THU0315 PULMONARY FIBROSIS IN SYSTEMIC SCLEROSIS (SSC) AND DERMATOMYOSITIS (DM) DEMONSTRATES MARKED IMPROVEMENT AFTER ADMINISTRATION OF MYCOPHENOLATE MOFETIL (MMF)

L. A. Saketkoo¹, L. R. Espinoza²
¹Rheumatology, Louisiana State University and Ochsner Clinic Foundation, ²Rheumatology, Louisiana State University, New Orleans, United States

Background: Interstitial lung disease (ILD) in (SSc) and (DM) herald a poor prognosis. In SSc, ILD portends a 9 year survival rate of 30%. 40% of patients with SSc have findings suggestive of ILD. In polymyositis (PM) and (DM), ILD has a prevalence of 32% with a mortality of 36%.

MMF's safety profile has caused replacement of azathioprine (AZA) in transplantation as prophylaxis against organ rejection and cyclophosphamide (CPh) and AZA in lupus nephritis. Recent literature supports MMF to be at least as effective as current therapies in SSc ILD. The immunosuppressant actions of MMF are multi-faceted with specific inhibition of T and B-cell proliferation by inhibitiing de novo synthesis of guanosine nucleotides upon which lymphocyte proliferation is reliant. Lymphocyte migration, through inhibition of adhesion molecules, is also prevented effecting inflammatory cell infiltration into organ tissue.

However, MMF as a potent modulator of non-immune cells potentially separates MMF from other agents in treatment of ILD. MMF inhibits fibroblast proliferation (phenotypically aberrant in SSc) as well as smooth muscle and endothelial cell proliferation all of which are implicated in parenchymal demise and morbidity in ILD. Inhibition effects prominent chemoattractant and mitogenic players produced by fibroblasts: transforming growth factor-beta, platelet derived growth factor, connective tissue growth factor and fibronectin ultimately intercepting collagen deposition and fibrosis.
Objectives: To examine the efficacy of exploiting the multi-faceted anti-fibroblastic activity and immunomodulating properties and safety of (MMF) for use in treatment of ILD associated with SSc or DM/PM. To encourage large scale investigations of MMF as a first line agent in treatment of these entities.
Methods: Prospective observation of 6 patients with ILD (4 SSc and 2 DM) placed on MMF due to severity or rapid decline in pulmonary status and failure (poor response or intolerance) of CPh or corticosteroids (CCS) are followed from 6 to 48 months with lung volumes, diffusing capacity for carbon monoxide, arterial blood gas, high resolution computed tomography (HRCT), exam findings, functional capacity and quality of life, obtained before administration of MMF and at intervals during treatment. New symptoms are recorded as side effects and monitored for resolution, progression and the need to discontinue or decrease dose of MMF.
Results: Data analysis in progress with presention at conference. Initially, all patients received CPh and/or steroids for 2 to 6 months to induce remission or stabilization, followed by initiation of MMF 1000 mg daily for 2 weeks, then increased to 3000 mg daily. Following initiation of MMF all patients had marked improvement or resolution of respiratory symptoms such as alveolitis, dyspnea, cough, fatigue and walking distance. Pulmonary function and HRCT stabilised or improved in all cases. Importantly, CCS dosage was tapered from an average of 40 to 5 mg daily without worsening of lung function. Patients have been maintained on MMF for up to 18 months. One patient had significant transient diarrhea, MMF was discontinued and restarted.

Conclusion: MMF's immunomodulatory and inhibitory effects on fibroblasts and other non-immune cells and a well established low side effect profile with high tolerance make MMF a potential alternative to CPh in the treatment of SSc or DM related ILD. MMF for this use merits imminent large scale investigation.
References: Citations available at conference or promptly by email saketkoo.md@gmail.com