Publications

Effects of One-Year Tofacitinib Therapy on Bone Metabolism in Rheumatoid Arthritis

Osteoporos Int 2021 Feb 9 DOI 10.1007/s00198-021-05871-0

Hamar A,

Szekanecz Z,

Pusztai A,

Czókolyová M,

Végh E,

Pethő Z,

Bodnár N,

Gulyás K,

Horváth Á,

Soós B,

Bodoki L,

Bhattoa H. P,

Nagy G,

Tajti G,

Panyi G,

Szekanecz É,

Domján A,

Hodosi K,

Szántó S,

Szűcs G,

Szamosi S

Thought to be the first study of its kind, Hamar, et al. have demonstrated the effect of one-year tofacitinib treatment on bone mineral density (BMD) in RA patients. While the association between RA and osteoporosis is well known, and evidence indicates that up to 70% of these patients have reduced BMD, little information is available on how the JAK inhibitor tofacitinib affects bone status, areal and volumetric BMD, and bone turnover markers. In this prospective study, 30 patients were assessed...

Keywords:

• JAK,
• Tofacitinib,
• Bone

Upadacitinib Monotherapy Versus Methotrexate Monotherapy in Methotrexate-naïve Japanese Patients with Rheumatoid Arthritis: A Sub-analysis of The Phase 3 SELECT-EARLY study

Mod Rheumatol 2021;26:1–16.

Takeuchi T,

Rischmueller M,

Blanco R,

Xavier RM,

Ueki Y,

Atsumi T,

Chen S,

Friedman A,

Pangan AL,

Strand V,

van Vollenhoven RF

In this sub-analysis of the Phase 3 SELECT-EARLY study, UPA demonstrated clinical efficacy superior to placebo in the Japanese subpopulation. Along with a favourable efficacy observed with the Japan-specific 7.5 mg dose of UPA for all secondary endpoints. SELECT-EARLY was designed to study the safety and efficacy of UPA 15 and 30mg as monotherapy, but it also included a subset of 138 Japanese patients, 40% of whom were randomised to receive UPA 7.5mg. This was designed to meet the requirements o...

Keywords:

• JAK,
• Updacitinib,
• Phase 3

The JAK/STAT Pathway: A Focus on Pain in Rheumatoid Arthritis

Semin Arthritis Rheum. 2021 Feb;51(1):278-284

Simon LS,

Taylor PC,

Choy EH,

Sebba A,

Quebe A,

Knopp KL,

Porreca F

Many cytokines associated with RA pathogenesis and pain are affected directly or indirectly by the JAK/STAT pathway, therapeutic targeting may offer promise. Having better understanding of these mechanisms can help clinicians make treatment decisions that optimise the control of inflammation and pain. However, pain in patients with RA is complex and involves multiple driving mechanisms that may differentially occur over time in different people. Although one known constant is that nociceptive ac...

Keywords:

• JAK,
• Basic Science,
• Review

Preclinical characterisation of itacitinib, a Novel Selective Inhibitor of JAK1, for the Treatment of Inflammatory Diseases

European Journal of Pharmacology. 2020 Oct 15;885:173505. doi: 10.1016/j.ejphar.2020.173505

Covington M,

He X,

Scuron M,

Li J,

Collins R,

Juvekar A,

Shin N,

Favata M,

Gallagher K,

Sarah S,

Xue CB,

Peel M,

Burke K,

Oliver J,

Fay B,

Yao W,

Huang T,

Scherle P,

Diamond S,

Newton R,

Zhang Y,

Smith

Itacitinib is an orally active JAK inhibitor and effectively delayed disease onset, reduced symptom severity, and accelerated recovery of inflammatory diseases in mouse models. Covington M et al demonstrated itacitinib’s high selectivity for JAK 1, its inhibition on IL-2 induced T cell proliferation and JAK/STAT signalling, its ability to also inhibit of the JAK/STAT pathway in response to IL-6 stimulation, and its effect on rat adjuvant induced arthritis model. The study used recombinant enzym...

Keywords:

• JAK,
• Itacitinib

Baricitinib, a drug with potential effect to prevent SARS-COV-2 from entering target cells and control cytokine storm induced by COVID-19

Journal of International Immunopharmacology. 2020 Sep;86:106749. doi: 10.1016/j.intimp.2020.106749.

Zhang X,

Zhang Y,

Qiao W,

Zhang J,

Qi Z

BARI may potentially interrupt the passage of SARS-CoV-2 into the target cells by binding to AAK1 and GAK, which are regulators of the ACE2 receptor regulator identified for its uptake, and could also treat cytokine storm through suppression JAK1/JAK2. Professor Zhang and et al reviewed BARI, as a potential drug to prevent SARS-COV-2 from entering target cells. They also evaluated BARI’s ability to control COVID-19 induced cytokine storm. As a cell surface protein, ACE2 is involved in receptor-m...

Keywords:

• JAK,
• Baricitinib

JAK Inhibition Increases Bone Mass in Steady state Conditions and Ameliorates Pathological Bone Loss by Stimulating Osteoblast Function

Sci Transl Med 2020;12(530):pii: eaay4447

Adam S,

Simon N,

Steffen U,

Andes FT,

Scholtysek C,

Müller DIH,

Weidner D,

Andreev D,

Kleyer A,

Culemann S,

Hahn M,

Schett G,

Krönke G,

Frey S,

Hueber AJ

JAKi significantly increased osteoblast function but showed no direct effects on osteoclasts.JAK signalling has emerged as an important therapeutic target for inflammatory disease, and the immunomodulation of JAK inhibition is well defined. Less well understood is the influence of this new class of drugs on bone homeostasis. This is important, as cytokine dysregulation triggers bone loss, and periarticular erosions contribute to the pathogenesis of RA. This study investigated the effect of BARI ...

Keywords:

• JAK,
• Bone

Filgotinib, a JAK1 Inhibitor, Modulates Disease Related Biomarkers in Rheumatoid Arthritis: Results from Two Randomized, Controlled Phase 2b Trials

Rheumatol Ther. 2020 DOI: 10.1007/s40744-019-00192-5

Tarrant JM,

Galien R,

Wanying L,

Goyal L,

Pan Y,

Hawtin R,

Zhang W,

Van der Aa A and Taylor PC

In this study examining the effect of FIL on a panel of biomarkers, FIL down-modulated several key inflammatory mediators of signalling pathways in RA - independent of MTX background therapy. This confirmed the strong network effects of the JAK1 node in autoimmunity, matrix and cartilage degradation, angiogenesis, and leukocyte adhesion and recruitment. Biomarkers key to RA pathophysiology were measured at baseline, Wk4 and Wk12 in FIL 100 mg, FIL 200 mg or PBO treatment groups from two phase 2b...

Keywords:

• JAK,
• Filgotinib,
• Phase 2,
• MOA,
• Biomarkers

Osteoimmunology In Rheumatoid and Psoriatic Arthritis: Potential Effects of Tofacitinib on Bone Involvement

Clin Rheumatol. 2020

Orsolini G,

Bertoldi I,

Rossini M.

Data showing that TOF can inhibit unbalanced osteoclastogenesis in RA suggests that targeting the JAK-STAT pathway can halt bone erosion, as TOF has been shown to reduce articular bone erosion in RA and PsA.The authors in this review summarise current knowledge on the relationship between the immune system and the skeleton before examining the involvement of JAK-STAT signalling in bone homeostasis while discussing the evidence on the benefit of TOF on prevention of bone involvement in RA and PsA...

Keywords:

• JAK,
• Tofacitinib,
• Basic Science

A systematic review and meta-analysis of infection risk with small molecule JAK inhibitors in rheumatoid arthritis

Rheumatology (Oxford) 2019;58(10):1755–66

Bechman K,

Subesinghe S,

Norton S,

Atzeni F,

Galli M,

Cope AP,

Winthrop KL,

Galloway JB

Absolute serious infection rates were low. However, across the JAKinibs, the incidence of HZ is higher than expected for the population. While the risk was numerically greatest with BARI, indirect comparisons between the drugs did not demonstrate any significant difference in risk. How JAKinibs increase the risk of HZ reactivation is unclear, but how different JAKs interact in the immune response suggest that there may be differences in safety profiles between JAKinib drugs, underpinned by their...

Keywords:

• Safety,
• Review

Evaluation of Pneumococcal and Tetanus Vaccine Responses in Patients with Rheumatoid Arthritis Receiving Baricitinib: Results from a Long-Term Extension Trial Substudy

Arthritis Res Ther. 2019 Apr 18;21(1):102

Winthrop KL,

Bingham CO III,

Komocsar WJ,

Bradley J,

Issa M,

Klar R,

Kartman CE

Approximately two thirds of long-term BARI treated patients achieved satisfactory humoral and functional responses to 13-serotype pneumococcal conjugate vaccine (PCV-13), whereas tetanus toxoid vaccine (TTV) responses were less robust. Both RA management guidelines and recommendations suggest vaccinating patients with RA against pneumococcal disease with PCV-13 and PPSV-23. The inhibition of the JAK mediated signal transduction pathways in RA treatment could diminish vaccine responses. Given the...

Keywords:

• JAK,
• Baricitinib,
• Vaccination