XELJANZ (REGISTERED) TABLETS 5MG SPECIAL INVESTIGATION (ALL-CASES SURVEILLANCE)
Conditions: Rheumatoid Arthritis
Sponsor: Pfizer

XeljanzTablets 5 mg
Special Investigation
(All-cases surveillance)
Surveillance protocol
(Version 2.1)
Pfizer Japan, Inc.
All information contained in this protocol is of confidential nature; disclosure thereof to third party without a written and advanced 
consent of Sponsor (Pfizer Japan Inc.) is prohibited.
Date prepared: June 18, 2013 (Ver. 1.1)
Date revised: January 6, 2017 (Ver. 2.0)
Date revised: February 27, 2018 (Ver. 2.1)
(Date issued: April 1, 2018)
(Portions changed: Underlined)
Protocol ID: A3921194
For Application for Reexamination

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Date revised: February 27, 2018 (Ver. 2.1)
(Date issued: April 1, 2018)
Protocol ID: A3921194
Introduction
XeljanzTablets 5 mg (nonproprietary name: tofacitinib citrate; hereinafter referred to as “Xeljanz”) is a strong 
inhibitor of Janus kinase (JAK) created by Pfizer U.S., and has been approved as an antirheumatic drug. It has also been 
approved overseas, particularly in the U.S.in November 2012.
The approval of the indication, “treatment for patients with rheumatoid arthritis who showed inadequate response to 
conventional treatments” was granted under approval conditions to “conduct a use-result surveillance in all patients 
receiving Xeljanz until post-marketing data on a certain number of cases is accumulated so as to collect safety and 
effectiveness data as early as possible to take measures necessary for proper use” and “conduct appropriate post-
marketing surveillance to adequately evaluate the safety of this product, and investigate the safety and effectiveness of 
long-term use including possible development of infections and related events.” Also, malignant tumors such as 
malignant lymphoma and solid cancer have been reported in clinical studies, while the causal relationship with Xeljanz 
is unknown. Therefore, in accordance with the approval conditions, and taking into consideration the fact that Xeljanz is 
a new drug with a new mechanism of action, and that serious infection has been identified as a risk associated with 
Xeljanz, “XeljanzTablets 5 mg Specific Use-result Surveillance (all-cases survey)” (hereinafter referred to as 
"Surveillance") with a control group shall be conducted.
This Surveillance is conducted by Pfizer Japan Inc. (hereinafter referred to as “Sponsor”), and is intended to investigate 
the actual use status of Xeljanz to confirm the occurrence of each adverse reaction associated with Xeljanz (for which, 
malignant tumors and serious infections will be compared with a control group), and to detect or confirm effectiveness 
and other safety data concerning Xeljanz. The information collected in this Surveillance will be used to prepare documents 
to be included in the Proper-Use Information and prepare documents to be included in the application for reexamination.
This Surveillance shall be conducted in compliance with the “Ordinance concerning Standards for Conducting Post-
Marketing Surveillance and Studies on Pharmaceutical Products” (MHLW Ordinance No. 171 dated December 20, 2004). 
Data obtained from the patients enrolled in this Surveillance will be reported to the MHLW pursuant to the
Pharmaceuticals and Medical Devices Act; pertinent to which, data may be publicly posted in MHLW’s “Pharmaceutical 
and Medical Device Safety Information” and Pharmaceuticals and Medical Devices Agency’s “Pharmaceuticals and 
Medical Devices Information Website (http://www.info.pmda.go.jp)” as a listing of patients, which will present the names 
of drugs, adverse reactions, gender, age (increment of 10 years), and other relevant information. Furthermore, data 
collected may also be disclosed if the MHLW is required to disclose such information in accordance with the “Act on 
Access to Information Held by Administrative Organs” (Law No. 42 dated May 14, 1999); provided that in no event will 
the names of physicians, medical institutions, and other personal information be subject to such disclosure, nor will it be 
posted or disclosed in any form or shape.

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Date revised: February 27, 2018 (Ver. 2.1)
(Date issued: April 1, 2018)
Protocol ID: A3921194
1
Objective
The objective of this Surveillance is to verify the following subject matters concerning XeljanzTablets (hereinafter 
referred to as “Xeljanz”) under post-marketing actual status of use. 
1)
Occurrence of adverse reactions, factors that may potentially affect safety, and effectiveness
2)
Long-term safety (particularly, malignant tumors and serious infections) and effectiveness
Occurrences of malignant tumors and serious infections will be compared with a control group.
[Approval conditions]
1.
To conduct a use-result surveillance in all patients receiving Xeljanz until post-marketing data on a certain 
number of cases is accumulated so as to collect safety and effectiveness data as early as possible to take 
measures necessary for proper use.
2.
To conduct appropriate post-marketing surveillance to adequately evaluate the safety of Xeljanz, and 
investigate the safety and effectiveness of long-term use including possible development of infections and 
related events.
2
Subjects
Among rheumatoid arthritis patients with poorly controlled disease in spite of continuous use of a methotrexate 
preparation (hereinafter, MTX) in a dosage exceeding 8 mg/week for 3 months or more, those meeting the following 
criteria:
1)
All patients who receive Xeljanz (Xeljanz group)
2)
Patients who have begun pharmacotherapy with another drug* (control group)
*Patients with no experience of treatment with Xeljanz (Patients participating in clinical trial cannot be registered 
in the control group)

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Date revised: February 27, 2018 (Ver. 2.1)
(Date issued: April 1, 2018)
Protocol ID: A3921194
Xeljanz group
∙Xeljanz alone
∙Xeljanz + MTX
Control group
∙Biologics ± MTX
∙Antirheumatic drug ± MTX
∙Increased dosage of MTX
Poorly controlled 
disease
Treatment with Xeljanz
Drug other than Xeljanz
When using Xeljanz, refer to “Guidelines for the use of tofacitinib in all-cases post-marketing surveillance” (revised version 
on June 29, 2014) (Japan College of Rheumatology) (hereinafter, “tofacitinib use guidelines”). Please consider using a 
pharmacotherapy other than Xeljanz for patients who do not meet the criteria shown below.
[Target patients]
1.
Rheumatoid arthritis patients with poorly controlled disease in spite of continuous use of a methotrexate preparation 
(MTX) in a dosage exceeding 8 mg/week for 3 months or more. Patients with the above treatment history after February 
23, 2011 when the approved dosage for MTX was increased to 16 mg/week are targeted. However, it is desirable not to 
target patients to whom MTX cannot be administered from the safety perspectives at this point, in principle.

Painful joint count of 6 or more

Swollen joint count of 6 or more

CRP of 2.0 mg/dL or more or ESR of 28 mm/hr or more
Even if patient does not meet the 3 criteria above, consider use if there is moderate or higher activity for any of

DAS28-ESR，SDAI, and CDAI.
2.
Moreover, out of consideration for safety with respect to opportunistic infections, it is strongly recommended that the 
following 3 criteria be met.

Peripheral blood count of 4000/mm3 or more

Peripheral lymphocyte count of 1000/mm3or more

Negative for blood β-D-glucan
Excerpted from “tofacitinib use guidelines”
MTX treatment
˃8 mg/week 
for 3 months

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Date revised: February 27, 2018 (Ver. 2.1)
(Date issued: April 1, 2018)
Protocol ID: A3921194
The indication and dose regimen for this Surveillance are as follows: (This surveillance targets rheumatoid arthritis 
patients with poorly controlled disease in spite of continuous use of a methotrexate preparation (MTX) in a dosage 
exceeding 8 mg/week for 3 months or more.)

Indication: Patients with rheumatoid arthritis who showed inadequate response to conventional treatments

Dosage and Administration: As a standard therapy, a patient should receive a daily oral administration of 
tofacitinib 5 mg BID.
Refer to the most updated package insert and “tofacitinib use guidelines” when administering Xeljanz.
3
Target sample size
Target sample size: Subjects who meet the conditions in “2. Subjects” for each group and the sample size is shown 
below.
1)
Xeljanz group: 4000 subjects for safety analysis
∙The target sample size is set to be 4000 subjects by adding a certain sample size a) b) of ≥3000 subjects 
beginning from the start of registration (3-year observation) to the subsequent number of subjects (6-month 
observation period). See “6.5 observation period” for more information. However, even if Xeljanz is 
administered to subjects who do not meet the conditions described in “2. Subjects” for inevitable reason(s), 
while such subjects will not be included in the above sample size, the request to enroll subjects and complete 
survey forms will be made for subjects in the Xeljanz group for the sake of all-cases survey.
2)
Control group: A certain sample size a) b) of ≥2000 subjects for safety analysis
  [Remarks]
a) The sample size in both groups will be set to be the number of subjects for whom the degree of statistical 
accuracy described in [Rationale for sample size] is maintainable. See the Appendix for more information. 
b) The registration period until a certain sample size is reached will be the same period for both groups.
  [Rationale for sample size]
The incidence of malignant tumor associated with Xeljanz in a domestic long-term administration study (Study No. 
A3921041) was 1.16 (/100 person-year). The drop-out rate in clinical studies was 31% among subjects who 
transferred from the domestic Phase II study (Study No. A3921039) to the domestic long-term administration study 
(Study No. A3921041) (treatment period: approximately 3 years), and 14% among subjects who transferred from 
another domestic Phase II study (Study No. A3921040) (treatment period: approximately 1.4 years); based on which, 
the drop-out rate at the completion of 3-year observation in daily medical practice is estimated to be approximately 
50%. 
If 4000 patients were to be enrolled in the Xeljanz group, the target events should be confirmable in 104 patients 
based on the incidence of malignant tumor in Japanese subjects, which was 1.16 (/100 person-year). 
Next, assuming that 4000 patients would be enrolled in the Xeljanz group and the incidence of malignant tumor in 
the control group would be equivalent to the Xeljanz group, at least 2000 subjects would need to be enrolled in the 
control group in order to enable a statistically appropriate inter-group comparison; thus, a sample size of 2000 subjects 
was selected for control. 
Depending on the progress of registration, if the registered number of patients in either group significantly exceeds 
the above number earlier than the other group, a sample size with 3-year observation period can be changed to the 
combination of a sample size for whom the degree of statistical accuracy is maintainable if it is compared with 4000 

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Date revised: February 27, 2018 (Ver. 2.1)
(Date issued: April 1, 2018)
Protocol ID: A3921194
patients in the Xeljanz group and 2000 patients in the control group (see the Appended Table). Also, the registration 
period for patients in the inter-group comparison needs to be the same.
4
Sites conducting this Surveillance
This Surveillance will be conducted in all sites (departments) where Xeljanz is prescribed; provided that doctors 
prescribing Xeljanz must meet the below criteria and consent to “Confirmation of Cooperation to Surveillance.”
4.1 Site requirements:
Sites must meet both of the following conditions 1) to 2):
1)
Cooperate with Xeljanz Tablets 5mg Specific Use-result Surveillance (hereinafter referred to as "Surveillance");
2)
Provide urgent medical intervention, etc. to adverse reactions that may occur in patients using Xeljanz 
(including the sites* which may provide in cooperation with other medial facilities).
*When diagnosing and treating serious infections, tuberculosis, or malignant tumors in collaboration with other 
medial facilities, information on safety measures and treatment for adverse drug reactions associated with 
Xeljanz will be shared with the collaborating medial facilities, and the system of cooperation will be confirmed.
4.2 Doctor requirements:
Doctors must meet all of the following conditions [1] to [5]:
[1] A doctor must meet all of the following Items (1) to (3):
(1) Is a rheumatologist certified by the Japan Rheumatism Association;
(2) Is a rheumatologist certified by the Japanese Orthopaedic Association; or
(3) Has taken part in clinical study(s) of Xeljanz.
[2] Doctors with abundant experience in using methotrexate drug
[3] Doctors with abundant experience in using biological drugs
[4] Doctors who can cooperate with this Surveillance
[5] Doctors who are available for interview with Medical Sponsor
5
Duration of surveillance
Duration of surveillance: 
From the date marketing of Xeljanz begins to the completion of assessment by regulatory authorities
Enrollment period: From initial marketing for Xeljanz to lifting approval conditions for all-cases survey
Completion of survey forms for the Xeljanz group will no longer be mandated after reaching the registration 
of 4000 subjectsc) in the Xeljanz group, which is the target sample size, after the approval from regulatory 
authorities is obtained. Meanwhile, registration will be continued until the final assessment is made by 
regulatory authorities. 
For the control group, both completion of survey forms and registration will no longer be mandated after the 
target sample size is reached and the approval from regulatory authorities is obtained. 
*The results of collecting and analyzing 6-months data on the 4000 subjectsc) in the Xeljanz group will be 
submitted to the regulatory authorities together with the results of collecting and analyzing 6-months data on 
the subjects in the Xeljanz group who do not meet the conditions described in “2. Subjects” and the control 
group.

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Date revised: February 27, 2018 (Ver. 2.1)
(Date issued: April 1, 2018)
Protocol ID: A3921194
c) Subjects who meet the conditions described in “2. Subjects”.
6
Surveillance procedures
6.1 Surveillance method
Subjects in this Surveillance will be enrolled with a central registration system.
6.2 Data collection method
Registration and surveillance data for this Surveillance will be collected and recorded in the registration form and 
survey forms to be supplied by Sponsor.
6.3 Contract and logistics
A contract for this Surveillance must be concluded in writing with the head of each site. Contract templates of 
surveillance site shall be used if available.
[1] The Medical Representative (hereinafter referred to as "MR") shall provide Xeljanz Proper-use Information to 
doctors, pharmacists, and other relevant site staff who will handle/use Xeljanz. 
[Safety information kit]
Product Summary, Proper Use Guide, explanation of “Precautions” for new pharmaceuticals, literature for 
use by patients, package inserts, etc.
[2] Sponsor will explain the proper use of Xeljanz to each investigator taking part in this Surveillance; after which, the 
investigator will sign or name/seal the "Confirmation of Cooperation to Surveillance", and submit it to the MR (this 
document is also required when the investigator is relocated to another site).
[Confirmation of Cooperation to Surveillance]
∙Cooperation to diagnosis and treatment of serious infection, tuberculosis and malignant tumor
∙Requirements for sites and doctors
∙Other relevant items requiring confirmation
∙Signature or name/seal of the investigator taking part in this Surveillance
[3] Upon receiving “Confirmation of Cooperation to Surveillance,” a contract for this Surveillance will be concluded 
between the site and Sponsor.
[4] The sample size ratio between the Xeljanz group and the control group to be specified in the contract will be in 
principle 2 to 1. However, depending on the conditions at the medical facility, the case ratio may be adjusted between 
2:1 and 1:1.
[5] Sponsor, upon confirming the conclusion of contract for this Surveillance, shall set up logistics necessary to deliver 
Xeljanz to the site.
6.4 Patient registration
[1] After the date on which the contract for this Surveillance is concluded, the investigator conducting surveillance will 
complete the registration form provided by Sponsor, and submit the form to Patient Registration Center via FAX.

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Date revised: February 27, 2018 (Ver. 2.1)
(Date issued: April 1, 2018)
Protocol ID: A3921194
[Patient Registration Center]
FAX 
0120-077176
Business 
hours:
9:00 to 17:15 (except for Saturdays, Sundays, National Holidays, and New Year Holidays)
*FAX transmission after 16:00 will be responded during the following business day. 
[2] Definition of start date
(1)
Xeljanz group
The date on which administration of Xeljanz begins will be considered the “start date of treatment.” However, for 
patients participating in the clinical trial, the start date will be considered the date on which administration of the 
commercially available Xeljanz product begins, and in the case of subjects administered Xeljanz at other medical 
facilities, it will be the date on which treatment at the physician’s own hospital begins.
(2)
Control group
For rheumatoid arthritis patients with poorly controlled disease in spite of continuous use of a methotrexate 
preparation (MTX) in a dosage exceeding 8 mg/week for 3 months or more, the date on which the change in 
pharmacotherapy began is regarded as the “start date of surveillance.”
[3] Enrollment method
(1)
Xeljanz group
The registration form should be submitted to the Patient Registration Center via FAX in principle no later than 1 
week prior to the start of Xeljanz therapy.
If the sponsor has made the judgment that there has been a deviation from the scope of proper use of Xeljanz on 
the basis of the registration information, this will be checked with the physician in charge of surveillance, and the 
proper use information will be explained. If any of the patients registered in the control group has been 
administered Xeljanz during the registration period, the patient will also need to be registered in the Xeljanz group.
(2)
Control group
The registration form should be faxed to the Case Registration Center within 2 weeks after surveillance start in 
the control group.
In principle, case selection in the control group should be performed according to the prescribing conditions for 
routine medical care under actual use conditions. 
Patients to whom any of the following apply will be excluded from candidates for registration in the control group.

Patients with past experience of treatment with Xeljanz (Patients participating in clinical trial cannot be 
registered in the control group)

Patients already registered as part of the control group (Patients switching to another type of 
pharmacotherapy, excluding Xeljanz will be handled as continued surveillance cases in this survey)
(3)
Completion of subject registration
The Case Registration Center will fax the results of registration (eligible/ineligible) to the physician in charge of 
surveillance.
In the Xeljanz group, the physician in charge of surveillance will begin prescribing after accepting the results on 
registration eligibility.
(4)
Confirmation of cases registered in Xeljanz group
The sponsor will periodically confirm with the physician in charge of surveillance that all Xeljanz cases are 

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Date revised: February 27, 2018 (Ver. 2.1)
(Date issued: April 1, 2018)
Protocol ID: A3921194
registered. If there are unregistered cases, the physician in charge of surveillance will immediately register the 
said cases.
6.5 Observation period
[1] Xeljanz group:
(1) Registered subjects up to a certain sample size exceeding 3000 subjects from the start of registration: 3 years 
(36 months) from the date of treatment start
(2) Registered subjects after the above (1): Only 6 months from the date of treatment start
[2] Control group: 3 years (36 months) from the date of treatment start
[3] Type of survey form
Booklet-type survey form will be used for this Surveillance. 
Safety and effectiveness will be evaluated on the day of the initial office visit after the end of the observation 
period for each booklet (including the day on which the observation period ends). However, the safety and 
effectiveness will be evaluated based on the information from the last known visit if the subject is lost to follow 
up during the treatment period. 
The effectiveness evaluation will be performed on Xeljanz group only.
[4] Follow-up surveillance
For a period of 3 years from the date of treatment start, follow-up surveillance for subjects in the Xeljanz group 
(1) and the control group will be conducted on the information related to the drug administration conditions and 
adverse events after discontinuation (serious infections [12 months], malignant tumors, adverse events leading to 
death).

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Date revised: February 27, 2018 (Ver. 2.1)
(Date issued: April 1, 2018)
Protocol ID: A3921194
Booklet No.
Observation period
Safety 
Effectiveness 
Xeljanz group
Control group
Xeljanz group
Control 
group
Booklet 1 d)
Treatment start to 
Month 6d)
All
adverse events
Serious 
infection,
Malignant 
tumor,
Death
Before treatment 
start,
At Month 6
-
Booklet 2
Months 7 to 12
At Month 12
Booklet 3
Months 13 to 24
Malignant 
tumor,
Death
At Month 24
Booklet 4
Months 25 to 36
At Month 36
Follow-up 
survey formd)
Performed for 3 years from the start of treatment for subjects who prematurely discontinue 
treatmentd)
d) For subjects who correspond to “[1] Xeljanz group (2)”; the observation period will be only the duration of 6 months 
from the date of treatment start (Booklet 1) and no follow-up surveillance will be conducted.
6.6 Reminders concerning completing, revising, and submission of survey form
[1] Completing
The doctor shall, upon confirming the survey items, complete the survey form based on medical charts and other 
medical records such as relevant test results, using a pen, or ballpoint pen.
[2] Revising
Upon receiving Sponsor’s inquiry on the contents of the survey form (resurvey), the investigator will again 
confirm the contents of medical records described earlier, and as required, correct relevant contents and resubmit 
the form. Corrections in the survey form should be struck out with a double line (=) with a "correction seal" on 
the double line; the double line should be drawn so that the original contents prior to correction are legible.
[3] Submission method
Survey forms should be submitted promptly upon completion in accordance with the procedures set out by 
Sponsor.
6 months
36 months
Booklet 3
Booklet 4
12 months
24 months
Treatment commenced
Booklet 1
Follow-up
Booklet 2
Xeljanz group
Control group

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Date revised: February 27, 2018 (Ver. 2.1)
(Date issued: April 1, 2018)
Protocol ID: A3921194
7
Survey items and schedule
This Surveillance should be conducted in accordance with the following observation schedule.
                       
               Observation period
Survey item
Subject
Registrat
ion form
Survey form
Booklet 1 *6
Booklet 
2
Booklet 
3
Booklet 
4
Pre-
dose*1
During 
treatmen
t*2
Start of 
surveilla
nce
Month 1
Month 3
Month 6
Month 
12
Month 
24
Month 
36
Registration form
Confirmation of target patients, 
prior treatment of MTX, drugs to 
be investigated, ID number, 
patient's initials, gender, date of 
birth or age at the start of 
treatment, and start date of 
treatment (or surveillance)
Xeljanz 
group
Control 
group
●
-
-
-
-
-
-
-
Contraindication, tuberculosis 
check, hepatitis B virus test, and 
clinical laboratory
Xeljanz 
group
●
-
-
-
-
-
-
-
Survey Form 
Patient characteristics
Both groups
-
●
-
-
-
-
-
-
Dose record
Both groups
-
Concomitant 
therapy
(Pharmacotherapy)
Xeljanz 
group 
-
Pneumococcus vaccination*3
Both groups 
-
Prophylactic administration*4
Both groups
-
Chest X-rays or CT
Xeljanz 
group 
-
●
●
●
●
Tuberculosis check
Xeljanz 
group
-
●
-
-
-
-
-
-
Hepatitis B/C virus test
Xeljanz 
group 
-
●
Blood pressures 
(systolic/diastolic)
Xeljanz 
group
-
●
-
-
●
●
●
●
Clinical laboratory
Xeljanz 
group
-
●
●
●
●
●
●
●
Tender/swollen 
joint 
count, 
patient/doctor-reported outcome, 
CRP, and ESR
Xeljanz 
group
-
●
-
-
●
●
●
●
Adverse events*5
Xeljanz 
group
-
Control 
group
-
Serious infection
-
Malignant tumor/adverse events leading to death
Tests/examinations related to 
adverse events
Xeljanz 
group 
-
Follow 
Follow-u*6
Both groups
-
Periodically performed for 3 years from the start of treatment 
for subjects who prematurely discontinue treatment*6
●: Essential data
*1: Patients in the Xeljanz group should be registered in principle no later than 1 week prior to the start of treatment.
*2: Patients in the control group should be registered in principle no later than 2 weeks after the start of surveillance.
*3: Information on patients in the control group should be collected until 12 months after the start of surveillance.
*4: Prophylactic administration to prevent tuberculosis, pneumocystis jiroveci pneumonia, and hepatitis B (nucleic acid analogs)
Information on patients in the control group should be collected until 12 months after the start of surveillance.
・Treatment start to Month 6: Malignant tumor and serious infection
*5: All adverse events in the Xeljanz group are subject to reporting.
In the control group, the following adverse events are subject to reporting.
・Serious infections: For 12 months from the start of surveillance

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Date revised: February 27, 2018 (Ver. 2.1)
(Date issued: April 1, 2018)
Protocol ID: A3921194
・Malignant tumor and adverse events leading to death: For 36 months from the start of surveillance
*6: For patients in the Xeljanz group (“1) Xeljanz group (2) in 6.5 observation period”) after the registration of patients in the control group is completed; only information 
until 6 months after the start of surveillance (Booklet 1) should be collected and no follow-up surveillance will be conducted.
7.1 Assessment variables
1)
Registration items
For pre-treatment information (including the start date of the treatment), all items for the Xeljanz group and items 
[1] to [7] for the control group will be completed. 
(1) Patient characteristics
[1] Confirmation of target patients
If the patient meets the conditions for target patients (answer “Yes”):
Timing of MTX treatment, weekly dosage at the prior treatment of MTX
If the patient does not meet the conditions for target patients (answer “No”):
[Only patients in the Xeljanz group] Reason for non-conformity with guidelines, reason for treatment of 
Xeljanz
[2] Drugs to be investigated

Xeljanz group: Patient category :Newly prescribed, transferred from clinical study, or prescribed at 
other medical facility (name of the medical facility)
Control group: Pharmacotherapy: whether of not MTX has been administered, whether or not 
biological preparations have been administered, whether or not disease-modifying antirheumatic 
drugs (DMARDs) or immunosuppressants have been administered
[3] ID number
[4] Patient's initials (as necessary) 
[5] Gender
[6] Date of birth (Western calendar) or age at the treatment start
[7] Start date of treatment (surveillance)

Xeljanz group: Since registration takes place before treatment, the scheduled date of treatment start 
should be recorded. 

Control group: For registration after surveillance start, write in “start date of surveillance.” 
(2) Pre-treatment observation
[8] Contraindication (presence/absence of contraindication)
[9] Tuberculosis check (imaging diagnosis/tuberculin test/interferon γ measurement (Quantiferon test, T-
SPOT test, etc.)/antituberculosis drug administration)
The results of tests within 3 months prior to the start of treatment should be recorded before the treatment. 
*Patients with concurrent or suspected tuberculosis should be given appropriate antituberculosis drug. 
[10]Hepatitis B virus test (HBs antigen, HBs antibody, and HBc antibody)
The results of tests within 3 months prior to the start of treatment should be recorded. 
[11]Laboratory tests (peripheral leukocyte count, peripheral lymphocyte count, β-D-glucan)

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Date revised: February 27, 2018 (Ver. 2.1)
(Date issued: April 1, 2018)
Protocol ID: A3921194
2)
Survey form
(1) Patient characteristics prior to and at the start of treatment
The following will be recorded for both treatment groups. 
[1] Height/weight
[2] Inpatient/outpatient status
Indication (Patients with rheumatoid arthritis), stage and grade (Steinbrocker stage), and functional class 
(Steinbrocker functional class)
[3] Duration of disease
[4] Clinical history (past history and concurrent illness)
[5] History of smoking (history of smoking at treatment start)
[6] Family history of malignant tumor
(2) Previous treatment drugs for rheumatoid arthritis (3 months before treatment start)
The following will be recorded for both treatment groups. 
[1] MTX

Past use (presence/absence)

Weekly dosage

Duration of treatment
[2] Oral steroid use for rheumatoid arthritis

Past use (presence/absence),period or treatment
[3] Tacrolimus

Past use (presence/absence)

Duration of treatment
(3) Dose record
[1] Xeljanz group
Number of doses per day, treatment period, reason for change (if there has been a change in 
administration) 
[2] Control group
If there has been a switch to another type of pharmacotherapy, excluding Xeljanz, during the observation period, 
the case will be handled as a continued surveillance case, and the treatment record should be continuously 
entered.
In cases where Xeljanz has been administered, surveillance as a member of the control group will be 
handled as discontinued, and registration in the Xeljanz group will be necessary.

MTX
Name of drug (name of product), weekly dosage, and duration of treatment

Pharmacotherapy 
with 
drugs 
other 
than 
MTX 
(biological 
preparation, 
DMARDs, 
immunosuppressants, oral steroid preparations)
Name of drug (name of product), daily dosage (oral steroids), and duration of treatment 
(4) Concomitant therapy (Xeljanz group)
For drug therapy, covering the period starting 3 months prior to the start of treatment in this Surveillance 

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Date revised: February 27, 2018 (Ver. 2.1)
(Date issued: April 1, 2018)
Protocol ID: A3921194
and ending at the completion or discontinuation of the observation period will be completed. Medications 
used for the treatment of adverse events should also be recorded. 
[Concomitant therapies coadministered with Xeljanz]
[1]
MTX
[2]
Biological preparations*
[3]
DMARDS other than MTX and immunosuppressants*
[4]
Oral steroid
[5]
Other drugs
Name of drug (product name), dosage (MTX, Oral steroids), duration of treatment, and reason for 
treatment (Other drugs) 
*Please do not coadminister biological preparations and immunosuppressants along with Xeljanz.
[Surgical treatment of rheumatoid arthritis]
Name of the surgical therapy for rheumatoid arthritis, the date of operation, and the reason for operation 
should be recorded. 
(5) Whether or not pneumococcus vaccine has been administered (both groups). *Until 12 months after 
surveillance start in control group
(6) Prophylactic administration to prevent tuberculosis, pneumocystis jiroveci pneumonia, and hepatitis B 
(nucleic acid analogs) (both groups). *For control group, until 12 months after surveillance start
7.2 Tests/examinations
In Xeljanz group, enter results of tests performed from before treatment start to end of observation period or date of 
discontinuation. 
For test/examination results, a copy of the original report may be attached; provided that personal information must 
be processed with masking (blackened) or other method to anonymize the data. 
1)
Clinical laboratory tests
The results of clinical laboratory to the start of treatment (within 1 month prior to the start of treatment 
including the date treatment is commenced) and during and until the completion/discontinuation of the 
observation period should be recorded. If the observation period is discontinued, the test results at the time of 
discontinuation should be recorded if at all possible. 
[1] Hematological test: WBC, neutrophil, lymphocyte, RBC, platelets, and hemoglobin
*Results of tests performed prior to the start of treatment (within 1 month prior to the start of treatment 
including the date treatment is commenced) and at 1, 3, 6, 12, 24, and 36 months of treatment will be 
essential. 
[2] Chemistry: AST (GOT), ALT (GPT), AL-P, LDH, HDL-C, LDL-C, γ-GTP, total bilirubin, triglyceride, 
serum creatinine and creatine kinase
*Results of tests performed prior to the start of treatment (within 1 month prior to the start of treatment 
including the date treatment is commenced) and at 1, 3, 6, 12, 24, and 36 months of treatment will be 
essential. 
[3] Other tests: KL-6, β-D-glucan, and BUN

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Date revised: February 27, 2018 (Ver. 2.1)
(Date issued: April 1, 2018)
Protocol ID: A3921194
2)
Chest X-ray or CT
Tests before treatment start and 12, 24, and 36 months after treatment start are considered essential.
3)
Interferon γ (Quantiferon test, T-SPOT test, etc.)/tuberculin reaction
Tests before treatment start are considered essential.
4)
Blood pressure (systolic/diastolic)
Tests before treatment start and 6, 12, 24, and 36 months after treatment start are considered essential.
5)
Hepatitis B/C virus tests (HBs antigen, HBs antibody, HBc antibody, HBV-DNA, and HCV-antibody)
Tests before treatment start are considered essential. After treatment start, indicate whether HBV-DNA tests 
have been performed.
6)
Assessment variables
The following assessment variables [1] to [6] will be evaluated. 
The observation period will be as follows. If the observation period is discontinued, the test results at the time 
of discontinuation should be recorded if at all possible. 

Essential assessment timepoints: Assessment performed prior to the start of treatment (within 1 month 
prior to the start including the date treatment is commenced) and at 6, 12, 24, and 36 months of treatment 
(until completion of the observation period). 
[Assessment variables]
[1] Tender joint count (evaluation of 28 joints)
[3] Patient-reported outcome (Patient VAS)
[5] C-reactive protein (CRP)
[2] Swollen joint count (evaluation of 28 joints)
[4] Doctor-reported outcome (Doctor VAS)
[6] Erythrocyte sedimentation rate (ESR): 1-hour 
value
7.3 End-of-surveillance (discontinuation) record
Confirm whether or not treatment can be continued by Xeljanz or control group at end of observation period. If treatment 
by Xeljanz group or control group cannot be continued, write date of discontinuation and select item that corresponds to 
reason (multiple responses possible).
However, even if a switch to another type of pharmacotherapy, excluding Xeljanz, has been made in the control group 
after registration is complete, it will be handled as a continuing surveillance case, and if the pharmacotherapy has been 
discontinued, it will be handled as a surveillance discontinued case.
If adverse event or death is selected as the reason, the details thereof should be recorded in the adverse event section. 
[Also, for the control group, if the reason selected is associated with malignant tumor and death of patient (treatment start 
to 36 months) or serious infection (treatment start to Month 12 of treatment), the details thereof should be recorded]. 

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Date revised: February 27, 2018 (Ver. 2.1)
(Date issued: April 1, 2018)
Protocol ID: A3921194
[1] Remission
[2] Inadequate clinical response
[3] Adverse event
[4] Death (date of death)
[5] No revisit
[6] Transfer to another hospital/department (name of hospital/department)
[7] Treatment with Xeljanz tablets (*Only applicable for
the survey form for the control group)
[8] Other
e) However, the observation period for subjects who correspond to “1) Xeljanz group (2) in 6.5 Observation period” will 
be only 6 months after the date of treatment start (Booklet 1) and no follow-up surveillance will be conducted.
7.4 Effectiveness evaluation
For the Xeljanz group, the following effectiveness evaluation will be performed. 
Effectiveness will be evaluated based on the results of "7.2, 6) [Assessment variables] [1] to [6]."
(1)
SDAI (Simplified Disease Activity Index)
Sponsor will calculate the values based on the results of [Assessment variables] [1] to [5], and based on which, 
disease activities will be evaluated. 
Also, Sponsor will calculate the values for CDAI (Clinical Disease Activity Index) based on the results of 
[Assessment variables] [1] to [4], and based on which, disease activities will be evaluated. 
(2)
DAS28 and the changes thereof (rate)
Sponsor will calculate the values based on the results of [Assessment variables] [1], [2], [3], and [6], and 
based on which, disease activities will be evaluated. In addition, changes in DAS28 (rate) prior to the start of 
treatment and at each assessment timepoint will be computed to evaluate the increase and decrease at each 
timepoint. 
7.5 Pregnancy status
For both treatment groups, female patients should be verified for presence/absence of pregnancy at the end of the 
observation period for each booklet. 
7.6 Adverse events
Pertinent to safety assessment, the status of adverse events after the start of treatment should be verified and the 
following information should be recorded. 
1)
Xeljanz group
Upon occurrence of any adverse event, the investigator shall provide appropriate treatment, promptly report to 
Sponsor, and follow up on the progress and outcome in principle until the symptom disappears. 
Also, occurrence of a serious adverse reaction or an adverse reaction identified as a key survey item should be 
separately investigated in detail if determined necessary by Sponsor. 
[1] Presence/absence of adverse event 
[1]-[3]: Subject to follow-up survey e)
[4]-[7]: End surveillance if any 
of the following apply

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Date revised: February 27, 2018 (Ver. 2.1)
(Date issued: April 1, 2018)
Protocol ID: A3921194
[2] Name of adverse event
[3] Diagnosis of malignant tumor (only if applicable) 
[4] Date of occurrence
[5] Intervention
[6] Seriousness
[7] Outcome and date of outcome 
[8] Causal relationship with Xeljanz
If the patient has died, describe the details in the course of death column.
[If the adverse event is associated with abnormal laboratory values, i.e., clinical laboratory tests, the following 
information should also be recorded.]
Laboratory parameter
Site reference value
Unit
Date measured
Results
2)
Control group
(1)
Malignant tumors (including lymphomas) and/or serious infections (including herpes zoster and 
tuberculosis)
Upon occurrence of any malignant tumor and/or serious infection, the investigator shall promptly report to 
Sponsor, and follow up on the progress and outcome in principle until the symptom disappears. Moreover, if an 
adverse event has been found, the investigator
will immediately contact the MR and/or others in charge of the 
company that sells the product utilized as control group.
[1] Presence/absence of malignant tumor and serious infection (For serious infections, from treatment start to 
12 months after)
[2] Name of adverse event for malignant tumors and serious infections (for serious infections, from treatment 
start to 12 months after)
[3] Diagnosis of malignant tumor (only for malignant tumors)
[4] Date of occurrence
[5] Treatment
[6] Seriousness
[7] Outcome and date of outcome
[8] Causal relationship to the drug subject to surveillance
(2)
Detailed information
If there has been a malignant tumor, serious infection, or death of the patient, write the details.
[1]
Detailed information on malignant tumors (including lymphomas)
[2]
Detailed information on serious infections (including herpes zoster and tuberculosis),
[3]
Adverse events leading to death, course of death

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Date revised: February 27, 2018 (Ver. 2.1)
(Date issued: April 1, 2018)
Protocol ID: A3921194
Definition of [Malignant tumor]
An event to which definitive diagnosis of malignant tumor (including lymphoma) is given
*"Suspected malignant tumor (including lymphoma)" should also be reported as an adverse event. 
Definition of [Serious infection]
Of the infections occurred during this Surveillance, a "serious infection" is defined as an event that;
[1] Results in or may result in death;
[2] Results in or may result in disability/incapacity;
[3] Requires hospitalization or prolongation of existing hospitalization; or
[4] Is another serious event equivalent to the above. 
Note: Adverse events are any and all untoward events (including clinically significant abnormal changes in 
laboratory tests) occurred in subjects after starting Xeljanz treatment regardless of their causal 
relationship with Xeljanz. Serious adverse events are any untoward medical occurrences that result 
in death, are life-threatening, require (or prolong) hospitalization, cause persistent or significant 
disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which 
represent significant health hazards. 
7.7 Follow-up
In cases that discontinued (excluding those where the reason for discontinuation was “death of patient,” “did not 
return to hospital,” or “transferred to another hospital/department”), a follow-up survey will be conducted on 
information related to the drug administration conditions after discontinuation and adverse events (serious infections 
(12 months), malignant tumors, adverse events leading to death) for a period of 3 years after the date of treatment start, 
if possible f). If the subject is lost to follow up, follow-up survey will not be required. 
f) However, the observation period for subjects who correspond to “1) Xeljanz group (2) in 6.5 Observation period” 
will be only 6 months after the date of treatment start (Booklet 1) and no follow-up survey will be conducted.
For cases that discontinued in the 24-month period following treatment start (booklets 1 to 3), information from the 
date of discontinuation onward should be written on the follow-up survey form issued by the sponsor. Cases 
discontinuing during the observation period from treatment start to the 25th month after (booklet 4) should be 
confirmed in the reinvestigation of information from the date of discontinuation onward for the period from treatment 
start to 36 months after.
7.8 Key survey items
The following events should be evaluated in this surveillance as key survey items; patients applicable to any of the 
key survey items in the Xeljanz group will be separately investigated in detail. 
[1] Serious infection (including herpes zoster and tuberculosis) 
[2] Neutrophil decreased and neutropenia
[3] Lymphocyte count decreased and lymphocytopenia
[4] Hemoglobin decreased and anemia
[5] Lipids increased and hyperlipemia

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Date revised: February 27, 2018 (Ver. 2.1)
(Date issued: April 1, 2018)
Protocol ID: A3921194
[6] Malignant tumor (including lymphoma) 
[7] Gastrointestinal perforation
[8] Cardiovascular-related adverse events
[9] Impaired hepatic function
[10]Interstitial pneumonia
Priority survey items in the control group will be “serious infections (including herpes zoster and tuberculosis) and 
“malignant tumors (including lymphomas).”
8
Statistical analysis plan
8.1 Statistical analysis plan
The details of the analytical plan should be decided upon after consultation with experts on rheumatology.
8.2 Analysis set
The analysis sets for safety and effectiveness will consist of all evaluable cases in which there has been confirmed 
to be at least one administration of Xeljanz or the control drug. The details of the evaluable cases will be described in 
the statistical analysis plan. Both treatment groups will be included in the safety analysis set while only the Xeljanz 
group will be included in the effectiveness analysis set. 
8.3 Analytical method
1)
Safety analysis
The primary analysis on the safety analysis set will be performed on major adverse reactions, the proportion 
thereof, and the incidence of adverse reaction per exposure. Also, each factor that may affect the occurrence of 
adverse reactions will be evaluated, for instance, based on tabulation of factors such as patient characteristics. 
2)
Risk factor analysis for malignant tumors and serious infections
Proportion of malignant tumors and serious infections should be calculated along with incidence rates of 
adverse reactions per amount of exposure and their 95% confidence intervals. The hazard ratio adjusted by the 
proportional hazard model should be calculated along with its 95% confidence interval. In addition, comparison 
should also be made with the control group subset with patient background matched to that of the Xeljanz group. 
3)
Effectiveness analysis 
The primary analysis on the effectiveness analysis set will be changes (rate) in SDAI and DAS28. 
 
 
4)
Based on the above analytical methods in (1) and (3), an interim analysis on the 6-month data of 4000 subjects 
of Xeljanz group will be performed and the results thereof will be submitted to regulatory authorities (see “5. 
Duration of surveillance” for submission”). 
9
Public release
The safety information accumulated and the progress of this Surveillance shall be publicly released as appropriate 
on the sponsor's website.
9.1 Public release by Pfizer Japan, Inc (hereinafter Pfizer). 
Pfizer by posting the results of this Surveillance in ClinicalStudyResults.org, shall fulfill its obligations concerning 
public release of medical information. The results of surveillance to be released by Pfizer. shall be either of the 
CCI

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Date revised: February 27, 2018 (Ver. 2.1)
(Date issued: April 1, 2018)
Protocol ID: A3921194
following. In addition, as required, the results may be presented at academic conferences or in medical journals for the 
purpose of providing proper-use information. 
・
Surveillance registered to www.clinicaltrials.gov (ClinicalTrials.gov) by Pfizer, regardless of the reason for 
such registration. 
・
Surveillances other than above with the results that are of scientific and medical importance as determined 
by Pfizer. 
The timing of public release will be dependent on the presence of any country in which the product has been approved 
at the completion of surveillance using the Pfizer product. 
Any surveillance involving an already-approved Pfizer product in any country will require Pfizer to publicly 
release the results within 1 year of the finalization of last-patient last-visit data. 
The information to be posted by Pfizer in ClinicalStudyResults.org. shall include; "The title of the implementation 
guideline for post-marketing surveillance, and study phase and indication," "Labeling of the product approved," 
"Summary of findings," "Citation of literature references," and "Disclaimer." 
Literature references used by Pfizer are limited to those widely recognized and accessible through searchable 
literature databases. 

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Date revised: February 27, 2018 (Ver. 2.1)
(Date issued: April 1, 2018)
Protocol ID: A3921194
10 Reference
・Package Insert of Xeljanz Tablets 5 mg
Appendix
“3. Target sample size”
A list of combinations for “certain sample size” in the Xeljanz and control groups
Sample size for safety analysis in “3. Target sample size” g)
“Certain sample size h)” that requires 3-year 
observation
6-month observation
(1) Sample size in 
the control 
group
(2) Sample size in 
the Xeljanz
group
(3) Sample size in 
the Xeljanz 
group
(4) Sample size in 
the Xeljanz 
group Total 
[(2)+(3)]
2000
4000
0
4000
2050
3814
186
4000
2100
3653
347
4000
2150
3511
489
4000
2200
3385
615
4000
2250
3273
727
4000
2300
3173
827
4000
2350
3082
918
4000
2400
3000
1000
4000
      g) Subjects who meet the conditions described in “2. Subjects”.
      h) A “certain sample size” will be reached when both the sample size in the control group and the sample size in 
the Xeljanz group exceed the number of subjects in any line of the combination of (1) and (2).

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Date revised: February 27, 2018 (Ver. 2.1)
(Date issued: April 1, 2018)
Protocol ID: A3921194
References
1. Staging of rheumatoid arthritis and classification of progress (Steinbrocker 
staging system)
Stage I 
(Initial stage)
○1. No radiological finding of osteolysis
2. Radiological finding of osteoporosis (bone atrophy) may be present.
Stage II
(Medium stage)
○1. Radiological finding of osteoporosis (bone atrophy) with or without mild fracture 
of subchondral bone. There may be mild cartilage destruction. 
○2. Articular movement may be restricted, but no joint deformity
3. Muscle atrophy around the joint 
4. Lesions in the extracapsular soft tissue such as subcutaneous nodule and 
peritendinitis may be present. 
Stage III
(Progressive 
stage)
○1. Osteoporosis (bone atrophy) and radiological finding of bone and cartilage 
destruction
○2. Joint deformity such as subluxation, ulnar malposition or extension is present. There 
is no fibrous or osseous ankylosis. 
3. Severe muscle atrophy
4. Lesions in the extracapsular soft tissue such as subcutaneous nodule and 
peritendinitis may be present. 
Stage IV
(Terminal)
○1. Fibrous or osseous ankylosis is present. 
2. Meet all criteria applicable to Stage III
○: Essential criteria required for categorizing patients based on disease stage and progress. 
<Excerpt: Steinbrocker O. et al. therapeutic criteria in rheumatoid arthritis. JAMA 140:659,1949>
2. Steinbrocker functional classification of rheumatoid arthritis
Class 1
Complete ability to carry out all the usual duties without handicaps
Class 2
Adequate for normal activities despite handicap of discomfort or limited motion of one of the joints
Class 3 
Limited to little or none of the duties of usual occupation or self-care
Class 4
Incapacitated, largely or wholly bed-ridden or confined to a wheelchair with little or no self-care 
<Excerpt: Steinbrocker O. et al. therapeutic criteria in rheumatoid arthritis. JAMA 140:659,1949>

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Date revised: February 27, 2018 (Ver. 2.1)
(Date issued: April 1, 2018)
Protocol ID: A3921194
3. SDAI / CDAI / DAS28
[Joints subject to assessment]
Right and left shoulders, elbows, wrists, 
and PIP (proximal interphalangeal joints), 
MCP (metacarpophalangeal joints) 
and knees; 28 joints in total.
[Assessment variables]
ESR (mm/hr)
CRP (mg/dL)
Tender joint count: TJC
Swollen joint count: SJC
Patient/doctor-reported outcome [visual analog scale: 
VAS (0 to 100 mm)]

SDAI (Simplified Disease Activity Index)
TJC (28 joints) + SJC (28 joints) + Patient VAS + Doctor VAS + CRP (mg/dL)

CDAI (Clinical Disease Activity Index)
TJC (28 joints) + SJC (28 joints) + Patient VAS + Doctor VAS

DAS28 (Disease Activity Score in 28 joints)
    ・With measurement of ESR:
     DAS28（4/ESR）= 0.56×√(TJC)+0.28×√(SJC)+0.70×ln(ESR)+0.014×(VAS)
     DAS28（3/ESR）=[0.56×√(TJC)+0.28×√(SJC)+0.70×ln(ESR)]×1.08+0.16
    ・With measurement of CRP:
     DAS28（4/CRP）= 0.56×√(TJC)+0.28×√(SJC)+0.36×ln(CRP+1)+0.014×(VAS)+0.96
     DAS28（3/CRP）=[0.56×√(TJC)+0.28×√(SJC)+0.36×ln(CRP+1)]×1.10+1.15
Note) DAS28 (3/ESR) and DAS28 (3/CRP) will be in place only if VAS is not performed. "ln" stands for 
natural logarithm. 
<Source: DAS Website (http://www.das-score.nl)>
[Assessment criteria]
Assessment 
criteria
Criteria for disease activities
Remission
Low disease activity
Moderate disease 
activity
High disease 
activity
DAS28
＜2.6
≧2.6 ~＜3.2
≧3.2 ~≦5.1
＞5.1
SDAI
≦3.3
>3.3 ~≦11
>11 ~≦26
＞26
CDAI
≦2.8
>2.8 ~≦10
>10 ~≦22
＞22
<Source: 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>
Shoulder
Elbow
Wrist
proximal interphalangeal 
metacarpophalangeal 
Knee

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Date revised: February 27, 2018 (Ver. 2.1)
(Date issued: April 1, 2018)
Protocol ID: A3921194
4. Tuberculosis tests
【Tuberculin reaction】Criteria for interpretation
Determination
Code
Reaction
Negative
-
Diameter of reddening 9mm or less
Positive
Weakly positive
1+
Diameter of reddening 10 mm or more
Moderately 
positive
2+
Diameter of reddening 10mm or more, accompanied by induration
Strongly 
positive
3+
Diameter of reddening 10mm or more with induration accompanied by 
double redness, blisters, or necrosis
(Excerpted from package insert of Purified Protein Derivative (PPD) Tuberculin (revised Sept
ember 2013 (Ver. 6))
【Quantiferon TB Gold】Interpretation of results
Measured value for M
（IU/mL）
Measured value for A
（IU/mL）
Result
Interpretation
Irrelevant
0.35 or more
Positive
Tuberculosis infection suspected
0.5 or more
0.1 or more
< 0.35
Indeterminate
Make a comprehensive 
determination, taking into account 
the degree of infection risk
< 0.1
Negative
Not infected with tuberculosis
< 0.5
< 0.35
Indeterminable
Not determined because 
immunodeficiency etc. is suspected
(Cite from QuantiferonTB Gold package insert (revised September 2016 （Ver. 10))
【T-SPOT.TB】Assessment criteria
1.
With the use of the following formulas, calculate (1) and (2).
[(spot count in wells of panel A)(- spot count in wells of negative control) ]…(1)
[(spot count in wells of panel B)(- spot count in wells of negative control）]…(2)
2.
With the use of figures (1) and (2) calculated in 1, assess the results according to the following 
assessment criteria.
Positive: If spot count for both (1) and (2) or one of them is 6 or more
Negative: If spot count for both (1) and (2) is 5 or less.
Indeterminate: If the count for both (1) and (2) or the maximum of the value for both is 5 to 7
*If the result is “indeterminate,” the result of a determination of “positive” or “negative” is itself valid, but it is 
possible that the reliability will be somewhat less than in cases where the figure is 8 or higher or 4 or lower. For 
this reason, it is recommended that the test be repeated in cases where the result is “indeterminate.”
(Cited from home page for T-SPOT.TB product information)