Scleroderma
- Epoprostenol
- Autologous Bone Marrow Transplant
- Thalidomide
- Cyclosporine A
- Iloprost
- Prostacyclin
- Halofuginone
- Cyclophosphamide
- Bucillamine
- Etanercept
- PGE1-a-cyclodextrin IV
Epoprostenol
Scleroderma Study Group Report: Epoprostenol is now approved for the treatment of scleroderma related pulmonary hypertension (PHT). It is given via a central IV infusion of the medication using a small pumping device worn by the patient. Patients with severe PHT who are failing conventional therapy are considered candidates. Conventional therapy includes use of anti-coagulation, diuretics and spironolactone and in some cases a calcium channel blocker (CCB) as a vasodilator. Patients who have severe PHT should have a right heart catherization to confirm the diagnosis and to undergo a vasodilator challenge (e.g. epoprostenol, adenosine, CCB). If they have a positive response (20% fall in PA pressure) then oral therapy using the highest tolerated doses of a CCB is the preferred therapy. If they do not respond to the vasodilator challenge than epoprostenol can be started for its long-term benefit. Studies in scleroderma find that epoprostenol improved quality of life, decreased symptoms, increased distance of walking in 6 minutes and improved hemodynamics with improved cardiac output and decreased pulmonary vascular resistance compared to placebo in scleroderma patients with PHT. Abstract 1499 points out that while epoprostenol improved survival in 24 months compared to conventional therapy, there was no survival advantage at 48 months. Epoprostenol therapy is complex and expensive. It requires a fully trained specially team to manage the central line, the mixture of the medication and the infusion pump. Sudden disruption of the medication can lead to life-threatening rebound of the PHT. Therefore, epoprostenol should be used as a bridge allowing time to move toward lung transplantation.
Abstract #1499 Long-Term outcomes of Epoprostenol in Scleroderma-Associated Pulmonary Hypertension.
L Schachna, J Tarver, J Krishnan, T houston-harris, R Wigley, B White, S Gaine, I Rosas. Maryland.
Epoprostenol delivered by continuous central IV infusion is now approved for the treatment of pulmonary hypertension in scleroderma. This study reported a retrospective review of the investigators experience with epoprostenol in scleroderma patients. 19 patients were treated with active drug and 15 patients were not treated due to lack of insurance, patient preference or inability to handle the complex deliver system. This was not a randomized trial. However, the data demonstrated no difference in various clinical and hemodynamic outcomes including survival at 48 months between the two groups despite the fact that both groups were very similar at onset. Epoprostenol does improve survival in primary pulmonary hypertension (PPH). Scleroderma patients may have a different outcome due to heart and other systemic disease not present in PPH.
Editorial Comment: Lung transplant may be the ultimate option in scleroderma related pulmonary hypertension.
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Autologous Bone Marrow Transplantation
Scleroderma Study Group Report: Autologous Bone Marrow Transplantation is being tested as a treatment for scleroderma. Approximately 50 patients have been treated worldwide. The rationale is that scleroderma is thought to be an autoimmune disease driven by an active cellular immune process. If auto reactive cells can be eliminated by ablative therapy followed by stem cell replacement then the disease may go into and remain in remission. Eligible patients are those with active diffuse disease with a high skin score and some internal organ involvement. These patients are considered to be at high risk with a 50% five-year survival if the disease is not controlled. The exact treatment protocol varies from site to site. Thus far 15-20% mortality is reported from the procedure. One site (Abstract #1953 D Furst, et al) reported that 2/8 died from radiation pneumonitis following total body irradiation. This procedure is now done with lung screening and since then 10 more patients have not had this reaction. One of these 10 died from an EBV viral induced lymphoproliferative disease; making the overall mortality at this site 3/18 or 17%. Open-labeled data presented a general improvement in skin score and improvement in measures of overall functional status, stabilization of lung function but no other clear effect on other internal organs. Three children with severe scleroderma were treated with autologous bone marrow transplantation (Abstract #1538 A Martini, et al). Two of the three improved with stabilization of lung function; but one did not improve having progression of pulmonary fibrosis.
Editorial Comment: The data is still very preliminary and the benefit of the procedure is still unknown, but clearly these investigators report a significant mortality rate. One needs to be very selective and enter only severe life-threatening disease into this protocol.
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Thalidomide
Scleroderma Study Group Report: Thalidomide was reported to potentially be helpful in scleroderma. 11 patients have participated in an open-labeled studied designed to explore the biological effects of thalidomide in scleroderma. There was clinical benefit reported but the data were limited. Most patients develop a nonspecific dermatitis manifested as a pruritic dry skin. Although not reported in this short-term trial, approximately 30% of patients treated for other diseases with thalidomide develop a profound peripheral neuropathy. Studies suggested that thalidomide moved T-cell responses from a Th2 type response to a Th1 response, thus moving the immune response toward an anti-fibrotic phenotype.
Editorial Comment: The studies were very preliminary and much work needs to be done before we can recommend thalidomide for scleroderma.
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Cyclosponine A
Abstract #1492 Cyclosporine A in the Treatment of Systemic Sclerosis: A Long-Term Controlled Pilot Study
C Ferri, D Giuggioli, M Sebastiani, M Cazzato, P Fazzi, O Casa-Alberighi. Italy.
Cyclosporine A has immunosuppressive activity by selectively inhibiting the release IL-2, an important cytokine released by activated T-cells that enhances the immune response. Patients were randomized to isradipine (a calcium channel blocker) plus cyclosporine A versus isradipine alone. Only in the cyclosporine A group did the skin score improve and only in this group was there stabilization of lung function. The study was small but patients were followed for 2 years. There are reports of cyclosporine A inducing a scleroderma renal crisis. Two patients in this trial developed renal impairment despite the fact that all patients were on a calcium channel blocker. While several studies suggest that cyclosporine A may be helpful in scleroderma its use is limited by the renal toxicity that can be life threatening.
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Iloprost
Abstract #1498 Long-Term outcome of Patients with Crest Syndrome-Related-Pulmonary Hypertension Treated by Aerosolized Iloprost
D Launay, E Hachulla, P Hatron, L Goullard, T Onimus, S Robin, V Queyrel, U Michon-Pasturel, M Hebbar, F Saulnier, B Devulder. France.
Five patients with CREST and severe pulmonary hypertension were treated with aerosolized iloprost, a prostacyclin (PGI2) analogue. All patients improved subjectively. NYHA classification, ability to walk and hemodynamic measurements also improved in 4 of 5. One patient died and another patient had no improvement of exercise tolerance or hemodynamic measurements.
Editorial Comment: The delivery of prostaglandins by inhalation to treat pulmonary hypertension is attractive because it is potentially easier and safer than the current method of continuous IV epoprostenol. It also might provide a method to treat patients who have interstitial lung disease (ILD) Patients with ILD develop hypoxia when treated with an oral or IV nonselective vasodilator due to mismatching of ventilation and perfusion that occurs as unventilated portions of the lung have local vasodilatation. Iloprost is not available in the USA. The ideal dose schedule and delivery system is not established nor does this open experience prove efficacy. Rebound of the hypertension may occur if iloprost is stopped. There is a large placebo controlled trial using aerosolized iloprost in pulmonary hypertension underway in Europe.
Abstract #1156 Inhibition of Connective Growth Factor (CTCF) Synthesis in Normal and Scleroderma Fibroblasts Treated with TGFß and in Patients Fluids with Iloprost
R Stratton, X Shiwen, G Martini, D Abraham, G Martin, C Black. England and California.
Iloprost is a synthetic prostacyclin derivative available in Europe and now used by intermittent intravenous infusion for the treatment of Scleroderma vascular disease. Data was presented demonstrating that iloprost blocks the induction of Connective Tissue Growth Factor (CTGF) and the increase in collagen production that occurs following exposure of fibroblast to TGF-beta.
Editorial Comment: This suggests that treatment with iloprost not only be a vasodilator but may also alter tissue fibrosis. Studies are underway in Europe investigating if iloprost will have a disease modifying effect in scleroderma.
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Prostacyclin
Long-term intravenous prostacyclin infusion is being used for the treatment of severe pulmonary hypertension secondary to scleroderma and intermittent prostaglandin E1 infusion is used for the peripheral vascular disease and severe Raynauds phenomenon. Data was presented (Abstract #1148 Kahaleh, et al) that demonstrated that following prostaglandin infusion endothelial functional phenotype improved with increased expression of vasodilatory genes and reduced expression of mitogenic and inflammatory genes. In addition, circulating levels of adhesion molecules were decreased consistent with improvement in endothelial cell activation (Abstract #1166 Angotti, et al).
Editorial Comment: These studies are very limited but give some rationale for chronic used of prostaglandin therapy in scleroderma.
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Halofuginone
Abstract #1502 Halofuginone Prevents the Development of Cutaneous Hyperplasia by Interfering with TGF-ß Mediated Signaling Events
T McGatha, H Spiera, C Bona. New York.
Halofuginone is a new anti-fibrotic agent discovered during its use as a coccidiostat in poultry. Clinical trials are underway with both topical and systemic forms of delivery. This study found that Halofuginone prevented skin sclerosis in the murine model of scleroderma, the TSK/+ mouse. Data suggest no affect on normal matrix production but that halofuginone interferes with type 1 collagen promoter gene. It inhibits TBG-beta stimulation of collagen production by fibroblast. We must now await the results of the clinical trials.
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Cyclophosphamide
Abstract #1503 Effects of Cyclophosphamide/Prednisolone Therapy on the Clinical Findings and Endothelial Functions of Patients with Early Diffuse Systemic Sclerosis
M Calguneri, S Apras, I Ertenli, S Kiraz, V Cobankara, M Erman, M Ozturk. Turkey.
An open-labeled experience of a combination of cyclophosphamide and corticosteroids in early diffuse disease reports improvement in skin score, oral aperture, finger flexion, tender joints, and lung function. In addition, there was a reduction in blood levels of sE-selectin and s-thrombomodulin, measures of endothelial activation. The use of biomarkers to assess disease activity is an important area of new investigations.
Editorial Comment: Although the treatment in this study needs confirmation, it is very interesting that clinical improvement correlated with reduction in biomarkers. Renal function must be closely monitored if corticosteroids are used in early diffuse scleroderma.
Abstract #1510 Pulse Intravenous Cyclophosphamide in the Treatment of Interstitial Lung Disease in Patients with Systemic Sclerosis
J Font, S Jimenez, M Ramos-Casals, R Cervera, O Trejo, G De la Red, V Gil, M Garcia-Carrasco, M Ingelmo. Spain/
Evidence suggests that daily oral cyclophosphamide stabilizes lung function in scleroderma patients with active alveolitis defined by BAL study. This study reports 11 patients HRCT scan defined active lung disease that are treated with monthly IV cyclophosphamide (750mg/m2) for six months and oral prednisone (1mg/kg/day, in descending doses). Lung scans improved in 73% without change in lung function. Skin scores improved in 50% and all felt subjectively better.
Editorial Comment: There is a need to prove that cyclophosphamide is effective in the treatment of scleroderma lung disease. A placebo-controlled blinded trial is underway in the US using daily oral cyclophosphamide without corticosteroids. Uncontrolled studies may lead to use of this potentially toxic drug before efficacy is established. Evidence suggests that HRCT scans are inaccurate in defining active disease. Most agree that a differential of BAL obtained fluid is needed to fully determine if active alveolitis is present. Care must be taken in interpreting the results of this uncontrolled experience.
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Bucillamine
Abstract #1505 Successful Treatment with Bucillamine for Intractable Interstitial Lung Disease in Systemic Sclerosis
T Ogawa, K Ogawa, T Ogura, M Akutsu, E Saito. Japan.
Bucillamine is an anti-rheumatic drug with SH-groups like D-peniclliamine. Six patients with diffuse cutaneous scleroderma were treated in an opened labeled uncontrolled trial. All six patients improved with subjective measures of lung "alveolitis" by a reduction of ground glass findings on HRCT scan. Three patients showed improvement in skin thickening and range of movement of finger function.
Editorial Comment: Many uncontrolled studies that suggest improvement in scleroderma have not been confirmed when well designed controlled clinical trials are done. We must remember that scleroderma may improve spontaneously. This study is not adequate to make judgment about the efficacy of bucillamine in the treatment scleroderma.
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Etanercept
Abstract #1955 Etanercept as Treatment for Diffuse Scleroderma: A Pilot Study
M Ellman, P MacDonald, F Hayes. Chicago and Seattle.
Entanercept (25 mg subcutaneously twice weekly for 6 months) was given to 10 patients with diffuse scleroderma in an open-labeled study to determine safety and determine clinical outcomes. One patient discontinued after 4 weeks due to new digital ischemia. Nine patients completed the trial. Four of nine had a 44% improvement in skin score and five remained unchanged. Three patients with digital ulcers noted improvement. Lung function remained stable and functional status improved. This uncontrolled experience suggests that entanercept is safe to administer to scleroderma patients, although the number of patients and duration of follow-up is small. The data also supports no benefit in that only 4 improved. However, the four that improved were in the early stages of disease while those that did not improve were in late disease. One cannot conclude anything from the clinical outcome data without a proper control group. The exact role of TNF in the scleroderma disease process is unknown but inhibition of TNF may benefit the vascular disease more than tissue fibrosis.
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PGE1-a-cyclodextrin IV
Abstract #1958 Treatment of Raynaud's Phenomenon with PGE1-a-cyclodextrin IV Improves Parameters of Endothelial Cell Injury in Systemic Sclerosis (SSC)
M Gardinali, M Pozzi, M Bernareggi, E Allevi, M Cugno, R Stabilini. Italy.
Twenty-four patients with scleroderma were treated with PGE1-a-cyclodextrin IV for five consecutive days, three times with six-week intervals during the winter months. Raynauds symptoms improved subjectively in 87% of the patients and lasted greater than 4 weeks in 75%. A reduction in frequency of attacks was reduced compared to baseline. Interestingly, a variety of plasma markers of endothelial cell activation were elevated compared to normals at baseline and were reduced following PGE1-a-cyclodextrin IV treatment. The improvement in the measurements in endothelial cell biomarkers suggest that the prolonged benefit of prostaglandin therapy in scleroderma related Raynauds phenomenon may be due to improvement in endothelial function rather than just its vasodilator effect. This study was not a controlled clinical trial. In the past studies in patients with Raynauds phenomenon always have a very high response rate to placebo. Therefore, the clinical data of this study will need confirmation.
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Clinical Trials Consortium (SCTC)
Relaxin Update:
The results of a large placebo control trial of relaxin, a small peptide that down-regulates collagen and increases collagenase production, was reported. This study involved multiple centers with over 200 patients with early diffuse cutaneous scleroderma. Patients were randomized to either receive placebo or active drug by continuous subcutaneous infusion. There was no benefit of relaxin versus placebo in skin score after six months of treatment. A variety of other measures including quality of life, hand extension, oral aperture, functional status and lung function was also not different in the two treatment arms of the study. There was evidence that the group received biologically active drug in that they had a lower hemoglobin, lower blood pressure and improved renal function compared to placebo; all measurements returnedto baseline after stopping relaxin. This well designed study clearly showed no important clinical benefit from 6 months of relaxin therapy. Therefore, there will be no future studies investigating relaxin in the treatment of scleroderma.
United Kingdom Plans Coorperative Studies:
A cooperative study will start in the UK in which scleroderma patients with active disease will be placed solely by preference of the treating doctor into one of four protocols: 1) ATG plus mycophenolate mofetil, 2) Cyclophosphamide for six months followed by mycophenolate mofetil, 3) mycophenolate mofetil alone, or 4) no treatment. This observational study plans to capture every scleroderma patient that is not in another randomized protocol and will use uniform measurement instruments and follow-up protocol. The intent of this cooperative study is to try to organize management of the patients into a database that is large enough to collect valuable information about the course and response to treatment. Thus far the role of mycophenolate mofetil in the treatment of scleroderma is unknown.
Abstract #1145 Et-1 Induced ICAM-1 Expression in Fibroblasts: Functional Consequences and Signaling Pathways in Systemic Sclerosis
X Shi-wen, C Denton, M Dashwood, A Holmes, V Rajkumar, M Binks, C Black, D Abraham. United Kingdom.
This study demonstrates that endothelin-1, a potent vasoconstrictor produced by endothelial cells, is capable of up-regulating I-CAM on the surface of human fibroblast. This finding suggests that endothelin-1 may be mediate adhesion of inflammatory cells to fibroblast and thus promote tissue fibrosis. Endothelin-1 is increased in the serum and tissues of patients with scleroderma and it is capable of a variety of biological activities including vasoconstriction, stimulation of cell proliferation and induction of extracellular matrix synthesis. Thus, endothelin-1 could be the link between vascular disease and tissue fibrosis. An inhibitor of endothelin-1 is currently being studied in scleroderma patients with pulmonary hypertension.
Abstract #1145 A Summary of Abstract 襶 Siatta, et al, Abstract #193 Cicchillitti, et al, and Abstract #611 Jimenez, et al)
It is known that the fibrosis of tissue in scleroderma is associated with activated tissue fibroblast producing excess collagen and other extra cellular matrix. Furthermore, increased gene transcription accounts for the increased collagen production. Studies have identified regions in the promoter gene that increase or decrease collagen gene activation. Increased binding of CCAAT binding factor (CBF), a transcription-binding factor, may also account for up-regulation of collagen gene expression in scleroderma. Rotterlin, a selective inhibitor of protein kinase C is a potent inhibitor of promoter gene activity.
Editorial Comment: This finding and the new insight into the regulation of the collagen gene provide the opportunity for novel therapy in scleroderma.
Abstract #1147 Activation In Vitro of Scleroderma Skin Fibroblasts is Sustained by Increased Generation of Free Radicals Through the NADPH-Oxidase Pathway
P Sambo, S Svegliati, P Paroncini, D Amico, M Luchetti, A Gabrielli. Italy.
N-acetly-L-cysteine (NAC; mucomyst) inhibited fibroblast proliferation and down regulated collagen mRNA in scleroderma fibroblast. This suggests that free radicals (ROS) contribute to the activation of scleroderma fibroblast.
Editorial Comment:The only clinical trial of NAC in the treatment of scleroderma showed no improvement in skin score compared to placebo.
Abstract #71 Role of CD154-CD40 Interactions in Collagen Production by Fibroblasts
V Yurovsky, B White. Maryland.
T cells activate fibroblast by CD154-CD40 intermolecular interactions. CD40 is expressed on fibroblast while CD154 is present on activated CD8+ cells.
Editorial Comment: Although this abstract had no treatment data it suggest that a novel approach to treatment of scleroderma would be to interfere with T cell-fibroblast interactions with anti-CD40.
Abstract #1957 Inhibition of TGF-ß Stimulated Collagen Synthesis and Myofibroblast Induction by a Monoclonal Antibody to TGF-ß.
G Breuer, A Jelaska, S Ledbetter, J Korn. Massachusetts.
Transforming growth factor-beta (TGF-ßbeta) is known to promote fibrosis by stimulating collagen production from tissue fibroblast.
Editorial Comment: This study demonstrates that a monoclonal antibody to TGF-beta will inhibit the TGF-beta effects on human dermal fibroblast metabolism. Interestingly, the monoclonal antibody inhibited basal levels of scleroderma fibroblast production suggesting that scleroderma fibroblast have endogenous TGF-beta production using an autocrine pathway in collagen regulation. Anti-TGF-beta therapy with monoclonal antibody is a viable mode of therapy to be tested in scleroderma.
It is important to predict the course of disease in order to determine how aggressive to be with treatment. This study (Abstract #1493 Artlett, et al#041; compared 83 women with prior pregnancies with 32 nulligravid women. It found that nulligravid women had the onset of scleroderma at an earlier age, had more severe lung disease and a higher mortality rate. Multiple pregnancies are associated with a later age of onset of disease. The cause for this difference is not apparent. Another study (Abstract #1497 Launay, et al) found that women with more children were more likely to have limited skin disease but worse pulmonary fibrosis. Both these studies are in relatively small numbers of patients and need confirmation.
