1. FlorentinaEller
8/12/2014
Citation:
 Lee EB, Fleischmann R,Hall S, et al. Tofacitinib versus methotrexate in rheumatoid arthritis.
N Engl J Med. 2014 Jun 19; 370(25):2377-86.doi:10.1056/NEJMoa1310476.
Background:
 Rheumatoid arthritis (RA) is a systemic diseasecharacterized by symmetrical inflammation of the joints.
Control of inflammation is thekey to slowingor preventing diseaseprogression and for symptoms control.
 The 2012 American College of Rheumatology (ACR) guidelines recommend disease-modifyingantirheumatic
drugs (DMARDs) or biologicsagents to be started early in the course of the disease and shortly after diagnosis
of RA.
 Tofacitinib (Xeljanz): FDA approved for the treatment of moderate to severe activeRA (as monotherapy or in
combination with methotrexate (MTX) or other nonbiologic [DMARDs]) in adults who have failed or are
intolerantto MTX. The approved dose is 5 mg BID.
 MOA: Tofacitinib is Janus Kinaseinhibitor (JAK) inhibitor which mediates the signal transduction from
cytokines responsiblefor leukocyte functioning.Thus, inhibition of JAK results in modulation and suppression
of the immune system through cytokine signal reduction
 Metabolism: 70% by the liver (CYP3A4 and CYP2C19) and 30% by the kidney.
 Pharmacokinetics: Vd: 87 L; Protein binding:~40% (predominantly to albumin);Half-lifeelimination:~3 hours;
Time to peak: 0.5-1 hour; Excretion: Primarily urine(30%) as unchanged drug.
 Adverse Reactions: The most common: upper respiratory tractinfections,headache,diarrhea,
nasopharyngitis,and hypertension.Tofacitinib has a BBW for increased risk of serious infections,including
tuberculosis (TB) and other opportunistic infections,lymphoma and other cancers. Pregnancy Category C.
 Previous trials: In 2013,He Y, et al.,performed a systematic review of 8 RCT (n = 3,791) and found that
significantly greater ACR20 responserates were observed in patients receivingtofacitinib 5 and 10 mg BID
versus placebo atweek 12, with (RR) of 2.20 (95% CI 1.58-3.07) and 2.38 (95% CI 1.81-3.14) respectively.The
effect was maintained atweek 24 for 5 mg BID (RR 1.94; 95% CI 1.55- 2.44) and 10 mg BID (RR 2.20; 95% CI
1.76- 2.75). Patients in the tofacitinib group had significantly lower mean neutrophil counts, higher serum
creatinine,higher percentage change of LDL/HDL and a higher risk of ALT/AST > 1 ULN (upper limitof normal).
There were no significantdifferences in AEs and discontinuation dueto AEs compared to placebo.
Methods:
 Study Design: Phase3, randomized, doubleblind, parallel-group study in 151 centers worldwide.
 Inclusion criteria: At least18 years of age; with active RA (defined as the presence of 6 or more joints that
were tender or painful);and had either an erythrocyte sedimentation rate (ESR) of >28 mm/h or a C-reactive
protein level of >7 mg/L; ≥ 3 distinctjointerosionsdetected on hand and wristor foot radiographs,or a
positivetest for IgM rheumatoid factor or antibodies to cyclic citrullinated peptide.
 Key exclusion criteria: Hemoglobin <9.0 g/dL or hematocrit <30%, WBC <3.0 × 109/L, ANC <1.2 × 109/L, or
platelet count <100 × 109/L; estimated GFR <60 mL/min; AST or ALT >1.5× ULN; history of another
autoimmune rheumatic diseaseexcept Sjögren’s syndrome;
 Intervention: 5mg BID tofacitinib,10 mg BID tofacitinib,MTX at a startingdose of 10 mg per week, with
increments of 5 mg per week every 4 weeks to 20 mg per week by week 8.
 Endpoints: The primary efficacy end points were mean change from baselinein van der Heijde-modified Total
Sharp Score (mTSS) at month 6 and the proportion of patients who achieved an ACR70 responseat month 6.
 Statistical Analysis: Preservation of jointstructure, as measured by the modified total Sharp score, was used
to determine the sample size, which was planned to provide the study with 90% power. Analysis of
covariance was used to assess theprimary end point of the modified total Sharp scoreat month 6; For the
month 6 analysisof the coprimary end point of the ACR 70 responseand of other binary end points,the
normal approximation for the difference in binomial proportionswas used to test the superiority of each dose
of tofacitinib over methotrexate.

2. FlorentinaEller
8/12/2014
Results:
 Demographics: Overall,958 patients underwent randomization,of whom 956 patients received tofacitinib ata
dose of 5 mg twice daily (373 patients),tofacitinib ata doseof 10 mg twice daily (397 patients),or
methotrexate (186 patients). Baselinecharacteristicswere similar amongthe treatment groups.
 Mean Change from Baseline in mTSS at Month 6: 0.2 points in the 5-mg tofacitinib group,0.1 points in the
10-mg tofacitinib group,0.8 points in the methotrexate group (P<0.001 for both comparisons).
 ACR70 at Month 6- 26% (94 of 369 patients) in the 5-mg tofacitinib group and 38 % (148 of 393 patients) in
the 10-mg tofacitinib group,as compared with 12% (22 of 184 patients) in the methotrexate group (P<0.001).
Adverse Events:
Conclusion: Tofacitinib monotherapy at a dose of 5 or 10 mg twice daily was associated with significantreductions
in signs and symptoms of RA in patients who have never received MTX, improvements in physical functioning,and
modest reductions in the progression of structural damage,as compared with methotrexate (mean dose, 18.5 mg
per week). Tofacitinib was associated with reductions in neutrophil and lymphocyte counts and increases in low-
density lipoprotein cholesterol and creatininelevels and infections. Results at12 and 24 months were similar.
Critique
 Strengths: Study design (randomized, double-blind); Study duration; Study samplesize; Appropriate
statistical tests to assess primary endpoint
Imitations:
 Multiplecenters with no stratification; Notall patients had early RA; Radiograph studies in multiple
countries- introduces some sources of imprecision.
Clinical impact: This trial excluded patients with GFR < 60 ml/min, AST and ALT > 1.5 X ULN, Hct < 30%, and history
of another autoimmune rheumatic diseases- thus we have to be careful when extrapolatingthe findings.
Tofacitinb is availableas an oral tablet,so itdistinguishes itself fromthe IV or IM biologics. However, tofacitinib is
dosed at 5 mg twice daily dueto its shorthalf-life,whilemethotrexate is dosed once a week. This might decrease
adherence in some patients. Even though tofacitinib increases thepill burden for the patients and is very
expensive, I believe this is an adequate alternativefor patients with RA who have failed MTX, becausedisease
progression is slowed significantly with tofacitinib.Inducingthe remission or controlling thediseaseactivity with a
$3,000 drug, and then switchingto MTX for diseasemaintenance, itmi ght be worth it to some patients.
References:
Singh JA, FurstDE, Bharat A, et al.2012 update of the 2008 American College of Rheumatology recommendations
for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis.
Arthritis Care Res (Hoboken). 2012 May; 64(5):625-39.doi: 10.1002/acr.21641.
He Y, Wong AY, Chan EW, et al.Efficacy and safety of tofacitinib in thetreatment of rheumatoid arthritis:a
systematic review and meta-analysis.BMC MusculoskeletDisord.2013 Oct18;14:298.doi: 10.1186/1471-2474-14-
298.