Rapamycin vs Methotrexate in Diffuse SSc
Condition: Systemic Sclerosis
MeSH terms: Scleroderma, Systemic; Scleroderma, Diffuse; Sclerosis
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      This is a study to determine the safety of the immunosuppressive rapamycin in patients with
      systemic sclerosis with diffuse cutaneous scleroderma. The effects (both good and bad) are
      being compared to another group of systemic sclerosis patients receiving methotrexate
    

Detailed description: 
      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.
    

Intervention name(s): rapamycin; methotrexate
Intervention type(s): Drug; Drug
Other intervention name(s): rapimmune
Intervention MeSH terms: Sirolimus; Methotrexate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Investigator)
Primary purpose: Treatment
Keywords: Systemic sclerosis; Scleroderma; Rapamycin; Methotrexate