A detailed description of Role of Tofacitinib in management of Rheumatoid Arthritis

1. RHEUMATOIDARTHRITIS &
THE ROLE OFTOFACITINIB
Dr. Bodhisatwa Choudhuri
MBBS, MD(Med), MRCEM(UK), MRCP (Acute Medicine),
Dip. Rheumatology (UK), Fellowship in Rheumatology (USA),
FCCS, CCEBDM
Consultant Critical Care & Rheumatologist, Parkview Super-specialty
Hospital, Saltlake, Kolkata
VisitingConsultant – AMRI Hospital Saltlake, ILS Hospital Howrah

2. RHEUMATOID ARTHRITIS
(RA)
• RA is a chronic inflammatory disorder
• Progressive, systemic,Autoimmune inflammation
• RA affects the lining of joints, causing painful
swelling, bone erosion and joint deformity.
• Often aggressive, devastating consequences
• Unknown etiology (auto immune, ?infection,
smoking)

3. Epidemiology
• Prevalence of - 0.8% to 2.1% of the population
• Gender predilection ratio – Women: Men – 3:1
• Prevalence increases with age – Juvenile RA
• About 40-60% have severe disease – 3 fold  mortality
• Median life expectancy is shortened by 3 to 7 years
• Onset mostly between ages of 35 – 60 years
• Genetic – HLA-DR1(1*0101, 0401) – Class II HCA
• Exact etiology is not known

5. The Natural Course of RA
Undifferentiated
Polyarthritis
Early RA – Mild
Disease
Severe RA with
Deformities

6. Rheumatoid Arthritis: Diagnosis – ACR/EULAR Criteria

7. Rheumatoid Arthritis:Typical Involvement
• Wrist joints and MCP joints - very commonly involved
• Index and middle Metacarpophalangeal joints
• Proximal interphalangeal joints (PIP)
• Metacarpophalangeal joints (MCP)
• Metatarsophalangeal joints (MTP)
• Elbows, Shoulders
• Knees, Ankles, Hips
• Spine: only Atlanto-axial joint (C1-C2) subluxation; Lumbosacral area
is not involved
• Distal interphalangeal (DIP) joints are not involved

8. The Joints Involved in RA

11. The
Problem in
RA

13. Extra Articular Manifestations of RA
• Systemic involvement
• Musculoskeletal wasting
• Tenosynovitis, Bursitis
• Osteoporosis, Rheumatoid nodules
• Vasculitis,Arteritis
• Pericarditis, Myocarditis, Endocarditis,
Atherosclerosis
• Special Features
• Episcleritis, Scleromalacia
• Pleural effusion, Nodules, ILD, lung
fibrosis
• Cervical cord compression
• Mononeutitis, carpel tunnel syndrome
• Felty’s syndrome, Caplan’s syndrome

14. Diagnostic parameters in RA
Rheumatoid Factor:
• Positive in 5% of normal persons and in only 70-80% of RA, Low specificity & sensitivity
• It is not a screening or diagnostic tool – More a prognostic tool
• It is negative in 30% cases of RA – Sero negative RA
Anti Cyclic Citrullinated Peptide Antibody (ACPA):
• Similar sensitivity for RA (70%), Specificity for RA (>95%) better than RA Factor
• In early polyarthritis anti-CCP are useful for Dx.
• Associated with more severe disease, spell a poor prognosis and rapid progression
Inflammatory markers: Erythrocyte sedimentation rate (ESR) & C-Reactive protein (CRP) – to
determine presence of inflammatory mediators.
X-ray: Narrowing of joint spaces, periarticular osteopenia, juxta articular erosions
Magnetic resonance imaging (MRI): Helps to find out the severity of the disease condition.
Arthrocentesis: A procedure during which a sterile needle is used to withdraw joint fluid to
determine the cause of symptoms

15. RA disease activity measures
• DAS28 (Disease Activity Score with 28 joint counts)
• DAS28-ESR
• DAS28-CRP
• CDAI (Clinical Disease Activity Index)
• SDAI (Simplified Disease Activity Index)

16. Treatment Should Aim for “Best Care”
16
Treatment should be
goal-oriented and
governed by a strategic
treatment approach
Primary target for
treatment of RA:
Remission or low disease
activity
Patients should be closely
monitored using composite
disease activity measures
Treatment should be adapted
if the treatment aim is not
reached within preferably 3
to 6 months
Modern treatment for RA
Smolen JS et al. Ann Rheum Dis. 2010;69:964-975.

17. Non Pharmacological Management
• Rest
• Exercise
• Flexibility/stretching
• Muscle conditioning
• Cardiovascular/aerobic
• Diet
• Weight management
• Physical and occupational therapy

18. Medical Management – Drug Classes
NSAIDs – Cox-1 & Cox-2 inhibitors
Glucocorticoids – Prednisolone, Methylprednisolone, Deflazocort
IAS – Intra articular steroids
DMARDs – MTX, Leflunomie, SSZ, HCQ
Immunosuppressive Rx.– AZT, Cyclosporine,Tacrolimus
Cytotoxic agents – Cyclophosphamide
Biologics –TNF antibodies, IL-1 R antagonist, JAK inhibitors

19. NSAIDS in RA
NSAIDs
COX 1 COX2
• Selective COX 2 Inhibitors
• Improved GI tolerability
• Reduced effects on RBF
• No effect on platelets
• Called as COXIBs
• May have adverse effect
on heart
• Celecoxib, Etoricoxib,
Meloxicam
Constituent pathway
Renal and GI
homeostasis
Inducible
pathway
Inflammation

20. Pros and Cons of NSAIDTherapy
PROS
• Effective control of
inflammation and pain
• Effective reduction in
swelling
• Improves mobility, flexibility,
range of motion
• Improve quality of life
• Relatively low-cost
CONS
• Does not affect disease
progression
• GI toxicity common
• Renal complications (eg.
Irreversible renal
insufficiency, papillary
necrosis)
• Hepatic dysfunction
• CNS toxicity

21. Pros and Cons of CorticosteroidTherapy
PROS
• Anti-inflammatory and
immunosuppressive effects
• Can be used to bridge gap between
initiation of DMARD therapy and onset of
action
• Intra-articular steroid (IAS) injections can
be used for individual joint flares
CONS
• Does not conclusively affect disease
progression
• Tapering and discontinuation of use often
unsuccessful
• Low doses result in skin thinning,
ecchymoses, and Cushingoid appearance
• Significant cause of steroid-induced
osteopenia

22. Methotrexate (MTX)
• MTX is given 10 to 30 mg orally, IM, or SC per week
• It is DHF reductase inhibitor – Supplemental folic acid
• The clinical improvement takes one to two months
• Nausea, diarrhea; mouth ulcers; rash, alopecia; Abnormal LFT
• Rare: lowWBC & platelets; pneumonitis; sepsis; liver disease; EBV related
lymphoma;
• CBC, creatinine, and LFTs monthly for six months, then every one to two
months; repeat AST or ALT in two to four weeks if initially elevated, and
adjust dose as needed;
• Rapid onset (six to 10 weeks); tends to produce more sustained results over
time than other DMARDs and lowers all-cause mortality;
• Can be used when cause of polyarthritis uncertain;
• Often combined with other DMARDs like Leflunomide, SSZ, HCQ
• Stop at least 6 months before planning to conceive

23. Other DMARDS
• Sulphasalazine:
• For moderate disease; Elimination hepatic
• Dyspepsia, rashes, BM suppression
• Safe in pregnancy
• Hydroxychloroquine:
• For mild disease
• Skin darkening, Irreversible retinal toxicity, corneal deposits – annual eye
checkup
• Safe in pregnancy
• Leflunomide:
• Efficacy similar to MTX; Elimination hepatic
• Avoid in unmarried women or married woman planning to conceive
• Hepatotoxicity, BM suppression, diarrhea, rashes

24. RATreatment:TargetedTherapies
1998
Etanercept
1999
Infliximab
2012
Tofacitinib
2002
Adalimumab
2005
Abatacept
2006
Rituximab
2009
Golimumab
Certolizumab
2010
Tocilizumab
2018
Baricitinib
2017
Sarilumab
2001
Anakinra
TNF Biologics
Non-TNF Biologics
JAK Inhibitors
1. Etanercept PI. 2. Infliximab PI. 3. Anakinra PI. 4. Adalimumab PI. 5. Abatacept PI. 6. Rituximab PI.
7. Golimumab PI. 8. Certolizumab PI. 9. Toclilizumab PI. 10. Tofacitinib PI. 11. Sarilumab PI. 12. Baricitinib PI.
2019
Upadacitinib
2020 (EU)
Filgotinib

25. Biological Agents in RA
• TNFα antagonists
• Adalimumab, Etanercept, Golimumab, Certolizumab Pegol, Infliximab
• Interleukin-1 antagonist
• Anakinra
• Interleukin-6 antagonist
• Tocilizumab
• Suppressors ofT-Cell activation
• Abatacept
• Anti B-Cell (CD-20) monoclonal antibody
• Rituximab
• JAK Inhibitors
• Tofacitinib, Baricitinib, Upadacitinib

26. Biologics: Relative Contraindications
26
• Active Hepatitis B Infection
• Multiple sclerosis, optic neuritis
• Active serious infections
• Chronic or recurrent infections
• Current neoplasia
• History ofTB or evidence of Koch’s
• Congestive heart failure (Class III or IV)

27. Recommendations
for the treatment
of Established
Rheumatoid
Arthritis (RA)
Arthritis Care Res (Hoboken). 2016 Jan;68(1):1-25. doi: 10.1002/acr.22783.
27

28. EULARTreatment Recommendation
• Remission is the primary therapeutic aim1
• Especially in early RA
• Low disease activity is a good alternative for patients who cannot attain
remission, e.g. patients with longstanding RA
• 2015 ACR-EULAR definition of remission* should be used1
• DAS28<2.6 is not considered stringent enough
“Treatment should be aimed at reaching a target of remission
or low disease activity in every patient”1
*Remission based on one of two definitions: 2
1.When scores on the tender joint count, swollen joint count, CRP (in mg/dl), and patient global
assessment (0–10 scale) are all ≤1, or
2.When the score on the Simplified Disease Activity Index is ≤3.3
1. Smolen JS, et al. Ann Rheum Dis 2014;73:492-509.
2. Felson DT, et al. Ann Rheum Dis 2011;70:404–413.

29. Factors
affecting
drug
choices
• (eg, mild versus moderate to severe)
Level of disease activity
Presence of comorbid conditions
• (eg, initial versus subsequent therapy in patients resistant to a
given intervention)
Stage of therapy
• (eg, governmental or health insurance company coverage limitations)
Regulatory restrictions
• (eg, route and frequency of drug administration, monitoring
requirements, personal cost, fertility planning)
Patient preferences
Presence of adverse prognostic signs

30. Efficacy of treat-to-target
strategy
The treat-to-target strategy, more than the specific agents used, results in better
outcomes for patients with RA
Excellent treatment responses achieved
• Biologics
• Small molecule – Jak Inhibitors -Tofacitinib

31. Limitations of Biologics
• Delayed onset of action
• Failure or intolerance to therapy
• Side effects – infections, allergic reactions
• Injectable option doesn’t suit to patients
• Absences of pan cytokines activity
• Cost

32. Expectation from ideal treatment
• Efficacy:
• Ability to achieve true remission
• At par with or superior to
DMARDS/Biologics
• Safety:
• Established short term and long-term
safety
• Cost:
• Affordable
• Compliance
• Oral preferred over parenteral
• Pain Free
• Can be self administered
• No stringent storage and
transportation conditions (as in
biologics)
32

33. Tofacitinib, as a Pan-JAK Inhibitor,
Modulates the Signaling of Multiple JAK-Dependent Cytokine Families
JAK, Janus kinase inhibitors; TYK2, Tyrosine kinase 2; IL, interleukin ; IFN, interferon; EPO, erythropoietin; GM-CSF,
Granulocyte-macrophage colony-stimulating factor; TPO, Thrombopoietin; IC50, half maximal inhibitory concentration; nM,
nanomolar; mM, millimolar
JAK1
JAK3
JAK1 TYK2
TYKb
JAK2
JAK1 JAK1
JAK2b
JAK2
TYK2
JAK2
JAK2
γ-chain cytokines
IL-2, IL-4, IL-7, IL-9,
IL-15, IL-21
IL-6
IL-11
IFN-γ IL-12
IL-23 EPO
TPO
GM-CSF
IL-10a
IL-22
IFN-/

34. JAK-STAT pathway
The Janus kinase (JAK) and
signal transducer and activator
of transcription (JAK-STAT)
pathway is utilized by
cytokines including
interleukins, interferons (IFNs),
and other molecules to
transmit signals from the cell
membrane to the nucleus.
34
JAK-STAT Pathway
STAT: signal transducer and activator of transcription proteins

35. JAK STAT inhibitors

36. TOFACITINIB
• Tofacitinib : JAK Inhibitor which binds to JAK1, JAK2, JAK3 family of
tyrosine kinases
• FIRST APPROVED JAK INHIBITOR
• Approved by FDA in 2012 and EMA 2017
• India (DCGI) Approved: Rheumatoid Arthritis (RA), Psoriatic
arthritis (PsA)
• Globally approved: RA, PsA ,Ankylosing spondylitis, Ulcerative colitis,
pJIA (polyarticular juvenile idiopathic arthritis)
• Dose: 5mg tablet BD or 11mg extended-release tablet OD

37. 37
Adverse Reactions
• Upper respiratory tract
infection
• Nasopharyngitis
• Diarrhea
• Headache.
System organ class Common
≥1/100 to <1/10
Infections and infestations Pneumonia
Influenza
Herpes zoster
Urinary tract infection
Sinusitis
Bronchitis
Nasopharyngitis
Pharyngitis
Blood and lymphatic system disorders Anaemia
Nervous system disorders Headache
Vascular disorders Hypertension
Respiratory, thoracic and mediastinal disorders Cough
Gastrointestinal disorders Abdominal pain
Vomiting
Diarrhoea
Nausea
Gastritis
Dyspepsia
Skin and subcutaneous tissue disorders Rash
Musculoskeletal and connective tissue disorders Arthralgia
General disorders and administration site conditions Pyrexia
Oedema peripheral
Fatigue
Investigations Blood creatine
phosphokinase increased

38. 38
Contra-indications
• Hypersensitivity to the active substance or to any of the excipients of
the formulation.
• Active tuberculosis (TB), serious infections such as sepsis, or
opportunistic infections.
• Severe hepatic impairment.
• Pregnancy and lactation

39. Dosing and Administration
Patient population Recommended Dosage Strength and Frequency
Adult RA and PsA 5 mg twice daily or 11 mg ER tablet once daily
Do not initiate tofacitinib tablets in patients:
• absolute lymphocyte count < 500
cells/mm3
• absolute neutrophil count (ANC) < 1,000
cells/mm3
• Hemoglobin levels < 9 g/dL.
• Dose interruption is recommended for the
management of lymphopenia,
neutropenia, and anemia.
• Interrupt use of tofacitinib tablets if a
patient develops a serious infection until
the infection is controlled.
• Take tofacitinib tablets with or without
food.

40. 40
Warnings and Precautions
• Serious Infections: Avoid use of tofacitinib during an active serious infection, including
localized infections.
• Thrombosis, including pulmonary, deep venous and arterial, some fatal: Avoid
tofacitinib in patients at risk.
• Gastrointestinal Perforations: Use with caution in patients that may be at increased
risk.
• Laboratory Monitoring: Recommended due to potential changes in lymphocytes,
neutrophils, hemoglobin, liver enzymes and lipids.
• Immunizations:
• Recommended: Pneumococcal (PCV13, PPSV23), Influenza, Varicella/Zoster
• Conditional: Hepatitis,Typhoid, MMR
• Live vaccines: Avoid use with tofacitinib

41. Use In Special Population
06-09-2023
PregnantWomen There are risks to the mother and the fetus associated with RA. Risk/benefit ratio
-considered prior administeringTOFAJAK
LactatingWomen No data on the presence of tofacitinib in human milk, effects on a breastfed infant,
or effects on milk production.Tofacitinib is present in the milk of lactating rats.
Breastfeeding is not recommended during treatment and for at least 18 hours after
the last dose of tofacitinib.
Females and Males of Reproductive Potential
Contraception
FEMALES
Pre-clinical findings -demonstrated adverse embryo/fetal findings
Consider pregnancy planning and prevention for females of reproductive potential.
Infertility
FEMALES
Pre-clinical findings -reduced fertility in females of reproductive potential.
Pediatric Patients Efficacy and safety - not been established in the pediatric population.
Geriatric Patients Caution in elderly-higher incidence of infections
Diabetic Patients Caution in patients with diabetes- higher incidence of infections 41
Reference:
Prescribing information, TOFAJAK-Tablets. Last updated: November 2020

42. Use In Special Population
06-09-2023
Patients with Renal Impairment
Moderate and Severe
Impairment
Dosage adjustment of tofacitinib is recommended (5 mg once daily)
Mild Impairment No dosage adjustment required.
Patients with Hepatic Impairment
Severe Impairment Use of tofacitinib in patients with severe hepatic impairment is not studied &
not recommended.
Moderate Impairment Dosage adjustment of tofacitinib is recommended in patients (5 mg once daily)
Mild Impairment No dosage adjustment of tofacitinib is required
Patients with Hepatitis B or
C Serology
Safety and efficacy of tofacitinib - not studied in patients with positive hepatitis
B virus or hepatitis C virus serology.
Effects on Ability to Drive
and Use of Machines
No or negligible influence on the ability to drive and use machines.
42
Reference:
Prescribing information, TOFAJAK-Tablets. Last updated: November 2020

43. Combination with other therapies
• Should be avoided because of the possibility of increased immunosuppression and increased risk of
infection in combination with
• Biologics such as
• TNF antagonists
• Interleukin (IL)-1R antagonists
• IL-6R antagonists
• Anti-CD20 monoclonal antibodies
• IL-17 antagonists
• IL-12/IL-23 antagonists
• Anti-integrins
• Selective co-stimulation modulators
• Potent immunosuppressants such as azathioprine, 6-mercaptopurine, cyclosporine and
tacrolimus
43

44. Tofacitinib
Overview of
the Oral
Rheumatoid
Arthritis
(ORAL)Trials

45. Tofacitinib has been Evaluated in One of the Most
Extensive RA Clinical Development Programs to Date
ORAL
Scan1,2
ORAL
Standard3
ORAL
Strategy4
PatientType MTX-IR MTX-IR MTX- IR
Comparator Placebo Placebo or active
Adalimumab
Adalimumab + MTX
Study Duration, months
24 12 12
Treatment
Tofacitinib 5 or 10 mg
BID + MTX
Tofacitinib 5 or
10 mg BID + MTX
Tofacitinib 5 mg BID +
MTX orTofacitinib 5 mg
Patients Enrolled 797 717 1146
Published
Arthritis Rheum. 2013 &
2019
N Engl J Med. 2012 The Lancet. 2017
BID=twice daily ; MTX-IR=methotrexate-inadequate responder
Reference: 1) Arthritis & Rheumatism. 2013;65(3):559-70. 2) Arthritis & Rheumatology. 2019;71(6):878-91 3) New England Journal of
Medicine. 2012;367(6):508-19. 4) The Lancet. 2017;390(10093):457-68.

46. ORAL SCAN
Tofacitinib in CombinationWith Methotrexate in PatientsWith Rheumatoid
Arthritis: Clinical Efficacy, Radiographic, and Safety Outcomes From aTwenty-
Four–Month, Phase III Study
Reference:
1) Arthritis & Rheumatism. 2013;65(3):559-70.
2) Arthritis & Rheumatology. 2019;71(6):878-91

47. ORAL SCAN Study Design
Phase III, DB, parallel-group,placebo-controlled RCT - efficacy and safety of tofacitinib-
methotrexate combination in RA patients (inadequate response to MTX).
Primary Endpoint (At Month 6)
● ACR 20
● Sharp/van der Heijde score (SHS)
● HAQ DI
● DAS28-ESR
Randomization
4:4
1:1
Screening
Methotrexate
(MTX)-IR
Active RA
Patients (N=797)
receiving stable
doses of MTX
Month 6 (primary endpoint) Month 12
Secondary endpoints Mo 6, 12 and 24
● ACR 20,50,70
● DAS28-ESR
● Change from baseline in SHS score, erosion
score and joint space narrowing (JSN) score
Tofacitinib 5 mg BID (N=321) + Background MTX
Tofacitinib 10 mg BID (N=311) + Background MTX
Placebo -3 months
Background MTX
(N=81)
Switched to tofacitinib 5
mg BID + Background MTX
Placebo -3 months
Background MTX
(N=81)
Switched to tofacitinib 10
mg BID + Background MTX
Month 24
Reference:
1) Arthritis & Rheumatism. 2013;65(3):559-70.
2) Arthritis & Rheumatology. 2019;71(6):878-91
BID=twice daily; IR=inadequate responder; MTX=methotrexate; RA=rheumatoid arthritis; N=Number, DB- double
blinded, RCT- randomized controlled trial

48. Patients
(%)
Proportion of patients achievingACR 20, ACR 50 & ACR 70 at Month 6
10
0
20
30
40
50
60
70
80
90
100 Placebo
Tofacitinib 5 mg BID
Tofacitinib 10 mg BID
ACR20
63.8
ACR50 ACR70
1.3
Statistically significant improvements
in ACR 20, ACR50,ACR 70 with
tofacitinibVs. placebo [P<0.0001]
CLINICAL OUTCOMES
51.5
14.6
Primary Endpoint Secondary Endpoint
8.4
32.4
43.7
22.3
25.3
Reference:
1) Arthritis & Rheumatism. 2013;65(3):559-70.
2) Arthritis & Rheumatology. 2019;71(6):878-91
No statistically significant difference between
Tofacitinib 5 mg BID vsTofacitinib 10 mg BID

49. Proportion of patients achieving DAS-28-Defined Remission
Changes from baseline in DAS28-ESR were significant for both
tofacitinib groups versus placebo (P<0.0001). Reference:
1) Arthritis & Rheumatism. 2013;65(3):559-70.
2) Arthritis & Rheumatology. 2019;71(6):878-91
CLINICAL OUTCOMES

50. Changes from baseline to 12 & 24 months in erosion and joint space narrowing (JSN) scores
• Less Radiographic progression (erosion/JSN) score from baseline to 24 months –
tofacitinib
• Radiographic effects were sustained in patients for 12- 24 months
RADIOGRAPHIC OUTCOMES
Reference:
1) Arthritis & Rheumatism. 2013;65(3):559-70.
2) Arthritis & Rheumatology. 2019;71(6):878-91

51. Tofacitinib 5 mg or 10 mg twice daily plus MTX
demonstrated maintenance of efficacy including
limited structural damage through 24 months in RA
patients having an inadequate response to MTX
CONCLUSION
Reference:
1) Arthritis & Rheumatism. 2013;65(3):559-70.
2) Arthritis & Rheumatology. 2019;71(6):878-91

52. ORAL STANDARD
Tofacitinib or Adalimumab versus Placebo in Rheumatoid Arthritis (RA): 12-month
randomized, phase III trial in RA patients receiving stable doses of Methotrexate.
Reference:
1) New England Journal of Medicine. 2012;367(6):508-19.

53. ORAL STANDARD Study Design
Phase III, DB, parallel-group, placebo-controlled RCT investigating clinical efficacy of tofacitinib as compared with placebo or
Adalimumab in rheumatoid arthritis patients taking methotrexate.
Primary Endpoint (At Month 6)
● ACR 20
● HAQ DI
● DAS28-ESR
Randomization
4:4
1:1
Screening
MTX_IR
Active RA
Patients
(N=797)
receiving stable
doses of MTX
Month 6 (primary endpoint)
Secondary endpoints Mo 6 and 12
● ACR 20,50,70
● Change from baseline in HAQ DI & DAS28 score
ADA=adalimumab; BID=twice daily; IR=inadequate responder; MTX=methotrexate; Q2W=every other week;
RA=rheumatoid arthritis; N=Number, DB- double blinded, RCT- randomized controlled trial
Tofacitinib 5 mg BID (N=204) + Background MTX
Tofacitinib 10 mg BID (N=201) + Background MTX
Placebo -3-6
months Background
MTX (N=56)
Switched to tofacitinib 5 mg
BID + Background MTX
Placebo -3-6
months
Background MTX
(N=52)
Switched to tofacitinib 10
mg BID + Background MTX
Month 12
Adalimumab 40 mg Q2W (N=204) + Background MTX
Reference:
1) New England Journal of Medicine. 2012;367(6):508-19.

54. Proportion of patients achieving ACR 20 and DAS 28 remission at Month 6
06-09-2023
Reference:
1) New England Journal of Medicine. 2012;367(6):508-19.
In comparison to placebo, tofacitinib and adalimumab led to :
• Significantly greater % patients with ACR 20 response (P<0.001)
• Significantly greater % patients with DAS28-4(ESR) < 2.6 (P<0.001)
CLINICAL OUTCOMES

55. ACR 20, ACR 50 & ACR 70 response over 12 months
06-09-2023
Significantly greater outcomes in terms of all ACR responses with tofacitinib & adalimumab vs. placebo
TOFACITINIB 5 or 10 mg BID maintainedACR20,ACR50,ACR 70 response rates over 12 months
Reference:
1) New England Journal of Medicine. 2012;367(6):508-19.
CLINICAL OUTCOMES

56. MeanChange from Baseline in DAS 28 and HAQ-DI Scores during 12 months
06-09-2023
Significantly greater outcomes with tofacitinib and adalimumab vs placebo in terms of DAS28 and HAQDI
(P<0.001)
Reference:
1) New England Journal of Medicine. 2012;367(6):508-19.
CLINICAL OUTCOMES

57. Efficacy of tofacitinib 5 mg or 10 mg twice daily
was significantly superior to that of placebo and
similar to that of adalimumab with respect to all
clinical outcomes
CONCLUSION
Reference:
1) New England Journal of Medicine. 2012;367(6):508-19.

58. ORAL Strategy
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
Reference:
1) The Lancet. 2017;390(10093):457-68.

59. ORAL Strategy Study Design
A 1-year, DB, triple-dummy, phase 3b/4, active comparator, head-to-head, RCT, assessing non-inferiority
between treatment groups.
Patient Population
● MTX-IR
● N=1146
Primary Endpoint
● ACR50 at Mo 6
Randomization
1:1:1
Screening
MTX-IR
Moderate-
Severe RA
Patients
Month 6 (primary endpoint) Mo 12
Secondary endpoints
At Wk 6, Mo 3, 6, 9 and 12
• ACR20 and ACR70 response rates
• Change from baseline in SDAI, CDAI, DAS28, HAQ-DI
, SF-36, FACIT-Fatigue scale
Tofacitinib 5 mg BID
Tofacitinib 5 mg BID + MTX
Adalimumab 40 mg Q2W + MTX
Reference:
1) The Lancet. 2017;390(10093):457-68.
ADA=adalimumab; BID=twice daily; IR=inadequate responder; MTX=methotrexate; Q2W=every other week;
RA=rheumatoid arthritis; N=Number, DB- double blinded, RCT- randomized controlled trial

60. ACR20, ACR50, and ACR70 Response Rates
ACR20 ACR50 ACR70
0
20
40
60
80
100
BL Mo 3 Mo 6
Wk 6 Mo 9 Mo 12
0
20
40
60
80
100
Response
Rate
(%)
BL Mo 3 Mo 6
Wk 6 Mo 9 Mo 12
0
20
40
60
80
100
BL Mo 3 Mo 6
Wk 6 Mo 9 Mo 12
60
ACR20,ACR 50 & ACR70 response rates were maintained over 12 months
Tofacitinib + methotrexate was non-inferior to adalimumab + methotrexate combination
Reference:
1) The Lancet. 2017;390(10093):457-68
60
CLINICAL OUTCOMES

61. DAS28(ESR) Change From Baseline
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
Mean
Change
From
Baseline
BL Mo 3 Mo 6 Mo 12
DAS28(ESR)
61
Mean changes from Baseline in DAS28(ESR) at months 6 and 12 were higher in TOFACITINIB + MTX or
Adalimumab + MTX vs. TOFACITINIB monotherapy
Reference:
1) The Lancet. 2017;390(10093):457-68.
61
CLINICAL OUTCOMES

62. Mean Change From Baseline in HAQ-DI
-0.7
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0.0
Mean
Change
From
Baseline
BL Mo 3 Mo 6 Mo 9 Mo 12
Wk 6
MCID=-0.22
62
Mean changes from Baseline in HAQ-DI response at 6 months was similar across treatment arms.
Reference:
1) The Lancet. 2017;390(10093):457-68.
62
CLINICAL OUTCOMES

63. Tofacitinib 5 mg twice daily + methotrexate was
non-inferior to adalimumab and methotrexate
combination therapy in the treatment of
rheumatoid arthritis patients with an inadequate
response to methotrexate
CONCLUSION
Reference:
1) The Lancet. 2017;390(10093):457-68.

64. ORAL
Scan
ORAL
Standard
ORAL
Strategy
ACR20   
ACR50  

ACR70   
Radiographic effects
(Erosion & JSN scores)

HAQ-DI   
DAS28-4(ESR) <2.6   
Signs &
Symptoms
Additional
outcomes
Summary:Tofacitinib ORALTrials
 = Primary endpoint
 = Secondary endpoint.
Radiographic
outcomes

65. SAFETY OF
TOFACITINIB

66. ORAL Sequel long-term
extension (LTE) study
Evaluated safety and efficacy of tofacitinib 5 mg and 10 mg twice daily (BID) for
up to 9.5 years in patients with rheumatoid arthritis (RA).
Reference:
1) Arthritis research & therapy. 2019;21(1):89.

67. ORAL Sequel long-term extension (LTE) study
Long-Term Efficacy & Safety -Tofacitinib 5 mg and 10 mg twice daily (BID) for up to 9.5 years in RA patient
Primary Objective
● Evaluation of safety & tolerability of tofacitinib (5 &10 mg) BID (AE report & clinical laboratory
data).
Secondary Objective
• Efficacy with tofacitinib 5 mg and 10 mg BID via (ACR20/50/70 response rates; HAQ-DI;
DAS28; CDAI; SDAI scores)
Included RA patients had completed a phase 1,
2, or 3 study – Clinical trials tofacitinib
Received open-label tofacitinib 5 mg or 10 mg
BID
Stable background therapy- csDMARDs, was
continued
Reference:
1) Arthritis research & therapy. 2019;21(1):89.
Global Open label Follow up
long term extension study
Conducted in 414 centers across 43
countries

68. Consistent Efficacy withTOFACITINIB -8 years
ACR20 response rates were maintained from
months 1 and 96 with tofacitinib treatment
Mean DAS28-4(ESR) decreased at month 1
and remained consistent over time with
tofacitinib treatment
Reference:
1) Arthritis research & therapy. 2019;21(1):89

69. Incidence rates (IR) for serious infections
• Total tofacitinib exposure: 16,291
patient-years
• Serious adverse event reported:
Serious infections (herpes zoster),
malignancies, major adverse
cardiovascular event (MACE),
gastrointestinal perforation,
interstitial lung disease, deep vein
thrombosis (DVT), pulmonary
embolism (PE).
• Safety profile remained consistent
with that observed in prior phase 1, 2, 3,
or LTE studies.
Consistent safety profile - 9.5 years
IR is the number of patients with events per 100 patient-years
(4683 patient-years in the 5 mg BID population and 11,608 patient-years in the 10mg BID population).
06-09-2023 69

70. Tofacitinib 5 mg and 10mg BID demonstrated a
consistent safety profile and sustained efficacy in RA
patients with RA.
Safety data are reported up to 9.5 years and efficacy
data up to 8 years
CONCLUSION
Reference:
1) Arthritis research & therapy. 2019;21(1):89.

71. Switchover
from
Adalimumab

72. IsTofacitinib Effectiveness in Patients with Rheumatoid
Arthritis Better After Conventional Than After Biological
Therapy? – A Cohort Study in a Colombian Population
Tofacitinib as first-line
in 85 patients (55.9%)
after failure on
conventional DMARDs
Second-line in 67
patients (44.1%) after
failure on biologic
DMARDs.
Higher proportion of
first-line patients
achieved remission
(45% vs 23%)
Ref: https://doi.org/10.2147/BTT.S361164

73. Effects of one-yearTofacitinib therapy on
bone metabolism in rheumatoid arthritis
Tofacitinib therapy significantly increased OC, OPG, and vitamin D3 and
decreasedCTX levels (p < 0.05).
Tofacitinib treatment stabilized BMD in RA patients and resulted in a positive
balance of bone turnover as indicated by bone biomarker
Ref: Hamar A, Szekanecz Z, Pusztai A, Czókolyová M, Végh E, Pethő Z, Bodnár N, Gulyás K, Horváth Á, Soós B, Bodoki L, Bhattoa HP, Nagy G, Tajti G, Panyi G,
Szekanecz É, Domján A, Hodosi K, Szántó S, Szűcs G, Szamosi S. Effects of one-year tofacitinib therapy on bone metabolism in rheumatoid arthritis. Osteoporos Int.
2021 Aug;32(8):1621-1629. doi: 10.1007/s00198-021-05871-0. Epub 2021 Feb 9. PMID: 33559714; PMCID: PMC8376736.

74. Tofacitinib monotherapy and erectile
dysfunction in rheumatoid arthritis: a
pilot observational study
According to the IIEF-5, 17 (35.4%) patients had severe ED, 10 (20.8%) patients moderate
ED, 10 (20.8%) patients mild to moderate ED and 11 (22.9%) patients mild ED in RA
Baseline median IIEF-5 score was significantly increased from 9.35 (5.30-19.40) to 9.90
(5.20-24.90)
Tofacitinib monotherapy improve ED severity and as well as disease activity and health
related quality of life in male patients with RA complaining of ED
Ref: Karabulut Y, Gezer HH, Esen S, Esen İ, Türkoğlu AR. Tofacitinib monotherapy and erectile dysfunction in rheumatoid arthritis: a pilot
observational study. Rheumatol Int. 2022 Sep;42(9):1531-1537. doi: 10.1007/s00296-022-05132-1. Epub 2022 Apr 25. PMID: 35469090.

75. In ClinicalTrials to Date,Tofacitinib Demonstrated Clinically
Meaningful and Statistically Significant Results
Health quality improved in 3 days
Onset of action as measured by significant ACR 20 response as
early as 2 weeks
Significant Improvements in signs and symptoms and disease
severity
Decreased joint erosion progression in radiographic at six month
Improvements in patient reported outcomes, such as physical
function, pain and fatigue
Efficacy across patient populations – prior DMARD use, TNF
failures – and over time, with sustained improvements over 3
years
Tofacitinib
Tofacitinib a Pan – Jak inhibitor
Better response than biologics and higher remission as first line after
conventional therapy
Tofacitinib monotherapy Non-inferior to MTX,TOFA + MTX, ADA +
MTX
Tofacitinib improve bone health
Improves ED and Insulin resistance in RA
Established safety up to 9.5Years

77. Do you have any questions?
bodhi.doc@gmail.com
+91 9830636315
www.rheumatologistinkolkata.in