Methotrexate Treatment of Arthritis Caused by Chikungunya Virus (MARCH)

Inclusion Criteria:

1. Provision of signed and dated informed consent form.

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

3. Male or female, aged >18 years

4. Ability to take oral medication and be willing to adhere to the methotrexate regimen

5. For females of reproductive potential: use of highly effective contraception for atleast 1 month prior to screening and agreement to use such a method during studyparticipation and for an additional 3 months after the end of methotrexateadministration.

6. For males of reproductive potential: use of condoms or other methods to ensureeffective contraception with partner.

7. Have a diagnosis of CHIKV by CHIKV IgM or IgG antibody.

8. The disease duration should be greater than 3 months (based on onset of symptoms).

9. Screen laboratory tests must meet the following criteria: Hemoglobin ≥ 9 g/dL, WBCs ≥ 3.5 x 109 cells/L, Neutrophils ≥ 1.5 x 109 cells/L, Platelets ≥ 100 x 109 cells/L,serum transaminase levels not exceeding 1.5 times the upper limit of normal, serumcreatinine ≤ 1.6 mg/dL, and negative for hepatitis B surface antigen and hepatitis Cantibodies.

10. Have a chest radiograph at screening that shows no clear evidence of malignancy oractive infection.

11. Have active moderate arthritis defined as at least 4 tender joints and at least onejoint with definite clinical synovitis (swelling). Joints that may be considered inthe count include the temporomandibular joints (0-2), sternoclavicular joints (0-2),acromioclavicular joints (0-2), glenohumeral joints (0-2), elbows (0-2), wrists (0-2), metacarpal phalangeal joints (0-10), finger proximal interphalangeal joints (0-10), finger distal interphalangeal joints (0-8), hips (0-2), knees (0-2), ankles (0-2), tarsus/midfoot (0-2), metatarsal phalangeal joints (0-10), toe proximalinterphalangeal joints (0-10).

12. Status-post complete Covid vaccination defined as at least 2 weeks after completevaccination series.

Exclusion Criteria:

1. Pregnancy or lactation

2. Known allergic reactions to components of methotrexate or folic acid.

3. Treatment with another investigational drug or other intervention within 1 month.

4. History of chronic infection such as hepatitis and HIV. Patients with acuteinfection will have enrollment deferred until the infection resolves.

5. Current signs or symptoms of uncontrolled renal, hepatic, hematologic,gastrointestinal, endocrine, pulmonary, cardiac, neurologic or cerebral disease.

6. Patients with a current diagnosis of class III or IV CHF.

7. History of lymphoproliferative disease including lymphoma.

8. Overt or laboratory evidence of immunodeficiency syndromes.

9. Any opportunistic infections, including but not limited to evidence of activecytomegalovirus, active Pneumocystis carinii, aspergillosis, histoplasmosis oratypical mycobacterium infection, within the previous 6 months at screening visit.

10. History of substance abuse (drug or alcohol) within the previous 2 years.

11. Intra-articular, soft tissue or intra-muscular corticosteroid injection during the 4weeks prior to screening.

12. History of prior use of methotrexate or biologic therapy.

13. Evidence of active infection with fever >38°

14. Current use of any other disease modifying arthritis medication including but notlimited to sulfasalazine, methotrexate, hydroxychloroquine, leflunomide, orbiologics in the previous 2 months. Patients on stable doses of prednisone up to 10mg per day for at least 4 weeks prior to enrollment may participate. Non-steroidalanti-inflammatories (NSAIDS) and acetaminophen are permitted for pain during thestudy.

15. Hematuria or proteinuria on urinalysis.

16. The presence of anti-cyclic citrullinated peptide (Anti-CCP) antibodies >2 times theupper limit of normal.

17. For patients who participate in synovial biopsy substudy the following additionalexclusion criteria apply:

18. Known prior reactions or allergies to local anesthetics or antibiotics (specifically bupivocaine, lidocaine, or cephalexin) 2. Preexisting advanced structural or functional damage to joint of interest such as prior history of trauma requiring orthopedic surgery and hardware placement, and presence of prosthetic devices (artificial joints, pacemakers, other implantable devices) 3. History of diabetes, skin infections (cellulitis), bleeding disorders, deep vein thrombosis, pulmonary embolism, history or active cancer of any kind 4. Use of blood thinners (anticoagulants) 5. History of or current chronic pain syndrome such as fibromyalgia, chronic back pain, migraines, and history of current complex regional pain syndrome, and /or current or past chronic opiate treatment 6. Significant other comorbidities and /or medication use which in physician's clinical judgment may pause procedure or post-procedure complication risk.