of CD4 + T cells and did not prevent occurrence of colitis, treatment after start of symptoms of colitis ameliorated disease activity on a clinical basis and in histological analyses. Discussion: Tofacitinib is effective in the treatment of murine experimental T cell transfer colitis, however does not prevent occurrence of disease.

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“…In vitro, tofacitinib, upadacitinib, and baricitinib were shown to inhibit lymphocyte activation and proliferation in peripheral blood mononuclear cells. Moreover, tofacitinib and baricitinib indicated capabilities of DNA damage repair [82].…”

Section: Dmardsmentioning

confidence: 99%

The Effect of Acknowledged and Novel Anti-Rheumatic Therapies on Periodontal Tissues—A Narrative Review

et al. 2021

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Rheumatoid arthritis (RA) and periodontal disease (PD) are chronic complex inflammatory diseases with several common susceptibility factors, especially genetic and environmental risk factors. Although both disorders involve a perturbation of the immune–inflammatory response at multiple levels, one major difference between the two is the different locations in which they develop. RA is triggered by an exaggerated autoimmune response that targets joints, while periodontal disease occurs as a consequence of the subgingival periodontopathogenic microbiota. Current treatment models in both pathologies involve the stratification of patients to allow therapeutic individualization according to disease stage, complexity, progression, lifestyle, risk factors, and additional systemic diseases. Therapeutic guidelines for RA comprise of five main classes of drugs: non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, glucocorticoids, and disease-modifying anti-rheumatic drugs (DMARDs): biologic and non-biologic. Although various treatment options are available, a definitive treatment remains elusive, therefore research is ongoing in this area. Several alternatives are currently being tested, such as matrix metalloproteinases (MMP) inhibitors, toll-like receptors (TLR) blockers, pro-resolution mediators, anti-hypoxia inducing factors, stem cell therapy, NLRP3 inhibitors and even natural derived compounds. Although the link between PD and rheumatoid arthritis has been investigated by multiple microbiology and immunology studies, the precise influence and causality is still debated in the literature. Furthermore, the immunomodulatory effect of anti-rheumatic drugs on the periodontium is still largely unknown. In this narrative review, we explore the mechanisms of interaction and the potential influence that anti-rheumatoid medication, including novel treatment options, has on periodontal tissues and whether periodontal health status and treatment can improve the prognosis of an RA patient.

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Impact of Different JAK Inhibitors and Methotrexate on Lymphocyte Proliferation and DNA Damage

Cited by 14 publications

References 75 publications

JAK inhibitors and COVID-19

JAK inhibitors and COVID-19

Tofacitinib fails to prevent T cell transfer colitis in mice but ameliorates disease activity

The Effect of Acknowledged and Novel Anti-Rheumatic Therapies on Periodontal Tissues—A Narrative Review

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