Rheumatol Int (2007) 27:357–361 DOI 10.1007/s00296-006-0217-1
O RI G I NAL ART I C LE
Combination of intravenous pulses of cyclophosphamide and methylprednizolone in patients with systemic sclerosis and interstitial lung disease George Yiannopoulos · Vassilios Pastromas · Ioannis Antonopoulos · George Katsiberis · George Kalliolias · Stamatis-Nick Liossis · Andrew P. Andonopoulos
Received: 8 April 2006 / Accepted: 12 August 2006 / Published online: 22 September 2006 © Springer-Verlag 2006
Abstract The purpose of the study was to examine prospectively the eYcacy and safety of the combination of intravenous pulses of cyclophosphamide and methylprednizolone, in the treatment of scleroderma lung disease. Thirteen patients were treated with the above combination for up to 24 months. Prior to this treatment, they underwent a pulmonary function evaluation and high resolution computed tomography (HRCT). Carbon monoxide diVusion lung capacity and forced vital capacity were repeated at 6, 12, 24 and 48 months. HRCT was repeated at the end of the treatment period, but in between and afterwards in some patients, as well. A signiWcant percentage of patients (66.6%) showed stabilization or improvement of their pulmonary function. Patients with already seriously compromised function, before treatment, were the least likely to exhibit this evolution pattern. There was a tendency in some individuals to deteriorate on later evaluations, oV treatment, although they had stabilized at the end of the treatment. There was rather a poor correlation between functional evolution and HRCT appearance. Finally, the regimen was well tolerated. Our results suggest that the employed combination is safe and eVective, mainly in stabilizing the respiratory function of the patients. This goal is more realistic
G. Yiannopoulos · I. Antonopoulos · G. Kalliolias · S.-N. Liossis · A. P. Andonopoulos (&) Department of Medicine, Division of Rheumatology, University of Patras School of Medicine, 265 00 Rio, Patras, Greece e-mail:
[email protected] V. Pastromas · G. Katsiberis Department of Radiology, University of Patras School of Medicine, Patras, Greece
when treatment is given before signiWcant functional compromise has ensued. The need for long-term immunosuppression to maintain the initial favorable response is suggested. Keywords Scleroderma · Pulmonary function · Cyclophosphamide · Methylprednizolone
Introduction Interstitial lung disease, aVecting a signiWcant portion of the scleroderma population, is the most common cause of death in this disease. Although a direct correlation between early alveolar inXammation and progression to Wbrosis has not been deWnitely established, it is widely believed that treatment of alveolitis is of critical importance, in order to avoid Wbrosis and signiWcant compromise of respiratory function. Since the early 1990s, cyclophosphamide has been used, alone or in combination with steroids, in the treatment of scleroderma lung disease. Experience so far suggests that this drug, administered orally [1–4] or intravenously [5–12], may have some modifying eVect upon the course of this process [1–7]. However, because of lack of double blind placebo controlled studies, this treatment is still considered empirical. Recently, at the ACR 2005 meeting, the results of a double blind placebo controlled study, involving 162 patients for 12 months, were presented. Orally administered cyclophosphamide had a statistically signiWcant, but clinically mild, eVect on the course of forced vital capacity (FVC) over 1 year [4]. Since the combination of intravenous pulses of cyclophosphamide and methylprednizolone has only
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been reported in two studies so far [8, 10], we decided to present our own experience with this combination upon the respiratory function and the HRCT chest appearance of a cohort of systemic sclerosis patients with lung involvement, studied in a prospective manner.
Patients and methods
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lines, four to honeycombing and Wve to subpleural cysts. A severity score was obtained by adding the above points. An extent of disease score was obtained by counting the number of lung segments presenting the described abnormalities. One point was given for involvement of 1–3 lung segments, two points for 4–9 segments involvement and three points for disease of 10 or more segments. The total HRCT score was obtained by adding the severity score and the disease extent score (range between 0 and 30).
Patients Treatment We studied prospectively 13 patients (9 women and 4 men) with systemic sclerosis, with mean age 54.5 § 16.4 years (range between 18 and 76) and mean disease duration, except for one patient who presented 20 years after diagnosis, 14.2 § 8.3 months (range between 3 and 33 months), attending our rheumatology outpatient clinic. Besides Raynaud’s phenomenon and skin and lung involvement, six patients had severe esophageal disease and two developed pulmonary hypertension (severe, functional class IV according to NYHA in one), secondary to the interstitial lung disease. All patients reported dyspnea on exertion and dry cough. Lung disease in all the patients, except for one who presented to us quite late, had appeared within the Wrst year after the onset of disease symptoms. Fluorescent ANA were present in all, anti-Scl70 in seven and anti-U1nRNP in two. Assessment of respiratory function After enrollment, all patients had their respiratory function examined before commencement of treatment and after 6, 12, 24 and 48 months. FVC and carbon monoxide diVusion lung capacity (DLCO) were the two parameters speciWcally evaluated and the results were given as percentages of predicted. An increase of 15% or more suggested improvement, a decrease of the same magnitude was considered deterioration, whereas stabilization was suggested by a less than 15% change. HRCT assessment All the patients had an HRCT before the onset of treatment and at the end of that, whereas eight of them underwent additional HRCTs in between and during follow up. Films were read blindly by a radiologist with expertise in HRCT. Lung parenchymal abnormalities were graded according to Warrick et al. [13]. One point was assigned to ground glass appearance, two points to irregular pleural margins, three to septal/subpleural
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All the patients, except for one who presented very late with advanced disease, received treatment within 1 year (mean 6.0 § 4.1 months) after lung disease had manifested itself. Criteria for enrollment in the study included HRCT abnormality (ground glass appearance) and/or recent deterioration of FVC and/or DLCO. Treatment consisted of monthly intravenous pulses of cyclophosphamide (750–1,000 mg/m2) combined with 1 g of methylprednizolone. In between, the patients had been receiving small dose oral daily steroids (6–8 mg of methylprednizolone). Three patients received only six monthly pulses, whereas ten continued for 12 to 18 more months with bimonthly administered pulses. Statistical analysis For statistical analysis of the results, Student’s t test was used, where indicated.
Results Twelve out of the thirteen patients completed the study whereas one has not yet completed the 18-month period of bimonthly pulses. The values of DLCO of the individual patients as well as the mean values at each time point are shown in Table 1. There were no statistically signiWcant diVerences between the mean values, at any time point, compared to each other in any combination. After the Wrst 6 months of treatment, DLCO deteriorated in three patients (23.1%), improved in two (15.3%) and stabilized in eight (61.5%). The picture remained virtually unchanged for six more months. However, at the completion of treatment, 24 months after the start, four of the twelve patients exhibited deterioration of DLCO (33.3%), two improvement (16.6%) and six stabilization (50.0%). The patients were further evaluated at 48 months after treatment onset. At that point, compared to baseline, DLCO had deteriorated in Wve
Rheumatol Int (2007) 27:357–361 Table 1 DLCO (% predicted) values of the patients at various time points
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Patient #
Baseline
6 months
12 months
1 2 3 4 5 6 7 8 9 10 11 12 13 Mean § SD
44 51 93 59 51 80 29 28 86 50 51 74 74 59.2 § 20.7
44 41 107 29 51 77 26 23 86 51 80 92 73 60.0 § 27.4
44 41 100 30 50 74 26 23 92 51 83 91 66 59.3 § 26.7
(41.6%), improved in four (33.3%) and remained stable in three (25.0%). It should be noted that of the Wve patients who exhibited deterioration of DLCO at 48 months, two had stabilized this parameter at the end of the 24-month treatment. However, it is also important to notice that three of the Wve patients, who deteriorated, had already very low DLCO values before treatment had been started, ·51% of predicted value. Table 2 shows the FVC values of each patient and their mean values at each time point. Again, the diVerences between the values at any time point, compared to each other in any possible combination, were not statistically signiWcant. Six months after treatment onset, FVC deteriorated in two patients (15.3%), improved in one (7.6%) and stabilized in ten (76.9%). Respective Wgures at 12 months of treatment are three (23.0%), two (15.3%) and eight (61.5%), whereas at 24 months these Wgures are modiWed to four (33.3%), two (16.6%) and six (50.0%), respectively. Finally, 48 months after treatment was commenced, the Wgures were exactly the same as at the end of 24 months. Five of the 13 patients showed deterioration of the total HRCT score (38.4%) whereas in eight, it Table 2 FVC (% predicted) values of the patients at various time points
24 months
48 months
45 52 89 33 41 74 27 22 84
33 74 86 32 36 72 35 Died 98
62 85 57 55.9 § 23.3
83 103 61 61.3 § 28.5
improved or stabilized (61.5%). The mean HRCT score value was 11.8 § 6.1 pretreatment and 12.7 § 6.9 afterwards (P not signiWcant) (Table 3). It is important to notice that the evolution of this score did not accurately correlate, in all the patients, with that of the pulmonary function. Two of them showed functional deterioration despite improvement of their HRCT score, and another two exhibited the opposite. One patient (#8), who had presented very late with advanced disease and had completed the study, died 32 months after the start of treatment, because of severe pulmonary hypertension and cor pulmonale. Our treatment was not complicated by any serious side eVects. Furthermore, scleroderma renal crisis did not appear in any of the patients, up to the point of the Wnal evaluation.
Discussion In this study, we aimed at determining the eVectiveness of the combination of cyclophosphamide and methylprednizolone, given in intravenous pulses, in retarding
Patient #
Baseline
6 months
12 months
24 months
48 months
1 2 3 4 5 6 7 8 9 10 11 12 13 Mean § SD
72 96 117 59 57 96 64 39 104 69 100 123 94 83.8 § 25.5
73 96 116 57 54 119 72 29 102 65 88 104 101 82.8 § 26.9
74 94 116 49 52 127 76 29 104 65 88 104 107 83.5 § 29.0
74 94 117 46 48 132 76 28 100
61 107 125 42 35 129 77 Died 102
91 101 102 84.1 § 30.9
92 118 102 90.0 § 32.3
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the progression of pulmonary disease of systemic sclerosis. Our results suggest that a signiWcant percentage of aVected individuals beneWt from this treatment, by stabilizing their FVC and DLCO and even improving, albeit to a much lesser degree, these parameters. It should be noted though that the mean value of both these parameters did not show a statistically signiWcant change. The latter may be related to the small number of our patients. Changes of the FVC in the range of 1% were considered to be signiWcant statistically in the recent ACR study [4] that involved 162 patients, but such changes in our study were not. Our results are in agreement with those of previous studies. In all of those, either open prospective or retrospective, cyclophosphamide, administered orally [1–4] or intravenously in pulses [5–12], resulted in improvement or stabilization of the respiratory function. Our prospective study helps to expand the limited, so far, experience with intravenous pulses of cyclophosphamide in scleroderma lung disease and to answer positively the question about a comparable to oral cyclophosphamide eVectiveness, but with less toxicity, of this regimen. Combined administration of high dose methylprednizolone in intravenous pulses has been reported in two more studies [8, 10]. The question about the role of this particular combination remains to be answered. Our study cannot answer that because we had not included a control population, receiving small oral dose steroids. In the study by Pakas et al. [8], a statistically signiWcant diVerence between the small oral and high intravenous steroid administration, in favor of the latter, was noted. On the other hand, in the study by Giacomelli et al. [9], in which the most noticeable improvement by cyclophosphamide had been reported, high dose methylprednizolone pulses had not been given. Another important observation that we made, during the long follow up period of our patients, was the fact that a portion of them, although they had improved or stabilized their respiratory function at the end of the 24-month treatment period, at a later evaluation, oV treatment, showed deterioration. More precisely, the percentage of our patients that showed improvement or stabilization of DLCO at the end of the 24-month treatment, 76.6%, fell to 58.3% at subsequent evaluations, oV treatment. These Wgures were more pronounced in the study by GriYths et al. [10]. The above Wndings raise questions about the probable necessity of additional courses of the treatment or the introduction of other long-term immunosuppressive regimens, in order to maintain the initial favorable response. Which such treatment might be more suitable and for how long are still unresolved issues. In one of our patients who showed deterioration after the ini-
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Rheumatol Int (2007) 27:357–361 Table 3 HRCT scores of the patients Patient #
Baseline
1 2 3 4 5 6 7 8 9 10 11 12 13 Mean § SD
11 20 8 9 5 18 17 21 17 10 6 3 8 11.8 § 6.1
After 24 months 10 20 4 9 18 10 17 23 22 6 10 2 14 12.7 § 6.9
tial 24-month course, a second cycle was repeated at 3 years unsuccessfully. Two more such patients have been placed on mofetil mycophenolate and are being currently evaluated. Another patient, after stabilization, has been placed on azathioprin. Regarding the HRCT evaluation, we noticed a discrepancy between the functional and the radiologic processes in four of our patients, with two of them showing functional deterioration despite improvement of their HRCT score, and the other two exhibiting the opposite. In any case though, the radiologic scores were low, just above the cut-oV of clinical importance [13]. Furthermore, we were unable to correlate the evolution of respiratory function parameters with the presence or absence of ground glass appearance on HRCT. These discrepancies are somewhat diYcult to be explained, given the lack of pathologic information. Similar discrepancies have been noted in the study by GriYths et al. [10]. Our above Wndings and those of other relevant studies emphasize the fact that the most realistic approach of the evolution of sceroderma lung disease is by close follow up of the pulmonary function parameters, DLCO and FVC. Another point worth noting is that, in the present study, a signiWcant percentage of patients with pulmonary function already compromised signiWcantly, before treatment was started, deteriorated despite treatment. This emphasizes the need for early aggressive immunosuppressive treatment, before the establishment of severe functional impairment. Finally, our therapeutic regimen was safe and well tolerated. The fact that scleroderma renal crisis had not been encountered in any of our patients, as well as in any of the patients of the other two studies where intravenous pulses of methylprednizolone were employed [8, 10], suggests that this regimen may be safer than moderate daily oral dose steroid administration.
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In conclusion, the combination of intravenous pulses of cyclophosphamide and methylprednizolone appears to beneWt the patients with sleroderma lung disease, by stabilizing or improving a signiWcant percentage, especially of those without already established severe functional impairment. Deterioration of a signiWcant number of these patients, after completion of the regimen and during the oV treatment follow up period, strongly suggests the need for employment of an appropriate maintenance treatment, probably according to the paradigm of systemic lupus erythematosus and vasculitis. For this purpose, double blind controlled studies will need to be performed in the near future. References 1. Silver RM, Warrick JH, Kinsella MB, Staudt LS, Baumann MH, Strange C (1993) Cyclophosphamide and low-dose prednisone therapy in patients with systemic sclerosis (scleroderma) with interstitial lung disease. J Rheumatol 20:838–844 2. Steen VD, Lanz JK, Conte C, Owens GR, Medsger TA (1994) Therapy for severe interstitial lung disease in systemic sclerosis: a retrospective study. Arthritis Rheum 37:1290– 1296 3. Akesson A., Scheja A, Lundin A, Wollheim F (1994) Improved pulmonary function in systemic sclerosis after treatment with cyclophosphamide. Arthritis Rheum 37:729–735 4. Clements P, Furst DE, Silver RM, Tashkin DP, Roth MD, Goldin J, ElashoV RM,Sterz MG, for the SLS Investigators (2005) The Scleroderma Lung Study (SLS) shows the beneWcial eVects of cyclophosphamide over placebo in systemic sclerosis patients with active alveolitis. Arthritis Rheum 52(Suppl:s257) 5. Schnabel A, Reuter M, Gross WL (1998) ntravenous pulse cyclophosphamide in the treatment of interstitial lung disease
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