To the Editor:
Systemic sclerosis (SSc) is a rare multisystem connective tissue disease of unclear etiology in which vascular dysfunction, fibrosis of the skin and internal organs, and autoimmunity occur. Until recently, few treatments have been successful at reducing mortality associated with the disease. The use of angiotensin-converting enzyme (ACE) inhibitors and targeted therapies such as endothelin receptor antagonists, prostacyclins, and PDE5 inhibitors have improved outcomes with respect to renal crisis and pulmonary hypertension, respectively. However, given the natural history of the disease, treatment of severe SSc is problematic. Physicians treating SSc are torn between the principles “do no harm” and “doing good,” largely the latter in many SSc treatments that lack randomized controlled trial data.
The mechanism of immune dysregulation is not entirely clear, although it seems to play a pivotal role in disease progression. Activated T2-helper lymphocytes producing fibrogenic interleukin 4 (IL-4) and IL-13 are thought to contribute. In addition, it has been shown that early in the course of disease, activation of B cells causes fibroblasts to adopt a profibrotic phenotype via the production of antibodies. Also, activated macrophages in perivascular infiltrates produce specific chemokines, transforming growth factor-ß, and platelet-derived growth factor, all thought to play a role in fibrosis1,2. Given that altered immune function is thought to contribute to disease progression, several immunosuppressive regimens have been explored as possible treatment options.
Some investigators have reported on the mechanism of immune regulation with mycophenolate mofetil (MMF). Via its metabolite mycophenolic acid (MPA), MMF interferes with the metabolic pathway of de novo purine synthesis through inhibition of inosine monophosphate dehydrogenase, suppressing both B and T lymphocyte proliferation3. MMF is currently indicated as prophylaxis against allogeneic cardiac, renal, or hepatic transplant rejection. MMF use in transplants gives fewer malignancies than other transplant medications4,5 …
Address reprint requests to Dr. Pope; E-mail: janet.pope{at}sjhc.london.on.ca