A randomized, controlled pilot trial to evaluate the efficacy and safety of subcutaneous Abatacept in treating interstitial lung disease associated with the anti-synthetase syndrome.

This is a proof of concept study to evaluate the efficacy, safety and tolerability of abatacept in Syn-ILD in a multi-center randomized, placebo-controlled 6-month (24-week) pilot study.

Inclusion Criteria:

1. Age ≥ 18 years.

2. Anti-synthetase syndrome defined as the patient possessing 1 antisynthetase autoantibody (Jo-1, PL-12, PL-7, KS, OJ, EJ, Zo) in the presence of autoimmune ILD.

3. ILD defined by radiographic (HRCT chest) findings of reticulation, honeycombing or ground glass opacities (GGO) without another plausible explanation. HRCT chest defining ILD for inclusion criteria, should be within last 1 year done as SOC.

4. Active ILD (see Section 4.2).

5. Baseline FVC a) % <80% b) FVC 80-100% with > = 10% decline in FVC in last 12 months as minimal threshold of ILD severity (PFT done within last 3 months is acceptable for inclusion criteria determination)

6. SOC immunosuppressive therapy (IS) therapy:

   1. Steroids (prednisone or other forms of steroid in equivalent doses) OR one of the other immunosuppressive agent (either Mycophenolate (MMF) or Azathioprine (AZA) OR a combination of steroid and an immunosuppressive agent. MMF (maximum of 3 gm/day) or azathioprine (maximum of 200 mg/day).Goal is to start the trial drug (or placebo) soon after starting SOC (MMF/AZA/Steroids) and their doses are stable. Note that patients on steroids alone as well as not on steroids can be enrolled in the trial as well.
   2. Desired dose of the SOC therapy should be reached 4 weeks prior to first study visit (Visit 1). No dose changes are allowed 4 weeks prior to first study visit.
   3. Dose of concomitant therapy (SOC) cannot be changed during the 24 weeks of the trial unless safety/toxicity issues supervene.
   4. If on steroid, the steroid dose must be stable for 2 weeks prior to Visit 1.

7. No other concomitant IS medications including methotrexate, cyclosporine, intravenous immunoglobulin (IVIG), tacrolimus, cyclophosphamide or tofacitinib.

8. No concomitant biologic agents (i.e. rituximab, anti-tumor necrosis factor (TNF) agents, tocilizumab).

9. Additional IS therapy: Patient cannot begin any new IS therapy or new steroid taper for the 24-week study period, except if severe clinical worsening (flare up) of the disease requiring rescue therapy occurs (i.e. documentation of worsening of PFT/HRCT and patient and physician determination of worsening). See section of rescue medication below for details.

10. If the enrolling physician is planning to discontinue current IS agent or steroid before clinical trial, then following washout period is required prior to Visit 1.

    Medication Washout Period methotrexate 4 weeks Other IS agent (e.g. azathioprine, cyclosporine, tacrolimus, leflunomide, mycophenolate mofetil) 4 weeks IVIg or cyclophosphamide 3 months rituximab 6 months infliximab or adalimumab 8 weeks glucocorticoids 2 weeks etanercept 2 weeks anakinra 1 week pirfenidone 4 weeks

11. Men and women of reproductive potential must agree to use an acceptable method of birth control during the trial period.

12. Subject has provided written informed consent.

Exclusion Criteria:

A patient will be excluded if any of the following Exclusion Criteria are met:

1. Severe end stage lung disease:

   1. FVC ≤30% or Forced expiratory volume (FEV1) ≤ 30% or
   2. Requirement of high O2 requirement ≥ 6 L/min at rest for >1 month before the study enrollment or
   3. Listed for lung transplantation or
   4. PI feels that ILD is severe and end stage fibrosis is such that there is low potential for improvement with any disease modifying intervention.

2. Subjects under the age of 18.

3. Known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infections (including but not limited to tuberculosis and atypical mycobacterial disease, hepatitis B and C, and herpes zoster, but excluding fungal infections of nail beds).

4. Any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening.

5. Active tuberculosis (TB) requiring treatment within the previous 3 years. Patients should be screened for latent TB using purified protein derivative (PPD)/or quantiferon gold within last 1 year and, if positive, treated following local practice guidelines prior to initiating abatacept (ABT). Patients treated for active tuberculosis with no recurrence in 3 years are permitted.

6. Primary or secondary immunodeficiency (history of or currently active) unless related to primary disease under investigation.

7. Pregnant women or nursing (breast feeding) mothers.

8. History of alcohol, drug or chemical abuse within 1 year prior to screening or any medical condition or physical or psychological state that the PI feels would not allow the subject to safely complete the study.

9. Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following randomization.

10. Treatment with any other investigational agent within 4 weeks (or 5 half-lives of the investigational drug, whichever is longer) of screening.

11. Previous treatment with the following cell-depleting therapies, including investigational agents or approved therapies: CAMPATH, anti-CD4, anti-CD5, and anti-CD3.

12. Previous treatment with ABT.

13. History of severe allergic or anaphylactic reactions to monoclonal antibodies.

14. Evidence of serious uncontrolled concomitant cardiovascular, nervous system, renal, hepatic, endocrine (include uncontrolled diabetes mellitus) or gastrointestinal disease (including complicated diverticulitis, ulcerative colitis, or Crohn's disease.)

15. Evidence of concomitant lung disease which PI feels may interfere with clinical assessment of ILD for example severe active chronic obstructive pulmonary disease (COPD), asthma, occupational lung disease, pulmonary sarcoidosis, etc.

16. Prisoners or subjects who are compulsory detained

Adverse events were collected from Baseline (week 0) through end of study Visit 5 (week 48)

Only the site pharmacist is unblinded.