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Qiao Yang, Yumo Zhao, Chen Li, Yaping Luo, Weixin Hao, Wen Zhang
INTRODUCTION: Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is an autoinflammatory disorder without standardized treatment. Janus kinase (JAK) inhibitors can block a range of cytokines and might possess significant anti-inflammatory activity. Here, we report the first case of efficacious treatment of refractory SAPHO syndrome with the JAK inhibitor tofacitinib. CASE PRESENTATION: A 44-year-old woman presented with arthralgia in the right wrist and complained of having difficulty in doing housework...
June 2018: Medicine (Baltimore)
Hiromi Shiratori, Carmen Feinweber, Sonja Luckhardt, Nadja Wallner, Gerd Geisslinger, Andreas Weigert, Michael J Parnham
Macrophages undergo activation by pathophysiological stimuli to pro-inflammatory and bactericidal, or wound-healing and anti-inflammatory phenotypes, termed M1 or M2, respectively. Dysregulation of the M1-M2 balance is often associated with inflammatory diseases. Therefore, mechanisms of macrophage polarization may reveal new drug targets. We profiled six compounds with claimed modulatory effects on macrophage polarization using peripheral blood monocyte-derived macrophages. Based on the distinct mRNA or protein expression in macrophages stimulated either with M1 [lipopolysaccharide (LPS) + interferon-γ, IFNγ] or M2 interleukin-4 (IL-4) stimuli, we selected a combination of M1 (IL1β, tumor necrosis factor-α,TNFα, CC chemokine receptor 7, CCR7 and CD80) and M2 (chemokine (C-C motif) ligand 22, CCL22, CD200R and mannose receptor C type 1, MRC1) markers to monitor drug effects on "M1 polarization" or cells "pre-polarized to M1"...
June 16, 2018: European Journal of Pharmacology
Lindsay Claxton, Matthew Taylor, Arif Soonasra, Jeffrey A Bourret, Robert A Gerber
BACKGROUND: Treatment cycling with biologic disease-modifying anti-rheumatic drugs, such as tumor necrosis factor inhibitors (TNFi), is common among patients with rheumatoid arthritis (RA) and can result in reduced clinical efficacy and increased economic burden. Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. OBJECTIVE: To evaluate and compare the economic effect of tofacitinib 5 mg twice daily (BID) treatment directly after methotrexate (MTX) in the MTX-inadequate responder population, or after MTX and 1 TNFi (adalimumab [ADA] or etanercept [ETN]) or 2 TNFi (ADA and ETN) in TNF-inadequate responder patients with RA, from a U...
June 13, 2018: Journal of Managed Care & Specialty Pharmacy
Alison O'Mahony, Markus R John, Hannah Cho, Misato Hashizume, Ernest H Choy
BACKGROUND: Clinical trials have shown combinations of anti-tumor necrosis factor biologicals plus methotrexate (MTX) are more effective treatments for rheumatoid arthritis than biological monotherapies, based, in part, on the assumption that MTX reduces the immunogenicity of biologicals. However, co-treatment with the anti-interleukin-6 receptor-alpha antibody tocilizumab (TCZ) and MTX does not demonstrate the same level of incremental benefit over TCZ monotherapy. Using the human primary cell based BioMAP phenotypic profiling platform, we investigated the impact of TCZ, adalimumab (ADA), and the small molecule drug tofacitinib (TOF), alone and in combination with MTX, on translational biomarkers that could indicate unique pharmacodynamic interactions outside those of reduced immunogenicity...
June 7, 2018: Journal of Translational Medicine
Przemyslaw J Kotyla
The Janus Kinases (JAKs) are a family of intracellular tyrosine kinases that provide transmission signals from cytokine, interferons, and many hormones receptors to the nucleus resulting in synthesis of many biologically active compounds and changing cell metabolism and function. That was theoretical background to synthetize the JAK inhibitors (Jakinibs). In recent years a substantial battery of evidence has been collected indicating the potential role of Jakinibs to interact with the specific elements of the immune system, therefore changing the inflammatory response...
2018: BioMed Research International
Kevin L Winthrop, Gil Y Melmed, Séverine Vermeire, Millie D Long, Gary Chan, Ronald D Pedersen, Nervin Lawendy, Andrew J Thorpe, Chudy I Nduaka, Chinyu Su
Background: Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for ulcerative colitis (UC). Tofacitinib is approved for rheumatoid arthritis and psoriatic arthritis, where it has been shown to increase herpes zoster (HZ) risk. We evaluated HZ risk among UC patients using tofacitinib. Methods: HZ cases were identified in tofacitinib phase II/III/ongoing, open-label, long-term extension (OLE) UC trials. We calculated HZ incidence rates (IRs) per 100 patient-years of tofacitinib exposure within phase III maintenance (Maintenance Cohort) and phase II/III/OLE (Overall Cohort) studies, stratified by baseline demographics and other factors...
May 30, 2018: Inflammatory Bowel Diseases
Jesus K Yamamoto-Furusho
PURPOSE OF REVIEW: Treatment of inflammatory bowel disease (IBD) patients can vary depending on the degree of response, lack of response or intolerance to conventional or biological agents aimed at blocking various cytokines or integrins. Recent therapies targeting several cytokines were reviewed to evaluate efficacy in IBD patients. RECENT FINDINGS: Ustekinumab is an interleukin inhibitor which blocks the p40 subunit of IL-12 and IL-23 axis and is already approved for the treatment of Crohn's disease patients, specially those who had inadequate response or intolerance to conventional treatment with anti-TNF-α agents...
July 2018: Current Opinion in Gastroenterology
Young Eun Kim, Hyung Chul Choi, Gaewon Nam, Bu Young Choi
BACKGROUND: Costunolide (COS), a naturally occurring sesquiterpene lactone, is known to exert anti-inflammatory, antioxidant, and anticancer effects. This study was undertaken to investigate the effects of costunolide on the promotion of hair growth. METHODS: Real-time cell analyzer (RTCA), measurement of 5α-reductase activity, mRNA expression, and Western blotting were adopted to address whether COS can stimulate the proliferation of human hair follicle dermal papilla cells (hHFDPCs)...
May 28, 2018: Journal of Cosmetic Dermatology
Hakan Babaoglu, Ozkan Varan, Nuh Atas, Hasan Satis, Reyhan Salman, Abdurrahman Tufan
No abstract text is available yet for this article.
May 24, 2018: Journal of Clinical Rheumatology: Practical Reports on Rheumatic & Musculoskeletal Diseases
Paul Bird, William Bensen, Bassel El-Zorkany, Jeffrey Kaine, Bernadette Heizel Manapat-Reyes, Virginia Pascual-Ramos, David Witcombe, Koshika Soma, Richard Zhang, Krishan Thirunavukkarasu
BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We performed a comprehensive review of phase 3 studies of tofacitinib 5 mg twice daily (BID) (approved dose in many countries) in patients with moderate to severe RA and inadequate response to prior disease-modifying antirheumatic drugs. METHODS: A search of PubMed and identified 5 studies: ORAL Solo (NCT00814307), ORAL Sync (NCT00856544), ORAL Standard (included adalimumab 40 mg once every 2 weeks; NCT00853385), ORAL Scan (NCT00847613), and ORAL Step (NCT00960440)...
May 24, 2018: Journal of Clinical Rheumatology: Practical Reports on Rheumatic & Musculoskeletal Diseases
Trudy McGarry, Carl Orr, Sarah Wade, Monika Biniecka, Siobhan Wade, Lorna Gallagher, Candice Low, Douglas J Veale, Ursula Fearon
OBJECTIVE: To examine the effect of tofacitinib on metabolic activity, mitochondrial function and pro-inflammatory mechanisms in Rheumatoid Arthritis. METHODS: Ex-vivo RA synovial explants and primary RA synovial fibroblasts (RAFLS) were cultured with tofacitinib (1μM). RAFLS bioenergetics was assessed using the XF24-Flux-analyser, and key metabolic genes by real-time PCR. Mitochondrial function was assessed using specific cell fluorescent probes and by mitochondrial gene arrays...
May 23, 2018: Arthritis & Rheumatology
Jean-Frédéric Colombel
Increased risk of herpes zoster (HZ) has been observed in patients with immune-mediated diseases, including rheumatoid arthritis (RA), psoriasis (PsO), and inflammatory bowel disease; this risk can be further increased by the use of immunosuppressive therapy. One advancing modality of therapy for these diseases is Janus kinase (JAK) inhibition. Tofacitinib is an oral JAK inhibitor for the treatment of RA and psoriatic arthritis, which is currently under investigation for the treatment of ulcerative colitis (UC) and was previously investigated for psoriasis...
May 17, 2018: Inflammatory Bowel Diseases
F Valenzuela, N J Korman, R Bissonnette, N Bakos, T-F Tsai, M K Harper, W C Ports, H Tan, A Tallman, H Valdez, A C Gardner
BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor. Final safety and efficacy data from an open-label extension study of tofacitinib in psoriasis are reported. OBJECTIVE: To evaluate the long-term safety and durability of efficacy of tofacitinib in adults with moderate to severe chronic plaque psoriasis. METHODS: Eligible patients who completed qualifying Phase 2/3 tofacitinib studies received tofacitinib 10 mg twice daily (BID) until Month 3; subsequently, the dose could be adjusted by investigators to either 5 or 10 mg BID...
May 21, 2018: British Journal of Dermatology
A Cinats, E Heck, L Robertson
The class of medications known as Janus kinase inhibitors block cytokine-mediated signaling via the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, which plays an important role in immunoregulation and normal cell growth. This class includes the drugs tofacitinib, approved for the treatment of rheumatoid arthritis, and ruxolitinib, approved for the treatment of myelofibrosis and polycythemia rubra vera. The most common adverse events (AEs) reported in patients taking tofacitinib are infections, whereas the most common AEs in patients taking ruxolitinib are anemia and thrombocytopenia...
May 2018: Skin Therapy Letter
Milan Buc
Crohns disease (CD) and ulcerative colitis (UC) belong to chronic inflammatory bowel diseases, which are induced by autoimmune processes. While CD is characterized by over-activity of Th1, ILC1, and MAIT cells, UC is mediated by exaggerated activities of Th2 and ILC2 cells and cytokines they produce. Knowledge of the pathogenesis enabled a rational therapy based mostly on biologics and small molecules. TNF is the principal proinflammatory cytokine in both diseases. Anti-TNF monoclonal antibodies, mostly infliximab or adalimumab were therefore introduced to their treatment...
2018: Vnitr̆ní Lékar̆ství
Vibeke Strand, Arthur Kavanaugh, Alan J Kivitz, Désirée van der Heijde, Kenneth Kwok, Ermeg Akylbekova, Arif Soonasra, Mark Snyder, Carol Connell, Eustratios Bananis, Josef S Smolen
INTRODUCTION: Here we examine the relationship between achieving different levels of disease activity with tofacitinib (an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis), long-term structural progression, and patient-reported physical function. METHODS: This was a post hoc analysis of two 24-month, phase III randomized controlled trials in methotrexate (MTX)-naïve (ORAL Start [NCT01039688]) or MTX-inadequate responder (IR) patients (ORAL Scan [NCT00847613]) receiving tofacitinib 5 or 10 mg twice daily as either monotherapy or with background MTX...
May 14, 2018: Rheumatology and Therapy
Elana Putterman, Leslie Castelo-Soccio
No abstract text is available yet for this article.
June 2018: Journal of the American Academy of Dermatology
L Fitz, W Zhang, C Soderstrom, S Fraser, J Lee, A Quazi, R Wolk, C A Mebus, H Valdez, G Berstein
BACKGROUND: Psoriasis is a systemic inflammatory disease with a pathophysiology involving interleukin (IL)-17. Tofacitinib is an oral Janus kinase inhibitor. Etanercept is a tumour necrosis factor-α inhibitor used in the treatment of psoriasis. Neither agent inhibits IL-17 directly. AIM: To evaluate correlations between circulating IL-17A and clinical efficacy in patients with psoriasis treated with tofacitinib or etanercept. METHODS: Serum concentrations of IL-17A homodimer and IL-17A/F heterodimer were determined by immunoassays at weeks 0, 4 and 12 in patients with moderate to severe psoriasis treated with placebo (n = 60), tofacitinib 5 mg twice daily (n = 184), tofacitinib 10 mg twice daily (n = 190), or etanercept 50 mg subcutaneously twice weekly (n = 190)...
May 10, 2018: Clinical and Experimental Dermatology
Satoshi Motoya, Mamoru Watanabe, Hyo Jong Kim, Young Ho Kim, Dong Soo Han, Hirotoshi Yuasa, Junichi Tabira, Naoki Isogawa, Shoko Arai, Isao Kawaguchi, Toshifumi Hibi
Background/Aims: Tofacitinib is an oral, small-molecule Janus kinase inhibitor being investigated for ulcerative colitis (UC). In OCTAVE Induction 1 and 2, patients with moderately to severely active UC received placebo or tofacitinib 10 mg twice daily (BID) for 8 weeks. Clinical responders in OCTAVE Induction were re-randomized to 52 weeks' therapy with placebo, tofacitinib 5 mg BID, or tofacitinib 10 mg BID. Methods: We conducted post-hoc efficacy and safety analyses of East Asian patients in OCTAVE Induction 1 and 2 and OCTAVE Sustain...
April 2018: Intestinal Research
Ankit Srivastava, Mona Ståhle, Andor Pivarcsi, Enikö Sonkoly
Tofacitinib is a Janus kinase (JAK) inhibitor, which has shown efficacy in treating psoriasis. The mode of action of tofacitinib is not completely understood but it has been thought to be mediated by the inhibition of CD4+ T-cell activation. Here, we investigated whether the molecular targets of tofacitinib are expressed in keratinocytes, and whether tofacitinib can modulate the activity of the JAK/Signal Transducer and Activators of Transcription (STAT)-pathway in keratinocytes. Transcriptomic profiling of human keratinocytes treated with IL-22 in combination with tofacitinib revealed that tofacitinib could prevent the majority of IL-22-mediated gene expression changes...
May 8, 2018: Acta Dermato-venereologica
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