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Rheumatology 2001; 40: 84-88
© 2001 British Society for Rheumatology
Pilot study of anti-thymocyte globulin plus mycophenolate mofetil in recent-onset diffuse scleroderma
Royal Free Hospital, London NW3 2QG, UK
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Abstract |
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 Top Abstract IntroductionPatients and methodsResultsDiscussionReferences |
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Objective. To assess the safety and efficacy of anti-thymocyte globulin (ATG) followed by mycophenolate mofetil (MMF) in the treatment of diffuse scleroderma.
Methods. A pilot study of 13 patients with recent-onset diffuse scleroderma was carried out. Patients received ATG for 5 days, followed by MMF for 12 months. We recorded adverse events, scleroderma skin score, hand contractures, EuroQol score, scleroderma functional assessment, pulmonary function studies, echocardiogram and plasma creatinine concentration.
Results. Mean skin score decreased during the study from 28 at baseline to 17 after 12 months of MMF (P<0.01). Hand contractures worsened during the study. Mean measurements of systemic disease remained stable. One patient died after a scleroderma renal crisis. Five patients developed serum sickness after ATG treatment, but this was controlled by corticosteroid therapy. MMF therapy was well tolerated.
Conclusion. ATG and MMF appear safe in scleroderma. The improvement in skin score and the apparent stability of systemic disease during the study period suggest that controlled studies of these agents are justified.
KEY WORDS: Diffuse scleroderma, ATG, MMF.
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Introduction |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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Scleroderma is a condition characterized by progressive fibrosis of the skin and internal organs, by the development of proliferative vascular lesions, and by the production of autoantibodies [1]. The cause of scleroderma is not known. One possibility is that abnormalities of T-lymphocyte function underlie the development of the disease. Observations which support this model include the presence of perivascular T lymphocytes in early skin lesions [2], HLA-DR associations in certain subgroups of scleroderma [3], increased frequency of chimaerism for fetal stem cells, and clinical similarities to chronic graft-versus-host disease.
Rabbit anti-human lymphocyte globulin (ATG) is a polyclonal immunoglobulin preparation made by immunizing rabbits with human T-cell lymphoma cells which express CD3 and CD4 but not CD8. ATG therapy has proven beneficial as induction immunosuppression for the prevention of acute renal allograft rejection [4]. After the administration of ATG, a period of lymphopenia is followed by reversal of the normal CD4:CD8 ratio with predominance of the CD8-positive suppressor T-cell subset lasting up to 90 days [5, 6]. Anecdotal evidence suggests a beneficial response to ATG therapy in patients with severe scleroderma, and this further supports a role for abnormal T-lymphocyte function in the pathogenesis of the disease [7].
Mycophenolate mofetil (MMF) is an inhibitor of inosine monophosphate dehydrogenase and therefore inhibits the de novo pathway of purine synthesis [8]. MMF exerts a relatively specific inhibitory effect on lymphocyte proliferation, possibly because lymphocytes are dependent on this pathway for RNA-primed DNA synthesis, in contrast to other cells which employ a salvage pathway of purine synthesis [9]. MMF is a drug of choice for the long-term suppression of acute renal allograft rejection, for which purpose it has been shown to be effective and well tolerated [10]. Therefore, MMF has a proven in vivo suppressive effect on human T-lymphocyte function and should be studied as a possible treatment for scleroderma.
In the present pilot study we used a staged immunosuppressive regimen, with ATG as induction therapy designed to remove the T lymphocytes driving the disease, followed by 12 months of MMF therapy designed to prevent recurrence of the autoimmune process.
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Patients and methods |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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The patients satisfied the American Rheumatism Association criteria for scleroderma and were classified as having diffuse scleroderma according to internationally agreed guidelines [11, 12]. Local ethics committee approval was obtained, and the patients gave written informed consent to participation. The patients who were included had a disease duration of less than 2 years since the onset of skin change. Sequential new referrals to the connective tissue diseases unit were asked to participate in the study. The baseline characteristics of the patients studied are shown in Table 1
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Clinical assessment of disease severity
Clinical assessments were made at baseline and after 3, 6 and 12 months of MMF therapy. The severity of skin disease was measured by skin score by one of three trained observers (CMB, HW and RJS) using a standard technique as described previously [13]. Flexure contractures, reflecting mostly tendon and local muscle involvement, were measured from the tip of the right-hand middle finger to the distal wrist crease, using a steel rule.
Quality of life was measured with the EuroQol questionnaire (five items scored 1–3), completed by the patient, and a global health thermometer rating. Health-related quality of life was quantified using a time trade-off tariff ascribed to each EuroQol health state (perfect health=1, dead=0; scores less than 0 are possible for some health states) [14].
Functional capacity was studied using a functional assessment questionnaire with 11 items and four grades, specifically designed for patients with scleroderma [15] (score for no disability=0, total disability=33).
Laboratory investigation of internal organ function
Blood samples were taken at each follow-up visit for the determination of creatinine concentration and full blood count. Chest X-ray and pulmonary function tests were performed at baseline and after 12 months of MMF therapy. An echocardiogram with Doppler colour flow estimation of pulmonary artery pressure was recorded at baseline and after 12 months of MMF therapy.
Treatment
Patients received 2 days of i.v. Iloprost therapy followed by i.v. Fresenius ATG according to the following regimen: a test dose of ATG at 1 mg was followed by 3 mg/kg on day 1, 4 mg/kg on day 2, 5 mg/kg on day 3, 5 mg/kg on day 4, and 5 mg/kg on day 5. The lymphocyte count was checked daily and the dose of ATG was adjusted as follows: if the lymphocyte count was greater than 0.5x109/l, the full dose of ATG was given; if the lymphocyte count was 0.2–0.5x109/l, the ATG dose was reduced by 50%; if the lymphocyte count was less than 0.2x109/l, ATG therapy was delayed for 24 h. The ATG therapy was followed by a further 2 days of Iloprost therapy. As prophylaxis against the serum sickness reaction to ATG, prednisolone was given at a dose of 20 mg/day for 7 days, then reduced by 5 mg each week to a dose of 0 mg/day. Mycophenolate mofetil was commenced at week 4 at 0.5 g twice a day and increased to 1 g twice a day after a further 2 weeks, and was continued until 12 months.
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Results |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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Adverse events
ATG therapy was associated with the development of a severe serum sickness reaction in five of the 13 patients. Two of these patients required hospital admission for strong analgesic drugs and nursing care. In all cases the symptoms responded to a temporary increase in corticosteroid therapy. None of the patients developed major opportunistic infection during induction with ATG.
MMF was generally well tolerated. There were no episodes of neutropenic sepsis while on MMF. No patient withdrew because of abnormal liver function tests. Two patients complained of nausea during MMF therapy, which responded to temporary dose reduction to 0.5 g twice a day. One patient experienced diarrhoea during MMF therapy. One patient developed bronchopneumonia during MMF therapy; this was treated with oral antibiotics and temporary withdrawal of MMF. One patient developed shingles after 10 months of MMF.
Two patients withdrew from the study after 3 months because of inefficacy of treatment. Both patients were followed up for the 12-month study period and their clinical and laboratory measurements are included in the analysis.
There was one death during the study period, from scleroderma renal crisis 4 weeks after ATG had been given and before MMF therapy commenced (see below under Renal function).
Lymphopenic effect of treatment
The mean lymphocyte count at baseline was 1.82 (S.E.M. 0.18), the mean nadir lymphocyte count during ATG therapy was 0.61x109/l (S.E.M. 0.13), the mean lymphocyte count at 3 months was 1.3x109/l (S.E.M. 0.21), the mean lymphocyte count at 6 month s was 1.3x109/l (S.E.M. 0.27), and the mean lymphocyte count at 12 months was 1.2x109/l (S.E.M. 0.16).
Skin score
The mean scleroderma skin score decreased from 28 (S.E.M. 3.2) at baseline to 17 (S.E.M. 3.0) after 12 months of MMF (Wilcox signed rank test: Z=-2.6, P<0.01) (Table 2).
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Finger-to-palm distance
Finger-to-palm distance increased during the study from a mean of 13 mm (S.E.M. 6.6) at baseline to 26 mm at 3 months (S.E.M. 7.1, P<0.05), 30 mm at 6 months (S.E.M. 5.2, P<0.05) and 25 mm at 12 months (S.E.M. 3.7, no significant difference from baseline) (Table 2
). This suggests a worsening of hand contractures during the study period.
EuroQol score
There was no significant change in EuroQol score over the study period (mean EuroQol at baseline 0.54, S.E.M. 0.073; mean EuroQol at 12 months 0.49, S.E.M. 0.076; difference not significant) (Table 2).
Patient global health thermometer rating
There was no significant change in thermometer rating over the study period (mean score at baseline 57, S.E.M. 4.8; mean score at 12 months 60, S.E.M. 6.9) (Table 2).
Scleroderma functional assessment
There was no significant change in functional assessment score over the study period (mean score at baseline 10, S.E.M. 2.1; mean score at 12 months 9.1, S.E.M. 3.0) (Table 2).
Pulmonary function studies
There was no significant change in mean forced vital capacity (FVC) over the study period (mean FVC at baseline 87% of predicted value, S.E.M. 3.9%; mean FVC after 12 months 88% of predicted value, S.E.M. 7.1%). Also, the mean carbon monoxide transfer factor (TLCO) did not change significantly (mean TLCO at baseline 66% of predicted value, S.E.M. 5.0%, mean TLCO after 12 months 63%, S.E.M. 6.0%).
One patient developed severe fibrosing alveolitis during the study period, with a deterioration of over 20% in FVC and the development of ground-glass shadowing on pulmonary CT scan.
Echocardiogram
No patient developed evidence of left ventricular impairment during the study period. One patient developed echocardiogram evidence of pulmonary hypertension during the study, with a mean systolic pulmonary artery pressure of 35 mmHg after 12 months of MMF therapy.
Renal function
Two patients developed a raised plasma creatinine concentration outside the normal range during the study. In one patient, scleroderma renal crisis developed shortly after induction with ATG, with progression to end-stage renal failure and death from orthostatic pneumonia. A second patient developed scleroderma renal crisis after 3 months of MMF therapy. In this patient the peak creatinine concentration was 238 µmol/l and renal function improved on ACE inhibitor therapy, the creatinine concentration falling to 146 µmol/l at the end of the study period. The mean serum creatinine concentration did not change over the study period (mean creatinine concentration at baseline 81 µmol/l, S.E.M. 3.6; mean creatinine concentration after 12 months 87 µmol/l, S.E.M. 7.9; difference not significant).
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Discussion |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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In the present study we pursued a course of aggressive immunosuppression in a group of patients with diffuse scleroderma. The overriding principle of this approach is that diffuse scleroderma is a severe disabling condition with a poor prognosis, comparable to that of a malignant disease [16]. For several years we have been using ATG to treat diffuse scleroderma and have observed a beneficial effect. However, some patients have experienced a relapse months or years after the course of treatment. Therefore, in the present study we chose to use induction therapy with ATG, followed by maintenance therapy with MMF designed to prevent relapse. This treatment protocol is analogous to the regimens used to prevent allograft rejection.
A biological anti-lymphocyte effect of ATG therapy was observed in the present study, with lymphopenia during the ATG treatment period and resolution to normal lymphocyte counts by 3 months. This supports our study design using maintenance immunosuppressive therapy following ATG induction.
In the present study there was a high incidence of serum sickness reaction following induction with ATG. Subsequently, we have found that by using a higher level of prednisolone cover (30 mg for the first week after ATG, then reducing by 5 mg each week), this complication can be avoided. One patient died from scleroderma renal crisis in the weeks following ATG induction. This patient suffered a typical scleroderma renal crisis with accelerated hypertension, microangiopathic haemolytic anaemia and typical renal histology. Accelerated hypertension and renal failure are not described as complications of ATG, and we do not believe that this death was a complication of ATG therapy. One further patient developed renal impairment during the fourth month of the study period, again with typical features of scleroderma renal crisis. A previous study found that scleroderma renal crisis affected about 8% of patients with scleroderma who were followed over a 25-yr period, although patients with recent-onset diffuse scleroderma were predominantly affected [17]. Therefore, we do not believe that the incidence of scleroderma renal crisis was excessive during the period of our study. No other serious adverse events were recorded following ATG therapy, although opportunistic infections, especially with cytomegalovirus, have been reported following this treatment [18].
No previous study has measured the effect of MMF in scleroderma. In the present study we found that MMF therapy was well tolerated by scleroderma patients, with a low incidence of side-effects, all of which were benign and self-limiting. Measures of quality of life, functional assessment and global health were unchanged during the 12 months of MMF treatment. The skin score was found to improve during this period, whereas hand contractures were found to deteriorate. Although this appears conflicting or counter-intuitive, we suggest that the observed hand contractures were due to subdermal sclerosis involving the forearm muscles and tendons, which would not be reflected in the skin score. Measures of pulmonary function did not change during MMF therapy, although one patient developed active fibrosing alveolitis during the study.
The natural history of recent-onset diffuse scleroderma is one of progressive skin disease accompanied by the development of internal organ involvement. No firm conclusions regarding efficacy can be drawn from the present pilot study. The observed improvement in skin score and the stability of quality of life scores and functional assessment are consistent with some beneficial effect. The observed worsening of hand contractures and the development of major systemic complications of scleroderma in a minority of patients during the present study undermine this conclusion.
The major phenotypic abnormalities found in scleroderma include excessive collagen production by fibroblasts [19] and the development of occlusive vascular lesions [20], in addition to the abnormalities of lymphocyte function described above. Future treatment protocols for severe scleroderma may include additional therapies designed to suppress fibroblast function, and therapies to inhibit endothelial cell activation.
A large multicentre controlled study using a staged approach in the treatment of diffuse scleroderma is planned. There is reluctance in a number of centres to include a placebo arm in any study, and an alternative approach is a comparison of treatments of possible efficacy. ATG and MMF can now be considered amongst these therapies.
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Acknowledgments |
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The authors wish to acknowledge with grateful thanks the following physicians, who helped to recruit the patients included in this study and to monitor the laboratory results during MMF therapy: Dr J. Gibson, Dr N. Hurst, Dr J. A. Innes, Dr R. Jacoby, Dr Mowat, Dr J. Reardon, Dr M. Snaith and Dr G. R. Struthers.
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Notes |
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Correspondence to: C. M. Black, Department of Rheumatology, Royal Free Hospital, London NW3 2QG, UK
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References |
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