***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Objective Tofacitinib is an oral Janus kinase ( JAK ) inhibitor for the treatment of rheumatoid arthritis ( RA ) . The pathways affected by tofacitinib and the effects on gene expression in situ are unknown . Therefore , tofacitinib effects on synovial pathobiology were investigated . Methods A r and omised , double-blind , phase II serial synovial biopsy study ( A3921073 ; NCT00976599 ) in patients with RA with an inadequate methotrexate response . Patients on background methotrexate received tofacitinib 10 mg twice daily or placebo for 28 days . Synovial biopsies were performed on Days -7 and 28 and analysed by immunoassay or quantitative PCR . Clinical response was determined by disease activity score and European League Against Rheumatism ( EULAR ) response on Day 28 in A3921073 , and at Month 3 in a long-term extension study ( A3921024 ; NCT00413699 ) . Results Tofacitinib exposure led to EULAR moderate to good responses ( 11/14 patients ) , while placebo was ineffective ( 1/14 patients ) on Day 28 . Tofacitinib treatment significantly reduced synovial mRNA expression of matrix metalloproteinase (MMP)-1 and MMP-3 ( p<0.05 ) and chemokines CCL2 , CXCL10 and CXCL13 ( p<0.05 ) . No overall changes were observed in synovial inflammation score or the presence of T cells , B cells or macrophages . Changes in synovial phosphorylation of signal transducer and activator of transcription 1 ( STAT1 ) and STAT3 strongly correlated with 4-month clinical responses ( p<0.002 ) . Tofacitinib significantly decreased plasma CXCL10 ( p<0.005 ) at Day 28 compared with placebo . Conclusions Tofacitinib reduces metalloproteinase and interferon-regulated gene expression in rheumatoid synovium , and clinical improvement correlates with reductions in STAT1 and STAT3 phosphorylation . JAK1-mediated interferon and interleukin-6 signalling likely play a key role in the synovial response . Trial registration number NCT00976599 Introduction Rheumatoid arthritis ( RA ) is a complex and clinical ly heterogeneous autoimmune disease . Currently , the relationship between pathogenic molecular drivers of disease in RA and therapeutic response is poorly understood . Methods We analyzed synovial tissue sample s from two RA cohorts of 49 and 20 patients using a combination of global gene expression , histologic and cellular analyses , and analysis of gene expression data from two further publicly available RA cohorts . To identify c and i date serum biomarkers that correspond to differential synovial biology and clinical response to targeted therapies , we performed pre-treatment biomarker analysis compared with therapeutic outcome at week 24 in serum sample s from 198 patients from the ADACTA ( ADalimumab ACTemrA ) phase 4 trial of tocilizumab ( anti-IL-6R ) monotherapy versus adalimumab ( anti-TNFα ) monotherapy .  Results We documented evidence for four major phenotypes of RA synovium – lymphoid , myeloid , low inflammatory , and fibroid - each with distinct underlying gene expression signatures . We observed that baseline synovial myeloid , but not lymphoid , gene signature expression was higher in patients with good compared with poor  European league against rheumatism ( EULAR ) clinical response to anti-TNFα therapy at week 16 ( P = 0.011 ) . We observed that high baseline serum soluble intercellular adhesion molecule 1 ( sICAM1 ) , associated with the myeloid phenotype , and high serum C-X-C motif chemokine 13 ( CXCL13 ) , associated with the lymphoid phenotype , had differential relationships with clinical response to anti-TNFα compared with anti-IL6R treatment . sICAM1-high/CXCL13-low patients showed the highest week 24 American College of Rheumatology ( ACR ) 50 response rate  to anti-TNFα treatment as compared with sICAM1-low/CXCL13-high patients ( 42 % versus 13 % , respectively , P = 0.05 ) while anti-IL-6R patients showed the opposite relationship with these biomarker subgroups ( ACR50 20 % versus 69 % , P = 0.004 ) . Conclusions These data demonstrate that underlying molecular and cellular heterogeneity in RA impacts clinical outcome to therapies targeting different biological pathways , with patients with the myeloid phenotype exhibiting the most robust response to anti-TNFα . These data suggest a path to identify and vali date serum biomarkers that predict response to targeted therapies in rheumatoid arthritis and possibly other autoimmune diseases . Trial registration Clinical Trials.gov BACKGROUND Effective new therapies are needed for rheumatoid arthritis . Current therapies target the products of activated macrophages ; however , T cells also have an important role in rheumatoid arthritis . A fusion protein -- cytotoxic T-lymphocyte-associated antigen 4-IgG1 (CTLA4Ig)--is the first in a new class of drugs known as costimulation blockers being evaluated for the treatment of rheumatoid arthritis . CTLA4Ig binds to CD80 and CD86 on antigen-presenting cells , blocking the engagement of CD28 on T cells and preventing T-cell activation . A preliminary study showed that CTLA4Ig may be effective for the treatment of rheumatoid arthritis . METHODS We r and omly assigned patients with active rheumatoid arthritis despite methotrexate therapy to receive 2 mg of CTLA4Ig  per kilogram of body weight ( 105 patients ) , 10 mg of CTLA4Ig per kilogram ( 115 patients ) , or placebo  ( 119 patients ) for six months . All patients also received methotrexate therapy during the study . The clinical response was assessed at six months with use of the criteria of the American College of Rheumatology ( ACR ) , which define the response according to its extent : 20 percent ( ACR 20 ) , 50 percent ( ACR 50 ) , or 70 percent ( ACR 70 ) . Additional end points included measures of the health-related quality of life . RESULTS Patients treated with 10 mg of CTLA4Ig per kilogram were more likely to have an ACR 20 than were patients who received placebo ( 60 percent vs. 35 percent , P<0.001 ) . Significantly higher rates of ACR 50 and ACR 70 responses were seen in both CTLA4Ig groups than in the placebo group . The group given 10 mg of CTLA4Ig per kilogram had clinical ly meaningful and statistically significant improvements in all eight subscales of the Medical Outcomes 36-Item Short-Form General Health Survey . CTLA4Ig was well tolerated , with an overall safety profile similar to that of placebo . CONCLUSIONS In patients with active rheumatoid arthritis who were receiving methotrexate  , treatment with CTLA4Ig significantly improved the signs and symptoms of rheumatoid arthritis and the health-related quality of life . CTLA4Ig is a promising new therapy for rheumatoid arthritis Objective Despite the fact that rituximab depletes B cells in all treated patients with RA , not all patients show a favourable clinical response . The goal of this study was to provide insight into pharmacological changes in peripheral blood that are associated with clinical response to rituximab . Methods Gene expression profiling was performed on peripheral blood RNA of 13 patients with RA ( test group ) using Illumina HumanHT beadchip microarrays . An independent group of nine patients was used for validation using TaqMan quantitative PCR . Clinical responder status was determined after 6 months using change in 28-joint Disease Activity Score ( ΔDAS28 ) and European League Against Rheumatism ( EULAR ) response criteria . Significance analysis of microarrays and ontology analysis were used for data analysis and interpretation . Results Pharmacogenomic analyses demonstrated marked interindividual differences in the pharmacological responses at 3 and 6 months after start of treatment with rituximab . Interestingly , only differences in the regulation of type I interferon (IFN)-response genes after 3 months correlated with the ΔDAS28 response . Good responders ( ∆DAS>1.2 ; n=7 ) exhibited a selective increase in the expression of type I IFN-response genes , whereas this activity was unchanged or hardly changed in non-responders ( ∆DAS<1.2 ; n=6 ) ( p=0.0040 at a cut-off of 1.1-fold induction ) . Similar results were obtained using EULAR response criteria . These results were vali date d in an independent cohort of nine patients ( five non-responders and four responders , p=0.0317 ) . Conclusions A good clinical response to rituximab in RA is associated with a selective drug-induced increase in type I IFN-response activity in patients with RA . This finding may provide insight in the biological mechanism underlying the therapeutic response to rituximab The aim of this prospect i ve multicenter study was to identify biomarkers that can be used to predict therapeutic responses to tocilizumab in patients with rheumatoid arthritis ( RA ) 
    Output:
    
Many studies report the association between type I interferon signature gene expression and response to therapy