High-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis: analysis of a two-year, double-blind, randomized, controlled clinical trial

Arthritis Rheum. 1999 Jun;42(6):1194-203. doi: 10.1002/1529-0131(199906)42:6<1194::AID-ANR16>3.0.CO;2-7.


Objective: To test the hypothesis that systemic sclerosis (SSc) patients taking high-dose D-penicillamine (D-Pen) would have greater softening of skin, lower frequency of renal crisis, and better survival than patients taking low-dose D-Pen.

Methods: Seventeen centers enrolled 134 SSc patients with early (< or =18 months) diffuse cutaneous scleroderma into a 2-year, double-blind, randomized comparison of high-dose D-Pen (750-1,000 mg/day) versus low-dose D-Pen (125 mg every other day). All 134 patients were followed up for a mean+/-SD of 4.0+/-1.1 years to assess the frequencies of new-onset scleroderma renal crisis (SRC) and mortality.

Results: Sixty-eight patients completed 24 months of drug treatment. The course of the modified Rodnan skin thickness score in the 32 high-dose and the 36 low-dose D-Pen completers was not different at 24 months: the skin score dropped 4.8+/-10.3 (mean+/-SD) units in the high-dose group and 6.9+/-8.4 units in the low-dose group (P = 0.384 by t-test; favoring low-dose D-Pen) from 20.4+/-10.3 in the high-dose and 19.9+/-6.6 in the low-dose D-Pen group at study entry. The incidences of SRC and mortality were not different (P > 0.38 by Cox proportional hazards and by chi-square test) in the 66 high-dose patients (8 developed SRC and 8 died) compared with the 68 low-dose patients (10 developed SRC and 12 died). Of the 20 adverse event-related withdrawals, 80% occurred in the high-dose D-Pen group.

Conclusion: The course of the skin score and the frequencies of SRC and mortality in the high-dose D-Pen group were not different from those in the low-dose D-Pen group. Eighty percent of the adverse event-related withdrawals occurred in the high-dose D-Pen patients. Although this study cannot answer the question of whether low-dose D-Pen is effective, it does suggest that there is no advantage to using D-Pen in doses higher than 125 every other day.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Antirheumatic Agents / administration & dosage*
  • Antirheumatic Agents / adverse effects
  • Creatine Kinase / blood
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Health Status
  • Humans
  • Male
  • Middle Aged
  • Penicillamine / administration & dosage*
  • Penicillamine / adverse effects
  • Scleroderma, Systemic / complications
  • Scleroderma, Systemic / drug therapy*
  • Scleroderma, Systemic / mortality
  • Scleroderma, Systemic / pathology
  • Skin / drug effects
  • Skin / pathology
  • Surveys and Questionnaires
  • Survival Rate
  • Treatment Outcome


  • Antirheumatic Agents
  • Creatine Kinase
  • Penicillamine