title: Baricitinib in Patients with Refractory Rheumatoid Arthritis.
abstract: BACKGROUND
  In phase 2 studies, baricitinib, an oral Janus kinase 1 and 2 inhibitor, reduced disease activity in patients with rheumatoid arthritis who had not previously received treatment with biologic disease-modifying antirheumatic drugs (DMARDs).
  
  
  METHODS
  In this phase 3 study involving 527 patients with an inadequate response to or unacceptable side effects associated with one or more tumor necrosis factor inhibitors, other biologic DMARDs, or both, we randomly assigned the patients in a 1:1:1 ratio to baricitinib at a dose of 2 or 4 mg daily or placebo for 24 weeks. End points, tested hierarchically at week 12 to control type 1 error, were the American College of Rheumatology 20% (ACR20) response (primary end point), the Health Assessment Questionnaire-Disability Index (HAQ-DI) score, the 28-joint Disease Activity Score based on C-reactive protein level (DAS28-CRP), and a Simplified Disease Activity Index (SDAI) score of 3.3 or less (on a scale of 0.1 to 86.0, with a score of 3.3 or less indicating remission). Comparisons with placebo were made first with the 4-mg dose of baricitinib and then with the 2-mg dose.
  
  
  RESULTS
  Significantly more patients receiving baricitinib at the 4-mg dose than those receiving placebo had an ACR20 response at week 12 (55% vs. 27%, P<0.001). Differences between the higher-dose baricitinib group and the placebo group were also significant for the HAQ-DI score and the DAS28-CRP but not for an SDAI score of 3.3 or less. Adverse-event rates through 24 weeks were higher for patients receiving the 2-mg dose of baricitinib and those receiving the 4-mg dose than for patients receiving placebo (71% and 77%, respectively, vs. 64%), including infections (44% and 40%, vs. 31%). The rates of serious adverse events were 4%, 10%, and 7% in the three groups, respectively. Two nonmelanoma skin cancers and two major adverse cardiovascular events, including a fatal stroke, occurred in the higher-dose group. Baricitinib was associated with a small reduction in neutrophil levels and increases in serum creatinine and low-density lipoprotein cholesterol levels.
  
  
  CONCLUSIONS
  In patients with rheumatoid arthritis and an inadequate response to biologic DMARDs, baricitinib at a daily dose of 4 mg was associated with clinical improvement at 12 weeks. (Funded by Eli Lilly and Incyte; ClinicalTrials.gov number, NCT01721044.).
authors.affiliation: From the Stanford University Medical Center, Palo Alto, CA (M.C.G.); Albany Medical College, Albany, NY ( J.K.); Rheumazentrum Favoriten (O.Z.) and the Medical University of Vienna ( J.S.S.) - both in Vienna; East Penn Rheumatology, Bethlehem, PA (C.L.); Rheumatology Clinic, MAK-MED, Nadarzyn, Poland (M.K.); and Eli Lilly, Indianapolis (L.X., S.D.B., A.E.K., T.E.C., T.P.R., W.L.M., S.B., D.E.S.).
authors.forename: Mark C
authors.initials: MC
authors.lastname: Genovese
authors.affiliation: From the Stanford University Medical Center, Palo Alto, CA (M.C.G.); Albany Medical College, Albany, NY ( J.K.); Rheumazentrum Favoriten (O.Z.) and the Medical University of Vienna ( J.S.S.) - both in Vienna; East Penn Rheumatology, Bethlehem, PA (C.L.); Rheumatology Clinic, MAK-MED, Nadarzyn, Poland (M.K.); and Eli Lilly, Indianapolis (L.X., S.D.B., A.E.K., T.E.C., T.P.R., W.L.M., S.B., D.E.S.).
authors.forename: Joel
authors.initials: J
authors.lastname: Kremer
authors.affiliation: From the Stanford University Medical Center, Palo Alto, CA (M.C.G.); Albany Medical College, Albany, NY ( J.K.); Rheumazentrum Favoriten (O.Z.) and the Medical University of Vienna ( J.S.S.) - both in Vienna; East Penn Rheumatology, Bethlehem, PA (C.L.); Rheumatology Clinic, MAK-MED, Nadarzyn, Poland (M.K.); and Eli Lilly, Indianapolis (L.X., S.D.B., A.E.K., T.E.C., T.P.R., W.L.M., S.B., D.E.S.).
authors.forename: Omid
authors.initials: O
authors.lastname: Zamani
authors.affiliation: From the Stanford University Medical Center, Palo Alto, CA (M.C.G.); Albany Medical College, Albany, NY ( J.K.); Rheumazentrum Favoriten (O.Z.) and the Medical University of Vienna ( J.S.S.) - both in Vienna; East Penn Rheumatology, Bethlehem, PA (C.L.); Rheumatology Clinic, MAK-MED, Nadarzyn, Poland (M.K.); and Eli Lilly, Indianapolis (L.X., S.D.B., A.E.K., T.E.C., T.P.R., W.L.M., S.B., D.E.S.).
authors.forename: Charles
authors.initials: C
authors.lastname: Ludivico
authors.affiliation: From the Stanford University Medical Center, Palo Alto, CA (M.C.G.); Albany Medical College, Albany, NY ( J.K.); Rheumazentrum Favoriten (O.Z.) and the Medical University of Vienna ( J.S.S.) - both in Vienna; East Penn Rheumatology, Bethlehem, PA (C.L.); Rheumatology Clinic, MAK-MED, Nadarzyn, Poland (M.K.); and Eli Lilly, Indianapolis (L.X., S.D.B., A.E.K., T.E.C., T.P.R., W.L.M., S.B., D.E.S.).
authors.forename: Marek
authors.initials: M
authors.lastname: Krogulec
authors.affiliation: From the Stanford University Medical Center, Palo Alto, CA (M.C.G.); Albany Medical College, Albany, NY ( J.K.); Rheumazentrum Favoriten (O.Z.) and the Medical University of Vienna ( J.S.S.) - both in Vienna; East Penn Rheumatology, Bethlehem, PA (C.L.); Rheumatology Clinic, MAK-MED, Nadarzyn, Poland (M.K.); and Eli Lilly, Indianapolis (L.X., S.D.B., A.E.K., T.E.C., T.P.R., W.L.M., S.B., D.E.S.).
authors.forename: Li
authors.initials: L
authors.lastname: Xie
authors.affiliation: From the Stanford University Medical Center, Palo Alto, CA (M.C.G.); Albany Medical College, Albany, NY ( J.K.); Rheumazentrum Favoriten (O.Z.) and the Medical University of Vienna ( J.S.S.) - both in Vienna; East Penn Rheumatology, Bethlehem, PA (C.L.); Rheumatology Clinic, MAK-MED, Nadarzyn, Poland (M.K.); and Eli Lilly, Indianapolis (L.X., S.D.B., A.E.K., T.E.C., T.P.R., W.L.M., S.B., D.E.S.).
authors.forename: Scott D
authors.initials: SD
authors.lastname: Beattie
authors.affiliation: From the Stanford University Medical Center, Palo Alto, CA (M.C.G.); Albany Medical College, Albany, NY ( J.K.); Rheumazentrum Favoriten (O.Z.) and the Medical University of Vienna ( J.S.S.) - both in Vienna; East Penn Rheumatology, Bethlehem, PA (C.L.); Rheumatology Clinic, MAK-MED, Nadarzyn, Poland (M.K.); and Eli Lilly, Indianapolis (L.X., S.D.B., A.E.K., T.E.C., T.P.R., W.L.M., S.B., D.E.S.).
authors.forename: Alisa E
authors.initials: AE
authors.lastname: Koch
authors.affiliation: From the Stanford University Medical Center, Palo Alto, CA (M.C.G.); Albany Medical College, Albany, NY ( J.K.); Rheumazentrum Favoriten (O.Z.) and the Medical University of Vienna ( J.S.S.) - both in Vienna; East Penn Rheumatology, Bethlehem, PA (C.L.); Rheumatology Clinic, MAK-MED, Nadarzyn, Poland (M.K.); and Eli Lilly, Indianapolis (L.X., S.D.B., A.E.K., T.E.C., T.P.R., W.L.M., S.B., D.E.S.).
authors.forename: Tracy E
authors.initials: TE
authors.lastname: Cardillo
authors.affiliation: From the Stanford University Medical Center, Palo Alto, CA (M.C.G.); Albany Medical College, Albany, NY ( J.K.); Rheumazentrum Favoriten (O.Z.) and the Medical University of Vienna ( J.S.S.) - both in Vienna; East Penn Rheumatology, Bethlehem, PA (C.L.); Rheumatology Clinic, MAK-MED, Nadarzyn, Poland (M.K.); and Eli Lilly, Indianapolis (L.X., S.D.B., A.E.K., T.E.C., T.P.R., W.L.M., S.B., D.E.S.).
authors.forename: Terence P
authors.initials: TP
authors.lastname: Rooney
authors.affiliation: From the Stanford University Medical Center, Palo Alto, CA (M.C.G.); Albany Medical College, Albany, NY ( J.K.); Rheumazentrum Favoriten (O.Z.) and the Medical University of Vienna ( J.S.S.) - both in Vienna; East Penn Rheumatology, Bethlehem, PA (C.L.); Rheumatology Clinic, MAK-MED, Nadarzyn, Poland (M.K.); and Eli Lilly, Indianapolis (L.X., S.D.B., A.E.K., T.E.C., T.P.R., W.L.M., S.B., D.E.S.).
authors.forename: William L
authors.initials: WL
authors.lastname: Macias
authors.affiliation: From the Stanford University Medical Center, Palo Alto, CA (M.C.G.); Albany Medical College, Albany, NY ( J.K.); Rheumazentrum Favoriten (O.Z.) and the Medical University of Vienna ( J.S.S.) - both in Vienna; East Penn Rheumatology, Bethlehem, PA (C.L.); Rheumatology Clinic, MAK-MED, Nadarzyn, Poland (M.K.); and Eli Lilly, Indianapolis (L.X., S.D.B., A.E.K., T.E.C., T.P.R., W.L.M., S.B., D.E.S.).
authors.forename: Stephanie
authors.initials: S
authors.lastname: de Bono
authors.affiliation: From the Stanford University Medical Center, Palo Alto, CA (M.C.G.); Albany Medical College, Albany, NY ( J.K.); Rheumazentrum Favoriten (O.Z.) and the Medical University of Vienna ( J.S.S.) - both in Vienna; East Penn Rheumatology, Bethlehem, PA (C.L.); Rheumatology Clinic, MAK-MED, Nadarzyn, Poland (M.K.); and Eli Lilly, Indianapolis (L.X., S.D.B., A.E.K., T.E.C., T.P.R., W.L.M., S.B., D.E.S.).
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Schlichting
authors.affiliation: From the Stanford University Medical Center, Palo Alto, CA (M.C.G.); Albany Medical College, Albany, NY ( J.K.); Rheumazentrum Favoriten (O.Z.) and the Medical University of Vienna ( J.S.S.) - both in Vienna; East Penn Rheumatology, Bethlehem, PA (C.L.); Rheumatology Clinic, MAK-MED, Nadarzyn, Poland (M.K.); and Eli Lilly, Indianapolis (L.X., S.D.B., A.E.K., T.E.C., T.P.R., W.L.M., S.B., D.E.S.).
authors.forename: Josef S
authors.initials: JS
authors.lastname: Smolen
mesh_terms: D000368:Aged; D018501:Antirheumatic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D001384:Azetidines / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011687:Purines; D011720:Pyrazoles; D012720:Severity of Illness Index; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D018501:Antirheumatic Agents; D001384:Azetidines; D047428:Protein Kinase Inhibitors; D011687:Purines; D011720:Pyrazoles; D013449:Sulfonamides; D053613:Janus Kinase 1; D053614:Janus Kinase 2; C000596027:baricitinib