Background 
In patients with RA who achieve sustained remission with biological DMARDs, stopping or tapering biological DMARDs can be considered when the treatment is combined with a conventional synthetic DMARD. Previous clinical trials that have investigated cessation of TNFi have reported high rates of RA recurrence.

1) Primary objective
•	To evaluate the feasibility of switching from TNFi to tacrolimus as maintenance therapy in patients with RA with stable LDA following combination therapy with TNFi and MTX

 2)  Secondary objectives 
A.	Safety of switching from TNFi to tacrolimus
B.	Assessment of physical function and disability 
C.	Measuring health outcomes

Treatment

This trial is a multicenter, non-randomized, open, comparative, parallel, 24-week clinical trial. Subjects are RA patients who fulfilled the 2010 ACR/EULAR RA classification criteria and achieved stable LDA with TNFi. 
 After the subject agrees to participate in the clinical trial, a screening test is performed. The screening test results are evaluated, and subjects that meet the inclusion criteria and do not meet the exclusion criteria are enrolled in the clinical trial. Depending on the selection of the registered subjects, they are included in either the test group (MTX+ Prograf®) or the control group (MTX+ TNFi) and receive the investigational drug according to the prescribed dosage of the group.
Subjects in the test group (MTX+ Prograf®) receive clinical drugs and take them orally once a day and subjects in the control group (MTX+ TNFi) receive investigational drugs.
Subjects participating in this clinical trial should receive a minimum dose of 7.5 mg/week of MTX prior to the baseline visit and maintain the same dosage and regimen used at the time of study registration, except for reductions due to toxicity during the clinical trial period. Subjects are evaluated for safety and efficacy at baseline and 2, 4, 8, 12, 16, 20, and 24 weeks.
If DAS28 is >2.6 at each visit after baseline and the increase in DAS28 relative to baseline is ≥0.6, this is considered a relapse and treatment failure. The investigator should discontinue administration of the clinical drug and change to another drug.

Arm Label

Target Number of Participant

Arm Type

Arm Description

Tacrolimus 1 mg is administered orally once a day after dinner.
If it is deemed necessary according to the judgment of the investigator, the amount can be increased up to 3 mg.

Arm Label

Target Number of Participant

Arm Type

Arm Description

The anti-TNF-α agent corresponds to one of the following. Subjects should be administered the same anti-TNF agent as previously used.
(1) Enbrel® 50 mg/syringe, subcutaneous injection, 1 syringes/week (Reduced dose: 1 syringe/2 week)
(2) Humira® 40 mg/syringe, subcutaneous injection, 1 syringe/2 weeks (Reduced dose: 1 syringe/3–4 weeks)
(3) Remicade® 100 mg/vial, intravenous injection, 3–5 mg/kg at 0 weeks, 2 weeks, 6 weeks, and then every 8 weeks until 22 weeks

Gender

Age

Description

1) Patients with RA for at least 12 months to less than 15 years
2) 20–70 years of age at the time of the screening visit
3) Patients who received TNFi for ≥24 weeks and had DAS28-CRP < 3.2 for ≥ 12 consecutive weeks before screening
4) Subjects who can understand the information provided to them and who can voluntarily sign written consent
5) Subjects who understand the difference between tacrolimus treatment and TNFi treatment and can choose their treatment
6) If a female of child-bearing age, a negative pregnancy test at the time of the screening visit
A.	For female subjects, there must be at least one year of menopause, surgical sterilization, or effective use of acceptable contraception methods. For contraception, subjects must agree to use an appropriate method during the clinical trial period and for 12 weeks after the end of administration of the investigational drug.
B.	For male subjects, the subject or subject's female partner must agree to use an appropriate method of contraception during the trial period and for 12 weeks after the end of the investigational drug administration.
7) Subjects with LDA (as defined below) at screening and baseline:
A. Stable treatment with TNFi and MTX for ≥24 weeks without alterations in dose and interval for ≥12 weeks
B. ESR <28 mm/h or CRP <10 mg/dL for at least 4 consecutive weeks before screening
C. Tender and swollen joint count ≤ 5 for at least 4 consecutive weeks before screening
8) Subjects who received TNFi and MTX treatment (regardless of folic acid administration) for at least 24 weeks prior to baseline visit. The minimum acceptable stabilizing dose of MTX is 7.5 mg per week.

1) Subjects diagnosed with other forms of inflammatory arthritis (e.g., psoriatic arthritis, ankylosing spondylitis, or reactive arthritis)
2) Subjects with secondary noninflammatory arthritis (e.g., osteoarthritis or fibromyalgia) with symptoms sufficient to interfere with evaluation of the efficacy of the investigational drug for the main diagnosed RA disease, in the opinion of the investigator
3) Subjects who continue to have prostheses that have been infected at least once

Exclusion criteria for concomitant drugs
Subjects who have used the following medications for a certain period before the baseline visit

Exclusion criteria related to medical history
1) Female subjects who are lactating, pregnant, or planning to become pregnant during the clinical trial period or for 12 weeks after the administration of the investigational drug
2) Subjects with a history of chronic infection, recent severe infection, or life-threatening infection (within 24 weeks, including shingles), or signs or symptoms that may be considered infection (e.g., fever, cough)
3) In the opinion of the investigator, subjects with high risk of infection
4) Subjects who received any live vaccine within 8 weeks prior to baseline visit
5) Subjects known to be infected with HIV
6) Subjects with a history of lymphoma or lymphoproliferative disease, or subjects with signs and symptoms suggestive of lymphoproliferative disease
7) Subjects with active malignancies or a history of malignant tumors. However, cervical cancer or basal cell carcinoma that has completely responded to treatment for >5 years before screening is allowed.
8) Subjects with a current or recent history of severe, ongoing, and/or uncontrolled kidney, liver, blood, gastrointestinal, endocrine, lung, heart, neurological, or brain disease and deemed inappropriate for clinical trial selection by the investigator.
9) Subjects with NYHA grade III or IV congestive heart failure
10) Subjects diagnosed with systemic inflammatory diseases (e.g., scleroderma, systemic lupus erythematosus, and mixed connective tissue disease)
11) Subjects with positive hepatitis B surface antigen test and/or hepatitis C antibody test results
12) Subjects with current or history of central nervous system disease, demyelinating disease, or convulsive disease (e.g., multiple sclerosis, and epilepsy)
13) Subjects who are scheduled for or need a surgical joint procedure
14) Persons considered to be unsuitable for participation in clinical trials by the investigator for other reasons such as alcohol or drug abuse
15) Subjects with pancreatitis or diabetes history or complications
16) Patients with genetic problems such as lactose intolerance and glucose-galactose malabsorption
17) Subjects whose clinical laboratory test results show one of the following, or who exhibit abnormal clinical laboratory test values considered to be clinically meaningful by the investigator
A.	WBC < 3,500/mm3
B.	Neutrophils < 1,500/mm3
C.	Hemoglobin < 8.5 g/dL
D.	Platelet count < 100,000/mm3
E.	Serum creatinine > 1.5 × the upper normal limit or 2 mg/dL (whichever is smaller) 
F.	Total bilirubin > 2 × the upper normal limit
G.	AST > 2 × the upper normal limit
H.	ALT > 2 × the upper normal limit
I.	ALP > 2 × the upper normal limit
J.	Glucose: Fasting > 110 mg/dL or postprandial > 200 mg/dL
18)	Subjects who are not cooperative with or are unable to follow the clinical trial procedure

The proportion of subjects who maintain LDA

24 weeks

The proportion of subjects who maintain LDA

12 weeks

Remission rate

12 and 24 weeks

Changes in HAQ-DI

24 weeks