The effect of D-penicillamine on pulmonary findings in systemic sclerosis

D-penicillamine has been used for the treatment of systemic sclerosis for 2 decades. Forty-four systemic sclerosis patients who received a mean dose of 636 mg of D-penicillamine for 2.3 years and 48 untreated patients, who had repeat pulmonary function tests performed after a mean of 3.5 and 4.8 years, respectively, were evaluated. There were no significant changes in the vital capacity or the forced expiratory volumes during this time in either group. However, the diffusing capacity for carbon monoxide improved from 76% of predicted to 87% of predicted in D-penicillamine-treated patients. Untreated patients changed slightly, from 73% of predicted to 76% of predicted. When multiple logistic regression analysis was used to account for factors which could have biased treatment comparisons, the improvement related to use of the D-penicillamine was significant (P less than 0.05). This improvement in the D-penicillamine-treated patients was associated with no further progression of dyspnea or fibrosis on chest radiograph, as well as reduced skin thickening. These data suggest that D-penicillamine may be useful in the treatment of systemic sclerosis that involves the lung; however, further studies are needed.     

D-penicillamine is not an effective treatment in systemic sclerosis

Based on open studies. D-penicillamine (DPA) has been used for the treatment of systemic sclerosis (SSc) but we believe the controlled trial of this drug in SSc does not support its use to treat this disease. Open trials are inevitably biased by selection bias and randomized, blinded, controlled studies are required to minimize both known and unknown confounding variables. The high vs. low dose DPA trial was a well-controlled, randomized, double-blind study which met criteria for a high quality study, although it was not placebo-controlled. Toxicity was increased in the high dose group, thus showing a biologic response, although the study showed no clinical efficacy differences between a mean dose of 120mg DPA every other day (equivalent to 60mg qd) and a mean dose of 822mg DPA daily. One might argue that 60mg DPA is effective, but we believe this is highly unlikely, as doses significantly higher than this have been shown to be ineffective in other connective tissue diseases such as rheumatoid arthritis. In our opinion. D-penicillamine is, unfortunately, ineffective in treating early, diffuse, systemic sclerosis.     

The progress of oesophageal involvement in progressive systemic sclerosis during D-penicillamine treatment

In 21 patients with initial signs of progressive systemic sclerosis, oesophageal motility was monitored manometrically from the start of D-penicillamine treatment and over a period of up to 5 years. Urinary excretion of the collagen-specific amino acids hydroxyproline and hydroxylysine, and of proline was used as a guideline for monitoring the bioavailability of D-penicillamine. D-penicillamine therapy was found to be unable to arrest the progress of oesophageal involvement. A downward trend over time--statistically significant at p = 0.03, p = 0.02, and p less than 0.005--was found for lower oesophageal sphincter pressure, peristaltic wave pressure in the distal third, and peristaltic wave pressure in the middle third of the oesophagus, respectively.     

Bioavailability of D-penicillamine in a patient with gastrointestinal progressive systemic sclerosis

D-penicillamine pharmacokinetics were studied in a patient with gastrointestinal progressive systemic sclerosis possibly complicated by malabsorption. D-penicillamine bioavailability was examined after oral, duodenal, intravenous and rectal administration. No D-penicillamine was detectable in plasma after administration to the gastrointestinal tract. The pharmacokinetics after intravenous administration agreed closely with the corresponding situation in healthy volunteers.     

Massive breast enlargement in a patient receiving D-penicillamine for systemic sclerosis

Breast enlargement is an unusual complication of D-penicillamine therapy for rheumatoid arthritis. We observed breast enlargement and hyperprolactinemia in a woman receiving D-penicillamine for systemic sclerosis. Treatment with danazol was associated with a reduction in both the breast size and the prolactin level.     

Dermal elastin and collagen in systemic sclerosis. Effect of D-penicillamine treatment

Skin biopsies from 4 systemic sclerosis (SSc) patients, 6 SSc patients treated with D-penicillamine (from 8 to 60 months) and 4 normal subjects were analyzed by light and electron microscopy. By light microscopy, collagen bundles of SSc dermis were thicker and more compact than in age-matched controls; D-penicillamine treatment did not significantly modify their organization. On the contrary, a stereological analysis showed that the elastin volume density was higher in patients than in controls, and increased again after D-penicillamine treatment: moreover, the number of elastin fibers per unit area was significantly higher in the dermis of patients compared to controls, and became even higher after D-penicillamine treatment. The phenomena were evident in all strata of the dermis; however, the most significant increase of elastin in SSc patients compared to controls was in the superficial dermis, whereas after D-penicillamine treatment, all the strata of the dermis showed a significant increase in the percentage of elastin and in the number of elastin fibers per unit area compared to untreated patients and to controls. There were no relationships between elastin increase and time from the onset of SSc or time and dose of D-penicillamine treatment. At the ultrastructural level, collagen fibrils had rather heterogeneous diameters and formed more compact fibers, especially in the reticular and in the deep dermis of SSc patients compared to controls. After D-penicillamine, collagen fibril diameters in three of 5 patients examined were statistically wider and more heterogeneous than in controls and in untreated patients, whereas in the other 2 subjects both the mean diameter and the distribution of the class diameter were similar to both controls and untreated patients. This could suggest a specific individual reaction to the drug. Elastin fibers were smaller, more numerous and polymorphous in all patients compared to controls. After D-penicillamine, elastin fibers became even more numerous and smaller than in untreated patients. There was no correlation between the number and size of the elastin fibers and the time or dose of D-penicillamine. The internal organization of the elastin fibers was normal. These data indicate that the amount and distribution of collagen and elastin are altered in the dermis of SSc patients, and that D-penicillamine interferes with the deposition of both fibrous proteins in the dermal extracellular space.     

Progressive systemic sclerosis complicated with immune thrombocytopenia during D-penicillamine therapy.

Immune thrombocytopenia is a rare complication of progressive systemic sclerosis (PSS). A 47-year-old female with PSS treated with D-penicillamine developed immune thrombocytopenia, which promptly responded to prednisolone and withdrawal of D-penicillamine. Platelet-associated IgG was elevated and the bone marrow megakaryocyte count was normal. There was an inverse relationship between the level of platelet-associated IgG and the platelet count. A lymphocyte stimulation test sensitized by D-penicillamine was positive. The present case suggests that immune thrombocytopenia may be regarded as one of the D-penicillamine-related immune abnormalities. To our knowledge, its association with PSS has never been reported.     

Minimally important difference in diffuse systemic sclerosis: results from the D-penicillamine study

OBJECTIVE: To estimate minimally important differences (MIDs) in scores for the modified Rodnan Skin Score (mRSS) and Health Assessment Questionnaire-Disability Index (HAQ-DI) in a clinical trial on diffuse systemic sclerosis (SSc). PARTICIPANTS AND METHODS: 134 people participated in a 2-year, double-blind, randomised clinical trial comparing efficacy of low-dose and high-dose D-penicillamine in diffuse SSc. At 6, 12, 18 and 24 months, the investigator was asked to rate the change in the patient's health since entering the study: markedly worsened, moderately worsened, slightly worsened, unchanged, slightly improved, moderately improved or markedly improved. Patients who were rated as slightly improved were defined as the minimally changed subgroup and compared with patients rated as moderately or markedly improved. RESULTS: The MID estimates for the mRSS improvement ranged from 3.2 to 5.3 (0.40-0.66 effect size) and for the HAQ-DI from 0.10 to 0.14 (0.15-0.21 effect size). Patients who were rated to improve more than slightly were found to improve by 6.9-14.2 (0.86-1.77 effect size) on the mRSS and 0.21-0.55 (0.32-0.83 effect size) on the HAQ-DI score. CONCLUSION: MID estimates are provided for improvement in the mRSS and HAQ-DI scores, which can help in interpreting clinical trials on patients with SSc and be used for sample size calculation for future clinical trials on diffuse SSc.     

High-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis trial: lessons learned

Objectives

To review important findings, or lessons, that were learned about measures of response, design, conduct, and analysis of a randomized, controlled trial (RCT), even though the trial failed to demonstrate efficacy of d-penicillamine.

Methods

One hundred thirty-four patients with early (≤18 months), diffuse systemic sclerosis (SSc) were entered into an RCT (high-dose [822 mg daily] vs low-dose [120 mg every other day] d-penicillamine) and were followed up regularly for up to 4 years. Because analysis failed to show efficacy for d-penicillamine in early diffuse SSc, all data were pooled for additional secondary analyses.

Results

This RCT showed that trials of potential disease-modifying interventions can be completed in SSc using the American College of Rheumatology guidelines. This RCT used an active control. After analysis, we were not able to tell whether either dose was effective or ineffective. That experience argues in favor of using placebo controls until such time as an active control can be found that truly modifies the disease. Skin score and the disability index of the Health Assessment Questionnaire (HAQ-DI) were valid predictors of outcome. Along with the physician global assessment, they also were valid measures of response.

Conclusions

Even in studies that are therapeutically “negative,” careful evaluation of the data can examine other hypotheses and thereby provide important insights into other aspects of trial design, outcome measures, patient function, and trial conduct.     

In vitro inhibition of hematopoiesis in a patient with systemic sclerosis treated with D-penicillamine.

A 66-year-old Japanese woman with severe scleroderma developed anemia and thrombocytopenia due to D-penicillamine (D-Pen) treatment, although the leukopenia was not markedly severe. Cessation of D-Pen and the start of corticosteroid therapy were followed by recovery from bicytopenia. We examined the in vitro inhibition of the clonogenic capacity of bone marrow hematopoietic progenitor cells of this patient by D-Pen, and found strong inhibition in burst-forming unit-erythroid and colony-forming unit-megakaryocyte assays, but not in colony-forming unit-granulocyte/macrophage assays. These findings suggest that bicytopenia in this patient was caused by D-Pen and may be due to different sensitivities in the hematopoietic lineage.     

The heart in systemic sclerosis

The heart is one of the major organs involved in scleroderma. Cardiac involvement can be manifested by myocardial disease, conduction system abnormalities, arrhythmias, or pericardial disease. Additionally, scleroderma renal crisis and pulmonary hypertension lead to significant cardiac dysfunction secondary to damage in the kidney and lung. This report summarizes the recent advances to further understand the types and mechanism of abnormalities in the heart in scleroderma. New cardiac technology shows significant frequencies of asymptomatic cardiac abnormalities. Further long-term studies are necessary to determine the outcome and the best approach to treatment of such abnormalities. Diastolic dysfunction has been carefully evaluated in scleroderma in recent years and appears to be more common than once realized. There is controversy as to whether this is a significant finding independent to other cardiopulmonary problems. More extensive evaluation of the conduction and the arrhythmia ablative therapy has helped manage these life-threatening complications.     

The micro-circulation in systemic sclerosis

Damage to the micro-circulation forms a fundamental part of systemic sclerosis (SS) and may be responsible not only for the various vascular features of the disease but also for the connective tissue changes. Figure 1 suggests a possible mechanism integrating these various microvascular changes. Various parts of this scheme may be amenable to therapeutic intervention particularly if undertaken before irreversible vascular damage has occurred. Studies are in progress examining various ways of treating the microvascular disease, examining their effects on the vascular problems and on the progress of the disease.     

Cholestatic jaundice induced by D-penicillamine and oral steroid contraceptive in progressive systemic sclerosis (author's transl)

A 25-year-old woman with progressive systemic sclerosis was treated with D-penicillamine. (DPA) 30 days after starting therapy cholestatic jaundice was observed. Moreover, for two years she has taken the pill. Both drugs were discontinued, the jaundice disappeared and the laboratory findings of liver became normal. A rechallenge of D-penicillamine after 9 months induced no reaction. An underlying chronic liver disease before cholestasis could be excluded by liver biopsy. Allergic cutantests and lymphocyte transformation test with D-penicillamine and penicillin gave normal results. The frequency of cholestatic jaundice caused by DPA-therapy is discussed and the possible pathomechanism analyzed.     

Goodpasture-like syndrome induced by D-penicillamine in a patient with systemic sclerosis: report and review of the literature

We report a case of Goodpasture-like syndrome developing in a patient who was treated with D-penicillamine for the diffuse form of systemic sclerosis. This unusual pulmonary-renal syndrome has been described on rare occasions in patients receiving D-penicillamine. This complication appeared to be uniformly fatal unless treated with aggressive immunotherapy. We review the cases reported to date in the literature and describe the clinical characteristics, therapy, and outcome of this group of patients.     

The cost of systemic sclerosis

Objective

To assess costs related to systemic sclerosis (SSc) and their determinants.

Methods

The Canadian Scleroderma Research Group is comprised of 15 centers contributing to a registry of adult patients with SSc. Available cross‐sectional data included clinical variables and standardized measures of health resource use and time loss. Annualized averages of direct medical costs were calculated by multiplying health service utilization levels by the appropriate unit prices, determined from government fee schedules, professional associations, and other sources. Indirect costs were calculated from the subjects' self‐reported time loss related to illness and to seeking health care, as well as caregiver time losses. Costs were represented in 2007 Canadian dollars.

Results

In the sample of 457 patients with SSc, the average direct cost per patient was $5,038 per year (95% confidence interval [95% CI] $4,400, $5,676). Regarding indirect costs, the value of potential productivity loss related to paid labor was estimated at an average of $5,345 per patient per year (95% CI $4,598, $6,092), and the cost of lost productivity related to unpaid labor contributed another $8,070 per patient annually. The average total annual cost was estimated at $18,453 (95% CI $16,598, $20,308) per patient. Total annual costs were strongly associated with younger age, greater disease severity, and poorer health status.

Conclusion

Costs related to SSc are considerable, and there is a high impact of disease severity and health status on economic burden.     

The genetics of systemic sclerosis

The etiopathogenesis of systemic sclerosis (SSc) is unclear. With no definitive evidence supporting an environmental cause, recent attention has focused on genetic factors. Familial clustering and ethnic influences have been demonstrated. Human leukocyte antigen (HLA) associations exist but are more related to the presence of particular autoantibodies rather than to the disease. In addition, no single major histocompatibility complex (MHC) allele predisposes to SSc in all ethnic groups. The role of microchimerism in SSc is a novel yet unproven hypothesis that may be related to intergenerational HLA compatibility. Recent studies investigating polymorphisms in genes coding for extracellular matrix proteins and cell-signaling molecules implicate non-MHC areas in SSc pathogenesis. The data reviewed suggest that SSc is a multigenic complex disorder.