Rapamycin vs Methotrexate in Diffuse SSc

Systemic sclerosis (SSc) is a disorder characterized by overproduction and deposition of
collagen in the skin and visceral organs, abnormalities of the microcirculation, and
autoimmunity. Patients who develop extensive skin thickening (diffuse cutaneous scleroderma)
usually do so within the first 5 years. In add tion they are at significant risk of early
death, severe involvement of heart (10%), lung (15%) and kidney (15-20%) and loss of
functional capacity (moderate to severe disability in about 50% within the first few years).
there is as yet no proven cure or treatment which prevents heart, lung or kidney damage,
prevents disability or improves survival.

In a previsou study, we treated 10 SSc patients with diffuse cutaneous scleroerma with
cyclosporin A (CsA), an agent which suppresses the immune response by reducing production of
the pro-inflammatory cytokine, interleukin-2 (IL-2). Significant improvement in skin
thickening was noted in 6 of the 10 SSc patients. Unfortuantely, significant reduction in
kidney function and/or new onset high blood pressure occurred in 8 of the 10. This frequency
and degree of adverse events ina population already at risk of kidney failure and high blood
pressure is unacceptable.

More recently an immunosuppressive agent with little kidney toxicity, rapamycin, has been
found to block the effects of the same pro-inflammatory cytokine as cyclosporin (IL-2) in
transplant patients as part of its immunosuppressive action. Since improvement in skin
thickening was seen in our patients who received CsA, we postulate that blocking the effects
of IL-2 by rapamycin will also result in improvement in skin thickening in SSc patients with
extensive skin thickening. There is growing evidence (from our work and the work of others)
that softening thick skin in diffuse SSc is associated with improvement in hand function,
joint mobility, arthritis signs, overall functional ability, and survival.

The effectiveness of another immunosuppressive, methotrexate, has been compared to placebo
(a dummy) in two SSc studies that had a combined total of 100 patients with estensive skin
thickening. In both studies there was a trend to greater softening of the thick scleroderma
skin. In one study a greater sense of general well being was also noted in the methotrexate
group and in the other study the physician global assessment improved to a greater extent in
the methotrexate group. Because there is a suggestion of benefit from methotrexate, the
present trial evaluating rapamycin is being compared to methotrexte. During a 48 week period
rapamycin and methotrexate will be taken as randomly assigned (9 patients in each arm for a
total of 18 patients). Over 48 weeks, the status of these patients' scleroderma will be
assessed by simple but validated techniques, including simple palpation of the skin to
assess skin thickness; lung function texts, electrocardiogram and chest x-ray to assess
heart and lungp; blood pressure and serum creatinine to assess kidney; 3 questionnaires
(completed by patients) to assess function, quality of life and shortness of breath; and
CBC, chemistries and rapamycin levels to assess safety. Statistical analysis of the courses
of the two treatment groups will help us determine whether rapamycin has excessive toxicity
and whether there are suggestions of efficacy of rapamycin.

Inclusion Criteria:

- Satisfy American College of Rheumatology classification criteria for systemic
sclerosis

- Have skin thickening proximal to the elbows and/or knees (diffuse scleroderma)

- Cutaneous involvement for less than 5 years from the onset of the first non-Raynaud's
manifestation

Exclusion Criteria:

- Severe intractable malabsorption

- Chronic debilitation from any underlying disease

- Off putative disease modifying therapies for one month prior to entry