Scleroderma Treatments
- Cyclophosphamide
- Methlyprednisolone & Cyclophosphamide
- Transforming growth factor beta antibody
- Angiotensin II Receptor Inhibitor
- Camptothectin
- Aerosolized Ilomedine
- Prostacyclin
- Thalidomide
- Calcitriol Therapy
- PUVA Therapy
- Methotrexate and Corticosteroids
Cyclophosphamide
Abstract #593 High Dose Cyclophosphamide Followed by Autologous Peripheral Blood Stem Transplantation for the Treatment of Systemic Sclerosis
F van den Hoogen, J van Laar, A Schattenberg, W Fibbe, F Preijers, F Breedveld, T de Witte, R Willemze, L van de Putte Nijmegen, The Netherlands
There has been an increase in the use of aggressive immunosuppressive therapy in severe scleroderma. This abstract reviews the experience of the investigators in 5 patients (one with skin only, three with pulmonary and skin and 1 with skin, lung and kidney disease) with cyclophosphamide and autologous bone marrow transplantation (ABMT). The aplastic period lasted 3 weeks in all patients. A 45% improvement in skin score that was sustained for the 2-16 month follow-up period was reported. A transient fall in the DLCO was seen in 2 of the 5 patients. Another survey of over 40 patients reported 20% mortality among the scleroderma patients treated with ABMT. This increased mortality for ABMT was thought to be unique to scleroderma patients.
Editorial Comment: This larger experience suggests that we take great caution in when recommending this aggressive therapy. There are now ongoing NIH funded trials in the USA investigating the role of ABMT in the treatment of severe scleroderma.
Abstract #698 Scleroderma Patients with Alveolitis Who are Treated with Cyclophosphamide Have Better Survival Than Untreated Patients
B White, F Wigley, R Wise Baltimore, MD
This study is a retrospective review of the outcome of scleroderma patients managed for alveolitis with cyclophosphamide (CTX) and represents the largest reported series to date. The data suggest that patients with active alveolitis who are treated with daily oral CTX at a dose of 2mg/kg (average dose 100 mg/day) did better than patients with alveolitis who were not treated. The outcomes that improved included both forced vital capacity and survival. The study also showed data to support the fact that an abnormal bronchoalveolar lavage (neutrophils greater than 3%) can predict active disease and poor outcome.
Editorial Comment: This study supports others that have found the same trends but a controlled trial needs to be done before the use of CTX becomes general practice. It should be remember that only patients with proven active alveolitis should be considered for treatment. A NIH funded controlled trial investigating the role of cyclophosphamide is underway.
Methlyprednisolone & Cyclophosphamide
Abstract #717 Pulse Intravenous Methlyprednisolone and Cyclophosphamide is Effective in Treating Interstitial Lung Disease in Patients with Systemic Sclerosis
B Griffiths, S Miles, A Morgan, T Lian, S Bingham, D Veale, P Emery Leeds United Kingdom
The definition for Interstitial Lung Disease (ILD) used in this study was an abnormal High resolution CT scan (HRCT) scan. Fifteen patients were treated with 6 pulses of methlyprednisolone (10 mg/kg) and cyclophosphamide (CTX) (15 mg/kg) at 3 weekly intervals (3 times) then 4 weekly intervals (3 times). The HRCT scan improved in over half the patients and lung functions remained stable. Skin score improved by a median of 33%. This study supports the finding by many that ILD can be controlled by immunosuppressive therapy. It suggests that intermittent CTX (with high dose corticosteroids) may be an alternative to the more popular daily CTX method.
Editorial Comment: We must remember that these data are uncontrolled and that a large blinded controlled trial will be needed to define the best treatment for ILD in scleroderma. Such a trial is now funded and underway in the USA.
Transforming growth factor beta antibody
Abstract #1213 Effects of Transforming Growth Factor Beta-Inhibition on Disease Progression in a Murine Scleroderma Graft versus Host Disease Model for Human Scleroderma
LL McCormick, Y Zhang, E Tootell, AC Gilliam Cleveland, OH
These investigators have used a murine model of graft versus host disease to demonstrate the potential for preventing fibrosis of skin and lung by using a monoclonal antibody directed against Transforming growth factor beta (TGF-beta). TGF-beta is thought to play a major role in upregulating collagen synthesis and producing tissue fibrosis in many disorders. Although the murine model does not completely mimic scleroderma, this work defines a potential role in inhibiting TGF-beta in the early active stages of scleroderma.
Angiotensin II Receptor Inhibitor
Abstract #801 Influence of Angiotensin II Receptor Type-1 Blockage on Normal and Scleroderma Fibroblast Proliferation and Matrix Production
M Dziadzio, B Gao, D Abraham, C Black London, United Kingdom
Angiotensin II (AII) is known to be a potent vasoconstrictor and to enhance extra-matrix production and TGB-beta expression thus potentially increasing fibrosis of tissues. This abstract gives in vitro evidence that losartan, a selective AT-1 receptor inhibitor reduced collagen synthesis induced by TGF-beta in scleroderma fibroblast Thus AT-1 blockade may be a useful target I the treatment of early active scleroderma. Obviously, a clinical trial will be needed to prove if losartan or other inhibitors are helpful.
Camptothectin
Abstract #804 The effect of Camptothectin, a Topoisomerase Inhibitor, on Collagen Synthesis in Fibroblast from Patients with Systemic Sclerosis
J Czuwar-Ladykowska, M Trojanowska, E Smith, L Rudnicka Charleston, SC, Warsaw, Poland
Topoisomerase I (Topo) is a nuclear enzyme that relaxes DNA and it may affect transcription of genes thus affecting collagen production. Camptothectin (CPT) inhibits Topo and is now used I the treatment of cancer. This investigation demonstrated in vitro that CPT reduced the production of collagen from scleroderma fibroblast. The data suggest that CPT reduced the COLIA2 gene expression at the transcription level. This interesting study demonstrates the potential of controlling collagen production by altering gene activity.
Aerosolized Ilomedine
Abstract #693 Aerosolized Ilomedine (Seems to be Effective) in Severe Pulmonary Hypertension in Systemic Sclerosis
D Launay, E Hachulla, U Michon-Pasturel, F Saulnier, L Goullard, PY Hatron, B Devulder, Lille Cedex, France
Recent studies have suggested that continuous intravenous infusion of prostacyclin can improve the clinical outcome of patients with scleroderma and severe pulmonary hypertension (PHT). These investigators provide preliminary data to suggest that Ilomedine (Iloprost, an analogue of prostacyclin), can improve exercise tolerance, dyspnea and lower pulmonary artery pressure. The study was open -labeled and involved only three patients with severe PHT, but still is quite encouraging that this simpler method of delivering prostaglandins will work. In addition, the aerosol delivery prostacyclin may avoid the development of hypoxia caused by intravenous delivery of non-selective vasodilators to patients with PHT and interstitial lung disease.
Prostacyclin
Abstract #704 Long-term Treatment with Prostacyclin for Pulmonary Hypertension in connective tissue diseases: sustained Improvement After Cessation of Therapy
C Torres, PE Carreira, J Delgado, MA Gomez-Sanchez, JJ Gomez-Reino Madrid, Spain, Coruna, SpainThis abstract reports a survey of 3 scleroderma and 2 patients with MCTD who had severe pulmonary hypertension (PHT) (functional class III/IV) and were treated with continuous prostacyclin intravenously for more than a year. All patients improved clinically in 2 weeks and 3 were able to get off the prostacyclin infusion and maintained improvement on oral vasodilator therapy 9,11,and 36 months respectively. One patient died from right heart failure. This study supports the use of prostacyclin for PHT in scleroderma and related disorders, but our experience is that it is the exception rather than the rule that the patient will maintain improvement off the prostacyclin infusion. We need to wait for more studies to know how to handle these patients long-term.
Thalidomide
Abstract #699 Reduced Fibrosis and Normalization of Skin Structure in Scleroderma Patients Treated with Thalidomide
Oliver, A Moreira, G Kaplan New York, NY
This abstract has a misleading title in that the skin structure changes were subjective and in vitro. It is not clear that the clinical situation improved in that no formal assessment was presented. It appeared that the patients developed a thalidomide-related dermatitis that has also been seen in sarcoidosis patients treated with thalidomide. This study does not give us much guidance on the role of thalidomide in the treatment of scleroderma and I recommend that great care be taken given the potential of a significant degree of peripheral neuropathy occurring with thalidomide use.
Calcitriol Therapy
Abstract #701 Safety and Tolerability of Calcitriol Therapy as a Disease-Modifying Agent in Systemic Sclerosis: An Open Pilot Study
JE Santana-Sahagun, J Lemire, S Albani, L Eichenfield, MH Weisman San Diego, CA
Vitamin D derivatives have been used to treat localized scleroderma, but there a re no good controlled trials to clearly define its role in the treatment of scleroderma. This is a small (n=9) open-labeled trial that showed some improvement in total skin score, oral aperture opening and hand extension in these patients comparing the start to the six month follow-up. While this type of trial is interesting, we can not make any judgement about the usefulness of Calcitriol in the treatment of scleroderma. The significance of the changes was borderline significance and it is known that the natural history of the skin manifestations is to improve. The authors tell us that a controlled trial would be needed.
PUVA Therapy
Abstract #718 PUVA Therapy of Skin Sclerosis and Limited Sclerosis
B Griffiths, A Murphy, J Smith, DJ Veale, P Emery, M Goodfield Leeds, United Kingdom
There are several uncontrolled reports that UVA irradiation following psoralen ingestion is helpful in localized scleroderma. This report supports these findings by showing that patients with localized scleroderma improved after PUVA therapy. The improvement in the systemic patients was less clear. This therapy has few side effects but one must be careful not to damage skin with the UVA exposure. This becomes a significant issue when treating diffuse scleroderma. We will have to wait until a good placebo-controlled trial is done because the natural history of localized scleroderma is one of improvement.
Methotrexate and Corticosteroids
Abstract #957 Methotrexate and Corticosteroids in Pediatric Localized Scleroderma
Y Uziel, BM Feldman, BR Krafchik, R Yeung, RM Laxer Toronto Canada, Kfar-Saba, Israel
Methotrexate (MTX) 0.3-0.6 mg/kg/week was given to 10 patients (mean age 6.8 years) with active localized scleroderma (LS). Nine of the children were also treated with pulse methlyprednisolone monthly for three days for three cycles. Of the nine children who continued the MTX all were reported to respond (skin softened/ no progression and no new lesions). Unfortunately, the study design does not allow us to define if the corticosteroids or the MTX or both (or neither) accounted for the response, but it seems that early immunosuppressive therapy may be warranted in early active disease. It was reported at the Scleroderma Study Group that a placebo-controlled trial for localized scleroderma in children is being planned.
Abstract #961 Evaluation and Treatment of Childhood Onset Localized Scleroderma 1988-1999
J Walsh, G Martini, KJ Murray, P Woo, CM Black London, United Kingdom
This study was a retrospective case study of 40 children less than 16 years old with localized scleroderma (linear, morphea or mixed). 22 of the patients were treated with methotrexate and corticosteroids (either pulse (19) or orally (n3)). Data on 19 of the 22 treated patients was available and it showed improvement in 12 (64%). This survey suggests that immunosuppressive therapy can be useful in localized scleroderma but the investigators point out that a placebo controlled trial needs to be done. It was reported at the Scleroderma Study Group that a placebo-controlled trial for localized scleroderma in children is being planned.