Cytokine Signalling Forum

Publications





June 20

Comparative effectiveness of antitumour necrosis factor agents, biologics with an alternative mode of action and tofacitinib in an observational cohort of patients with rheumatoid arthritis in Switzerland

Finckh A, Tellenbach C, Herzog L, Scherer A, Moeller B, Ciurea A, von Muehlenen I, Gabay C, Kyburz D, Brulhart L, Müller R, Hasler P, Zufferey P.
RMD Open 2020;6:e001174 doi:10.1136/rmdopen-2020-001174

This nested cohort study found that, in Switzerland, there was a generally limited overall drug maintenance for b/tsDMARD options in RA. Using data from SCQM-RA – a prospective longitudinal registry, overall maintenance (drug survival) was calculated for TNFi, bDMARD-OMA or JAKi in patients with RA. After adjusting for potential confounding factors, there was a higher hazard of drug discontinuation with TNFi compared with tofacitinib; no significant difference was observed between non-TNF ...

Temporary Interruption of Baricitinib: Characterization of Interruptions and Effect on Clinical Outcomes in Patients With Rheumatoid Arthritis

Emery P, Tanaka Y, Cardillo T, Schlichting D, Rooney T, Beattie S, Helt C, Smolen JS.
Arth Res Ther 2020;22:115 doi.org/10.1186/s13075-020-02199-8

This study aimed to characterize temporary interruptions of baricitinib and describe their impact on efficacy and safety. Brief interruptions during phase 3 baricitinib trials were associated with minor increases in symptoms which were resolved following treatment. In life-long, chronic conditions such as RA, interruption of therapy is common for various reasons, such as side effects, non-compliance, or because a patient requires surgery. Concerns have been raised that these treatment breaks c...

Safety Profile of Baricitinib For the Treatment of Rheumatoid Arthritis Over a Median of 3 Years of Treatment: An Updated Integrated Safety Analysis

Genovese MC, Smolen JS, Takeuchi T, Burmester G, Brinker D, Rooney TP, Zhong J, Daojun M, Saifan C, Cardoso A, Issa M, Wu W-S, Winthrop KL.
Lancet Rheumatol 2020;2:e347–57

RA is a chronic, life-long disease requiring long-term treatment. As such, it is important to understand the long-term safety profile of DMARDs. In this analysis, baricitinib maintained a stable safety profile during long-term exposure. This baricitinib safety analysis included integrated data from nine Phase 3, 2, and 1b clinical trials, and one long-term extension, with data up to 360 weeks. 3700 patients were included, with maximum follow-up of almost 7 years – representing an additio...

Baricitinib In Patients with Rheumatoid Arthritis With Inadequate Response to Methotrexate: Results From A Phase 3 Study

Li Z, Hu J, Bao C, Li X, Li X, Xu J, Spindler AJ, Zhang X, Xu J, He D, Li Z, Wang G, Yang Y, Wu H, Ji F, Tao H, Zhan L, Bai F, Rooney TP, Zerbini CAF.
Clin Exp Rheumatol 2020

This study conducted mainly in Chinese patients with RA, and an inadequate response to MTX, showed that baricitinib 4mg was associated with significant improvements and consistent with the findings from previous clinical trials. The efficacy and safety of baricitinib have been assessed in several clinical trials, predominantly in Caucasian populations. However, evidence on the efficacy and safety of baricitinib in Chinese patients is limited, with only one of the main clinical trial program stu...

May 20

Fénébrutinib Versus Placebo ou Adalimumab Dans la Polyarthrite Rhumatoïde : un Essai de Phase II Randomisé, en Double Aveugle (Étude ANDES)

Cohen S, Tuckwell K, Katsumoto TR, Zhao R, Galanter J, Lee C, Rae J, Toth B, Ramamoorthi N, Hackney JA, Berman A, Damjanov N, Fedkov D, Jeka S, Chinn LW, Townsend MJ, Morimoto AM, Genovese MC.
Arthritis Rheumatol 2020. DOI 10.1002/art.41275.

In this randomised phase II trial with MTX treatment-refractory RA patients, greater efficacy was observed with fenebrutinib 150 mg once daily or 200 mg twice daily compared to placebo, while response rates were numerically similar to those observed with adalimumab. BTK inhibitors have demonstrated clinical efficacy in B cell malignancies and multiple sclerosis, although there is limited clinical evidence of its efficacy in RA. Fenebrutinib (FEN) an orally active and selective non-covalent inh...

Mots clefs: BTK, Clinical, Phase 2

Traduit par: Melissa Noack

Évaluation du Virus de l'Hépatite B Dans les Essais Cliniques du Baricitinib Dans la Polyarthrite Rhumatoïde

Harigai M, Winthrop K, Takeuchi T, Hsieh T-Y, Chen Y-M, Smolen JS, Burmester G, Walls C, Wu W-S, Dickson C, Liao R, Genovese MC.
RMD Open 2020;6:e001095

Although hepatitis B virus (HBV) reactivation was seen in patients with RA treated with DMARDs, including BARI, who had serology suggestive of prior infection, reactivation was transient even with continued BARI treatment and did not account for any clinically relevant AEs. Reactivation of HBV replication is a recognised complication in patients receiving biologic agents for RA, such as DMARDs. Limited data exist on prevalence of occult infection and the incidence of reactivation in RA patients...

Mots clefs: JAK, Baricitinib, Clinical, Safety

Traduit par: Melissa Noack

Analyse Intégrée de l‘Innocuité du Tofacitinib Dans le Rhumatisme Psoriasique À Travers des Études de Phase III et de Prolongation à Long Terme en Comparaison Avec les Données D'observation du Monde Réel

Burmester GR, Curtis JR, Yun H, FitzGerald O, Winthrop KL, Azevedo VF, Rigby WFC, Kanik KS, Wang C, Biswas P, Jones T, Palmetto N, Hendrikx T, Menon S, Rojo R.
Drug Saf. 2020;43:379-392

Patients with psoriatic arthritis (PsA) had similar safety profile with TOF to that of other systemic therapies in real-world settings, except for the known risk of HZ. Treatment recommendations from EULAR and GRAPPA for patients with PsA vary according to adverse prognostic risk factors, disease manifestations and responsiveness to prior treatment. Safety concerns for most PsA therapies include gastrointestinal AEs, hepatotoxicity, opportunistic infections (OIs) including TB, and SIEs. This s...

Mots clefs: JAK, Tofacitinib, Real World, Safety

Traduit par: Melissa Noack

April 20

Efficacité et Innocuité Relatives du Tofacitinib, Baricitinib, Upadacitinib et Filgotinib par Rapport à l'Adalimumab Chez les Patients Atteints de Polyarthrite Rhumatoïde Active

Lee YH, Song GG.
Z Rheumatol. 2020 DOI: 10.1007/s00393-020-00750-1

This Bayesian network meta-analysis, comparing the relative efficacy and safety of JAK inhibitors, determined BARI 4mg + MTX and UPA 15mg + MTX were the most effective. The analysis included 5451 patients with an inadequate response to MTX and active RA, from four RCTs. Relative effects were converted into a probability allowing each treatment to be ranked. BARI and UPA had significantly higher ACR20 response rates than ADA 40mg + MTX whilst TOF 5mg and FIL 200mg had comparable ACR20 response ...

Mots clefs: JAK, Baricitinib

Traduit par: Melissa Noack

Efficacité à Long Terme du Vaccin Vivant Atténué Contre le VZV Chez les Patients Atteints de Polyarthrite Rhumatoïde Traités Consécutivement au Tofacitinib

Winthrop KL, Wouters A, Choy EH, Chen C, Biswas P, Wang L, Soma K, Needle E, Valdez H, Rigby WFC.
Ann Rheum Dis. 2020 DOI: 10.1136/annrheumdis-2019-216566

The results of ORAL Sequel suggest that the live zoster vaccine (LZV) may not provide adequate long-term protection in patients with RA receiving TOF. This LTE study enrolled 100 patients with RA, 14 weeks post LZV vaccination. Patients received either TOF 5 mg BID, or TOF 10 mg BID in addition to any background csDMARDs. Incidence rates and 95% CIs for HZ post-vaccination were calculated based on time to first event. Short-term varicella zoster vaccine (VZV) specific immunity was evaluated a...

Mots clefs: JAK, Tofacitinib, Clinical, Safety

Traduit par: Melissa Noack

La Vascularite à IgA , Effet Indésirable du Tofacitinib Pris Pour la Polyarthrite Rhumatoïde

Itoh I, Kasuno K, Yamamoto C, Takahashi N, Shimizu H, Ojima T, Hayashi S, Kimura H, Iwano M.
Intern Med. 2020;59(6):817-821

Nephrotoxicity is a key side effect of NSAIDs and DMARDs used to treat RA, while biologics can reportedly cause proliferative glomerulonephritis or crescentic glomerulonephritis. This report reviews a patient on TOF presenting IgA vasculitis as an adverse effect that fully resolved following termination of TOF. Drug induced IgA vasculitis has been previously described for anti-TNFɑ therapies, but this is the first report with JAK inhibitor therapy. This is a case report of a 67-year old woman w...

Mots clefs: JAK, Tofacitinib, Real World, Safety

Traduit par: Melissa Noack

March 20

Exposition au Baricitinib Pendant la Grossesse en Cas de Polyarthrite Rhumatoïde

Costanzo G, Firinu D, Losa F, Deidda M, Barca MP, Del Giacco S.
Ther Adv Musculoskelet Dis. 2020;12:1759720X19899296

Broad and focused studies are required to have an insight of safety for small molecules, such as JAK inhibitors in the case of accidental exposure before or during pregnancy. This case study’s objective describes a case report of a 43-year-old woman affected by RA who became pregnant during BARI treatment. She has had two previous pregnancies at term without complications. After failure of bDMARDs due to loss of efficacy and adverse drug reactions, the patient was started on BARI when i...

Mots clefs: JAK, Baricitinib, Real World, Safety

Traduit par: Melissa Noack

Impact de l'Inhibition de Janus Kinase par le Tofacitinib sur les Processus Fondamentaux de la Régénération Osseuse

Gaber T, Brinkman ACK, Pienczikowski J, Diesing K, Damerau A, Pfeiffenberger M, Lang A, Ohrndorf S, Burmester G-R, Buttgereit F, Hoff P.
Int J Mol Sci 2020;21:865

TOF demonstrated a dose-dependent promotion of human mesenchymal stromal cell (hMSC) recruitment under hypoxia, while inhibiting recruitment under normoxia. TOF also dose-dependently enhances osteogenic differentiation of hMSCs and reduces osteoclast differentiation and activity. As people age, they are more likely to suffer from fractures and delayed bone healing, as well as degenerative joint diseases or osteoporosis. Bone metabolism and fracture healing may be negatively affected by underl...

Mots clefs: JAK, Tofacitinib, Clinical

Traduit par: Melissa Noack

L‘Inhibition De JAK Augmente La Masse Osseuse À L'état Stable Et Améliore La Perte Osseuse Pathologique En Stimulant La Fonction Ostéoblastique

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

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 B...

Mots clefs: JAK, Baricitinib, Preclinical

Traduit par: Melissa Noack

February 20

Recommandations EULAR Pour la Prise en Charge de la Polyarthrite Rhumatoïde - Mise à Jour 2019 et Déclaration de Consensus sur les JAKinibs

Smolen JS, Landewé RBM, Bijlsma JWJ, Burmester GR, Dougados M, Kerschbaumer A, McInnes IB, Sepriano A, et al.
Ann Rheum Dis. 2020 Jan 22. pii: annrheumdis-2019-216655.

The EULAR recommendations for the management of RA have become increasingly useful in providing rheumatologists, patients, payers and other stakeholders with the evidence-based guidance and views of experts on the optimal use and sequence of pharmaceutical therapies in patients with RA. Over the course of the last decade, the evolution of the treatment landscape has already required two updates. The release of the new addition updates the 2016 recommendations. An international task force consid...

Mots clefs: JAK

Traduit par: Melissa Noack

Le Filgotinib, Un Inhibiteur de JAK1, Module les Biomarqueurs Liés à la Maladie dans la Polyarthrite Rhumatoïde : Résultats de Deux Essais Contrôlés Et Randomisés de Phase 2b

Tarrant JM, Galien R, Wanying L, Goyal L, Pan Y, Hawtin R, Zhang W, Van der Aa A and Taylor PC.
Rheumatol Ther. 2020 DOI: 10.1007/s40744-019-00192-5

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 ...

Mots clefs: JAK, Filgotinib, Clinical, Phase 2

Traduit par: Melissa Noack

Inhibition Préférentielle de JAK1 Par Rapport à JAK3 par l'Upadacitinib : Analyses Exposition-Réponse des Données Ex Vivo de 2 Essais Cliniques de Phase 1 et Comparaison Avec le Tofacitinib

Mohamed MF, Beck D, Camp HS, Othman AA.
Pharmacodynamics. 2020

Ex vivo pharmacodynamic assay results demonstrated a greater selectivity of UPA on JAK1 versus JAK3 compared to TOF. This analysis conducted ex vivo stimulation of STAT3 phosphorylation by IL-6 as a measure of JAK1 activity and STAT5 phosphorylation by IL-7 as a measure of JAK1/JAK3 activity. Change in pSTAT3 and pSTAT5 were calculated at 1, 6 and 12 hours following drug administration using samples collected from healthy subjects and subjects with RA, from 2 phase 1 studies. Exposure-response...

Mots clefs: JAK, Upadacitinib, Preclinical, MOA

Traduit par: Melissa Noack

January 20

Safety, Tolerability, Pharmacokinetics, Target Occupancy, and QT Analysis of the Novel BTK Inhibitor Evobrutinib in Healthy Volunteers

Becker A, Martin EC, Mitchell DY, Grennigloh R, Bender AT, Mackenzie H and Johne A.
Clin Transl Sci. 2019

In this first in-human phase I, double-blind, placebo-controlled trial, the Bruton’s tyrosine kinase (BTK) inhibitor evobrutinib was well-tolerated, showed linear and time-independent PK, induced long-lasting BTK inhibition, and was not associated with prolongation of QT/QTc interval in healthy subjects. Evobrutinib is an oral BTK inhibitor that has demonstrated efficacy in pre-clinical and autoimmune disease models. BTK is a key regulator of B cell receptor and Fc receptor signalling, an...

Tofacitinib in Combination with Methotrexate in Patients with Rheumatoid Arthritis: Patient-reported Outcomes from the 24-month Phase 3 ORAL Scan study

Strand V, van der Heijde D, Tanaka Y, Keystone E, Kremer J, Zerbini C A F, Cardiel M H, Cohen S, Nash P, Song Y-W, Tegzová D, Gruben D, Wallenstein G, Connell C A, Fleischmann R.
Clin Exp Rheumatol. 2019

In the ORAL SCAN study, patients receiving TOF 5 mg or 10 mg BID reported significant improvements in patient-reported outcomes at month 3 compared with placebo, which were maintained through 24 months of treatment. RA causes a significant health and socioeconomic burden and affects all aspects of health related quality of life. ORAL Scan included patients with active RA and inadequate response to MTX who were randomised to receive TOF 5 mg or 10 mg BID plus MTX or PBO. This study evaluated the ...

Effects of Upadacitinib on Patient-Reported Outcomes: Results from SELECT-BEYOND, a Phase 3 Randomized Trial in Patients with Rheumatoid Arthritis and Inadequate Responses to Biologic Disease-Modifying Antirheumatic Drugs

Strand V, Schiff M, Tunida N, Friedman A, Meerwein S, Pangan A, Ganguli A, Fuldeore M, Song Y, Pope J.
Arthritis Research & Therapy 2019

In SELECT-BEYOND, UPA demonstrated clinically meaningful improvements in patient reported outcomes compared to PBO in patients with RA who had an inadequate response to bDMARDs. In this post-hoc analysis of the SELECT-BEYOND study, the effect of UPA 15 or 30 mg on patient reported outcomes were assessed and compared to PBO. Eligible patients (498) with an inadequate response to bDMARDs were randomly assigned 1:1:1 to receive UPA 15 mg, UPA 30 mg or PBO. PROs collected at Wk1, Wk4, and Wk12 inclu...

Upadacitinib Improves Patient-Reported Outcomes in Patients with Rheumatoid Arthritis and Inadequate Response to Conventional Synthetic Disease-Modifying Antirheumatic Drugs: Results from SELECT-NEXT

Strand V, Pope J, Tundia N, Friedman A, Camp H, Pangan A, Ganguli A, Fuldeore M, Goldschmidt D, Schiff M.
Arthritis Research & Therapy 2019

In SELECT-NEXT, UPA demonstrated clinically meaningful improvements in patient reported outcomes compared to PBO in patients with RA who had an inadequate response to csDMARDs. In this post hoc analysis, the effect of UPA 15 or 30 mg on patient reported outcomes were assessed and compared to PBO. Eligible patients (661) with an inadequate response to csDMARDs were randomly assigned 2:2:1:1 to receive background csDMARD therapy with either UPA 15 mg, UPA 30 mg or PBO. PROs collected at Wk4 and Wk...

December 19

Innocuité Et Efficacité Du Péficitinib Sur Deux Ans Dans La Polyarthrite Rhumatoïde Modérée À Sévère : Une Étude De Prolongation Ouverte De Phase IIb

Genovese MC, Greenwald MW, Gutierrez-Ureña SR.
Rheumatol Ther. 2019

Peficitinib (PEF) 100 mg QD demonstrated a stable safety profile and sustained effectiveness in patients with moderate-to-severe RA in a two-year extension of two global phase IIb studies. Patients enrolled in the LTE had completed one of two 12-week phase IIb PEF trials, one with MTX and one without. The primary objective of the LTE was to assess treatment-emergent adverse events and clinical laboratory evaluations for 105 weeks. As a secondary objective, an additional 2-years of effectivenes...

Mots clefs: JAK, Peficitinib, Clinical, Safety

Traduit par: Melissa Noack

Innocuité Du Baricitinib Chez Les Patients d‘Asie De l‘Est Atteints De Polyarthrite Rhumatoïde Active Modérée À Sévère : Une Analyse Intégrée À Partir d‘Essais Cliniques

Chen YC, Yoo DH, Lee CK.
Int J Rheum Dis 2019

Post-hoc analyses of five completed phase II and III trials and an ongoing LTE suggested that BARI QD is well tolerated in East Asian patients with moderate-to-severe RA, with a similar safety and tolerability profile to the overall population. The majority of clinical evidence for RA treatments has been obtained from a predominantly Caucasian population, which may not be relevant to East Asian patients. In this post-hoc safety analysis, 740 Japanese, Taiwanese, Korean and Chinese patients were...

Mots clefs: JAK, Baricitinib, Clinical, Safety

Traduit par: Melissa Noack

November 19

Analyses Exposition-Réponse de l'Efficacité et de l'Innocuité de l'Upadacitinib Dans des Études de Phases 2 et 3 Pour Étayer l'Évaluation Bénéfices-Risques Dans la Polyarthrite Rhumatoïde

Nader A, Mohamed M-EF, Winzenborg I, Doelger E, Noertersheuser P, Pangan AL, Othman AA.
Clin Pharmacol Ther 2019

UPA 15 mg provided the optimal benefit-risk in RA through maximizing efficacy with only small incremental benefit with 30 mg, and with consistency across RA subpopulations and with UPA monotherapy or combination with csDMARDs. Exposure-response analyses were conducted using combined data from two Phase 2b and five Phase 3 studies in order to characterise the relationship between plasma exposure and efficacy, as well as to select safety parameters using the totality of the data in subjects with...

Mots clefs: JAK, Upadacitinib, Clinical, Efficacy

Traduit par: Melissa Noack

Efficacité et Innocuité Comparées du Péficitinib 25, 50, 100 et 150 mg Chez les Patients Atteints de Polyarthrite Rhumatoïde Active : Une Méta-Analyse Bayésienne en Réseau d'Essais Contrôlés Randomisés

Lee YH, Song GG.
Clin Drug Investig 2019

PEF 50, 100, and 150 mg once daily was effective in treating active RA, without causing a significant risk for AEs. Intracellular pathways, including JAK and Tyk-2, are critical for immune cell activation, pro-inflammatory cytokine production, and cytokine signaling. PEF has been developed for use in RA, but the comparative efficacy and safety of regimens and dosages has not been established. A Bayesian network meta-analysis was conducted to combine direct and indirect evidence to assess the re...

Mots clefs: JAK, Peficitinib, Clinical, Efficacy

Traduit par: Melissa Noack

Une Revue Systématique et une Méta-Analyse du Risque d'Infections avec les Petites Molécules, Inhibiteurs de JAK dans la Polyarthrite Rhumatoïde

Bechman K, Subesinghe S, Norton S, Atzeni F, Galli M, Cope AP, Winthrop KL, Galloway JB.
Rheumatology (Oxford) 2019;58(10):1755–66

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 the...

Mots clefs: JAK, Baricitinib, Clinical, Safety

Traduit par: Melissa Noack

Le Tofacitinib Module la Réponse Immunitaire des Cellules T CD4+ Spécifiques du VZV in vitro Dans les Lymphocytes de Patients Atteints de Polyarthrite Rhumatoïde

Almanzar A, Kienle F, Schmalzing M, Maas A, Tony H-P, Prelog M.
Rheumatology (Oxford) 2019;58(11):2051–60

TOF significantly modulated the Th1 response to Varicella-zoster-virus (VZV). The poor VZV-specific cellular immune responses in patients with RA may be considered in recommendations regarding appropriate vaccination strategies for enhancing the VZV-specific Th1 response. Previous studies have shown that treatment with JAKinibs increases HZ incidence compared with conventional DMARDs. This cross-sectional in vitro study aimed to investigate the effect of TOF on the VZV-specific T cell immune re...

Mots clefs: JAK, Tofacitinib, Clinical, Safety

Traduit par: Melissa Noack

October 19

Facteurs de Risque d'Événements Cardiovasculaires Indésirables Majeurs Dans les Études de Phase III et de Prolongation à Long Terme du Tofacitinib chez les Patients Atteints de Polyarthrite Rhumatoïde

Christina Charles-Schoeman, Ryan DeMasi, Hernan Valdez, Koshika Soma, Lie-Ju Hwang, Mary G Boy, Pinaki Biswas, Iain B McInnes.
Ann Rheum Dis. 2019

Post hoc analyses of the six ORAL studies and two LTE’s suggested that after 24 weeks of TOF treatment, increases in HDL-c and decreases in the TC/HDL-c ratio appeared to be associated with reduced future MACE risk in RA patients. 52 MACE occurred in 4076 patients over 12873 patient-years of exposure. Separate Cox regression models were used to evaluate traditional CV risk factors’ association with time to first MACE at baseline and changes in lipid levels with time to future MACE ...

Mots clefs: JAK, Tofacitinib, Real World, Cardiovascular

Traduit par: Melissa Noack

Évolution des Taux Lipidiques et de l'Incidence des Événements Cardiovasculaires Après un Traitement au Tofacitinib chez les Patients Atteints de Rhumatisme Psoriasique : Une Analyse Regroupée des Études de Phase 3 et de Prolongation à Long Terme

Gladman DD, Charles-Schoeman C, McInnes IB, Veale DJ, Thiers B, Nurmohamed M, Graham D, Wang C, Jones T, Wolk R, DeMasi R.
Arthritis Care Res (Hoboken) 2019;71(10):1387–95

Serum lipid level increases at month 3 following TOF treatment in PsA were consistent with observation in RA and psoriasis. The risk of CV disease is higher in people with PsA versus the general population – comparable with the well-documented rates seen in RA and diabetes. The reasons for this are not fully elucidated, but it has been suggested that there is an association between peripheral joint inflammation and lipid dysregulation in PsA. This post hoc analysis of pooled data from ...

Mots clefs: JAK, Tofacitinib, Clinical, Safety

Traduit par: Melissa Noack

Effet du Baricitinib et de l'Adalimumab sur la Réduction de la Douleur et l'Amélioration Fonctionnelle Chez les Patients Atteints de Polyarthrite Rhumatoïde en Cas de Faible Activité de la Maladie : Analyses Exploratoires de la RA-BEAM

Fautrel B, Kirkham B, Pope JE, Takeuchi T, Gaich C, Quebe A, Zhu B, de la Torre I, De Leonardis F, Taylor PC.
J Clin Med. 2019 Sep 5;8(9). pii: E1394

Post hoc analyses from RA-BEAM concluded that BARI 4 mg QD or ADA 40 mg Q2W resulted in improvements in pain, physical function, fatigue and work productivity in patients with RA, independent of the treatment’s impact on inflammation. Among patients achieving remission or LDA, greater improvements in pain and physical function were seen with BARI than with ADA or PBO. Of 1010 patients included in the analysis at Week 24, 168 were in remission, 310 were in remission/LDA and 700 were not in...

Mots clefs: JAK, Baricitinib, Clinical, PRO

Traduit par: Melissa Noack

September 19

Devenir de la réduction de dose, du retrait et de la reprise du Tofacitinib chez des patients atteints de polyarthrite rhumatoïde: une étude prospective d'observation

Mori S, Ueki Y.
Clin Rheumatol. 2019 Aug 9. DOI: 10.1007/s10067-019-04721-z

Following achievement of remission or low disease activity (LDA), a dose reduction strategy of TOF to a 5mg QD dose was preferable to immediate withdrawal of TOF, with lower relapse rates. Clinical remission or LDA early in the disease course is a target for every RA patient. Although maintaining a state of remission or LDA is beneficial to patients, the AEs and costs associated with DMARDs, have significant burdens on patients during life-long RA treatment. This long-term study was performed t...

Mots clefs: JAK, Tofacitinib, Clinical, Efficacy

Traduit par: Farese

Comparaison du Baricitinib, Upadacitinib et Tofacitinib médié par la régulation de la signalisation des cytokines dans les sous-populations de leucocytes humains

McInnes IB, Byers NL, Higgs RE, Lee J, Macias WL, Na S, Ortmann RA, Rocha G, Rooney TP, Wehrman T, Zhang X, Zuckerman SH, Taylor PC.
Arthritis Res Ther. 2019 Aug 2;21(1):183

Different JAKinibs modulated distinct cytokine pathways to varying degrees, and no agent potently or continuously inhibited an individual cytokine signalling pathway throughout the dosing interval. This study aimed to compare the in vitro cellular pharmacology of BARI, TOF and UPA across relevant leukocyte subpopulations, coupled with their in vivo PK, to determine their effects on distinct cytokine pathways. Peripheral blood mononuclear cells from healthy donors were incubated with differen...

Mots clefs: JAK, Upadacitinib, Preclinical, Selectivity

Traduit par: Farese

August 19

Peficitinib | Methotrexate | Phase 3

Takeuchi T, Tanaka Y, Tanaka S, Kawakami A, Iwasaki M, Katayama K, Rokuda M, Izutsu H, Ushijima S, Kaneko Y, Shiomi T, Yamada E, van der Heijde D.
Ann Rheum Dis 2019 DOI: 10.1136/annrheumdis-2019-215164

Peficitinib (PEF) 100 and 150 mg demonstrated robust clinical and structural efficacy in patients with RA who have an inadequate response to MTX. In Japan, two JAK inhibitors, TOF and BARI are currently available for RA patients with an inadequate response to conventional therapies. This randomized phase 3 study (RAJ4), assessed the efficacy and safety of two PEF doses in combination with MTX compared to PBO, in Japanese MTX-IR. Patients were randomized 1:1:1 to PBO, PEF 100 mg and 150 mg with...

Mots clefs: JAK, Peficitinib, Clinical, Phase 3

Traduit par: Farese

Effet du Filgotinib par rapport au placebo sur la réponse clinique chez des patients atteints de Polyarthrite Rhumatoïde modérée à sévère réfractaire au traitement antirhumatismal modificateur de la maladie: l'essai clinique randomisé FINCH 2

Genovese MC, Kalunian K, Gottenberg JE, Mozaffarian N, �Bartok B, Matzkies F, Gao J, Guo Y, Tasset C, Sundy JS, de Vlam K, Walker D, Takeuchi T.
JAMA 2019 322(4):315-325

Among RA patients with an inadequate response or intolerance to bDMARDs, filgotinib (FIL) doses, compared to PBO resulted in significantly greater proportions achieving a clinical response at Wk12. Patients with active RA despite treatment with bDMARD therapy need treatment options. The FINCH 2 Phase 3 study compared the effects of FIL vs PBO for the treatment of RA patients with inadequate response or intolerance to ≥1 prior bDMARDs. Patients were randomized in a 1:1:1 ratio, receiving FI...

Mots clefs: JAK, Filgotinib, Clinical, Efficacy

Traduit par: Farese

Upadacitinib versus Placebo ou Adalimumab chez des patients atteints de polyarthrite rhumatoïde avec une réponse inadéquate au Méthotrexate: Résultats d'un essai contrôlé de phase 3, randomisé et à double aveugle

Fleischmann R, Pangan AL, Song IH, Mysler E, Bessette L, Peterfy C, Durez P, Ostor AJ, Li Y, Zhou Y, Othman AA, Genovese MC.
Arthritis Rheumatol 2019 DOI: 10.1002/art.41032

UPA demonstrated superiority to ADA in terms of clinical, functional and patient-reported outcomes with comparable radiographic inhibition. As many RA patients fail to achieve LDA and remission with TNF inhibitors and MTX there is a requirement for additional treatment options. In this SELECT-COMPARE study the clinical and functional outcomes of UPA were compared to ADA in MTX-IR patients. 1629 MTX-IR were randomly assigned 2:2:1 to; UPA 15mg QD, ADA 40mg Q2W or PBO, with background MTX. Key e...

Mots clefs: JAK, Upadacitinib, Clinical, Efficacy

Traduit par: Farese

Innocuité et efficacité de l'Upadacitinib ou de Adalimumab plus Méthotrexate chez les patients atteints de polyarthrite rhumatoïde pendant plus de 48 semaines avec passage à un traitement alternatif chez des patients présentant une réponse insuffisante

Fleischmann RM, Genovese MC,  Enejosa JV,  Mysler E, Bessette L, Peterfy C,  Ostor P,  Li Y,  Song I.
Ann Rheum Dis 2019 DOI: 10.1136/annrheumdis-2019-215764

Consistent with Wk26 data, significantly more UPA patients achieved LDA and remission versus ADA and PBO over 48 weeks. RA patients often change therapy due to inadequate response and intolerance. The SELECT COMPARE study was designed to explore switching to JAK inhibitors from TNF inhibitors without a wash-out period (and vice versa). The long-term safety and efficacy of UPA was compared to ADA and PBO in MTX-IR. 1629 patients were blindly assigned 2:2:1 to; UPA 15mg QD, ADA 40mg Q2W and PBO, ...

Mots clefs: JAK, Upadacitinib, Clinical, Efficacy

Traduit par: Farese

July 19

Vaccin contre le zona chez les patients atteints de polyarthrite rhumatoïde traités au Tofacitinib avec ou sans Méthotrexate ou Adalimumab avec Méthotrexate

Calabrese LH, Abud-Mendoza C, Lindsey SM, Lee SH, Tatulych S, Takiya L, Iikuni N, Soma K, Luo Z, Fleischmann R.
Arthritis Care and Research 2019 DOI: 10.1002/acr.24010

Live zoster vaccine (LZV) was well tolerated, and herpes zoster (HZ) incidence rates were generally similar between treatment groups in vaccinated versus non-vaccinated patients in a subset of RA who received LZV before TOF ± MTX, or ADA + MTX, in ORAL Strategy. It is known that patient with RA are at increased risk of developing HZ though the mechanisms behind this are currently not well understood though therapies, such as TOF, are thought to increase the risk. ACR and EULAR recommend...

Mots clefs: JAK, Tofacitinib, Clinical, Safety

Traduit par: Farese

Résultats cliniques chez les patients passant de l'adalimumab au baricitinib en non-réponse et / ou dans le plan de l'étude: phase III chez des patients atteints de polyarthrite rhumatoïde

Tanaka Y, Fautrel B, Keystone EC, Ortmann RA, Xie L, Zhu B, Issa M, Patel H, Gaich CL, de Bono S, Rooney TP, Taylor PC.
Ann Rheum Dis. 2019 Jul;78(7):890-898.

Switching from ADA to BARI without a lengthy washout period can be executed with acceptable safety and tolerability and was associated with maintained disease control. Switching therapies in RA is commonplace in myriad scenarios including inadequate responses, intolerances and patient preference. Assessing the safety and efficacy of new treatments such as BARI, in the context of use as a replacement therapy, is beneficial. A previous study (RA-BEACON) has demonstrated that safely switching fro...

Mots clefs: JAK, Baricitinib, Clinical, Phase 3

Traduit par: Farese

June 19

Efficacy and Safety of Filgotinib for Patients With Rheumatoid Arthritis Naïve to Methotrexate Therapy: FINCH 3 Primary Outcome Results

Westhovens R, Rigby WFC, van der Heijde D, Ching DWT, Bartok B, Matzkies F, Yin Z, Guo Y, Tasset C, Sundy JS, Mozaffarian N, Messina OD, Landewé RBM, Atsumi T, Burmester GR.
EULAR 2019 Abstract LB0003 Presentation

Filgotinib is an orally administered, selective inhibitor of JAK1. Filgotinib has shown good efficacy and was well tolerated for the treatment of RA in Phase 2 and 3 studies evaluating MTX-IR or bDMARD-IR patients. The objective of this study was to compare the efficacy and safety of filgotinib with and without MTX in patients with RA who were naïve to MTX therapy.

Efficacy and Safety of Filgotinib for Patients With Rheumatoid Arthritis With Inadequate Response to Methotrexate: FINCH 1 Primary Outcome Results

Combe BG, Kivitiz AJ, Tanaka Y, van der Heijde D, Matzkies F, Bartok B, Ye L, Guo Y, Tasset C, Sundy JS, Mozaffarian N, Landewé RBM, Bae SC, Keystone EC, Nash P.
EULAR 2019 Abstract LB0001 Presentation

Filgotinib is an orally administered, selective inhibitor of JAK1. Filgotinib has shown good efficacy and was well tolerated for the treatment of rheumatoid arthritis (RA) in Phase 2 studies.The objective of this Phase 3 study was to evaluate the efficacy and safety of filgotinib treatment in patients with RA who have had an inadequate response to methotrexate (MTX).

Efficacité et modélisation pharmacodynamique de l'évobrutinib, inhibiteur de BTK, dans les modèles de maladie auto-immune

Haselmayer P, Camps M, Liu-Bujalski L, Nguyen N, Morandi F, Head J, O’Mahony A, Zimmerli SC, Bruns L, Bender AT, Schroeder P, Grenningloh.
J Immunol 2019;202:2888–2906. DOI: 10.4049/jimmunol.1800583

BTK is involved in both adaptive and innate immune responses and mediates signalling of several immune receptors of relevance to RA and SLE pathogenesis. Targeting BTK is a promising approach therefore for autoimmune disorders with aberrant B cell responses. Evobrutinib is a novel, highly specific, and irreversible BTK inhibitor. In vivo and animal models showed that evobrutinib modulated B cell and innate immune cell activation, was efficacious, and prevented joint damage. The potency of evob...

Mots clefs: BTK, Preclinical, PK-PD

Traduit par: Farese

Impact des inhibiteurs de Janus kinase sur le risque d'événements cardiovasculaires chez les patients atteints de polyarthrite rhumatoïde: revue systématique et méta-analyse d'essais contrôlés randomisés

Xie W, Huang Y, Xiao S, Sun X, Fan Y, Zhang Z.
Ann Rheum Dis. 2019 Aug;78(8):1048-1054.

Existing evidence from RCTs indicated no significant change in CV risk for JAK inhibitor (JAKinib) treated RA patients in a short-term perspective compared to placebo. Patients with RA have an elevated risk of CV morbidity and mortality, which cannot be fully explained by traditional CV risk factors. Reaching remission or LDA in order to reduce CV events (CVE) is encouraged in the current EULAR recommendations. JAKinibs and their roles in the modulation of CV risk remain undetermined. This stud...

Mots clefs: JAK, Baricitinib, Clinical, Safety

Traduit par: Farese

Upadacitinib en monothérapie chez des patients atteints de polyarthrite rhumatoïde active et recevant une réponse inadéquate au méthotrexate (SELECT-MONOTHÉRAPIE): étude de phase 3 randomisée, contrôlée par placebo et à double insu

Smolen JS, Pangan AL, Emery P, Rigby W, Tanaka Y, Vargas JI, Zhang Y, Damjanov N, Friedman A, Othman AA, Camp HS, Cohen S.
Lancet. 2019 Jun 8;393(10188):2303-2311

UPA monotherapy showed statistically significant improvements in clinical and functional outcomes versus continuing MTX in MTX inadequate-responder patients with RA. Despite its proven effectiveness and safety, many patients are unable to tolerate MTX due to its side-effects. Therapies that can be used without concomitant MTX therefore, have an important place in RA management. In previous studies, UPA has shown efficacy in combination with stable background csDMARDs in RA patients who are DMA...

Mots clefs: JAK, Upadacitinib, Clinical, Efficacy

Traduit par: Farese

May 19

Revue systématique et méta-analyse du risque d'infection avec les inhibiteurs JAK à petite molécule dans la polyarthrite rhumatoïde

Bechman K, Subesinghe S, Norton S, Atzeni F, Galli M, Cope AP, Winthrop KL, Galloway JB.
Rheumatology (Oxford). DOI: 10.1093/rheumatology/kez087

How JAKinibs increase the risk of HZ reactivation is unclear. Roles of different JAKs in the immune response may suggest differences in safety profiles between drugs, underpinned by their differential JAK selectivity profiles. The authors undertook a systematic review and meta-analysis to evaluate SI and opportunistic indicator infections including HZ in RA Phase II/III clinic trials with JAKinibs. A literature review of RCT of TOF (5 mg BID), BARI (4 mg OD) and UPA (15 mg OD) was conducted. A...

Mots clefs: JAK, Tofacitinib, Clinical, Safety

Traduit par: Farese

Innocuité et efficacité du Tofacitinib allant jusqu'à 9,5 ans dans le traitement de la polyarthrite rhumatoïde: résultats finaux d'une étude de prolongation globale, ouverte et à long terme

Wollenhaupt J, Lee EB, Curtis JR, Silverfield J, Terry K, Soma K, Mojcik C, DeMasi R, Strengholt S, Kwok K, Lazariciu I, Wang L, Cohen S.
Arthritis Res Ther. 2019 Apr 5;21(1):89.

TOF 5 mg and 10mg BID demonstrated a consistent safety profile and sustained efficacy for up to 9.5 years in this open-label LTE ORAL Sequel study. TOF 5 mg and 10 mg BID demonstrated consistent safety (as monotherapy and combination therapy) and efficacy within this open-label LTE study of RA patients. As RA requires long-term treatment, it’s important to assess the long-term efficacy and safety of RA therapies to understand the potential lifelong impact on patient health and quality of ...

Mots clefs: JAK, Tofacitinib, Clinical, Efficacy

Traduit par: Farese

Évaluation des réponses au vaccin contre le pneumocoque et le tétanos chez les patients atteints de polyarthrite rhumatoïde recevant du Baricitinib: Résultats d'une sous-étude sur l’essai de prolongation à long terme

Winthrop KL, Bingham CO III, Komocsar WJ, Bradley J, Issa M, Klar R, Kartman CE.
Arthritis Res Ther. 2019 Apr 18;21(1):102

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 t...

Mots clefs: JAK, Baricitinib, Clinical, Safety

Traduit par: Farese

April 19

Tuberculose, hépatite B et zona chez des patients atteints de polyarthrite rhumatoïde traités au Tofacitinib

Zhang Z, Deng W, Wu Q, Sun L.
Immunotherapy. 2019 Mar;11(4):321-333.

The risk of TB and hepatitis B virus (HBV) appears to be no greater with TOF than with bDMARDs. Most cases of TB during TOF studies occurred in regions with high background rate of TB, including east Asian countries. TOF is also associated with a higher rate of herpes zoster (HZ) compared with bDMARDs. DMARDs used to treat RA can increase the risk of infections by causing a degree of immunosuppression. A range of bacterial and viral infections have been observed in association with DMARD thera...

Mots clefs: JAK, Tofacitinib, Clinical, Safety

Traduit par: Farese

Données relatives à l'efficacité et à l'innocuité fondées sur les conditions historiques ou préexistantes observées au départ chez les patients atteints de polyarthrite rhumatoïde active traités au baricitinib

Combe B, Balsa A, Sarzi-Puttini P, Tony HP, de la Torre I, Rogai V, Durand F, Witt S, Zhong J, Dougados M.
Ann Rheum Dis. 2019 Aug;78(8):1135-1138.

In a post-hoc analysis, BARI 4 mg showed similar efficacy and safety during placebo-controlled and LTE observation periods regardless of the presence or absence of select comorbidities in RA patients. Patients with RA have a high prevalence of comorbidities. This post-hoc analysis investigated the effect of select comorbidities (depression, osteoporosis, hepatic, cardiovascular or pulmonary disorders) on the efficacy and safety of BARI 4 mg QD in patients with moderate-to-severe active RA and i...

Mots clefs: JAK, Baricitinib, Clinical, Safety

Traduit par: Farese

March 19

Profil d’innocuité du Baricitinib chez des patients Japonais atteints d’une polyarthrite rhumatoïde avec un temps de traitement d’une moyenne d’1,6 ans : analyse intégrée des essais de phases 2 et 3

Harigai M, Takeuchi T, Smolen JS, Winthrop KL, Nishikawa A, Rooney TP, Saifan CG, Issa M, Isaka Y, Akashi N, Ishii T, Tanaka Y.
Mod Rheumatol. 2019 Feb 20:1-23. DOI: 10.1080/14397595.2019.1583711

In this integrated analysis, BARI showed an acceptable safety profile in Japanese patients with up to 3.2 years of exposure. Other than incidences of herpes zoster (HZ), no major differences were noted with BARI safety in Japanese patients with RA, compared to the patients in the integrated database. BARI has previously demonstrated significant clinical efficacy and acceptable safety. Japanese patients who participated in the BARI clinical development programme, were comparable to those from th...

Mots clefs: JAK, Baricitinib, Clinical, Safety

Traduit par: Farese

Augmentation de LDL-C et HDL-C induit par le Baricitinib dans le cas de la polyarthrite rhumatoïde: une méta-analyse d’essais contrôlés randomisés

Qiu C, Zhao X, She L, Shi Z, Deng Z, Tan L, Tu X, Jiang S, Tang B.
Lipids Health Dis. 2019 Feb 18;18(1):54.

This study confirmed that BARI induced a stable dose-dependent increase in LDL-C and HDL-C levels. There was no significant difference of CV risk between BARI and placebo groups. High risk of CV events is strongly associated with RA. Mechanisms underlying the excess risk of CV events in RA remains unclear. This study aims to provide additional insight into the clinical safety of BARI, focusing on the effects of BARI on LDL-C and HDL-C levels and CV risk. A Cochrane analysis was performed on s...

Mots clefs: JAK, Baricitinib, Clinical, Safety

Traduit par: Farese

Méta-analyse en réseau du traitement par le tofacitinib versus les traitements biologiques chez les patients atteints de polyarthrite rhumatoïde sévère à modérée

Camean‐Castillo M, Gimeno‐Ballester V, Rios‐Sanchez E, Fenix‐Caballero S, Vázquez‐Real M, Alegre‐del Rey E.
J Clin Pharm Ther. 2019 Jun;44(3):384-396.

This study suggests that many bDMARDs and tsDMARDs can be considered equivalent therapeutic alternatives in bDMARD-naïve RA patients, with inadequate response to csDMARDs. In the absence of randomised controlled trials comparing drugs, indirect comparisons and network meta-analysis may provide information to help select an optimal treatment alternative. In this network meta-analysis, 27 randomized controlled trials were analysed to assess the possibility that some drugs on the market may b...

Mots clefs: JAK, Tofacitinib, Clinical, Efficacy

Traduit par: Farese

February 19

Risque d‘Infection Grave chez les Patients Atteints de Polyarthrite Rhumatoïde en Soins Courants avec Abatacept, Rituximab et Tocilizumab au Danemark et en Suède

Grøn KL, Arkema EV, Glintborg B, Mehnert F, Østergaard M, Dreyer L, Nørgaard M, Krogh NS, Askling J, Hetland ML, ARTIS Study Group.
Ann Rheum Dis. 2019 Mar;78(3):320-327. DOI: 10.1136/annrheumdis-2018-214326

Differences in baseline characteristics and numerical differences in IR of SI between ABA, RRTX and TOZ were observed. The relative risk (RR) of SIs seemed to vary modestly with drug. TNFi treated RA patients in large observational studies have suggested an initial twofold increased risk of SIs compared with biologic-naïve patients. Long-term observational studies on the risk of SIs in patients treated with non-TNFi bDMARDs are sparse. This study aimed to estimate crude as well as age and...

Mots clefs: IL-6, Tocilizumab, Real World, Infections

Traduit par: Noack

Comparaisons de la Réplication du Virus de l‘Hépatite C chez des Patients Atteints de Polyarthrite Rhumatoïde Traités par le Tocilizumab, l‘Abatacept et le Tofacitinib

Chen YM, Huang WN, Liao TL, Chen JP, Yang SS, Chen HH, Hsieh TY, Hung WT, Chen YH, Chen DY.
Ann Rheum Dis. 2019 Jun;78(6):849-850.

Tocilizumab (TCZ), abatacept (ABA) and tofacitinib (TOF) appear to have no major safety concerns for treatment of RA patients with hepatitis C virus (HCV) infections. HCV is an infectious disease which continues to present a major therapeutic challenge for clinicians in treating patients with RA. Previous reports demonstrate that the use of TNF targeted therapies in RA patients with HCV infections appear to have no major safety concerns. During short-term therapy with TCZ and ABA, data has show...

Mots clefs: JAK, Tofacitinib, Clinical, Safety

Traduit par: Noack

Tofacitinib in Combination with Methotrexate in Patients with Rheumatoid Arthritis: Clinical Efficacy, Radiographic and Safety Outcomes from the 24-Month Phase 3 ORAL Scan Study

van der Heijde D, Strand V, Tanaka Y, Keystone E, Kremer J, Zerbini CAF, Cardiel MH, Stanley Cohen S, Nash P, Song YW, Tegzová D, Gruben D, Wallenstein G, Connell CA, Fleischmann R, ORAL Scan investigators.
Arthritis Rheumatol. 2019 Jun;71(6):878-891

RA patients receiving TOF 5 or 10 mg BID plus MTX showed sustained clinical and radiographic treatment effects through months 12-24. The safety profile was consistent with previous TOF studies. The 12-month data from the ORAL Scan study have been previously reported. This report assesses durability of responses, including structural damage progression, and safety with TOF through 24 months. Patients were randomized 4:4:1:1 to receive TOF 5 or 10 mg BID, or PBO advanced to TOF with stable, ba...

Innocuité Cardiovasculaire Pendant le Traitement par Baricitinib dans la Polyarthrite Rhumatoïde

Taylor PC, Weinblatt ME, Burmester GR, Rooney TP, Witt S, Walls CD, Issa M, Salinas CA, Saifan C, Zhang X, Cardoso A, González-Gay MA, Takeuchi T.
Arthritis Rheumatol. 2019 Jul;71(7):1042-1055.

This study indicates no association between exposure to BARI and MACE, arterial thrombotic events (ATE), or congestive heart failure (CHF). Overall IRs for venous thromboembolic event (VTE) in BARI-treated patients falls within the reported range for patients with RA. RA patients have a greater risk of cardiovascular (CV) diseases of arterial ischemic origin, and an increased risk of VTE. Studied frequencies of thromboembolic events in RA populations in the last decade has been reported as 2&nd...

Mots clefs: JAK, Baricitinib, Clinical, Safety

Traduit par: Noack

January 19

Analyse Groupée de l‘Innocuité du Tofacitinib en Monothérapie ou en Association avec des Antirhumatismaux Modificateurs de la Maladie dans une Population de Polyarthrite Rhumatoïde, en Phase 3

Kivitz AJ, Cohen S, Keystone E, van Vollenhoven RF, Haraoui B, Kaine J, Fan H, Connell CA, Bananis E, Takiya L, Fleischmann R.
Semin Arthritis Rheum. 2018 Dec;48(3):406-415. doi: 10.1016/j.semarthrit.2018.07.006.

In this pooled analysis of Phase 3 Tofacitinib (TOF) trials, safety profiles were generally similar between patients receiving monotherapy and combination therapy. Although selected adverse events of interest showed lower incidence rates (IRs) for TOF monotherapy patients. TOF has been studied as monotherapy and in combination with csDMARDs. In this post-hoc analysis, data were pooled from six Phase 3 TOF studies in RA patients to further examine the safety profile when used as monotherapy or i...

Mots clefs: JAK, Tofacitinib, Clinical, Safety

Traduit par: Noack

Caractérisation et Modifications des Sous-Types de Lymphocytes chez les patients traités au Baricitinib avec une Polyarthrite Rhumatoïde: Une Analyse Intégrée

Tanaka Y, McInnes IB, Taylor PC, Byers NL, Chen L, de Bono S, Issa M, Macias WL, Rogai V, Rooney TP, Schlichting DE, Zuckerman SH, Emery P.
Arthritis Rheumatol. 2018 Dec;70(12):1923-1932. doi: 10.1002/art.40680

This review shows that changes in lymphocyte subsets were largely within normal reference ranges and were not associated with efficacy or safety end points. BARI is a selective JAK1/JAK2 inhibitor, approved for the treatment of moderate to severe RA. BARI treatment is associated with changes to circulating lymphocyte and lymphocyte subsets, however detailed analyses of these effects, and their relevance to efficacy and safety is lacking. This study investigated the changes in lymphocyte cell s...

Mots clefs: JAK, Baricitinib, Clinical, Safety

Traduit par: Noack

Risque Comparatif de Thromboembolie Veineuse avec le Tofacitinib versus l‘Inhibiteur du Facteur de Nécrose Tumorale : Étude de Cohorte sur les Patients Atteints de Polyarthrite Rhumatoïde

Desai RJ, Pawar A, Weinblatt ME, Kim SC.
Desai RJ, et al. Arthritis Rheumatol. 2019 June;71(6):892-900.

Occurrences of venous thromboembolism (VTE) in 50, 865 RA patients initiating Tofacitinib (TOF) or a TNF inhibitor (TNFi) was infrequent. No significant risk of VTE for TOF versus TNFi was observed. Safety concerns of JAK inhibitor BARI include potentially increased risk of VTE at the higher 4 mg dose. It’s unclear if this is attributable to JAK-inhibition and extends to TOF. This study compared the risk of VTE with TOF, versus TNFi in real-world settings with RA patients. RA patients in...

Mots clefs: JAK, Tofacitinib, Clinical, Safety

Traduit par: Noack

December 18

Évaluation des Effets à Court, Moyen et Long Terme du Tofacitinib sur les Lymphocytes Chez les Patients Atteints de Polyarthrite Rhumatoïde

van Vollenhoven R, Lee EB, Strengholt S, Mojcik C, Valdez H, Krishnaswami S, Biswas P, Lazariciu I, Hazra A, Clark JD, Hodge J, Wang L, Choy E.
Arthritis Rheumatol 2018 DOI: 10. 1002/art.40780

Tofacitinib (TOF) treatment is associated with short-term transient increases in absolute lymphocyte counts (ALC), followed by a gradual decline to reach steady state by ~48 months. Changes in both ALC and lymphocyte subset counts (LSC) were reversible upon TOF discontinuation. Low ALC but not LSC were associated with an increased risk of serious infective episodes (SIEs) and herpes zoster (HZ). This data supported the treatment recommendations on ALC counts for starting and continuing therapy w...

Mots clefs: JAK, Tofacitinib, Clinical, Safety

Traduit par: Noack

Influence de l'Âge et de l'Insuffisance Rénale sur la Pharmacocinétique à l'État Stable du Filgotinib, un Inhibiteur Sélectif de JAK1

Namour F, Fagard L, Van der AA, Harrison P, Xin Y, Tasset C.
Br J Clin Pharmacol 2018 Dec;84(12):2779-2789. DOI:10.1111/bcp.13726

Age and renal impairment (RI) had limited impact on the pharmacokinetics (PK) of filgotinib (FIL) but, in subjects with severe RI, exposure to the FIL metabolite was increased. FIL is a selective JAK1 inhibitor that is extensively, rapidly and proportionately absorbed after oral dosing from 50–200mg. Its major metabolite has a similar JAK1 selectivity profile but with reduced potency. In humans, exposure to the metabolite is higher by approximately 16–20 fold compared with the pare...

Mots clefs: JAK, Filgotinib, Preclinical, PK-PD

Traduit par: Noack

November 18

Innocuité et efficacité du Baricitinib chez les patients recevant des médicaments antirhumatismaux synthétiques conventionnels modifiant la maladie ou des corticostéroïdes

van Vollenhoven R, Helt C, Arora V, Zhong J, Correia AP, de la Torre I, Muram D.
Rheumatol Ther 2018 Dec;5(2):525-536. DOI 10.1007/s40744-018-0128-0

Baricitinib (BARI) in combination with MTX and concomitant csDMARDs was shown to be efficacious, regardless of corticosteroid use in RA patients. MTX is prescribed to most RA patients but concomitant csDMARDs and/or corticosteroids can be added. This study assessed the efficacy and safety of BARI in two arms; with/without corticosteroids and; with MTX only/MTX plus csDMARD/csDMARDs only. Baseline characteristics and adverse reactions were also compared. Data were pooled from two phase 3 studie...

Mots clefs: JAK, Baricitinib, Clinical, Phase 3

Traduit par: Noack

Zona et Tofacitinib: Un risque encore plus élevé avec les Glucocorticoïdes mais pas avec le Méthotrexate

Curtis JR, Xie F, Yang S, Bernatsky S, Chen L, Yun H, Winthrop K.
Arthritis Care Res 2018 DOI 10.1002/acr.23769

The rate of Herpes Zoster (HZ) in tofacitinib (TOF) users with concomitant glucocorticoids (GC) was approximately double that of other TOF combination therapies. TOF is an effective treatment for RA. Increased HZ risk has been observed with the use of JAK inhibitors, whereas the HZ risk with biologics and targeted RA therapies are comparable. This study evaluated the HZ risk in TOF users according to concomitant GC, MTX, both, or neither. MarketScan and Medicare data were used to identify 8030 ...

Mots clefs: JAK, Tofacitinib, Clinical, Safety

Traduit par: Noack

Efficacy and Safety of Filgotinib, a Selective Janus Kinase 1 Inhibitor, in Patients with Active Ankylosing Spondylitis (TORTUGA): Results from a Randomized, Placebo-controlled, Phase 2 Trial

Van der Heijde D, Baraliakos X, Gensler LS, Maksymowych WP, Tseluyko V, Nadashkevich O, Abi-Saab W, Tasset C, Meuleners L, Besuyen R, Hendrikx T, Mozafarian N, Liu K, Greer JM, Deodhar A, Landewé R.
Lancet 2018 Dec 1;392(10162):2378-2387. DOI 10.1016/S0140-6736(18)32463-2

In this first clinical trial of filgotinib in patients with active AS, filgotinib significantly reduced disease activity, and the signs and symptoms of AS compared with placebo. The TORTUGA trial was a randomized, double-blind, placebo-controlled, Phase 2 trial, that enrolled 263 adult patients from 30 sites in seven countries. Patients with active AS and an inadequate response or intolerance to two or more NSAIDs were assigned 1:1 to receive filgotinib 200 mg or placebo once daily for 12 week...

Efficacy and Safety of Filgotinib, a Selective Janus Kinase 1 Inhibitor, in Patients with Active Psoriatic Arthritis (EQUATOR): Results from a Randomised, Placebo-controlled, Phase 2 Trial

Mease P, Coates LC, Helliwell PS, Stanislavchuk M, Rychlewska-Hanczewska A, Dudek A, Abi-Saab W, Tasset C, Meuleners L, Harrison P, Besuyen R, Van der Aa A, Mozafarian N, Greer JM, Kunder R, Van den Bosch F, Gladman DD.
Lancet. 2018 Dec 1;392(10162):2367-2377. DOI 10.1016/ S0140-6736(18)32483-8

In this first clinical trial of filgotinib in patients with PsA, filgotinib was effective in treating the signs and symptoms of active PsA across various disease manifestations. The EQUATOR trial was a randomized, double-blind, placebo-controlled, Phase 2 trial, that enrolled 191 adult patients from 25 sites in seven countries. Patients with active moderate-to-severe PsA and an insufficient response or intolerance to at least one csDMARD were assigned 1:1 to receive filgotinib 200 mg or placebo...

October 18

Comparaison de l’efficacité et de l’innocuité du Tofacitinib et du Baricitinib chez des patients atteints de polyarthrite rhumatoïde active: méta-analyse en réseau bayésien d’essais cliniques contrôlés randomisés

Bae SC and Lee YH.
Z Rheumatol. 2018 Sep 6. DOI 10.1007/s00393-018-0531-5

Tofacitinib (TOF) 10mg and baricitinib (BARI) 4mg, in combination with methotrexate (MTX), were the most efficacious treatments in RA patients with an inadequate response to DMARDs or biologics. Both combination treatments presented acceptable safety profiles and were not associated with a significant risk of serious adverse events. This study employed a Bayesian approach to Meta-Analysis; combining the available evidence across a network of Randomised Controlled trials (RCTs). Twelve RCTs cont...

Mots clefs: JAK, Tofacitinib, Clinical, Phase 3

Traduit par: Noack

Diminution de la dose de Baricitinib chez les patients atteints de polyarthrite rhumatoïde avec un contrôle durable de la maladie: résultats d'une étude prospective

Takeuchi T, Genovese MC, Haraoui B, Li Z, Xie L, Klar R, Pinto Correia A, Otawa S, Lopez-Romero P, de la Torre I, Rooney TP, Smolen JS.
Ann Rheum Dis. 2019 Feb;78(2):171-178. DOI 10.1136/annrheumdis-2018-213271

In active RA patients, with an inadequate response (IR) to DMARDs who achieve low disease activity (LDA) following baricitinib (BARI) 4 mg treatment, disease control is better maintained with continued BARI 4 mg compared to tapering to 2 mg. The objective of this study was to investigate the effect of BARI tapering in patients achieving sustained disease control with BARI 4 mg. In the long-term extension study RA-BEYOND, patients receiving BARI 4 mg who achieved sustained LDA or remission at two...

Mots clefs: JAK, Baricitinib, Clinical, Phase 3

Traduit par: Noack

Profil d'innocuité du Baricitinib chez les patients atteints de polyarthrite rhumatoïde active, traités plus de 2 ans en moyenne

Smolen J, Genovese M, Takeuchi T, Hyslop D, Macias W, Rooney T, Chen L, Dickson C, Riddle Camp J, Cardillo T, Ishii T and Winthrop K.
J Rheumatol. 2019 Jan;46(1):7-18. DOI: 10.3899/jrheum.171361

Baricitinib (BARI) showed an acceptable 5.5-year safety profile in this integrated analysis of patients with moderate-to-severe, active RA. This study evaluated the safety profile of the oral, once daily Janus kinase inhibitor, BARI, in adults with moderately to severely active RA. Data from eight randomised clinical trials and one long-term extension study were pooled and analysed for placebo comparison and dose response. There were 3492 patients who received BARI for a total of 6637 patient-y...

Mots clefs: JAK, Baricitinib, Clinical, Phase 3

Traduit par: Noack

September 18

Progression des Dommages Structuraux Chez les Patients Atteints de Polyarthrite Rhumatoïde Précoce Traités par Méthotrexate, Baricitinib ou Barictinib Plus Méthotrexate Selon la Réponse Clinique Dans l'Étude RA-BEGIN de Phase 3

van der Heijde D, Durez P, Schett G, Naredo E, Østergaard M, Meszros G, De Leonardis F, De La Torre I, López-Romero P, Schlichting D, Nantz E, Fleichmann R.
Clinical Rheumatology 2018;37:2381–90 DOI 10.1007/s10067-018-4221-0

Patients with active RA and little or no prior DMARD treatment, who achieved sustained clinical responses, were less likely to show structural damage progression, irrespective of treatment. RA-BEGIN was a 52-week double-blind, multicentre Phase 3 trial, which assessed the safety and efficacy of BARI as monotherapy or in combination with MTX versus MTX monotherapy, in RA patients with no or limited prior DMARDs use.1-4 This post-hoc analysis evaluated the structural damage progression in patients...

Mots clefs: JAK, Baricitinib, Clinical, Efficacy

Traduit par: Noack

Profil Lipidique et Effet du Traitement aux Statines dans des Études Groupées de Phase II et Phase III sur le Baricitinib

Taylor PC, Kremer JM, Emery P, Zuckerman SH, Ruotolo G, Zhong J, Chen L, Witt S, Saifan C, Kurzawa M, Otvos JD, Connelly MA, Macias WL, Schlichting DE, Rooney TP, de Bono S, McInnes IB.
Ann Rheum Dis. 2018 Jul;77(7):988-995. DOI 10.1136/annrheumdis-2017-212461

Baricitinib (BARI) was associated with increased lipid levels; baseline statins did not alter these profiles. The introduction of statins during treatment reduced total cholesterol and LDL-C. The use of anti-inflammatory drugs in RA patients has been shown to alter lipid levels and is associated with reduced atherogenic risk. Increases in lipid levels, specifically HDL-C and LDL-C, have been observed in Phase 2 BARI studies1. This study analysed data from seven randomised RA Phase 2/3 studies o...

Mots clefs: JAK, Baricitinib, Real World, Cardiovascular

Traduit par: Noack

Réponse soutenue après Arrêt du Méthotrexate ches des Patients Atteints de Polyarthrite Rhumatoïde Traités avec du Tocilizumab en Sous-Cutané Tocilizumab

Kremer JM, Rigby W, Singer NG, Birchwood C, Gill D, Reiss W, Pei J, Michalska M.
Arthritis Rheumatol 2018;70:1200–08 DOI 10.1002/art.40493

The COMP-ACT study showed patients achieving low disease activity (LDA) with tocilizumab (TCZ) plus methotrexate (MTX) can discontinue MTX, while maintaining disease control for up to 16 weeks. Previous studies have shown TCZ to be efficacious as a monotherapy or in combination with MTX in patients with RA1,2. Patients frequently discontinue taking DMARDs, such as MTX, due to intolerance or adverse events. COMP-ACT is a randomised, double-blind, 52-week study evaluating the sustained efficacy of...

Mots clefs: IL-6, Tocilizumab, Clinical, Efficacy

Traduit par: Noack

Efficacité de la Monothérapie avec des Biomédicaments et des Inhibiteurs de JAK pour le Traitement de la Polyarthrite Rhumatoïde : Analyse Complète

Emery P, Pope JE, Kruger K, Lippe R, DeMasi R, Lula S, Kola B.
ADV Ther 2018; 35(10):1525–63 DOI: 10.1007/s12325-018-0757-2

The b/tsDMARDs evaluated in this systematic literature review (SLR) were shown to be efficacious as monotherapies, although combination therapies usually achieved better treatment outcomes. Current treatment guidelines recommend combining b/tsDMARDs with MTX in the treatment of RA; however, up to a third of patients are treated with monotherapy. While previous SLRs1–3 have compared the efficacy of b/tsDMARD mono- versus MTX combination therapy they covered a limited number of randomised co...

Mots clefs: JAK, Baricitinib, Clinical, Efficacy

Traduit par: Noack

August 18

Arrêt du Tocilizumab après Rémission chez des Patients Atteints de Polyarthrite Rhumatoïde Traités avec du Tocilizumab Seul ou en Association Avec du Méthotrexate: Résultats d'une Étude Prospective Randomisée Contrôlée (deuxième année de l'étude SURPRISE)

Kaneko Y, Kato M, Tanaka Y, Inoo M, Kobayashi-Haraoka H, Amano K, Miyata M, Murakawa Y, Yasuoka H, Hirata S, Tanaka E, Miyasaka N, Yamanaka H, Yamamoto K, Takeuchi T, the SURPRISE study group.
Ann Rheum Dis 2018; 77:1268–1275 DOI: 10.1093/rheumatology/key121

The second-year results from the SURPRISE study show that low disease activity (LDA) can be maintained after discontinuation of tocilizumab with continued methotrexate after remission is achieved. Discontinuation of biologic agents in patients who have achieved remission or low disease activity (LDA) is desirable from a risk–benefit point of view. Compared with TNF inhibitors, little is known regarding TCZ-free remission or LDA, but studies indicate that only a small proportion of patien...

Mots clefs: IL-6, Tocilizumab, Clinical, Efficacy

Traduit par: Noack

Deux Ans de Sarilumab chez les Patients Atteints de Polyarthrite Rhumatoïde et Une Réponse Inadéquate au MTX : Innocuité, Efficacité et Résultats Radiographiques

Genovese MC, van Adelsberg J, Fan C, Graham NMH, van Hoogstraten H, Parrino J, Mangan EK, Spindler A, Huizinga TWJ, van der Heijde D, for the EXTEND study investigators.
Rheumatology 2018;57:1423–1431 DOI: 10.1093/rheumatology/key121

Two-year treatment of active, moderate-to-severe RA with sarilumab, along with dose reduction in the event of laboratory abnormalities, resulted in durable efficacy outcomes and a safety profile consistent with previous reports involving IL-6R inhibition. Durable long-term safety and efficacy, reduced joint damage progression, and conserving health-related quality of life and work productivity are important goals of therapy in RA.1 Sarilumab significantly reduced disease activity, improved phy...

Mots clefs: IL-6, Sarilumab, Clinical, Safety

Traduit par: Noack

Effets Indésirables, Considérations Cliniques et Recommandations de Prise en Charge chez les Patients Atteints de Polyarthrite Rhumatoïde Traités par des Inhibiteurs de JAK

Atzeni F, Talotta R, Nucera V, Marino F, Gerratana E, Sangari D, Masala IF, Sarzi-Puttini P.
Exp Rev Clin Immunol 2018 Nov;14(11):945-956. DOI: 10.1080/1744666X.2018.1504678

Janus kinase (JAK) inhibitors are efficacious in patients with moderate-to-severe RA and have a favourable safety profile. However adverse events (AE), in particular infections, are associated with the use of JAK inhibitors. This paper reviews the mechanism behind JAK inhibitors, the AEs associated with them, and provides consideration in the management of AEs in clinical practice. Data on two RA approved JAK inhibitors – tofacitinib (TOF) and baricitinib (BARI) – was obtained usin...

Mots clefs: JAK, Tofacitinib, Clinical, Safety

Traduit par: Noack

July 18

Sarilumab dans la polyarthrite rhumatoïde modérée ou sévère préalablement traitée: point de vue d'un groupe de revue de données factuelles d'une évaluation NICE à technologie unique

Bermejo I, Ren S, Simpson E, Clowes M, Scott DL, Young A, Stevenson M.
Pharmacoeconomics. 2018 Dec;36(12):1427-1437. doi: 10.1007/s40273-018-0677-7

In this National Institute for Health and Care (NICE) single technology appraisal of sarilumab (SAR) monotherapy and combination therapy with methotrexate (MTX), SAR was considered to have similar efficacy to other bDMARDs for treating moderate-to-severe RA with inadequate response to cDMARDs or TNFis. SAR was also considered a cost-effective use of National Health Service (NHS) resources versus some or all of its comparators in most considered populations. NICE is an independent organisation r...

Mots clefs: IL-6, Sarilumab, Clinical, Phase 3

Traduit par: Melissa Noack

Thromboembolie avec des inhibiteurs de Janus Kinase (JAK) dans le cas de la Polyarthrite Rhumatoïde : Quel est le risque réel ?

Scott IC, Hider SL, Scott DL.
Drug Safety 2018 Jul;41(7):645–53

Current data suggests that JAK inhibitors may increase the risk of thromboembolism and pulmonary thrombosis (PT) in RA. Two JAK inhibitors – baricitinib (BARI) and tofacitinib (TOF) – are considered effective treatments for RA, however, there are concerns about the thromboembolic risks associated with them. In August 2017, the summary of product characteristics for BARI was revised to include a warning of developing DVT and pulmonary embolism (PE), with recommendations that BARI sho...

Mots clefs: JAK, Baricitinib, Clinical, Safety

Traduit par: Helena Farese

Innocuité et efficacité de l'upadacitinib chez les patients atteints de polyarthrite rhumatoïde active réfractaires aux médicaments antirhumatismaux modifiants la maladie biologique (SELECT-BEYOND): essai de phase 3 à double insu, randomisé et contrôlé

Genovese MC, Fleischmann R, Combe B, Hall S, Rubbert-Roth A, Zhang Y, Zhou Y, Mohamed M-EF, Meerwein S, Pangan AL.
Lancet 2018;391:2513–24

Upadacitinib (UPA) extended release formulation was effective in treating patients with moderate-to-severe RA with an inadequate response to bDMARDs. Phase 2 study data has shown that UPA is an efficacious and safe treatment for active RA.1,2 SELECT-BEYOND was a double-blind, long-term extension, Phase 3 study to assess the efficacy of UPA in patients with RA who were bDMARD-IR. The first 12-weeks of SELECT-BEYOND were placebo-controlled, with a double-blind period followed by an ongoing double...

Mots clefs: JAK, Upadacitinib, Clinical, Phase 3

Traduit par: Helena Farese

Innocuité et efficacité de l'Upadacitinib chez les patients atteints de polyarthrite rhumatoïde et ayant une réponse inadéquate aux médicaments antirhumatismaux synthétiques classiques modifiant le syndrome pathologique (SELECT-NEXT): essai de phase 3 randomisé, à double aveugle et contre placebo

Burmester GR, Kremer JM, Van den Bosch F, Kivitz A, Bessette L, Li Y, Zhou Y, Othman AA, Pangan AL, Camp HS.
Lancet 2018;391:2503–12

Patients with moderate-to-severe active RA had significant improvements in clinical signs and symptoms with upadacitinib (UPA) compared with placebo. In Phase 2 studies, UPA showed favourable efficacy when administered twice daily as an immediate-release formulation at doses of 6–12 mg in patients with active RA who had TNFi-IR.1,2 An extended-release formulation allowing once-daily (QD) administration was developed for Phase 3 studies. SELECT-NEXT was a double-blind, multicentre, Phase 3...

Mots clefs: JAK, Upadacitinib, Clinical, Phase 3

Traduit par: Helena Farese

June 18

Patient Characteristics Influence the Choice of Biological Drug in RA, and will make non-TNFi Biologics appear more Harmful than TNFi Biologics

Frisell T, Baecklund E, Bengtsson K, Giuseppe DD, Forsblad-d’Elia H, Askling J, on behalf of the ARTIS Study Group.
Ann Rheum Dis 2018; 77:650–57 DOI: 10.1136/annrheumdis-2017-212395

Analysis of patient characteristics revealed that older and less healthy patients with RA were more likely to receive non-TNFi bDMARDs as a first bDMARD compared to other treatments. This study aimed to describe patient characteristics at initiation of bDMARD treatment at two-time points: first bDMARD initiation and switch to second bDMARD after TNFi treatment. The second aim of the study was to estimate the potential of treatment channelling to confound results in comparative treatment studies...

Effects of Baricitinib on Radiographic Progression of Structural Joint Damage at 1 year in Patients with Rheumatoid Arthritis and an Inadequate Response to Conventional Synthetic Disease-modifying Antirheumatic Drugs

van der Heijde D, Dougados M, Chen YC, Greenwald M, Drescher E, Klar R, Xie L, de la Torre I, Rooney TP, Witt SL, Schlichting DE, de Bono S, Emery P.
RMD Open. 2018 May 8;4(1):e000662. DOI: 10.1136/rmdopen-2018-000662

Once daily baricitinib (BARI) inhibited radiographic progression of structural joint damage in patients with an inadequate response or intolerance to csDMARDs over 48 weeks. Current treatment goals aim to use DMARDs to inhibit structural joint damage and prevent long-term functional disability. In RA-BUILD¹, BARI was shown to significantly reduce radiographic joint damage progression in patients with active RA, with an intolerance or inadequate response to csDMARDs. Here, the authors repor...

Long-term Radiographic and Patient-reported Outcomes in Patients with Rheumatoid Arthritis Treated with Tofacitinib: ORAL Start and ORAL Scan Post-hoc Analyses

Strand V, Kavanaugh A, Kivitz AJ, van der Heijde D, Kwok K, Akylbekova E, Soonasra A, Snyder M, Connell C, Bananis E, Smolen JS.
Rheumatol Ther. 2018 Dec;5(2):341-353. doi: 10.1007/s40744-018-0113-7

Tofacitinib (TOF) therapy reduced the progression of structural joint damage at 2 years, in patients of all disease states, compared with patients given methotrexate (MTX). Early intervention with DMARDs aim to prevent the development of future RA symptoms and inhibit the progression of structural damage to the joints. This post-hoc analysis uses data from two Phase 3 TOF studies, to examine the efficacy of early intervention with TOF on long-term radiographic outcomes and disease activity sta...

May 18

Pharmacocinétique de l’Upadacitinib avec des schémas cliniques de la formulation à libération prolongée utilisée dans les essais de phase 3 sur la polyarthrite rhumatoïde

Mohamed MEF, Zeng J, Marroum PJ, Song IH, Othman AA.
Clin Pharmacol Drug Dev. 2019 Feb;8(2):208-216. doi: 10.1002/cpdd.462

Upadacitinib (UPA) extended release (ER) formulation dosing achieved the target profile that enables single dosing in patients with RA. In early clinical studies, UPA was given as an immediate release (IR) formulation, however patients were noted to experience fluctuations in blood plasma concentrations. To enhance patient compliance in UPA Phase 3 trials, ER tablets have been developed. Here, authors aimed at characterising the pharmacokinetics of UPA single and multiple doses of ER compared ...

Mots clefs: JAK, Upadacitinib, Preclinical, PK-PD

Traduit par: Helena Farese

Analyse des rapports de cas spontanés post-marché soumis à la FDA concernant les effets indésirables thromboemboliques et les inhibiteurs de JAK

Verden A, Dimbil M, Kyle R, Overstreet B, Hoffman KB.
Drug Saf 2018 Apr; 41(4):357–61 DOI: 10.1007/s40264-017-0622-2

Thromboembolic-related adverse events (AEs) were, in general, not considered a class-wide safety concern after analysis of tofacitinib (TOF) and ruxolitinib (RUX) clinical data, though pulmonary thrombosis is considered a potential class-wide safety issue and portal vein thrombosis was considered a potential safety issue for RUX. During analysis of baricitinib (BARI) clinical trial data, the FDA expressed concerns regarding thromboembolic events. Following this, the CHMP have recently added a ...

Mots clefs: JAK, Tofacitinib, Clinical, Safety

Traduit par: Helena Farese

Tofacitinib dans la polyarthrite rhumatoïde: le manque de changement précoce dans l'activité de la maladie prédit une faible probabilité d’atteindre une activité faible de la maladie au 6ème mois

Van Vollenhoven RF, Lee EB, Fallon L, Zwillich SH, Wilkinson B, Chapman D, Demasi R, Keystone E.
Arthritis Care Res (Hoboken) 2019 Jan;71(1):71-79. DOI: 10.1002/acr.23585

This post-hoc analysis of two, Phase 3 studies, ORAL Start and ORAL Standard shows that early treatment response can predict long-term disease activity outcomes. EULAR recommendations suggest that treat-to-target strategies require regular target assessments with treatment approaches changed if targets are not reached at 6 months. To optimize this strategy, therapy outcomes should be known, and the relationship between short and long-term outcomes defined. The current analysis focused on the d...

Mots clefs: JAK, Tofacitinib, Clinical, Efficacy

Traduit par: Helena Farese

Évaluation de l'activité de la maladie chez des patients atteints de polyarthrite rhumatoïde traités au tofacitinib par RAPID3: analyses post-hoc de deux essais de phase 3

Strand V, Lee EB, Yazici Y, Dikranian A, Wilkinson B, Takiya L, Zang C, Bananis E, Bergman MJ.
Clin Rheumatol 2018 Aug; 37(8):2043–53

Patients given tofacitinib (TOF) who achieved Routine Assessment of Patient Index Data 3 (RAPID3) remission or low disease activity (LDA) at 6 months, had improved long-term outcomes at 2 years, compared to patients with moderate or high disease activity (MDA/HDA) at 6 months. RAPID3¹ is a patient-reported evaluation of disease activity, based on pooled PROs; patient global assessment, patient assessment of arthritic pain and HAQ-DI scores. Previous studies with tocilizumab have suggested ...

Mots clefs: JAK, Tofacitinib, Clinical, PRO

Traduit par: Helena Farese

April 18

Baricitinib for Previously Treated Moderate or Severe Rheumatoid Arthritis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

Ren S, Bermejo I, Simpson E, Wong R, Scott DL, Young A, Stevenson M.
Pharmacoeconomics 2018 Jul; 36(7):769–78

In this National Institute for Health and Care (NICE) single technology appraisal of baricitinib (BARI) monotherapy and combination therapy with methotrexate (MTX), BARI efficacy was considered comparable to bDMARDs and a cost-effective use of National Health Service (NHS) resources. NICE is an independent organisation responsible for providing national guidance on health technologies in England. To be recommended by NICE, the company must provide evidence to prove BARI’s effectiveness, b...

Tofacitinib for Treating Rheumatoid Arthritis After the Failure of Disease-Modifying Anti-Rheumatic Drugs: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

Uttley L, Bermejo I, Shijie R, Martyn-St James M, Wong R, Scott DL, Young A, Stevenson M.
Pharmacoeconomics 2018 Sep; 36(9): 1063–72

In this National Institute for Health and Care (NICE) single technology appraisal of tofacitinib (TOF) plus methotrexate (MTX), TOF had similar efficacy and comparable costs to recommended bDMARDs plus MTX in patients with RA. NICE is an independent organisation responsible for providing national guidance on health technologies in England. To be recommended by NICE, the company must provide evidence to prove TOF’s effectiveness, both clinically and costly. This evidence based review, rep...

Effectiveness and Safety of Tofacitinib in Rheumatoid Arthritis: a Cohort Study

Machado MAÁ, Moura CS, Guerra SF, Curtis JR, Abrahamowicz M, Bernatsky S.
Arthritis Res Ther 2018; 20(1):60 doi: 10.1186/s13075-018-1539-6

A retrospective cohort study of tofacitinib (TOF) revealed that patients previously treated with methotrexate who initiated TOF, presented no differences in hospitalised infections or effectiveness, compared with non-TNF biologics. Currently, TOF is recommended in ACR and EULAR guidelines as an alternative to biologics after first-line cDMARD therapy. Previous indirect comparisons have shown that patients with RA who experience cDMARD failure show similar efficacy when given TNFis, abatacept, ...

Effect of Filgotinib, a Selective JAK1 Inhibitor, with or without Methotrexate in Patients with Rheumatoid Arthritis: Patient-Reported Outcomes

Genovese MC, Westhovens R, Meuleners L, van der Aa A, Harrison P, Tasset C, Kavanaugh A.
Arthritis Res Ther 2018; 20(1):57 doi: 10.1186/s13075-018-1541-z

Patient-reported outcomes (PROs) from two, Phase 2b, filgotinib (FIL) studies, DARWIN 1 and 2, revealed that patients receiving FIL had improved and sustained PRO responses compared with placebo. With suboptimal RA treatment, patients lose joint functional ability, which heavily influences patient quality of life. The previously reported data from the DARWIN studies, concluded that patients given FIL achieved clinically relevant dose-dependent improvements compared with patients given placebo&s...

March 18

Etude de Surveillance Post-Autorisation de Mise sur le Marché de Tofacitinib dans la Polyarthrite Rhumatoïde sur 3 ans à l’Echelle Internationale

Cohen S, Curtis JE, DeMasi R, Chen Y, Fan H, Soonasra A, Fleischmann R.
Rheumatol Ther 2018 Jun; 5(1):283–91

This real-world analysis of tofacitinib (TOF) revealed that AEs reported by patients with RA from 2012 to 2015 were consistent with the known safety profile of TOF – no new safety risks were identified. As of August 2017, it is estimated that more than 102 000 patients worldwide have received TOF, but TOF safety has not been evaluated in patients with real-world experience. This analysis addressed this – by evaluating the safety of TOF from post-marketing surveillance (PMS) reports ...

Mots clefs: JAK, Tofacitinib, Real World, Safety

Traduit par: Audrey Beringer

Effet de l’Arrêt ou de l’Initiation du Methotrexate ou des Glucocorticoïdes sur l’Efficacité de Tofacitinib chez les Patients avec une Polyarthrite Rhumatoïde: une Analyse Post Hoc

Fleischmann R, Wollenhaupt J, Cohen S, Wang L, Fan H, Bandi V, Andrews J, Takiya L, Bananis E, Weinblatt ME.
Rheumatol Ther 2018 Jun; 5(1):203–14. DOI: 10.1007/s40744-018-0093-7

Methotrexate (MTX) or Glucocorticoid (GC) discontinuation has little effect on CDAI response in patients given tofacitinib (TOF) for up to 3 years. Patients receiving TOF who showed initial improvements benefitted from initiation of MTX or GCs. Concomitant treatments such as MTX or GC are commonly used in combination with RA therapies to improve or accelerate clinical responses. However, their use is associated with many adverse events so clinicians aim to use them for a minimal duration. This ...

Mots clefs: JAK, Tofacitinib, Clinical, Efficacy

Traduit par: Audrey Beringer

Réponse à Baricitinib Basée sur l’Utilisation de Traitements Biologiques Antérieurs chez les Patients avec une Arthrite Réfractaire

Genovese MC, Kremer JM, Kartman CE, Schlichting DE, Xie L, Carmack T, Pantojas C, Burston JS, Tony HP, Macias WL, Rooney TP, Smolen JS.
Rheumatology (Oxford) 2018 May; 57(5):900-908

Baricitinib (BARI) 2 or 4 mg had a beneficial treatment effect on patients with moderate to severe RA compared with placebo (PBO), irrespective of the number or nature of prior patient bDMARD use. The current therapeutic target for patients with established RA is low disease activity, but many patients fail to achieve this due to inadequate responses to DMARD therapies. With this patient population growing, therapies for these patients are considered one of the greatest unmet needs in RA. This...

Mots clefs: JAK, Baricitinib, Clinical, Efficacy

Traduit par: Audrey Beringer

February 18

Lésions Radiographiques Articulaires chez les Patients Atteints d’une Polyarthrite Rhumatoide Débutante : Comparaison des Statégies de Traitement Basées sur le Tocilizumab et le Methotrexate

Teitsma X, Jacobs JWG, Welsing PMJ, Pethӧ-Schramm A, Borm MEA, van Laar JM, Lafeber FPJG, Bijlsma JWJ.
Rheumatology (Oxford) 2018; 57(2):309–17

Tocilizumab (TCZ) therapy in DMARD-naïve patients with RA, is more effective at reducing erosion progression, particularly in the feet, compared with treat-to-target methotrexate (MTX) therapy. This analysis looked at radiographic joint damage, including separate examination of erosion progression and joint space narrowing (JSN) in the hands and feet of patients enrolled in the U-Act-Early trial. Radiographic damage is a common symptom of RA, with treat-to-target strategies aimed at pre...

Mots clefs: IL-6, Tocilizumab, Clinical, Radiographic

Traduit par: Audrey Beringer

Tofacitinib avec les Antirhumatismaux Modificateurs de la Maladie Conventionnels chez les Patients d’origine Chinoise avec une Polyarthrite Rhumatoïde : Résultats Rapportés par les Patients d’un Essai Randomisé Contrôlé de Phase 3

Li Z, An Y, Su H, Li H, Xu J, Zheng Y, Li G, Kwok K, Wang L, Wu Q.
Int J Rheum Dis 2018; 21(2):402–14

This Chinese sub-population of patients with RA from ORAL Sync reported significant improvements in patient-reported outcomes (PROs), which were maintained up to 12 months from tofacitinib (TOF) treatment initiation. ORAL Sync was a randomised, Phase 3 study investigating TOF therapy in combination with csDMARDs in patients with active RA who had previously had an inadequate response to csDMARDs. To date, this is the only Phase 3 study of TOF in patients from China with RA. This analysis inclu...

Mots clefs: JAK, Tofacitinib, Clinical, PRO

Traduit par: Audrey Beringer

Dosage Dégressif versus Dosage Stable du Methotrexate en combinaison avec Tocilizumab dans la Polyarthrite Rhumatoïde : un Essai Randomisé en Double insu

Edwards CJ, Ӧstӧr AJK, Naisbett-Groet B, Kiely P.
Rheumatology (Oxford) 2018;57(1):84–91

Methotrexate (MTX) tapering in patients with active, severe RA receiving intravenous tocilizumab (TCZ) was non-inferior to continuing stable MTX doses in maintaining a good/moderate EULAR response. Although MTX and bDMARD combination therapy may produce better response rates than bDMARD monotherapy, one third of patients discontinue or are non-compliant with MTX due to preference or toxicity. This randomised, non-inferiority study investigated the efficacy and tolerability of MTX tapering and ...

Mots clefs: IL-6, Tocilizumab, Clinical, Phase 3

Traduit par: Audrey Beringer

January 18

Tocilizumab en Sous-cutané dans la Polyarthrite Rhumatoïdes : Résultats du Cadre Commun du Programme d’Etude de Phase 4 TOZURA Conduit dans 22 Pays

Choy E, Caporali R, Xavier R, Fautrel B, Sanmarti R, Bao M, Bernasconi C, Pethö-Schramm A.
Rheumatology (Oxford). 2018 Mar 1;57(3):499-507. DOI: 10.1093/rheumatology/kex443

This multi-national TOZURA study programme confirmed the efficacy and safety profile of subcutaneous tocilizumab (TC-SC) when administered as either monotherapy or in combination with csDMARDs. TOZURA was a Phase 4 study programme that evaluated open-label, TCZ-SC in patients with moderate-to-severe RA. A total of 1804 patients with active RA were enrolled in the study programme. Patients had inadequate responses to csDMARDs, anti-TNF therapies, or they were MTX-naïve. TCZ-SC was administe...

Mots clefs: IL-6, Tocilizumab, Clinical, Phase 4

Traduit par: Audrey Beringer

Efficacité et Innocuité à 2 ans de Tocilizumab en Sous-Cutané Dans la Polyarthrite Rhumatoïde Combiné aux Antirhumatismaux Modificateurs de la Maladie Avec Une Augmentation des Doses Hebdomadaires

Kivitz A, Olech E, Borofsky MA, Zazueta B, Navarro-Sarabia F, Radominski SC, Merrill JT, Pacheco-Tena C, Pei J, Nasmyth-Miller, Pope JE.
J Rheumatol 2018 Apr; 45(4):456-464

This 2-year Phase 3 study, proved that subcutaneous tocilizumab (TC-SC) has long-term efficacy and an acceptable safety profile. Patients enrolled had been previously diagnosed with RA with an inadequate response to DMARDs. Patients were randomised 2:1 to receive doses of TCZ-SC (n=437) or PBO (n=219) every other week for 6 months. After this time, all patients received TCZ-SC. Escape therapy, defined as weekly TCZ-SC, was available to patients from Month 3. Efficacy was analysed using ACR resp...

Mots clefs: IL-6, Tocilizumab, Clinical, Phase 3

Traduit par: Audrey Beringer

Résultats Rapportés par les Patients chez les Patients avec une Polyarthrite Rhumatoïde Récemment Diagnostiquée avec une stratégie thérapeutique basée sur le Tocilizumab ou le Méthotrexate

Teitsma XM, Jacobs JWG, Welsing PMJ, Pethö-Schramm A, Borm MEA, Hendriks L, Denissen NHAM, van Laar JM, Lafeber FPJG, Bijlsma JWJ.
Rheumatology (Oxford) 2017 Dec 1;56(12):2179-2189 doi: 10.1093/rheumatology/kex319

Patient-reported outcomes (PROs) vastly improved in the first 24 weeks post-initiation of tocilizumab (TCZ) therapies compared to methotrexate (MTX) monotherapy in the U-Act-Early trial. U-Act-Early was a two-year, treat-to-target study that compared the safety and efficacy of TCZ and MTX treatment strategies in DMARD-naïve patients with early RA. Sustained remission was classed as more effective in patients given TCZ monotherapy or combination therapy with MTX compared to MTX alone. TCZ th...

Mots clefs: IL-6, Tocilizumab, Clinical, PRO

Traduit par: Audrey Beringer

December 17

Long-term Effectiveness of Tocilizumab in Patients with Rheumatoid Arthritis, Stratified by Number of Previous Treatment Failures with Biologic Agents: Results from the German RABBIT Cohort

Baganz L, Richter A, Kekow J, Bussmann A, Krause A, Stille C, Listing J, Zink A, Strangfeld A.
Rheumatol Int 2018 Apr; 38(4):579-87

In this observational study, the German RABBIT cohort was used to assess the long-term effectiveness and retention rates of tocilizumab (TCZ) in patients with prior bDMARD failures. Results of the study suggested that TCZ could be an effective treatment option for patients with difficult-to-treat RA. A total of 885 patients were involved in the study and these were categorised dependent on the number of bDMARD failures they had prior to TCZ treatment. Patient data recorded in the cohort include...

Effect of Glucocorticoids on the Clinical and Radiographic Efficacy of Tofacitinib in Patients with Rheumatoid Arthritis: A Posthoc Analysis of Data from 6 Phase III studies

Charles-Schoeman C, van der Heijde D, Bumester GR, Nash P, Zerbini CAF, Connell CA, Fan H, Kwok K, Bananis E, Fleischmann R.
J Rheumatol 2018 Feb; 45(2):177-87

In this post hoc analysis, six Phase 3 studies were used to analyse the effect of glucocorticoids (GC) on the efficacy of tofacitinib (TOF) in patients with RA. Concomitant use of GC did not affect the clinical or radiographic outcomes of patients treated with TOF. Data from all six clinical trials were evaluated, with four studies (ORAL Scan, ORAL Standard, ORAL Sync and ORAL Step) being pooled for analysis. In these studies, MTX was used as a comparison and patients were required to maintain ...

JAK Inhibition as a Therapeutic Strategy for Immune and Inflammatory Diseases

Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M, O’Shea JJ.
Nat Rev Drug Discov 2017;16:843–62 DOI: 10.1038/nrd.2017.201

Janus kinases (JAKs) are essential mediators of downstream signaling pathways in many inflammatory and autoimmune diseases. This review summarizes current clinical data on first- and second-generation JAK inhibitors (jakinibs) and discusses their use for the treatment of immune and inflammatory conditions. First generation jakinibs such as tofacitinib, baricitinib, and ruxolitinib, non-selectively inhibit JAK-dependent pro-inflammatory cytokines, which are major contributors to immunopathology. ...

Successful Treatment of Arthritis Induced by Checkpoint Inhibitors with Tocilizumab: a Case Series

Kim ST, Tayar J, Trinh VA, Suarez-Almazor M, Garcia S, Hwu P, Johnson DH, Uemura M, Diab A.
Ann Rheum Dis 2017;76:2061-64. doi: 10.1136/annrheumdis-2017-211560

This case series evaluated the use of tocilizumab (TCZ) as an effective treatment for patients who develop arthritis as an adverse event (AE) of immune checkpoint inhibitor (ICI) cancer treatment. Results suggested that TCZ was an effective treatment, as it reduced the arthritis disease progression. ICIs have been defined as a revolutionary treatment for metastatic melanomas; however, a common AE is the development of polyarthritis. Current arthritis treatments reduce the efficiency of ICI thera...

Tofacitinib Therapy for Rheumatoid Arthritis: A Direct Comparison Study between Biologic-naive and Experienced Patients

Mori S, Yoshitama T, Ueki Y.
Intern Med. 2018 Mar 1;57(5):663-670. doi: 10.2169/internalmedicine.9341-17

This 6-month prospective direct comparison study analysed the effectiveness of tofacitinib (TOF) therapy on bDMARD-naïve and bDMARD-experienced patients. bDMARD-naïve patients were more responsive to TOF therapy than bDMARD-experienced patients. The study analysed the data of 113 patients diagnosed with high or moderate disease activity, defined using CDAI scores. All patients had failed to achieve CDAI low disease activity or remission with MTX therapy for ≥3 months. Patients were...

November 17

Herpes Zoster and Tofacitinib: Clinical Outcomes and the Risk of Concomitant Therapy

Winthrop KL, Curtis JR, Lindsey S, Tanaka Y, Yamaoka K, Valdez H, Hirose T, Nduaka CI, Wang L, Mendelsohn AM, Fan H, Chen C, Bananis E.
Arthritis Rheumatol 2017;69(10):1960–68

The results of this analysis of patients with herpes zoster (HZ) within the global tofacitinib (TOF) RA programme suggest that there is likely to be a greater HZ risk in patients receiving TOF and glucocorticoids compared with patients receiving TOF monotherapy. The global TOF RA development programme comprised 2 Phase 1, 9 Phase 2, 6 Phase 3 and 2 long-term extension studies. These studies included 6192 patients; data were reviewed to identify cases of HZ. Crude incidence rates of number of pa...

Tofacitinib or Adalimumab versus Placebo for Psoriatic Arthritis

Mease P, Hall S, FitzGerald O, van der Heijde D, Merola J F, Avila-Zapata F, Cieslak D, Graham D, Wang C, Menon S, Hendrikx T, Kanik K S.
N Engl J Med 2017; 377:1537-50. DOI: 10.1056/NEJMoa1615975

In the Phase 3 OPAL Broaden trial of patients with active psoriatic arthritis (PsA) with inadequate response to ≥1 csDMARD, superior efficacy was observed in patients treated with tofacitinib (TOF) compared with those given placebo. Patients were randomised to: 5 mg TOF BID, 10 mg TOF BID, 40 mg adalimumab administered subcutaneously q2W, or placebo with a switch to 5 mg TOF at Month 3. Adalimumab was used as an active control in the study. A variety of primary and secondary endpoints wer...

Tofacitinib for Psoriatic Arthritis in Patients with an Inadequate Response to TNF Inhibitors

Gladman D, Rigby W, Azevedo VF, Behrens F, Blanco R, Kaszuba A, Kudlacz E, Wang C, Menon S, Hendrikx T, Kanik KS.
N Engl J Med 2017;377:1525–36.

The study data presented that tofacitinib (TOF) improves efficacy response rates in patients with severe psoriatic arthritis (PsA) who have an inadequate response to TNF inhibitors. The Phase 3 Oral Psoriatic Arthritis Trial (OPAL) Beyond study evaluated patients with active PsA who had inadequate responses to more than one TNFi. Patients were randomised 2:2:1:1 to 5 mg TOF BID or 10 mg TOF BID for 6 months; or PBO, with a switch to 5 mg TOF BID or to 10 mg BID at 3 months. Primary endpoints w...

Safety and Efficacy of Baricitinib in Elderly Patients with Rheumatoid Arthritis

Fleischmann R, Alam J, Arora V, Bradley J, Schlichting DE, Muram D, Smolen JS.
RMD Open. 2017; 3(2): e000546. doi: 10.1136/rmdopen-2017-000546

In this post hoc analysis of pooled data from two randomised controlled trials, RA-BUILD and RA-BEAM, age was shown not to be a contraindication for use of baricitinib. Patients in RA-BUILD were csDMARD-inadequate responder(IR) patients who received an oral placebo or 2 mg or 4 mg baricitinib once daily. Patients in RA-BEAM were MTX-IR patients and received an oral placebo, 4 mg baricitinib once daily or subcutaneous adalimumab every 2 weeks. Efficacy and safety of baricitinib in elderly patie...

Treatment Persistence and Healthcare Costs Among Patients with Rheumatoid Arthritis Changing Biologics in the USA

Chastek B, Chieh-I Chen, Proudfoot C, Shinde S, Kuznik A, Wei W.
Adv Ther. 2017 Nov;34(11):2422-2435. doi: 10.1007/s12325-017-0617-5

Updated treatment guidelines recommend the use of different mechanism of action (MOA) therapies earlier in the treatment course. Clinical studies have revealed that this approach may be better than TNFi cycling, and may be more cost effective. This study of Commercial and Medicare Advantage claims data showed that patients who switched MOA had higher treatment persistence and lower healthcare costs than TNFi cyclers. After the first TNFi claim, patients either cycled to another TNFi (n=935) or...

October 17

Impact of Tocilizumab Monotherapy On Patient-Reported Outcomes in Patients With Rheumatoid Arthritis from Two Randomised Controlled Trials

Strand V, Michalska M, Birchwood C, Pei J, Tuckwell K, Finch R, Gabay C, Kavanaugh A, Jones G.
RMD Open;3:e000496. doi: 10.1136/rmdopen-2017-000496

This post hoc analysis of 2 randomised controlled trials (RCTs) AMBITION and ADACTA found that tocilizumab monotherapy results in substantial and clinically meaningful improvements in patient-reported outcomes (PROs) over 24 weeks. PROs assessed included patient global assessment (PtGA), pain, HAQ-DI, Functional Assessment of Chronic Illness Therapy (FACIT-F) and Short-Form-36 (SF-36) physical component summary (PCS) and mental component summary (MCS) and eight domain scores. Tocilizumab (TCZ)...

Patient-reported Outcomes of Baricitinib in Patients with Rheumatoid Arthritis and No or Limited Prior Disease-modifying Antirheumatic Drug Treatment

Schiff M, Takeuchi T, Fleischmann R, Gaich CL, DeLozier AM, Schlichting D, Kuo W, Won J, Carmack T, Rooney T, Durez P, Shaikh S, Hidalgo RP, van Vollenhoven R, Zerbini C.
Arthritis Res Ther. 2017 Sep 18;19(1):208

RA-BEGIN was a Phase 3, double-blind randomised active comparator-controlled study to evaluate baricitinib as monotherapy or in combination with MTX in patients with active RA who were naïve to csDMARDS and bDMARDS. In this analysis of the RA-BEGIN study, baricitinib alone or with MTX when used as initial therapy resulted in significant improvements in most patient-reported outcome measures compared with MTX. At baseline, study participants had active RA, impaired physical function, mode...

Lymphoma in the Tofacitinib Rheumatoid Arthritis Clinical Development Program

Mariette X, Chen C, Biswas P, Kwok K, Boy MG.
Arthritis Care Res (Hoboken). 2018 May;70(5):685-694. doi: 10.1002/acr.23421

Analysis of 19 studies involving the use of tofacitinib to treat RA showed that lymphoma incidence rate and type were consistent with expectations in the RA population as a whole, and did not increase with tofacitinib exposure time. Previous research has suggested that there is a link between the likelihood of developing malignant tumours and RA. Previously, it has been unclear whether the increased rates seen are due to the use of immunomodulatory therapies, such as tofacitinib, which are used...

Transaminase Levels and Hepatic Events During Tocilizumab Treatment: Pooled Analysis of Long-Term Clinical Trial Safety Data in Rheumatoid Arthritis

Genovese MC, Kremer JM, van Vollenhoven RF, Alten R, Scali JJ, Kelman A, Dimonaco S, Brockwell L.
Arthritis Rheumatol. 2017 Sep;69(9):1751-1761. doi: 10.1002/art.40176

In this pooled analysis investigating liver enzyme abnormalities and hepatic adverse events (AEs) during long-term tocilizumab (TCZ) treatment for RA in clinical trials, although transaminase elevations were frequent, rates of hepatic serious AEs remained low. Data were pooled from patients who received ≥1 dose of IV TCZ with or without DMARDs in Phase 3 or 4 clinical trials, long-term extensions, and a pharmacology study. A total of 4171 patients were included in the all-exposure populati...

September 17

The Safety and Immunogenicity of Live Zoster Vaccination in Rheumatoid Arthritis Patients Before Starting Tofacitinib: A Randomized Phase II Trial

Winthrop KL, Wouters A, Choy E, Soma K, Hodge J, Nduaka C, Biswas P, Needle E, Passador MS, Mojcik C, Rigby W.
Arthritis Rheumatol. 2017 Oct;69(10):1969-1977. doi: 10.1002/art.40187

Patients with RA who started treatment with tofacitinib 2–3 weeks after being vaccinated against herpes zoster had similar varicella zoster virus (VZV)-specific humoral and cell-mediated responses to the live vaccine compared to patients who received placebo. In this Phase 2 study, humoral and cell-mediated immune responses were evaluated before receipt of live zoster vaccine (LZV) and at 2, 6 and 14 weeks after vaccination, having been randomised to tofacitinib 5 mg BID or placebo, 2&nda...

Herpes Zoster and Tofacitinib Therapy in Patients with Rheumatoid Arthritis

Winthrop KL, Yamanaka H, Valdez H, Mortensen E, Chew R, Krishnaswami S, Kawabata T, Riese R.
Arthritis Rheumatol 2014;66:2675–84

Patients who were treated with tofacitinib in the RA clinical development programme were more likely to develop herpes zoster than were those who received placebo. Cases of herpes zoster reported by investigators in the Phase 2, Phase 3 and long-term extension studies of tofacitinib were evaluated. Herpes zoster was noted in 5% of tofacitinib-treated patients; only 7% of these cases were serious, no patients with herpes zoster died and only 10% permanently discontinued tofacitinib treatment. T...

Patient-reported Outcomes from a Phase 3 Study of Baricitinib versus Placebo or Adalimumab in Rheumatoid Arthritis: Secondary Analyses from the RA-BEAM Study

Keystone EC, Taylor PC, Tanaka Y, Gaich C, DeLozier AM, Dudek A, Velasco Zamora J, Covarrubias Cobos JA, Rooney T, de Bono S, Arora V, Linetzky B, Weinblatt ME.
Ann Rheum Dis 2017;76(11):1853-1861. doi: 10.1136/annrheumdis-2017-211259

This paper describes the patient-reported outcome (PRO) data collected in RA-BEAM, a Phase 3 study of baricitinib compared with both placebo and adalimumab in patients with RA and an inadequate response to MTX. PRO measures evaluated include health-related quality of life (HRQOL), physical function, disability, fatigue, sleep, mental health status, work productivity and work activity impairment. The RA-BEAM study demonstrated that patients treated with baricitinib experienced a greater impro...

Safety and Efficacy of Baricitinib through 128 Weeks in an Open-label, Longterm Extension Study in Patients with Rheumatoid Arthritis

Keystone EC, Genovese MC, Schlichting DE, de la Torre I, Beattie SD, Rooney TP, Taylor PC.
J Rheumatol. 2018 Jan;45(1):14-21. doi: 10.3899/jrheum.161161

This open-label extension (OLE) of a Phase 2b randomised controlled trial (RCT) found that safety data collected over 2 years of treatment were generally consistent with previous findings for baricitinib in RA. In the RCT, baricitinib demonstrated significant improvement in disease activity compared with placebo and an acceptable safety profile in patients with RA and an inadequate response to MTX. Patients who completed the 24-week double-blind period of the study were eligible for the OLE. Ra...

August 17

Evaluation of Newly Proposed Remission Cut-points for Disease Activity Score in 28 Joints (DAS28) in Rheumatoid Arthritis upon IL-6 Pathway Inhibition

Schoels M, Alasti F, Smolen JS and Aletaha D.
Arthritis Res Ther. 2017 Jul 4;19(1):155. doi: 10.1186/s13075-017-1346-5

DAS28 is not currently included in the joint remission definitions of the ACR and the EULAR because its formula is disproportionately influenced by Acute Phase Response (APR). IL-6 pathway blockers or JAK inhibitors greatly reduce APR, causing patients to be classed as in DAS28 remission despite still having multiple swollen joints. To make DAS28 remission criteria more stringent, the alternative cut-points of <1.9 and <2.2 for CRP and ESR, respectively, have been proposed. This study q...

A Comparison of Discontinuation Rates of Tofacitinib and Biologic Disease-modifying Anti-rheumatic Drugs in Rheumatoid Arthritis: a Systematic Review and Bayseian Network Meta-analysis Regression

Park JS-K, Lee MY, Jang E-J, Kim H-L, Ha D-M, Lee E-K.
Clin Exp Rheumatol 2017;35:689–99

Based on a Bayesian network meta-analysis (NMA) in patients with RA who previously showed failure with csDMARDs or biologics, discontinuation rates between tofacitinib (TOF) and biologics (TNFis, abatacept [ABT], rituximab [RTX] and tocilizumab [TCZ]) differed based on previous treatments and reasons for discontinuation. Data were collected from randomised controlled trials (RCT) found from literature searches from the Cochrane Central Register of Controlled Trials (CENTRAL) and MEDLINE. Discon...

Treatment Persistence and Clinical Outcomes of Tumor Necrosis Factor Inhibitor Cycling or Switching to a New Mechanism of Action Therapy: Real-world Observational Study of Rheumatoid Arthritis Patients in the United States with Prior Tumor Necrosis Factor Inhibitor Therapy

Wei W, Knapp K, Wang L, Chen C-I, Craig GL, Ferguson K Schwartzman S.
Adv Ther. 2017 Aug;34(8):1936-1952. doi: 10.1007/s12325-017-0578-8

This retrospective, observational study used a real-world US clinical database to demonstrate greater effectiveness of switching to a therapy with an alternative mechanism of action (MOA) vs cycling between TNF inhibitors (TNFis) in patients in which TNFi therapy has failed. Between 1 April 2010 and 31 March 2015, a total of 613 of the observed patients failed a TNFi therapy and then either cycled to another TNFi therapy (54.2%) or switched to a therapy with an alternative MOA (45.8%). The most...

Analysis of Non-melanoma Skin Cancer across the Tofacitinib Rheumatoid Arthritis Clinical Programme

Curtis JR, Lee EB, Martin G, Mariette X, Terry TT, Chen Y, Geier J, Andrews J, Kaur M, Fan H, Nduaka CI.
Clin Exp Rheumatol 2017;35:614–22

Because non-melanoma skin cancer (NMSC) is one of the most common malignancies associated with RA immunomodulatory therapies, this analysis looked to determine the rate of NMSC incidence per 100 patient-years in patients with RA receiving TOF in the clinical trial programme. The Phase 1, 2, and 3 IRs (combined) for both TOF 5- and 10 mg were low and comparable to those of adalimumab, MTX and placebo, IRs remained stable over time. TOF doses used in the 2 Phase 1; 8 Phase 2; and 6 Phase 3 studi...

July 17

Long-term safety of tofacitinib for the treatment of rheumatoid arthritis up to 8.5 years: integrated analysis of data from the global clinical trials

Cohen BS, Tanaka Y, Mariette X, Curtis JR, Lee EB, Nash P, Winthrop KL, Charles-Shoeman C, Thirunavukkarasu K, DeMasi R, Geier J, Kwok K, Wang L, Riese R, Wollenhaupt J.
Ann Rheum Dis 2017;76:1253-1262. DOI 10.1136/annrheumdis-2016-210457

This analysis of exposure to tofacitinib, an oral JAKi for the treatment of RA, for up to 8.5 years allowed estimation of safety events with improved precision versus previous tofacitinib reports. Adverse events were generally stable over time; no new safety signals were observed compared with previous tofacitinib reports. Data were collated into an integrated safety summary of tofacitinib in adult patients with active RA, and included data spanning the tofacitinib clinical programme: from 2 P...

Treatment of Rheumatoid Arthritis with Anti-Tumor Necrosis Factor or Tocilizumab Therapy as First Biologic in a Global Comparative observational Study

Choy EH, Bernasconi C, Aassi M, Molina JF, Epis OM.
Arthritis Care Res (Hoboken). 2017 Oct;69(10):1484-1494. doi: 10.1002/acr.23303

To date, the comparative efficacy of tocilizumab and TNFi for patients with RA has only been investigated in a single head-to-head trial and network meta-analyses. This study, ACT-iON, is the first prospective, large-scale, global, multicentre, comparative effectiveness study comparing initiation of intravenous tocilizumab with initiation of a TNFi in patients with RA as the first-line biologic treatment after inadequate response to csDMARDs. Patients were observed in a real-world, clinical pra...

Efficacy and Safety of Tofacitinib Monotherapy, Tofacitinib with Methotrexate, and Adalimumab with Methotrexate in Patients with Rheumatoid Arthritis (ORAL Strategy): A Phase 3b/4, Double-Blind, Head-To-Head, Randomised Controlled Trial

Fleischmann R, Mysler E, Hall S, Kivitz A, Moots R, Luo Z, DeMasi R, Soma K, Zhang R, Takiya L, Tatulych S, Mojcik C, Krishnaswami S, Menon S, Smolen J, on behalf of the ORAL Strategy investigators.
Lancet. 2017 Jul 29;390(10093):457-468. doi: 10.1016/S0140-6736(17)31618-5

In this first head-to-head non-inferiority trial assessing a JAKi ± MTX directly compared with a TNFi + MTX in patients with RA, tofacitinib (TOF) + MTX showed non-inferiority to adalimumab (ADA) + MTX. Non-inferiority was not shown for TOF monotherapy versus TOF + MTX, or versus ADA + MTX. In this 52-week study, MTX-inadequate responder (IR) patients were randomised 1:1:1 to receive TOF 5 mg BID monotherapy, TOF 5 mg BID + MTX or ADA 40 mg every other week + MTX. The primary endpoint, A...

Pathogenetic Insights from the Treatment of Rheumatoid Arthritis

McInnes I, Schett G.
Lancet 2017;389:2328–37 DOI 10.1016/S0140-6736(17)31472-1

This review paper examines the understanding gained from looking at the effects of specific immune interventions in the treatment of RA. The introduction of novel IL-6 agents has provided the ideal opportunity to explore the distinct effect of cytokine inhibition, as opposed to receptor inhibition, at the molecular level. Mechanistic insights into TNF could also be obtained in the future with advanced molecular and informatics approaches, and future biopsy studies will be important to explore t...

Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Filgotinib, a Selective Janus kinase 1 Inhibitor, after Short-term Treatment of Rheumatoid Arthritis: Results of Two randomized Phase IIA Trials

Vanhoutte F, Mazur M, Voloshyn O, Stanislavchuk M, Van der Aa A, Namour F, Galien R, Meuleners L, van ‘t Klooster G.
Arthritis Rheumatol. 2017 Oct;69(10):1949-1959. doi: 10.1002/art.40186

In two 4-week exploratory Phase 2a trials in MTX-inadequate responder (IR) patients with RA, the highly selective JAK1 inhibitor filgotinib met the primary endpoint of ACR20 at Week 4, showing greater response than placebo. Study 1, a proof-of-concept study, included 127 patients randomised to placebo, filgotinib 100 mg BID or filgotinib 200 mg QD. Study 2, was a dose-ranging study and included 91 patients randomised to placebo, filgotinib 30 mg QD, filgotinib 75 mg QD, filgotinib 150 mg QD or ...

June 17

Biologics or Tofacitinib for People with Rheumatoid Arthritis Naïve to Methotrexate: a Systematic Review and Network Meta-analysis

Singh JA, Hossain A, Tanjong Ghogomu E, Mudano AS, Tanjong Ghogomu E, Suarez-Almazor ME, Buchbinder R, Maxwell LJ, Tugwell P, Wells GA.
Cochrane Database Syst Rev. 2017 May 8;5:CD012657. doi: 10.1002/14651858.CD012657

This Cochrane systemic review and network meta-analysis looked at the benefits and harms of biologics or tofacitinib in patients with RA not previously treated with MTX. Using data from 19 RCTs including 6,485 participants, the review found that biologics (abatacept, adalimumab, etanercept, golimumab, infliximab, rituximab) in combination with MTX improved signs and symptoms of RA (ACR50) and increased the chances of remission (DAS <1.6 or DAS28 <2.6). There was also some evidence of an ...

Filgotinib (GLPG0634/GS-6034), an oral selective JAK1 inhibitor, is effective as monotherapy in patients with active rheumatoid arthritis: results from a randomised, dose-finding study (DARWIN 2)

A Kavanaugh, J Kremer, L Ponce, R Cseuz, O V Reshetko, M Stanislavchuk, M Greenwald, A Van der Aa, F Vanhoutte, C Tasset and P Harrison.
Ann Rheum Dis 2017;76:1009–19

In these two Phase 2b studies, filgotinib (a selective JAK-1 inhibitor) was shown to improve the signs and symptoms of RA (compared with placebo), either as monotherapy or when added to MTX. DARWIN 1 included 594 patients with moderate to severe RA on a stable dose of MTX, while DARWIN 2 included 283 patients who stopped taking MTX before the start of the study. After 12 weeks’ treatment, significantly more patients who were receiving filgotinib 100 mg or 200 mg daily in DARWIN 1 or any ...

Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: results from a randomised, dose-finding study (DARWIN 1)

R Westhovens, P C Taylor, R Alten, D Pavlova, F Enríquez-Sosa, M Mazur, M Greenwald, A Van der Aa, F Vanhoutte, C Tasset and P Harrison.
Ann Rheum Dis 2017;76:998–100

In these two Phase 2b studies, filgotinib (a selective JAK-1 inhibitor) was shown to improve the signs and symptoms of RA (compared with placebo), either as monotherapy or when added to MTX. DARWIN 1 included 594 patients with moderate to severe RA on a stable dose of MTX, while DARWIN 2 included 283 patients who stopped taking MTX before the start of the study. After 12 weeks’ treatment, significantly more patients who were receiving filgotinib 100 mg or 200 mg daily in DARWIN 1 or any ...

Outcomes of Tumor Necrosis Factor Inhibitor Cycling versus Switching to a Disease-modifying Anti-rheumatic Drug with a New Mechanism of Action Among Patients with Rheumatoid Arthritis

Chastek B, Becker LK, Chen CI, Mahajan P and Curtis JR.
J Med Econ 2017;20:464–73

This retrospective study looked at claims-based datasets to establish whether it is preferable to switch to another TNF inhibitor (TNFi) or to a therapy with a different mechanism of action (MOA) when RA treatment failure occurs with an initial TNFi, due to inadequate response or lack of tolerability. Administrative claims data from a large US database were used to compare treatment patterns, treatment effectiveness (based on fulfillment of six criteria) and costs in in the 12 months after RA p...

May 17

Estimated Medical Expenditure and Risk of Job Loss among Rheumatoid Arthritis Patients undergoing Tofacitinib Treatment: Post Hoc Analyses of Two Randomized Clinical Trials

Rendas-Baum R, Kosinski M, Singh A, Mebus CA, Wilkinson BE and Wallenstein GV.
Rheumatology doi: 10.1093/rheumatology/kex087

The results of this post hoc analysis of two Phase 3 studies of tofacitinib (TOF) show that improvements in health-related quality of life related to TOF treatment are likely to translate into significant reductions in estimated medical expenditure and likelihood of current and future job loss. Data from 399 MTX inadequate responder (IR) patients from ORAL Step, and 716 TNF inhibitor (TNFi)-IR patients from ORAL Standard were included in this analysis. Patients were receiving 5 mg or 10 mg TOF...

Discontinuation of Tofacitinib after achieving Low Disease Activity in Patients with Rheumatoid Arthritis: a Multicentere, Observational Study

Kubo S, Yamaoka K, Amano K, Nagano S, Tohma S, Suematsu E, Nagasawa H, Iwata K and Tanaka Y.
Rheumatology. Doi 10.1093/rheumatology/kex068

This study showed that in patients who achieved low disease activity (LDA), it is possible to discontinue tofacitinib without flare in approximately one-third of patients. Patients from the tofacitinib Phase 3 programme and long-term extension study were enroled. Discontinuation was based on physician-patient decision making with informed consent. The primary endpoint was the proportion of patients who remained tofacitinib free at post-treatment Week 52. Of 64 patients treated with tofacitin...

Tocilizumab Combination Therapy or Monotherapy or Methotrexate Monotherapy in Methotrexate-naïve Patients with Early Rheumatoid Arthritis: 2-year Clinical and Radiographic Results from the Randomized, Placebo-controlled FUNCTION Trial

Burmester GR, Rigby WF, van Vollenhoven RF, Kay J, Rubbert-Roth A, Blanco R, Kadva A and Dimonaco S.
Ann Rheum Dis Published Online First: 7 April 2017. Doi 10.1136/annrheumdis-20160210561

Burmester et al. present data showing that 52-week efficacy and safety of intravenous tocilizumab plus methotrexate, or tocilizumab monotherapy are maintained through to Week 104 in patients with early rheumatoid arthritis. Patients were assigned to four treatment groups: 4 mg/kg TCZ + MTX, 8 mg/kg TCZ + MTX, 8 mg/kg TCZ + placebo or placebo + MTX. Patients not achieving DAS28 ≤3.2 at Week 52 and who were not receiving 8 mg/kg TCZ were rescued to 8 mg/kg TCZ + MTX. Of the 1162 randomly assi...

April 17

EULAR Recommendations for the Management of Rheumatoid Arthritis with Synthetic and Biological Disease-modifying Antirheumatic Drugs: 2016 Update

EULAR RA Management Task Force Smolen J, Landewé R, Bijlsma J, et al.
Ann Rheum Dis Published Online First: 06March2017. doi:10.1136/annrheumdis-2016-210715

The EULAR 2016 recommendations update, based on three systematic literature reviews (SLRs) and expert opinion, comprises four overarching principles and 12 recommendations compared with 14, respectively, in 2013. These recommendations intend to inform regarding EULAR’s most recent consensus on the management of RA, with the aim of attaining the best outcomes with current therapies. All DMARD types: csDMARDs, bDMARDs, tsDMARD and bsDMARD are addressed, and cost aspects are taken into consi...

Sarilumab improves Patient-reported Outcomes in Rheumatoid Arthritis Patients with Inadequate Response/Intolerance to Tumour Necrosis Factor Inhibitors

Strand V, Reaney M, Chen C-I, Proudfoot CWJ, Guillonneau S, Bauer D, Mangan E, Graham NMH, van Hoogstraten H, Lin Y, Pacheco-Tena C, Fleischmann R.
RMD Open 2017;3:e000416. DOI:10.1136/rmdopen-2016-000416

Evidence is presented that treatment with sarilumab demonstrates patient-reported benefits in TNF-IR patients with moderate to severe RA. These improvements complement the clinical efficacy previously reported for sarilumab, and are consistent with those seen in the MOBILITY trial (MTX-IR patients)1, yet in a more difficult-to-treat population. Data were analysed from the 24-week Phase 3 TARGET randomised controlled trial in adult patients with active RA and previous inadequate response or into...

March 17

A Phase IIb Study of ABT-494, a Selective JAK-1 Inhibitor, in Patients With Rheumatoid Arthritis and an Inadequate Response to Anti–Tumor Necrosis Factor Therapy

Kremer JM, Emery P, Camp HS, Friedman A, Wang L, Othman AA, Khan N, Pangan AL, Jungerwirth S and Keystone EC.
Arthritis Rheumatol 2016;68:2867–77

The summary and accompanying slide deck have been developed in conjunction with the Genovese et al. study (Study 1) which examined ABT-494 in MTX-IR patients in order to compare and contrast the data. In these two Phase 2b studies, ABT-494 (a novel selective JAK-1 inhibitor) was shown to be effective in patients with active RA who were non-responders to MTX or at least one TNF inhibitor. Patients with active RA who had an inadequate response to MTX (study 1) or were refractory to or intoleran...

Efficacy and Safety of ABT-494, a Selective JAK-1 Inhibitor, in a Phase IIb Study in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate

Genovese MC, Smolen JS, Weinblatt ME, Burmester GR, Meerwein S, Camp HS, Wang L, Othman AA, Khan N, Pangan AL and Jungerwirth S.
Arthritis Rheumatol 2016;68:2857–66

The summary and accompanying slide deck have been developed in conjunction with the Kremer et al. study (Study 2) which examined ABT-494 in TNF-IR patients in order to compare and contrast the data. In these two Phase 2b studies, ABT-494 (a novel selective JAK-1 inhibitor) was shown to be effective in patients with active RA who were non-responders to MTX or at least one TNF inhibitor. Patients with active RA who had an inadequate response to MTX (study 1) or were refractory to or intolerant ...

Cardiovascular Safety of Tocilizumab versus Tumor Necrosis Factor Inhibitors in Patients with Rheumatoid Arthritis – a Multi-database Cohort Study

Kim SC, Solomon DH, Rogers JR, Gale S, Klearman M, Sarsour K and Schneeweiss S.
Arthritis Rheumatol 2017 Feb 28. doi: 10.1002/art.40084

This multi-database population-based US cohort study found no evidence of an increased cardiovascular (CV) risk among RA patients who switched from a different biologic drug or tofacitinib to tocilizumab (TCZ) versus to a TNF inhibitor (TNFi). The study used claims data in patients with RA newly starting treatment with TCZ or a TNFi from three large databases: Medicare (n=7397), PharMetrics (n=8119) and MarketScan (n=12512). Included within the analysis were 9218 TCZ initiators propensity-score...

Efficacy and Safety of Tofacitinib in Older and Younger Patients with Rheumatoid Arthritis

Curtis JR, Schulze-Koops H, Takiya L, Mebus CA, Terry KK, Biswas P and Jones TV.
Clin Exp Rheumatol 2017 Jan 4

In this analysis of patients with moderate to severe RA treated with tofacitinib (TOF) in Phase 3 and long-term extension (LTE) studies, patients aged 65 years had similar efficacy and a numerically higher risk of SAEs and discontinuations due to AEs compared with younger patients. The Phase 3 population included patients from five trials (n=3111) of TOF 5 mg or 10 mg BID or placebo. The LTE population (n=4102) included patients from two studies who had participated in Phase 1, 2 or 3 TOF stud...

Efficacy and Safety of Sirukumab in Patients with Active Rheumatoid Arthritis Refractory to Anti-TNF Therapy (SIRROUND-T): A Randomised, Double-blind, Placebo-controlled, Parallel-group, Multinational, Phase 3 Study

Aletaha D, Bingham CO 3rd, Tanaka Y, Agarwal P, Kurrasch R, Tak PP and Popik S.
Lancet 2017;pii:S0140-6736(17)30401-4

In this Phase 3 multicentre, randomised controlled trial in patients with active RA who were refractory or intolerant to previous biological treatment with at least one TNF inhibitor, sirukumab 50 mg every four weeks (Q4W) or 100 mg every two weeks (Q2W) was well tolerated and significantly improved signs and symptoms of disease. Patients were randomised 1:1:1 to placebo (n=294), sirukumab 50 mg Q4W (n=292) or sirukumab 100 mg Q2W (n=292), while continuing any concomitant DMARDs. Of the 878 ran...

February 17

Analysis of Haematological Changes in Tofacitinib-treated Patients with Rheumatoid Arthritis across Phase 3 and Long-term Extension Studies

Schulze-Koops H, Strand V, Nduaka C, DeMasi R, Wallenstein G, Kwok K and Wang L.
Rheumatology 2017;56:46–57.

In this analysis examining haematological changes after tofacitinib (TOF) treatment in patients with RA from pooled Phase 3 and LTE studies, TOF decreased mean lymphocyte counts and slightly increased mean haemoglobin (Hb) levels. The Phase 3 population included patients from six trials (n=4271) of TOF 5- or 10 mg BID, placebo or active comparator up to 24 months. The LTE population (n=4858) included patients from two studies (of up to 84 months), who had participated in Phase 1, 2 or 3 TOF st...

Tocilizumab Use in Pregnancy: Analysis of a Global Safety Database Including Data from Clinical Trials and Post-marketing Data

Hoeltzenbein M, Beck E, Rajwanshib R, GøtestamSkorpen C, Berberb E, Schaefera C, Østensenc M, .
Semin Arthritis Rheum 2016;46:238–45. DOI 10.1016/j.seminarthrit.2016.05.004.

This dataset is the largest series of tocilizumab (TCZ)-exposed pregnancies to date; considering the limitations of global safety databases, the data presented provide information to assist physicians and patients in making informed decisions. At present, published experience on TCZ use during pregnancy is very limited. In the current analysis, all pregnancy-related reports in the Roche Global Safety Database until December 31, 2014 were analysed. Outcomes assessed included: spontaneous abortio...

Peficitinib, a JAK Inhibitor, in Combination with Limited Conventional Synthetic DMARDs in the Treatment of Moderate-to-severe Rheumatoid Arthritis

Genovese MC, Greenwald M, Codding C, Zubrzycka-Sienkiewicz A, Kivitz AJ, Wang A, Shay K, Wang X, Garg JP, Cardiel MH.
Arthritis Rheumatol DOI 10.1002/art.40054. Accepted article.

In this Phase 2b study in patients with moderate to severe RA, once-daily peficitinib in combination with limited csDMARDs reduced the symptoms of RA, demonstrated a dose-dependent ACR20 response rate over 12 weeks, and showed acceptable tolerability. This 12-week study included patients who had an inadequate response or intolerance to csDMARDs (N=289). Patients were randomised 1:1:1:1:1 to peficitinib 25-, 50-, 100, 150 mg or matching placebo. Statistically significant differences in the AC...

Baricitinib in Patients with Inadequate Response or Intolerance to Conventional Synthetic DMARDs: Results from the RA-BUILD Study

Dougados M, van der Heijde D, Chen Y-C, Greenwald M, Drescher E, Liu J, Beattie S, Witt S, de la Torre I, Gaich C, Rooney T, Schlichting D, de Bono S, Emery P.
Ann Rheum Dis 2017;76:88–95.

Baricitinib improved symptoms of RA in the RA-BUILD trial, a Phase 3 study of baricitinib in patients with moderately to severely active RA, refractory to or intolerant to csDMARDs. As well as providing a short-term (24 weeks) benefit, there appeared to be joint damage benefit, considered a marker of long-term disability. RA-BUILD was a 24-week randomised, double-blind, placebo-controlled parallel-group study. Patients were randomised 1:1:1 to receive once-daily doses of placebo (n=228) or bari...

January 17

Effects of Baricitinib on Lipid, Apolipoprotein, and Lipoprotein Particle Profiles in a Phase 2b Study in Patients with Active Rheumatoid Arthritis

Kremer J, Genovese MC, Keystone E, Taylor PC, Zuckerman SH, Ruotolo G, Schlichting DE, Crotzer VL, Nantz E, Beattie SD and Macias WL.
Arthritis Rheumatol 2017. DOI 10.1002/art.40036.

In this analysis of the effect of baricitinib on changes in lipid profile, lipoprotein particle size and apolipoprotein content, increases in serum lipids were observed with HDL-C increases correlating with improved clinical outcomes. Eligible patients (N=301) met the inclusion criteria for the Phase 2b randomised, double-blind, placebo-controlled study.1 Patients were assigned in a 2:1:1:1:1 ratio to once-daily doses of placebo or baricitinib 1, 2, 4, or 8 mg, respectively. Those receiving 2 m...

Five-year Efficacy and Safety of Tocilizumab Monotherapy in Patients with Rheumatoid Arthritis who were Methotrexate- and Biologic-naïve or Free of Methotrexate for 6 Months: the AMBITION Study

Jones G, Wallace T, McIntosh MJ, Brockwell L, Gómez-Reino JJ, Sebba A.
J Rheumatol 2017;44:2. DOI 10.3899/jrheum.160287.

Results from the AMBITION study (Actemra versus Methotrexate double-Blind Investigate Trial In mONotherapy), showed the continuing efficacy and safety of tocilizumab up to 264 weeks. AMBITION was a 24-week randomised controlled trial in patients with active RA who were either MTX-naïve or MTX-free for 6 months prior to study entry. Patients received TCZ 8 mg/kg IV Q4W or oral MTX weekly (7.5 mg dose escalating to 20 mg). For those patients who then entered the long-term extension (LTE) stu...

Evaluation of Real-World Experience with Tofacitinib Compared with Adalimumab, Etanercept, and Abatacept in RA Patients with 1 Previous Biologic DMARD: Data from a U.S. Administrative Claims Database

Harnett J, Gerber R, Gruben D, Koenig AS and Chen C.
J Manag Care Spec Pharm. 2016 Dec;22(12):1457-1471.

Data were examined to compare patient characteristics, treatment patterns and costs in patients with RA receiving tofacitinib (TOF) or common bDMARDs (adalimumab [ADA], etanercept (ETN) or abatacept [ABA]) who had previously received a single bDMARD. This study analyses real-world data from two US claims databases between November 2012 and October 2014. Data were collected from a total of 1252 patients in the Truven Marketscan Commercial and Medicare Supplemental databases. Pre-index (12-month...

December 16

Sarilumab and Non-biologic Disease-Modifying Antirheumatic Drugs in Patients with Active RA and Inadequate Response or Intolerance to TNF Inhibitors

Fleischmann R, van Adelsberg J, Lin Y, da Rocha, Castelar-Pinheiro G, Brzezicki J, Hrycaj P, Graham NMH, van Hoogstraten H, Bauer D, Burmester GR.
Arthritis Rheumatol 2016. DOI:10.1002/art.39944.

In this Phase 3 study (TARGET) of TNF-IR patients, sarilumab plus csDMARD(s) demonstrated clinical efficacy and improvements in physical function versus placebo plus csDMARD(s). Patients (N=546) were randomised 1:1:1 to sarilumab 150 mg, 200 mg Q2W or placebo (all plus csDMARD[s]). Two co-primary endpoints versus placebo were investigated: ACR20 response rate at Week 24, and HAQ-DI change from baseline at Week 12. As well as improvements in ACR20 responses (33.7% vs 55.8 and 60.9%, for placebo...

Efficacy and Safety of Sarilumab Monotherapy versus Adalimumab Monotherapy for the Treatment of Patients with Active Rheumatoid Arthritis (MONARCH): a Randomised, Double-blind, Parallel-group Phase III Trial

Burmester GR, Lin Y, Patel R, van Adelsberg J, Mangan EK, Graham NMH, van Hoogstraten H, Bauer D, Vargas JI, Lee E-B.
Ann Rheum Dis 2016. DOI 10.1136/annrheumdis-2016-210310

In this Phase 3 superiority study (MONARCH) of patients with active RA who should not continue treatment with MTX because of intolerance or inadequate response, sarilumab monotherapy demonstrated superior efficacy to adalimumab (ADA) monotherapy. Patients receiving sarilumab versus ADA also reported greater improvement in health status, including a trend towards greater improvement in fatigue. In this randomised, multicentre study, patients received sarilumab 200 mg Q2W plus placebo (n=184) or ...

Peficitinib, a JAK Inhibitor, in the Treatment of Moderate-to-severe Rheumatoid Arthritis in Methotrexate-inadequate Responders

Kivitz AJ, Gutierrez-Ureña SR, Poiley J, Genovese MC, Kristy R, Shay K, Wang X, Garg JP, Zubrzycka-Sienkiewicz A.
Arthritis & Rheum 2016; ePub ahead of print

This Phase 2b study of peficitinib (ASP015K), an orally administered once-daily JAK inhibitor, plus MTX, demonstrated efficacy across multiple secondary endpoints with higher peficitinib doses. Peficitinib in combination with MTX was well tolerated with a safety profile that was consistent with previous studies. A high placebo response rate was seen in both Latin and North America, when patient data were stratified. This high placebo rate is problematic for the accurate interpretation of pefic...

Efficacy of VX-509 (decernotinib) in Combination with a Disease-modifying Antirheumatic Drug in Patients with Rheumatoid Arthritis: Clinical and MRI Findings

Genovese M, Yang F, Østergaard M and Kinnman N.
Ann Rheum Dis 2016;75:1979–83

This Phase 2b study of VX-509 (decernotinib), a selective JAK3 inhibitor, showed that VX-509 in combination with stable DMARD therapy was effective for improving synovitis and osteitis as assessed by MRI in patients who had an inadequate response to DMARD therapy. Patients were randomised to treatment groups receiving either placebo, VX-509 100 mg, 200 mg or 300 mg for 12 weeks. Minimum inclusion criteria included Grade ≥2 clinical synovitis in either the wrist or two metacarpophalangeal joi...

Baricitinib, Methotrexate, or Combination in Patients with Rheumatoid Arthritis and no or Limited Prior Disease-Modifying Antirheumatic Drug Treatment

Fleischmann F, Schiff M, van der Heijde D, Ramos-Remus C, Spindler A, Stanislav M, Zerbini CAF, Gurbuz S, Dickson C, de Bono S, Schlichting D, Beattie S, Kuo W-L, Rooney T, Macias W, Takeuchi T.
Arthritis Rheumatol 2016. DOI 10.1002/art.39953. Accepted article

In this 52-week study of patients receiving initial therapy for RA, baricitinib alone or in combination with MTX demonstrated superior efficacy compared with MTX alone. Patients naïve to csDMARD (no or <3 doses of MTX) or bDMARD were randomised 4:3:4 (N=588) to MTX QW, baricitinib 4 mg QD or baricitinib 4 mg QD + MTX QW. The primary endpoint assessment was noninferiority of baricitinib monotherapy to MTX based on ACR20 response at Week 24. Not only was the primary endpoint met, baricit...

October 16

Tocilizumab as Monotherapy or Combination Therapy for Treating Active Rheumatoid Arthritis: a Meta-analysis of efficacy and Safety Reported in Randomized Controlled Trials

Teitsma XM, Marijnissen AKA, Bijlsma JWJ, Lafeber FPJ, Jacobs JWG.
Arthritis Res Ther 2016; 18:211. DOI 10.1186/s13075-016-1108-9

This is the first meta-analysis comparing efficacy and safety of TCZ monotherapy (TCZMONO) versus TCZ + csDMARD (TCZCOMBI) in patients with RA. The findings show that similar efficacy can be expected with TCZ monotherapy in patients with intolerance to csDMARDs compared with inadequate responders to csDMARDs who switch to TCZ add-on therapy. A total of 6679 patients from 13 studies were included, receiving: 1298, TCZMONO; 3077, TCZCOMBI; 2204, csDMARDs. Meta-analyses were performed for the foll...

Sarilumab plus Methotrexate Improves Patient-reported Outcomes in Patients with Active Rheumatoid Arthritis and Inadequate Responses to Methotrexate: Results of a Phase III Trial

Strand V, Kosinski M, Chen C-I, Joseph G, Rendas-Baum R, Graham NMH, van Hoogstraten H, Bayliss M, Fan C, Huizinga T, Genovese MC.
Arthritis Res Ther 2016; 18:198. DOI.10.1186/s13075-016-9

Evidence is presented that treatment with sarilumab improves patient-reported outcomes (PROs). These improvements complement the clinical efficacy previously reported for sarilumab. Data were analysed from the 52-week Phase 3 MOBILITY randomised controlled trial in adult patients with active RA and previous inadequate response to MTX. Patients received subcutaneous placebo or sarilumab 150 mg or 200 mg every 2 weeks in combination with MTX, for 52 weeks. PROs assessed were: Patient Global Asse...

Tofacitinib in Combination with Conventional DMARDs in Patients with Active Rheumatoid Arthritis: PROs from a Phase 3 Randomised Controlled Trial

Strand V, Kremer JM, Gruben D, Krishnaswami S, Zwillich SH, Wallenstein GV.
Arthritis Care Res 2016; Accepted article. DOI 10.1002/acr.23004

Further evidence is presented that treatment with tofacitinib improves patient-reported outcomes (PROs), in addition to improving underlying disease activity. Data were analysed from the Phase 3 ORAL Sync 12-month randomised controlled trial in adult patients with active RA and previous inadequate response to ≥1 conventional or biologic DMARD(s). Patients received (4:4:1:1) TOF 5mg or 10mg BID or Placebo advanced to 5 mg or 10 mg BID plus conventional DMARD(s). PROs assessed at Month 3 were...

RAPID3 and ACR/EULAR Provisional Definitions as Predictors of Radiographic Outcome in a Rheumatoid Arthritis Clinical Trial with Tocilizumab

Khawaja MN, Bergman MJ, Yourish J, Pei J, Reiss W, Keystone E.
Arthritis Care Res 2016; Accepted article. DOI 10.1002/acr.23008.

The findings reported represent the first validation of RAPID3 (Routine Assessment of Patient Index Data 3) remission ± SJC ≤1 as an alternative to the established SDAI or Boolean remission definitions, which can be time consuming and costly to measure. RAPID3 is a pooled index of the patient-reported measures: function, pain and Patient Global estimate of status. Data were analysed from the TociLIzumab Safety and THE Prevention of Structural Joint Damage (LITHE) study, a 2-year doubl...

September 16

Treating Experimental Arthritis with the Innate Immune Inhibitor Interleukin-37 Reduces Joint and Systemic Inflammation

Cavalli G, Koenders M, Kalabokis V, Kim J, Tan AC, Garlanda C, Manovani A, Dagna L, Joosten LAB, Dinarello CA.
Rheumatology (Oxford) 2016; DOI 10.1093/rheumatology/kew325

IL-37, a member of the IL-1 family, has recently been characterised as a fundamental inhibitor of innate inflammation. This study examines the effects of recombinant IL-37 on joint inflammation and pathology in a mouse model of arthritis, and also explores its potential in the treatment of human joint inflammation. In this mouse model of experimental arthritis, short-term, low-dose treatment with IL-37 suppressed joint and systemic inflammation. Wild-type mice received three intraperitoneal dos...

August 16

A Randomized Phase 2b Study of ABT-494, a Selective JAK Inhibitor in Patients with Rheumatoid Arthritis and an Inadequate Response to Methotrexate

Genovese M, Smolen J, Weinblatt M, Burmester G, Meerwein S, Camp H, Wang L, Othman A, Khan N, Pangan A, Jungerwirth S.
Arthritis Rheumatol 2016; Accepted article DOI 10.1002/art-39808 [Epub 2016]

This dose-ranging study evaluated the efficacy of the novel, selective JAK1 inhibitor ABT-494 versus placebo in patients with moderate-to-severe RA and inadequate response (IR) to MTX. In this 12-week, randomised, double-blind study (BALANCE II), the efficacy and safety of ABT-494 dosed at 3mg, 6 mg, 12 mg, 18 mg (all twice daily) and 24 mg (once daily) was assessed. Patients included had not received prior biologic therapy. Of the 299 patients included in the analysis, the proportions of pati...

Risk for Lower Intestinal Perforations in Patients with Rheumatoid Arthritis Treated with Tocilizumab in Comparison to Treatment with Other Biologic or Conventional Synthetic DMARDs

Strangfeld A, Richter A, Siegmund B, Herzer P, Rockwitz K, Demary W, Aringer M, Meißner Y, Zink A, Listing J.
Ann Rheum Dis 2016;0:1–7 DOI 10.1136/annrheumdis-2016-209773.

This real-life study confirms findings from the tocilizumab (TCZ) clinical development program that IL-6 inhibition with TCZ may be associated with increased risk of lower intestinal perforation (LIP). Data were analysed from the RABBIT register of patients. The primary outcome was the incidence of LIPs in patients exposed to TCZ, csDMARDs, TNFis, abatacept, or rituximab. Thirty-seven LIPs were observed in 53,972 patient years. The proportion of patients who developed a LIP was higher in pat...

July 16

Switching from Adalimumab to Tofacitinib in the Treatment of Patients with Rheumatoid Arthritis

Genovese, et al.
Arthritis Research & Therapy. 2016. DOI 10.1186/s13075-016-1049-3 [Epub ahead of print]

Results are reported from an analysis exploring the safety and efficacy of open-label tofacitinib (TOF) following blinded treatment with TOF or adalimumab (ADA) in patients with moderate to severe RA. The analysis included patients from ORAL Sequel, an open-label long-term extension study, which all patients entered following ORAL Standard (one of the studies in the TOF phase 3 program). Only those patients who had been randomized to ADA 40 mg Q2W + MTX or 10 mg TOF + MTX in ORAL Standard were...

Efficacy and safety of the oral Janus kinase inhibitor peficitinib (ASP015K) monotherapy in patients with moderate to severe rheumatoid arthritis in Japan:�a 12-week, randomised, double-blind, placebo-controlled phase IIb study

Takeuchi et al.
Ann Rheum Dis. 2016 Jun;75:1057-64. doi: 10.1136/annrheumdis-2015-208279. Epub 2015 Dec 15

Peficitinib (ASP015K) is a novel orally bioavailable JAK inhibitor in development for the treatment of RA. It inhibits JAK1, JAK2, JAK3 and Tyk2 enzyme activities and has moderate selectivity or JAK3 inhibition. Here the authors report the findings of a 12-week, randomized, double-blind, placebo-controlled phase IIb study evaluating efficacy, safety and dose response of peficitinib (25, 50, 100, or 150 mg) as once-daily oral monotherapy in Japanese patients with moderate to severe RA. The prim...

Two-year Efficacy of Tocilizumab in Patients with Active Rheumatoid Arthritis in Clinical Practice

Notario Ferreira, Ferrer González MA, Morales Garrido P, et al.
Reumatol Clin. 2016; May 10 doi: 10.1016/j.reuma.2016.03.014 [Epub ahead of print]

The efficacy and safety of tocilizumab has been studied in several randomized clinical trials (RCTs) but due to the strict inclusion and exclusion criteria of RCTs, real-life observational studies are needed to supplement the findings from these trials. This small longitudinal, open-label study from an outpatient clinic in Spain evaluated the effectiveness, survival rate and reasons for treatment discontinuations in 85 patients treated with tocilizumab over a 24-month period. The study also as...

Efficacy and Safety of Baricitinib in Japanese Patients with Active Rheumatoid Arthritis Receiving Background Methotrexate Therapy: A 12-week, Double-blind, Randomized Placebo-controlled Study

Tanaka Y, Emoto K, Cai Z, et al.
J Rheumatol. 2016;43(3):504–511.

Clinical trials have shown baricitinib once daily to be effective in patients with RA. However, this Janus kinase (JAK) 1/JAK2 inhibitor has not been evaluated in a Japanese population. In this 12-week, placebo-controlled study, 145 Japanese patients were enrolled and received placebo, 1 mg, 2 mg, 4 mg or 8 mg oral baricitinib daily. Efficacy results were encouraging and consistent with earlier trials. Significantly more baricitinib patients achieved ACR20 response at Week 12 of treatment compa...

May 16

The Efficacy and Safety of Clazakizumab, an Anti-Interleukin-6 Monoclonal Antibody, in a Phase 2b Study of Adults with Active Psoriatic Arthritis

Mease et al.
Arthritis Rheumatol. 2016 Mar 24. DOI 10.1002/art.39700 [Epub ahead of print]

Encouraging results have been seen with clazakizumab in RA, but the results of anti-IL6 therapy in patients with psoriatic arthritis (PsA) have so far been unclear. This Phase 2b dose-ranging study examined the efficacy and safety of clazakizumab given subcutaneously q4w, with or without MTX, in 165 patients with PsA who had inadequate response to NSAIDs. ACR20 response at Week 16, the primary endpoint, was significantly higher in patients receiving clazakizumab 100 mg compared with placebo (52...

Initial Experience with Tofacitinib in Clinical Practice: Treatment Patterns and Costs of Tofacitinib Administered as Monotherapy or in Combination with Conventional Synthetic DMARDs in 2 US Health Care Claims Databases

Harnett et al.
Clin Ther. 2016 Mar 28. doi: 10.1116/j.clinthera. 2016.03.038 [Epub ahead of print]

This study analyzes data from two US claims databases between November 2012 and June 2014. It was designed to build upon knowledge from tofacitinib Phase 3 clinical trials providing clinical insights from independent sources on treatment patterns and costs for tofacitinib. Data were collected from 337 patients in the Truven Marketscan (TM) and 118 patients in the Optum Clinformatics (OC) databases. In this early experience cohort for tofacitinib, approximately 75% of patients had previously re...

Real-world Comparative Risks of Herpes Virus Infections in Tofacitinib and Biologic-treated Patients with Rheumatoid Arthritis

Curtis et al.
Ann Rheum Dis. 2016 Apr 25;0:1–5 doi: 10.1136/annrheumdis-2016-209131

Herpes Zoster (HZ) complications can cause considerable morbidity including debilitating pain syndromes. Clinical trials of tofacitinib have suggested it may increase the risk of HZ. Although unclear, the mechanism may involve reduced CD4 T-cell function and interference of interferon signalling. Following approval of tofacitinib in the US in 2012, real-world data from Medicare (2006–2013) and from the US longitudinal database, Marketscan, (2010–2014) were analysed. A total of 252...

Extended-release once-daily formulation of tofacitinib: evaluation of pharmacokinetics compared with immediate-release tofacitinib and impact of food

Lamba et al.
J Clin Pharmacol. 2016 Mar 11. doi: 10.1002/jcph.734. [Epub ahead of print]

PK profile of TOF is rapid absorption and elimination with time to max concentration 0.5-1 hour and terminal half-life at 3 hours. It is currently approved for immediate release (IR) 5 mg BID, 10 mg total; however, decreasing the dosage to QD dosing may help increase compliance. This study performed in 24 healthy males compared the PK of XR and IR TOF under both single and multiple dose conditions and evaluated the effect of a high-fat meal on the PK of XR TOF. There were no clinically importa...

Baricitinib in Patients with Refractory Rheumatoid Arthritis

Genovese et al.
N Engl J Med. 2016 Mar 31;374(13):1243-52. doi: 10.1056/NEJMoa1507247

For patients who have an inadequate response or unacceptable side effects associated with biologic DMARDs, the options for treatment beyond conventional DMARDs are limited. This phase 3 trial of the JAK 1/2 inhibitor, baricitinib, studied its efficacy in bDMARD-IR patients. 527 patients were randomized to either baricitinib 2mg, 4mg or placebo for up to 24 weeks. At week 12 the primary endpoints were tested hierarchically to control type 1 error; these endpoints were ACR20, HAQ-DI score, DAS28...

March 16

Tofacitinib or adalimumab versus placebo: patient-reported outcomes from a phase 3 study of active rheumatoid arthritis

Strand V, van Vollenhoven R, Bong Lee E et al.
Strand et al. Rheumatology (Oxford). 2016 Feb 29. doi:pii: kev442. [Epub ahead of print]

RA not only affects the physical aspects of a patient’s health but also has an impact on the psychological well-being causing a significant disease burden. This paper reports on the patient-reported outcomes (PROs) from the ORAL Standard study. This study investigated tofacitinib 5mg BID, 10mg BID, adalimumab vs. placebo over 12 months with a primary endpoint at month 3. All treatment groups showed significant improvements over placebo in HAQ-DI, PtGA and Pain with LSM changes in baselin...

Clinical Relevance of VPAC1 Receptor Expression in Early Arthritis: Association with IL-6 and Disease Activity

Seoane I, Ortiz A, Piris L et al.
 PLoS ONE 11(2): e0149141. doi:10.1371/journal. pone.0149141

VPAC1 and VPAC2 both mediate anti-inflammatory and immunoregulatory responses in RA. Both these are receptors of vasoactive intestinal peptide (VIP), a broadly distributed peptide found in neural, endocrine and immune cells, which triggers biological response when interacting with the aforementioned receptors. It has recently been described in Martinez et al. that those patients with low levels of VIP have worse disease outcome.1 This study analyzed 250 blood samples from the Princesa early Art...

Comparative effects of biologics on cardiovascular risk among older patients with rheumatoid arthritis

Zhang et al.
Ann Rheum Dis 2016;0:1–6 doi:10.1136/ annrheumdis-2015-207870 [Epub ahead of print]

Since RA patients are at an increased risk of a CV event, there have been several studies to determine if RA treatments alter this risk. In a retrospective study, Zhang and colleagues assess the risk of CV events in patients initiating bDMARDs. Using Medicare medical and pharmacy claims data, the incidence rate (IR) of acute myocardial infarction (AMI) and of a composite CHD* was calculated across RA patients initiating 8 different biologics: ABA, ADA, CER, ETA, GOL, INF, RIT, and TOC. There we...

Pregnancy outcome after tocilizumab therapy in early pregnancy – a case series from the German Embryotox Pharmacovigilance Center

Weber-Schoendorfer et al.
Reproductive Toxicology doi:10.1016/j.reprotox.2016.01.002

MTX users have an increased incidence of spontaneous abortions (SABs) compared to baseline risk (42.5%1 vs. 13-17%2). Tocilizumab (TCZ) has been shown to have similar efficacy with or without MTX. There is currently limited data on the effect of TCZ on pregnancy, but with more safety data, TCZ could be an alternative for RA patients of reproductive age. The patients were enrolled at Embryotox Berlin, a pharmacovigilance center providing risk assessment during pregnancy, between 2011 and 2014 d...

Comparison of adding tocilizumab to methotrexate with switching to tocilizumab in patients with rheumatoid arthritis with inadequate response to methotrexate: 52-week results from a prospective, randomised, controlled study (SURPRISE study)

Kaneko et al.
Ann Rheum Dis 2016 Jan 5 DOI: 10.1136/annrheumdis-2015-208426 [Epub ahead of print

MTX is the primary drug in RA management because of its long-term effectiveness and safety profile; however, in patients who have insufficient response (IR) to MTX, treatment adjustments are needed – either to combine a bDMARD with MTX or to switch to a bDMARD from MTX. In the SURPRISE study, the efficacy and safety of adding TCZ to MTX (ADD-ON) or switching MTX to TCZ (SWITCH) was evaluated in 233 patients with moderate to highly active RA who were randomised 1:1. Both treatment groups we...

Early changes in blood-based joint tissue destruction biomarkers are predictive of response to tocilizumab in the LITHE study

Bay-Jensen A, Platt A, Siebuhr A, Christiansen C, Byrjalsen I, Karsdal M.
Arthritis Research & Therapy (2016) 18:13 DOI: 10.1186/s13075-015-0913-x

One of the major challenges of RA treatment is choosing the correct treatment and dose for the individual patient, as treatment response can be heterogeneous. To help select the appropriate treatment, there is a need for effective and non-invasive ways to monitor disease activity and progression. In the LITHE study, Bay-Jensen et al. investigate whether early biomarker measurements could predict early joint protection response to TCZ. The biomarkers (CRPM, VICM, C1M, C2M, C3M, and CTX-I/OC [bone...

January 16

Systematic review and meta-analysis of serious infections with tofacitinib and biologic disease-modifying antirheumatic drug treatment in rheumatoid arthritis clinical trials

Strand V, Ahadieh S, French J, Geier J, Krishnaswami S, Menon S, Checchio T, Tensfeldt TG, Hoffman E, Riese R, Boy M, Gomez-Reino JJ.
Arthritis Res Ther. 2015 Dec 15;17(1):362

Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. By modulating the signalling of cytokines that are integral to lymphocyte activation, proliferation, and function, tofacitinib may suppress multiple elements of immune response. A systematic literature search including all biologics and tofacitinib procured 66 RCTs and 22 LTEs that were included in a meta-analysis to provide estimated incidence rates, risk ratios, and risk differences of serious infection for each therapy. ...

VX-509 (Decernotinib), an Oral Selective JAK-3 Inhibitor, in Combination With Methotrexate in Patients With Rheumatoid Arthritis

Genovese MC, van Vollenhoven RF, Pacheco-Tena C, Zhang Y, Kinnman N.
Arthritis Rheumatol. 2016 Jan;68(1):46-55.

VX-509 (decernotinib) is a novel oral, selective inhibitor of JAK-3. JAK-3 is a member of the JAK signalling family that is primarily expressed in hematopoietic cells and associates with only the common γ-chain making it a promising therapeutic drug target. A phase IIb 24-week study of VX-509 in 358 patients with RA, who had prior inadequate response to MTX, uses ACR20 response rate and DAS28-CRP change at Week 12 to assess the efficacy of VX-509. Patients were administered either placebo+...

December 15

Comparison of lipid and lipid-associated cardiovascular risk marker changes after treatment with tocilizumab or adalimumab in patients with rheumatoid arthritis

Gabay C, McInnes IB, Kavanaugh A, Tuckwell K, Klearman M, Pulley J, Sattar N.
Ann Rheum Dis. 2015;0:1-7. doi:10.1136/annrheumdis-2015-207872 [Epub ahead of print]

RA patients have increased risk of CVD compared with the general population that is not fully explained by traditional risk factors. This is a post-hoc analysis of data from a clinical trial that compared IL-6 and TNF-α signaling inhibition to compare changes in lipids and lipid-associated CV risk markers in 324 patients treated with TCZ IV q4w or ADA SC q2w for 24 weeks. HDL-SAA and sPLA2 IIA is also measured in an additional subpopulation of 87 and 97 TCZ and ADA patients, respectively. ...

Incidence and complications of interstitial lung disease in users of tocilizumab, rituximab, abatacept and anti-tumor necrosis factor α agents, a retrospective cohort study

Curtis JR, Sarsour K, Napalkov P, Costa LA, and Schulman KL.
Arthritis Research & Therapy (2015) 17:319 DOI: 10.1186/s13075-015-0835-7

Interstitial lung disease (ILD) is a common extra-articular condition for RA patients. This retrospective cohort study of health insurance databases investigates the ILD incidence and exacerbation between ABA, TCZ, RTX, and anti-TNFα agents in adult RA patients with prior biologic therapy. Two definitions of ILD were used: one specific, one sensitive; descriptive results were produced for both. In patients with no history of ILD, the overall incidence rate of ILD ranged from 1.8% to 6.4%...

Effects of tofacitinib monotherapy on patient-reported outcomes in a randomized phase 3 study of patients with active rheumatoid arthritis and inadequate responses to DMARDs

Strand V, Kremer J, Wallenstein G, Kanik KS, Connell C, Gruben D, Zwillich SH, Fleischmann R.
Arthritis Research & Therapy (2015) 17:307 DOI: 10.1186/s13075-015-0825-9 [Epub ahead of print]

RA presents a significant health and socioeconomic burden particularly in physical functioning, fatigue, and emotional roles. A phase III 6-month study of tofacitinib in patients with active RA, who had prior inadequate responses to cDMARDs or bDMARDs, uses patient-reported outcomes (PROs) to assess the impact on quality of life. Patients were randomized 4:4:1:1 to receive tofacitinib 5 or 10 mg BID, or placebo for 3 months followed by tofacitinib 5 or 10 mg BID. At month 3, tofacitinib 5 and ...

October 15

Tofacitinib regulates synovial inflammation in psoriatic arthritis, inhibiting STAT activation and induction of negative feedback inhibition

W Gao, T McGarry, C Orr, J McCormick, D J Veale, U Fearon.
Annals of the Rheumatic Diseases. 2015 Sep 9. doi:10.1136/annrheumdis-2014-207201

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis (Ps) and characterised by synovitis and progressive destruction of articular cartilage and bone. Recently developed agents for PsA target IL12p40, IL-6 and IL-17, several of which signal through the JAK family of receptor-associated tyrosine kinases. Tofacitinib is a drug of the JAK inhibitor class and is currently approved for the treatment of RA in 27 countries. This study evaluated the effect of tofacitini...

Effectiveness of tocilizumab with and without synthetic disease-modifying antirheumatic drugs in rheumatoid arthritis: results from a European collaborative study

C Gabay, M Riek, ML Hetland, EM Hauge, K Pavelka, M Tomšič, H Canhao, K Chatzdionysiou, G Lukina, DC Nordström, E Lie, I Ancuta, MV Hernández, PLMC van Riel, R van Vollenhoven, TK Kvien.
Ann Rheum Dis. 2015 Sep 15. doi:10.1136/ annrheumdis-2015-207760

Biological DMARDs have markedly changed the management and outcome of rheumatoid arthritis. Most international guidelines recommend the use of biological DMARDs in combination with MTX or other synthetic DMARDs (sDMARDs) (where MTX is not tolerated or contraindicated), based primarily on the observation that MTX enhances the efficacy of TNF antagonists in both clinical trials and observational studies. This study examined the effectiveness of tocilizumab (TCZ), an anti-IL-6 monoclonal antibody,...

Efficacy and safety of olokizumab in Asian patients with moderate-to-severe rheumatoid arthritis, previously exposed to anti-TNF therapy: Results from a randomized phase II trial

Takeuchi T, Tanaka Y, Yamanaka H, Amano K, Nagamine R, Park W, Shiozawa K, Tsukano M, Wei J, Shao J, Togo O, Mashimo H.
Modern Rheumatology. 2015 Sep 10:1-9. [Epub ahead of print]

This Phase II study assessed the safety and efficacy of olokizumab in Asian patients with moderate-to-severe rheumatoid arthritis, previously exposed to anti-TNF therapy. After 12 weeks of treatment, olokizumab was found to rapidly improve disease activity in patients who had previously failed anti-TNF therapy. There was also a significant decrease in ACR20 and ACR50 responder rates at week 12. The safety findings were consistent with the safety profile expected for this drug class. These findin...

Cost-effectiveness of Tofacitinib in the Treatment of Moderate to Severe Rheumatoid Arthritis in South Korea

Min-Young Lee, Sun-Kyeong Park, Sun-Young Park, Ji-Hye Byun, Sang-Min Lee, Su-Kyoung Ko, and Eui-Kyung Lee.
Clinical Therapeutics. 2015:37(8). [Epub ahead of print]

This study evaluated the cost-effectiveness of introducing tofacitinib, an oral Janus kinase inhibitor, to the treatment of Korean patients with RA and an inadequate response to conventional DMARDs. The model showed that the inclusion of tofacitinib as a treatment strategy for moderate to severe RA is cost-effective; this conclusion was considered robust based on multiple sensitivity analyses. First-line tofacitinib used before the standard of care (base-case analysis) increased both treatment...

Comparison of the efficacies of abatacept and tocilizumab in patients with rheumatoid arthritis by propensity score matching

Kubo S, Nakayamada S, Nakano K, Hirata S, Fukuyo S, Miyagawa I, Hanami K, Saito K, Tanaka Y.
Annals of the Rheumatic Diseases. 2015 Aug 5. doi:pii: annrheumdis-2015-207784. 10.1136/annrheumdis-2015-207784. [Epub ahead of print]

This study compared the clinical outcomes at one year after the treatment either abatacept or tocilizumab in routine clinical practice. This study employed propensity score matching and demonstrated that abatacept and tocilizumab had comparable continuing efficacies, and that treatment with the drugs resulted in comparable clinical and functional remission rates. Additionally, abatacept and tocilizumab showed similar effectiveness with or without MTX. While clinical efficacies, including SDAI,...

Calprotectin more accurately discriminates the disease status of rheumatoid arthritis patients receiving tocilizumab than acute phase reactants

José Inciarte-Mundo, Virginia Ruiz-Esquide, Maria Victoria Hernández, Juan D Cañete, Sonia Raquel Cabrera-Villalba, Julio Ramirez, Jordi Yagüe and Raimon Sanmarti.
Rheumatology. 2015 Aug 4. doi:pii: kev251. [Epub ahead of print]

Calprotectin is a member of the S100 protein family that has strong pro-inflammatory effects that reflect local ongoing inflammation rather than systemic response, due to its release at local inflammation sites. High calprotectin levels have been found in SF and serum from RA patients and correlate with disease activity. This study analysed the accuracy of calprotectin compared to acute phase response in discriminating the clinical disease status of RA patients receiving TCZ. A clinical assessme...