Rheumatology 2006 45(Supplement 3):iii42-iii44; doi:10.1093/rheumatology/kel289
© The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
The role of DMARDs in systemic sclerosis therapy
N. Blank,
R. Max and
H.-M. Lorenz
Internal Medicine V, Division of Rheumatology, University of Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
Correspondence to: Dr Norbert Blank. E-mail: Norbert_Blank{at}med.uni-heidelberg.de
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Abstract
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The aim of this review is to evaluate the evidence for disease-modifying
anti-rheumatic drugs (DMARDs) for treatment of systemic sclerosis
(SSc). In the previously published trials, DMARD therapy was
usually initiated for severe skin thickening, organ involvement
and alveolitis. These studies suggest beneficial effects of
methotrexate, azathioprine, ciclosporine A and cyclophosphamide
therapy in SSc patients. However, many of these data were derived
from retrospective analyses with low numbers of patients, short-term
follow-up and often without an appropriate control group. Finally,
some of these studies led to inconsistent results. At the present
time there is no DMARD therapy of proven efficacy in SSc. Immunosuppressive
therapy should only be considered in patients with early diffuse
disease, overlap syndromes or pulmonary fibrosis. Current expert
recommendations suggest a therapy with methotrexate for skin
thickening or cyclophosphamide for acute alveolitis. However,
more clinical trials with larger numbers of patients with recent
onset SSc are needed.
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Introduction
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Systemic sclerosis (SSc) is a connective tissue disease characterized
by inflammatory lesions and widespread tissue fibrosis. The
inflammatory infiltrates and the experience with disease-modifying
anti-rheumatic drugs (DMARD) treatment for other inflammatory
connective tissue diseases led to the use of DMARDs for SSc
therapy. Preventing the development of vascular lesions, skin
atrophy and tissue fibrosis by early reduction of inflammation
and vascular symptoms is a major treatment focus [
1]. Therefore,
crucial trials included patients with recent disease onset (<3
yrs). Our review focuses on a few pivotal studies without being
able to acknowledge the contributions of many other authors.
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Azathioprine
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In a small retrospective analysis, 11 patients with interstitial
lung disease were treated with azathioprine and low-dose steroids.
Eight patients continued treatment for at least 12 months and
7 patients for 18 months or more. The mean dyspnoea score improved
from a baseline of 1.5 ± 0.19 to 0.50 ± 0.19 at
12 months (
P = 0.01) and to 0.43 ± 0.19 at 18 months
(
P =; 0.01) but the improvement of FVC (%) from a baseline of
54.3 ± 3.5% to 63.4 ± 6.2% at 12 months and 60.0
± 6.2% at 18 months was not statistically significant
[
2].
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Methotrexate
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A single-centre study from the Netherlands compared methotrexate
(MTX; 15 mg/week) with placebo injections in a 48-week randomized
double-blind trial. Seventeen patients with diffuse SSc were
allocated to MTX treatment and 12 patients to placebo. Patients
who responded favourably at week 24 continued with the same
regimen for another 24 weeks. MTX non-responders increased their
MTX dose to 25 mg per week and placebo non-responders were given
MTX. At week 48, 13 patients were on MTX from the beginning
and nine patients from week 24 onwards. Fifteen of 22 patients
(68%) responded favourably with improvement of skin score (
P = 0.04), patients general assessment (
P = 0.02), grip strength
(
P = 0.02) and sedimentation rate (
P = 0.01). These results
suggest that MTX is effective for SSc treatment [
3].
However, this was questioned by a recent multi-centre study from Canada. In this randomized controlled trial, 35 patients with diffuse SSc were treated with MTX and 36 patients with placebo, for 12 months. After 12 months, patients in the MTX group had a tendency for better skin scores, better diffusion capacities and favourable physician global assessments, but these parameters and the patient's global assessments were not significantly different from placebo-treated patients. However, an intent-to-treat analysis showed a significant improvement of skin scores with MTX (P < 0.01) [4].
Taken together, both studies suggest a favourable effect of MTX on SSc although the second study was inconclusive as to the overall efficacy of MTX.
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Ciclosporin A
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A retrospective open study from the United States evaluated
the outcome of 10 patients treated with Ciclosporin A (CsA)
over 48 weeks. The skin thickening decreased significantly (
P < 0.001), while pulmonary and cardiac involvement remained
unchanged in this study [
5].
Another retrospective study from Great Britain investigated data from 16 patients treated with CsA (dose range 2.4–4.1 mg/kg). Thirteen patients were treated for skin tightness and half of them noticed a significant softening of the skin, but 12 patients stopped CsA therapy within 1 yr of treatment. Though there are beneficial effects of CsA treatment, arterial hypertension and other side effects were common and often necessitated withdrawal [6].
A recent report from an Italian group showed data from nine patients treated with CsA 2.5 mg/kg for more than 3 yrs. These data show that beneficial effects on oesophageal, skin and lung scores and nailfold capillaroscopy might require therapy for up to 3 yrs to become significant. Moderate side effects occurred probably due to moderate CsA doses [7].
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Cyclophosphamide
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Oral cyclophosphamide (Cyc) or intravenous (i.v). Cyc pulse
therapy is considered for interstitial lung disease and alveolitis.
An Italian group reported a retrospective analysis of 16 patients
with SSc and alveolitis, treated with Cyc 750 mg and a pulse
of 125 mg methylprednisolone every 3 weeks. A significant deterioration
of FVC and DLCO occurred within 6 months before Cyc therapy.
After 6 months of Cyc therapy, a modest improvement of FVC and
DLCO was observed which failed significance. A pooled analysis
of the data from 53 patients reported from other groups, reached
statistical significance for improvement of pulmonary function
tests [
8].
A Greek group reported an open label study with a prospective evaluation of 28 patients with SSc and interstitial lung disease, which were treated with monthly i.v. pulses of Cyc 750 mg/m2 (maximum dose 1500 mg). Low-dose prednisolone (<10 mg, n = 12) or a pulse of high-dose steroids (1 mg/kg for 4 weeks, tapered to 5 mg/kg, n = 16) were administered. No improvement was detected in the low-dose steroid group after 6 or 12 months, but in the high-dose steroid group there was a significant improvement in parenchymal lung involvement, FVC, DLCO, dyspnoea severity and skin involvement [9]. These data indicate that high-dose steroids and i.v. Cyc pulse therapy are effective in SSc treatment. Furthermore, in a large American multi-centre trial, the Scleroderma Lung Study, 162 patients with acute alveolitis were treated with cyclophosphamide or placebo. Preliminary data show a very modest efficacy of Cyc and the results will be published soon.
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Anti-TGF-ß1
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In a phase I/II trial, 45 patients with recent onset SSc were
randomly allocated to three different concentrations of anti-TGF-ß1
(CAT-192: 10, 5, and 0.5 mg/kg) or placebo infusions. Treatment-related
morbidity was undetectable, but changes of serum markers and
improvement of skin scores with 5 and 10 mg/kg were not significant
[
10].
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Anti-thymocyte globulin and mycophenolate mofetil
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In a pilot study of 13 patients with recent onset, SSc patients
received anti-thymocyte globulin (ATG) for 5 days and mycophenolate
mofetil (MMF) for 12 months. After 12 months, the skin score
decreased from 28 at baseline to 17 after 12 months (
P <
0.01). Hand contractures worsened during the study. However,
the authors conclude that therapy with ATG + MMF is safe, and
controlled studies should be performed [
11].
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Alternative therapeutic options
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Several groups investigated extracorporal photochemotherapy
(ECP) for therapy of SSc patients. One report showed beneficial
effects for skin scores [
12], but another one did not show any
improvement in ECP-treated patients [
13]. Therefore, photopheresis
cannot be regarded as regular treatment for SSc. Interferon-
treatment of SSc was commonly associated with flu-like adverse
events and a tendency of improved skin changes was not significant
[
14]. Further options could be the use of i.v. immunoglobulins,
leflunomide or rapamycin. However, to date, there are only anecdotal
reports about these drugs. An American study of rapamycin
vs MTX in early diffuse SSc has been already closed, and results
will be published soon. SSc patients with refractory and rapid
progressive disease might benefit from a high-dose chemotherapy
followed by an autologous stem cell transplantation (SCT). This
therapeutic option is currently evaluated in the European ASTIS
trial and the North American SCOT trial. Preliminary results
from 25 patients with severe SSc receiving SCT in the ASTIS
trial indicate that this therapy is feasible [
15].
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Combination therapy
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Experience with combination therapy of rheumatoid arthritis
and connective tissue diseases suggests that combinations of
MTX and CsA or MTX and leflunomide might also be beneficial
for SSc patients. However, there are no data about combination
therapy at this time. The limited efficacy of single DMARDs
for SSc does not exclude the possibility that a DMARD combination
might be effective for SSc therapy. A combination therapy might
not require maximal DMARD doses and therefore side effects would
be less likely to occur.
N.B. received speaker's honoraria for participation at Actelion Winter School 2006.
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References
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- Dheda K, Lalloo UG, Cassim B, Mody GM. (2004) Experience with azathioprine in systemic sclerosis associated with interstitial lung disease. Clin Rheumatol 23:306–9.[ISI][Medline]
- van den Hoogen FH, Boerbooms AM, Swaak AJ, Rasker JJ, van Lier HJ, van de Putte LB. (1996) Comparison of methotrexate with placebo in the treatment of systemic sclerosis: a 24-week randomized double-blind trial, followed by a 24 week observational trial. Br J Rheumatol 35:364–72.[Abstract/Free Full Text]
- Pope JE, Bellamy N, Seibold JR, et al. (2001) A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma. Arthritis Rheum 44:1351–8.[CrossRef][ISI][Medline]
- Clements PJ, Lachenbruch PA, Sterz M, et al. (1993) Cyclosporine in systemic sclerosis. Results of a forty-eight-week open safety study in ten patients. Arthritis Rheum 36:75–83.[ISI][Medline]
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- Pakas I, Ioannidis JP, Malagari K, Skopouli FN, Moutsopoulos HM, Vlachoyiannopoulos PG. (2002) Cyclophosphamide with low or high dose prednisolone for systemic sclerosis lung disease. J Rheumatol 29:298–304.[ISI][Medline]
- Denton CP, Merkel PA, Furst DE, et al. (2004) Anti-TGFß1 Therapy for Diffuse Cutaneous Systemic Sclerosis: a multicenter, randomized, placebo-controlled Phase I/II Trial of CAT-192. Arthritis Rheum 50:Suppl, S691–2.
- Stratton RJ, Wilson H, Black CM. (2001) Pilot study of anti-thymocyte globulin plus mycophenolate mofetil in recent-onset diffuse scleroderma. Rheumatology 40:84–8.[Abstract/Free Full Text]
- Rook AH, Freundlich B, Jegasothy BV, et al. (1992) Treatment of systemic sclerosis with extracorporeal photochemotherapy. Results of a multicenter trial. Arch Dermatol 128:337–46.[Abstract]
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- van Laar JM, Farge D, Tyndall A. (2005) Autologous Stem cell Transplantation International Scleroderma (ASTIS) trial: hope on the horizon for patients with severe systemic sclerosis. Ann Rheum Dis 64:1515.[Free Full Text]
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Abstract
Introduction