Safety of Tofacitinib, an Oral Janus Kinase Inhibitor, in Primary Sjogren's Syndrome

• INCLUSION CRITERIA:

Adult primary SS participants with mild-to-moderate disease activity will be eligible for this study. Enrolled participants can be na(SqrRoot) ve or failed immunosuppressive therapy beyond antimalarials and glucocorticoids; to prevent bias in the cohort of participants with more

recalcitrant disease. We expect that Tofacitinib is a potential second line therapy, in addition to antimalarials and glucocorticoids, depending on the participant s initial presentation and response. Women and members of minority groups, if eligible, will be included in accordance with the NIH Policy on Inclusion of Women and Minorities as Participants in Research Involving Human Participants.

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

1. Ability of participant to understand and the willingness to sign a written informedconsent document.

2. Participation and enrollment in companion protocol, 15-D-0051, Characterization ofDiseases with Salivary Gland Involvement.

3. Stated willingness to comply with all study procedures and availability for theduration of the study

4. Male or female, aged between 18-75 years

5. In good general health as evidenced by medical history

6. Meets the 2002 American European Consensus Group classification criteria for primarySjogren's Syndrome or 2016 American College of Rheumatology/European League againstRheumatism Classification Criteria (ACR-EULAR) with mild to moderate diseaseactivity defined as ESSDAI between 0 to 13 at the screening visit and >0ml/min/gland stimulated saliva flow.

7. Ability to take oral medication and be willing to adhere to the study interventionregimen

8. If on glucocorticoids, the dose must be less than 10 mg daily and stable for the 4weeks (28 days) prior to screening visit.

9. If on hydroxychloroquine or other antimalarials such as chloroquine or quinacrine,the dose must have been stable for the 12 weeks (96 days) prior to screening visit.The maximum allowed dose is hydroxychloroquine up to 400 mg/day or 6.5 mg/kg/day ifmore than 400 mg/day. The maximum allowed dose for chloroquine phosphate is up to 500 mg daily and for quinacrine up to 100 mg daily.

10. Participants may be on lipid lowering medications if initiated at least 3 monthsprior to the screening visit and dose must be stable for 4 weeks (28 days) prior tostudy entry.

11. Males and females with potential for reproduction must agree to practice effectivebirth control measures. Females should be on adequate contraception if they are ofchild-bearing potential documented by a clinician, unless participants or spousehave previously undergone a sterilization procedure. Adequate birth control measuresare: intrauterine device (IUD) alone or hormone implants, hormone patches,injectable, or oral contraceptives plus a barrier method (male condom, female condomor diaphragm), abstinence or a vasectomized partner.

12. Agreement to adhere to Lifestyle Considerations throughout study duration

EXCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must not meet any of the following criteria:

1. Current or prior treatment with rituximab, belimumab or any other biologic agent inthe 6 months prior to screening.

2. Current treatment with methotrexate, azathioprine, mycophenolate mofetil,cyclosporine, tacrolimus, or other less common immunomodulatory drugs such as thosefalling into the class of disease-modifying antirheumatic drugs (DMARDs), nototherwise specified herein. Participants previously on methotrexate, azathioprine,mycophenolate mofetil, cyclosporine or tacrolimus, or other DMARDs should havewithdrawn drug for at least 8 weeks (56 days) at the time of screening.

3. Treatment with cyclophosphamide, pulse methylprednisolone or IVIG within 6 monthsprior to screening.

4. Current treatment with potent inhibitors of Cytochrome P450 3A4 (CYP3A4) (e.g.,ketoconazole) or receiving one or more concomitant medications that result in bothmoderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole)that would increase serum availability of Tofacitinib. Past treatment with theaforementioned agent is allowed if it was more than a week prior to theadministration of the first dose of study medication.

5. History of chronic liver disease, not including well-controlled Sjogren s-relatedchronic liver disease or elevated LFTs:

• ALT or AST >= 2x upper limit of normal at screening

• Serum unconjugated bilirubin > 2mg/dL at screening

6. Serum creatinine >1.5mg/dL.

7. Protein to creatinine ratio of more than 1mg/dL at screening (repeated and confirmedthree times or confirmed with 24 hours urine protein of more than 1000mg).

8. Active urinary sediment (WBC, RBC or mixed cellular casts 1+ or more /hpf).

9. Hypercholesterolemia: Values after 8-12 hour fasting blood specimen: totalcholesterol >250 mg/dL or LDL >180 mg/dL or hypertriglyceridemia (triglyceride >300mg/dL) within-45 days of screening visit.

10. WBC <2500/microliter or ANC <1,000/microliter, Hgb <9.0 g/dL or platelets <70,000/microliter or absolute lymphocyte count < 500/microliter.

11. Pregnant or lactating women. Women of childbearing potential are required to have anegative pregnancy test at screening.

12. A history of drug or alcohol abuse within the 6 months prior to screening.

13. Currently receiving hemodialysis, peritoneal dialysis, or intestinal dialysis.

14. Active infection that requires the use of oral or intravenous antibiotics unresolvedat least 14 days prior to the administration of the first dose of study medication.

15. Active chronic infections including but not limited to HIV, Hepatitis B, HepatitisC, and BK viremia at screening visit.

16. Current or previous diagnosis of malignant disease, except for basal cell orsquamous cell carcinoma of the skin with complete excision and clear borders oradequately treated in situ carcinoma of the cervix.

17. Known active tuberculosis. Participants with treated latent tuberculosis (LTB) willbe eligible to participate. Participants with untreated LTB will not be excluded butwill be evaluated by an infectious disease (I.D.) consultant and may become eligiblefor trial based on infectious disease consultant recommendations.

18. History of severe or systemic infection caused by common pathogens, or history ofinfection with pathogens that normally do not cause human disease.

19. Participants with active renal or central nervous system disease or a high activitylevel in any organ system (except articular) in ESSDAI^54.

20. Participants with known increased risk factors for major adverse cardiac event (MACE) including a history of:

• Ischemic heart disease (e.g., history of acute myocardial infarction)

• Heart failure

• Cardiomyopathy

• Severe valvular heart disease

• Significant arrhythmias

• Chronic renal failure

• Cerebrovascular accident or transient ischemic attack

• Uncontrolled diabetes mellitus

• Uncontrolled hypertension

• Current smokers or former smokers with less than 3 years since completecessation and/or >20 pack-years of smoking history.

21. Significant impairment of major organ function (lung, heart, liver, kidney) or anycondition that, in the opinion of the Investigator, would jeopardize the participants safety following exposure to the study drug.

22. Known history of arterial or venous thrombosis or at high risk for clotting disorder

23. Psychiatric illness or history of medical non-compliance that the study team feelswill make the patient unlikely to complete the study

24. Uncontrolled thyroid disease as per PI or medically responsible investigator.

25. Known allergic reactions to Tofacitinib or its components

26. Treatment with another investigational drug/intervention within six months exceptfor COVID-19 vaccines or therapies that have been granted an FDA emergencyauthorization.