• Treatments
• Mechanisms
• Epidemiology

Scleroderma patients (n=24) were enrolled in an open-labeled study of monthly intravenous cyclophosphamide (1000 mg/m 2 of body surface) for 6 months treatment for scleroderma lung disease. The patients were treated if there was evidence of an active alveolitis by bronchoalveolar lavage (BAL) or if there was a recent deterioration of forced vital capacity (FVC). Lung function remained the same in14/24; improved in 8/24 and worsened in 2/24. Although this data suggest that monthly cyclophosphamide is effective and may be an alternative to daily oral cyclophosphamide, one should be cautious because the study was small, uncontrolled and unblinded. Cases with a previous fall in FVC were not necessarily "active" at the time of therapy.

Editorial Comment: A placebo-controlled trial is needed to prove if cyclophosphamide is helpful in scleroderma lung disease.

Abstract #483 Combined Therapy with Cyclophosphamide and High Dose Steroids Improves Pulmonary Function in Systemic Sclerosis
M Caronni, M Raimondi, S Arienti, T Viscuso, M Vanoli, L Origgi, L Beretta, R Scorza.

A retrospective study of 49 scleroderma patients was done to determine the effect of immunosuppressive therapy. Patients were treated with high dose steroids alone (20/49), cyclophosphamide alone (19/49) or a combination of these two medications (10/49). The first two treatment groups demonstrated stability of lung function, while data suggested that the combination therapy improved lung function.

Editorial Comment: Unfortunately, there is little value from this type of study design and we will have to await a controlled trial that clearly defines active alveolitis in each treatment group. It is uncommon for established lung fibrosis to reverse or improve with any therapy.

Abstract #1284 Longterm Follow-up of Scleroderma Patients with Lung Inflammation Treated with Cyclophosphamide.
B White, R Wise, F Wigley.

This study is a retrospective review of cyclophosphamide treatment for scleroderma lung disease in 143 patients. Patients with BAL defined alveolitis were more likely to stabilize their lung function if treated with cyclophosphamide (n=59) compared to those who were not treated (n=35). However, patients without BAL defined alveolitis (n=49) who did not receive cyclophosphamide also tended to have a decline in lung function. Approximately 40% of patients with a "normal" BAL study had a greater than or equal to a 10% decline in FVC or DLCO during the follow-up period.

Editorial Comment: This study suggests that a new method of defining lung activity is needed in scleroderma.

Abstract #1668 High Dose Cyclophosphamide Followed by Autologous Blood Stem Cell Transplantation for the Treatment of Systemic Sclerosis.
R Verheesen, A Schattenberg, W Fibbe, F Breedveld, T de Witte, L van de Putte, F van den Hoogen.

The experience of 10 scleroderma patients treated with high dose cyclophosphamide followed by autologous blood stem cell transplantation (SCT) is reported. There was a 70% improvement in the skin score. The DLCO decreased after therapy but later recovered to baseline. No major complications occurred, however, side effects included alopecia (n=10), nausea and vomiting (n=10), and fever due to infection (n=2). One patient developed cardiac tamponade and two patients developed myositis.

Editorial Comment: SCT for the treatment of scleroderma is now underway at several centers and we must await the final results to make judgment. However, significant mortality has been reported if radiation therapy is part of the regimen.

(top of section) ((top of page))

A retrospective study of lung disease was reported in 46 scleroderma patients. Thirteen had been treated with lipomicrosphere-incorporated prostaglandin E1 (10 micrograms intravenously every week). Progressive fibrosis of the lung was seen in 71% in the untreated group (n=33) compared to only 13% (n=13) in the treated group. None received cyclophosphamide.

Editorial Comment: There is growing evidence that scleroderma vascular disease can be improved by prostaglandin therapy. Therefore, it is of interest to speculate that PGE1 therapy might help the lung disease or other aspects of scleroderma. This study design provides us with limited information but an interesting hypothesis that needs tested in a controlled trial.

Endothelin-1, a potent vasoconstrictor, is implicated in the pathogenesis of pulmonary hypertension (PTH). This abstract reports a multi-center, randomized, double- blind, placebo-controlled trial of bosentan an inhibitor of the endothelin A (ET A) and B (ET B) receptors. This well designed study included 213 patients with PTH: primary (n=150); scleroderma (n=47) and SLE (n=16). Patients were treated for 16 weeks. Using a 6-minute walk test as the primary outcome, the bosentan group had an improvement of 44 meters greater than the placebo group (95 % CI: 21m to 67m, p=0.0002). The secondary outcomes, the Borg Dyspnea Index and WHO functional Class, also improved in the bosentan group when compared to the placebo group. 2% of the bosentan group had to withdraw due to asymptomatic elevations in the liver function tests. Aggravation of the PTH occurred in 6 % of the placebo group and 1% of the bosentan group. This study demonstrated that bosentan at the recommended dose of 125 mg p.o. bid is effective for short term clinical improvement in both primary and secondary PTH.

Editorial Comment: The FDA has now approved bosentan for the treatment of PTH.

Most agree that an autoimmune process is an important part of the pathogenesis of scleroderma. Autologous stem cell transplant (SCT) is now being tested as treatment for severe scleroderma. This abstract summarized the one year outcome in 19 patients treated with SCT. A modified TBI lung shielding procedure is now being used because of an initial high mortality rate of 25% thought secondary to radiation injury to the lung during treatment procedure. Since reducing the radiation to the lung, the next 8 patients have had no lung toxicity. The skin score improved by 58% and the mHAQ improved by 87% from baseline among the evaluated survivors. Most patients show stabilization of lung and renal function. Autoantibodies have persisted after therapy and 1 patient has reactivated disease.

Editorial Comment: Revision of the protocol has reduced the initial high mortality from this procedure but we have little new information from the current data about this treatment beyond these safety issues.

Abstract #1668 High Dose Cyclophosphamide Followed by Autologous Blood Stem Cell Transplantation for the Treatment of Systemic Sclerosis.
R Verheesen, A Schattenberg, W Fibbe, F Breedveld, T de Witte, L van de Putte, F van den Hoogen.
(see above)

A major problem among patients with scleroderma is delayed gastric emptying and the associated symptoms. This study included 27 patients with scleroderma and delayed gastric emptying of >20 minutes. Erythromycin (E) (250 mg before a meal) and metoclopramine (M) (10 mg before a meal) were compared using scintigraphy to measure gastric emptying. Gastric emptying fell from a mean of approximately 47 minutes to 29.6 minutes in the E group compared to a change from 50 minutes to 43 minutes in the M group. There was also a decrease in vomiting in the E group compared to the M group. This study demonstrates that E can help gastric emptying and may be better than M.

Editorial Comment: However, this was a short term trial with small numbers of patients and further studies will be needed to confirm these findings.

This study reports the results of a brief infusion of prostacyclin (3-5 days) followed by persantine 7.9 mg/kg/day in 14 CREST patients with difficult to heal digital ulcers. Pain relief, skin temperature improvement and ulcer healing was seen in all patients. No new lesions occurred during therapy.

Editorial Comment: While this therapy is interesting and may be helpful, it is hard to come to any conclusion because of the study design and lack of placebo or control group. It is also difficult to determine if the persantine or prostacyclin alone would be effective.

Iloprost is a prostacyclin analogue that has been shown to be effective for short term therapy in Raynauds phenomenon (RP). This study investigated the use of iloprost in 20 patients with RP (11 scleroderma, 3 localized scleroderma, 2 SLE, and 4 with undifferentiated connective tissue disease). Iloprost was given intravenously for 3 days (0.5-2.0 ng/kg for 12 hours) and repeated 12 times at 3 week intervals. After the third infusion, 30% had greater than or equal to a 50% reduction of attacks and symptoms; while this reduction was seeen in 70% of patients by the 12th infusion.

Editorial Comment: Intermittent chronic iloprost or other prostaglandin may improve severe RP but this study falls short of giving full support for that conclusion. Studies in RP need to be placebo-controlled, double-blinded and temperature controlled using a uniform group of patients before we can decide efficacy.

It is attractive to consider that an anti-estrogen drug would be helpful in an autoimmune disease like scleroderma. This trial investigated the role of tamoxifen in scleroderma using an open label prospective study design in 15 patients with a mean duration of disease of 9.3 years (1-25). Two of 13 improved and 11 either did not improve or improvement was modest. The investigators conclude that tamoxifen is not helpful and should not be further studied.

Editorial Comment: The study design has several flaws including the lack of controls, the use of patients of long disease duration, and the lack of well defined outcome variables. The poor response in this trial is discouraging but maybe a uniform population of patients with early scleroderma would respond differently.

L-carnitine was studied using an open label control design in 50 patients with scleroderma. The outcome variables were the skin score, the number of ulcers, severity of Raynauds phenomenon (RP), HAQ score and SF-36 score. A statistically significant improvement occurred in the severity of ulcers and RP but not in the skin score or quality of life measurements in the L-carnitine treated group compared to the placebo group.

Editorial Comment: This trial is of some interest but has a flawed design of being open label, mixing diffuse and limited patients and perhaps not focusing on a primary outcome variable of interest. The investigators rightfully suggest that further controlled studies are needed.

Abstract #567 Prevalence and Clinical Significance of Antiphospholipid Antibodies in Patients with Scleroderma.
M Bertolaccini, G Sanna, A Mameli, M Khamashta, A Mathieu, G Hughes.

This study investigated the prevalence of anti-phospholipids (aPL) among scleroderma (n=25) patients compared to normal controls (n=100). IgG isotype anticardiolipins were found in 24% of patients versus 5% of controls: OR 6[1.7-21.7], p=0.008. Although the prevalence of aPL was higher among scleroderma patients, the clinical manifestations of anti-phospholipid syndrome were uncommon.

Abstract #771 The Novel Anticancer Agent, Ecteinascidin 743 (ET-743), Causes Potent Inhibition of Colia1 Gene Transcription in Systemic Sclerosis (Scleroderma) Fibroblasts.
B Saitta, N Louneva, S Jimenez.
and
Abstract #841 Inhibition of Expression of Several Extracellular Matrix Genes in Normal and Systemic Sclerosis Fibroblasts by Ecteinascidin 743.
N Louneva, S Jimenez, B Saitta.

There is no proven therapy for the skin fibrosis in scleroderma but excess collagen is known to be part of the pathological process. A novel approach to therapy is to attempt to selectively control transcription of the collagen genes that are up-regulated in scleroderma fibroblasts. Ecteinascidin 743 (ET-743) was used in vitro to treat cultured dermal fibroblast from scleroderma patients. The results show transcriptional activation of the collagen type I and type III genes is mediated by a CCAAT binding factor and that ET-743 can specifically modulate the gene activity without affect cellular morphology or viability.

Editorial Comment: We will need to wait for use of this type of approach in the treatment of patients with scleroderma.

Abstract #840 Inhibition of a1(1) Collagen Gene (COL1A1) Expression in Systemic Sclerosis (SSC) Fibroblasts by the Sp1 Binding Drugs WP631 and Mithoxanthrone.
S Gaidarova, S Jimenez.

There is no proven therapy for the skin fibrosis in scleroderma but excess collagen is known to be part of the pathological process. A novel approach to therapy is to attempt to selectively control transcription of the collagen genes that are up-regulated in scleroderma fibroblasts. Sp1 transcription factor is implicated in the up-regulation of the alpha1 (I) collagen gene in scleroderma fibroblast. Two DNA binding drugs (WP631 and Mithoxantrone) were tested in vitro using dermal fibroblast from scleroderma patients. Treatment with these agents shows a dose dependent decrease in collagen production without cytotoxcity or cell death.

Editorial Comment: This suggests that drugs that effect Sp1 transcription may be helpful in treating dermal fibrosis in scleroderma.

Abstract #844 Influence of Atorvastatin on Normal and Scleroderma Fibroblast Activation and Type 1 Collagen Production.
N Del Papa, W Maglione, D Comina.

There is increasing interest in the 3-hydroxy-3-methylglutaryl(HMG) CoA reductase inhibitors, or statins, as therapeutic agents in the treatment of scleroderma. This in vitro study demonstrated that atorvastatin down regulated the scleroderma phenotype in dermal fibroblast by reducing the expression of the adhesion molecule ICAM-1 and at the same time the production of type I collagen.

Editorial Comment: It is not clear that use of the currently available statins will have any important clinical benefit in scleroderma but this study demonstrates the broad biological effects and potential of these agents.

Forty-eight scleroderma patients without any treatment with cyclophosphamide were followed (mean follow-up 6 years) to define the course of the lung disease. HRCT scan remained stable in 45% and worsened in 23%. Forced vital capacity (FVC) declined in only 4%, while DLCO declined in 24%.

Editorial Comment: This study again emphasizes that the course of the lung disease in scleroderma is highly variable and care must be taken to select only those cases with active disease to treat with toxic immunosuppressive drugs.

Abstract #1659 Cigarette Smoking: A Risk Factor for Digital Vascular Complications in Systemic Sclerosis.
B Harrison, A Silman, S Hider, A Herrick.

Recurrent digital ulcers are a difficult problem among scleroderma patients. It makes sense that smoking would aggravate digital ischemic ulcers but studies to date have been controversial. This study evaluated 101 scleroderma patients and documented smoking status and complications. Smokers were more likely to require ulcer debridement (OR 4.5; CI: [1.1, 18.3]); admission for IV therapy (OR 3.8; CI: [1.1,12.9]); or digital amputation (OR 3.4; CI:[0.8,15.1]).

Editorial Comment: This provides further rational for scleroderma patients to stop smoking.

All information contained within the Johns Hopkins Arthritis Center website is intended for educational purposes only. Physicians and other health care professionals are encouraged to consult other sources and confirm the information contained within this site. Consumers should never disregard medical advice or delay in seeking it because of something they may have read on this website.