Intravenous cyclophosphamide pulse therapy in juvenile dermatomyositis. A review of efficacy and safety

P. Riley, S. M. Maillard, L. R. Wedderburn, P. Woo, K. J. Murray and C. A. Pilkington

Juvenile Dermatomyositis Research Centre, Institute of Child Health, Great Ormond Street, London, UK

Correspondence to: C. A. Pilkington, Juvenile Dermatomyositis Research Centre, Institute of Child Health, UCL, 30 Guilford Street, London WC1N 1EH, UK. E-mail: C.Pilkington{at}ich.ucl.ac.uk


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objectives. To assess the efficacy and safety of intravenous cyclophosphamide (CYP) used in severe and refractory juvenile dermatomyositis (JDM).

Methods. Retrospective case note review of the outcome of 12 patients.

Results. Assessment at 6 months of therapy in 10 of the 12 patients showed a significant improvement in muscle function as assessed by the Childhood Myositis Assessment Scale (CMAS) (P = 0.012), muscle strength (P = 0.008), global extramuscular disease score (P = 0.008), skin disease severity (P = 0.015) and lactate dehydrogenase (P = 0.028). There were reductions in creatine kinase, alanine aminotransferase, prednisolone dose and ESR, but these did not reach statistical significance. Clinical improvement was maintained after CYP until the most recent follow-up (between 6 months and 7 yr) and no severe side-effects were seen. Reversible complications included lymphopenia, herpes zoster infections and alopecia. The median cumulative dose was 4.6 g/m2 (range 3–9 g/m2). The available evidence suggests that, at the doses required, risks of malignancy, infertility and gonadal failure are low. Two patients with severe treatment-resistant disease died after one dose of CYP, both of whom were ventilated prior to commencement of CYP and were thought to have died as a result of their severe disease process, and too early for clinical benefit to be obtained from the drug.

Conclusions. In this cohort of children with severe and refractory JDM, CYP appeared to have provided major clinical benefit with no evidence of serious toxicity in the short term.

KEY WORDS: Juvenile, Dermatomyositis, Cyclophosphamide, Refractory, Ulcerative, Childhood, Vasculitis, Interstitial lung, Gastrointestinal.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Juvenile dermatomyositis (JDM) is a rare autoimmune disease characterized by non-suppurative inflammation of muscles, skin and other organs. Mortality is now limited to less than 10% but medium- to long-term morbidity is still experienced in over 25% of patients diagnosed with the disease [13]. Some patients are refractory to first- and second-line treatments, such as steroids and methotrexate. Others have a disease pattern which is associated with increased risk of morbidity, mortality and treatment resistance. Clinical features associated with such high risk include calcinosis, ulceration of the skin and gastrointestinal (GI) tract, and interstitial lung disease [24].

There is no current consensus on the management of such patients. A number of reports have described the use of cyclophosphamide (CYP) in JDM and adult DM patients, but the numbers have been too small to draw any conclusions and certainly no controlled trial evidence exists [57].

The Great Ormond Street paediatric rheumatology unit is a tertiary and quaternary referral centre. Approximately 12 new cases of JDM are seen each year. Since 1996 it has been the policy of the unit to treat patients with severe or refractory JDM with intravenous (IV) CYP. Clinical features which would warrant CYP treatment include severe muscle weakness, ulcerative skin disease, and organ involvement such as GI ulceration, interstitial lung disease and convulsions. This paper reviews our clinical experience with these patients.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Data collection and analysis
We identified 12 patients with a diagnosis of definite or probable JDM [8, 9] who were treated with IV pulse CYP therapy between 1996 and 2002. A retrospective case note review was undertaken documenting assessments of disease activity at initiation of treatment with CYP, after completion of 6 months of treatment and at the last clinic visit. Data recorded included sex, race, age at disease onset, duration of active disease prior to commencement of CYP, presence of calcinosis and previous therapy. Each cyclophosphamide dose was recorded as the dose per m2 and the overall cumulative dose was calculated.

Muscle involvement was measured using the Childhood Myositis Assessment Scale (CMAS) and MRC Oxford scale muscle strength scores. The CMAS has been validated as an assessment of muscle stamina and function in JDM [10]. A score is given for each of 14 exercises and the maximum total score is 53. The CMAS was not used in four of the patients who were treated before the score was being used at our centre. The Oxford Scale was used to document muscle strength, with five muscle groups analysed. These were neck flexors, hamstrings, hip abductors, shoulder abductors and quadriceps. 0.5 was added or subtracted if a plus or negative was attached to the score. (i.e. 4+ scored 4.5 and 4- scored 3.5). These were added together, so that the potential total score was 25.

At present there is no validated objective scoring system for assessment of extramuscular disease in JDM. An international collaborative group is developing such a tool (MITAX; Myositis Intention to Treat Index) [11]. This scoring system was used in a modified form, to enable data to be collected retrospectively. A three-point scale was used for each category of extramuscular disease manifestation. The seven areas assessed were constitutional, skin, skeletal, pulmonary, GI, cardiological and central nervous system (CNS). Table 1 illustrates the method for this score, for which there was a maximum of 21.


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TABLE 1. The scoring system for extramuscular disease

 
The laboratory measures used to document muscle disease activity were creatine kinase (CK), lactate dehydrogenase (LDH) and alanine aminotransferase (ALT). Aldolase and aspartate aminotransferase were not routinely tested during this time period. Full blood count with neutrophil and lymphocyte differential was recorded and, as a general marker of inflammation, ESR was noted. Any adverse effects or side-effects that occurred during and after the period of treatment were also noted.

Data were analysed using the SPSS software package. As the data were not normally distributed, a statistical comparison between the 0- and 6-month scores was made using the Wilcoxon signed ranks test. A P value of <0.05 was taken as significant.

Drug administration
Our CYP treatment protocol was based on the IV CYP protocol for lupus nephritis [12, 13]. Mesna (sodium 2-mercapto-ethanosulphate) (20% of CYP dose) was given with the hydration (85 ml/m2/h of 4% glucose/0.18% saline) during and until 12 h after CYP. Intravenous ondansetron (5 g/m2) was given prior to the CYP. The CYP was given over 1 h. The initial CYP dose of 0.5–1 g/m2 was given. This was increased by 0.25 g/m2 at the next dose if the white cell count 10–14 days afterwards did not fall significantly. The dose was reduced by 25% if this count was below 2000/mm3 or neutrophils were below 1000/mm3. No patient was given more than 1 g/m2. The CYP was administered monthly for six or seven doses, except with severe disease, when the second dose was given in the third week (after day 10–14 bloods). After this initial 6-month period, subsequent doses were then given at 3-monthly intervals. If no severe disease activity was noted 3 months after the last dose, the CYP treatment was considered completed. No patients were restarted on CYP after this period.

The project was registered at the Institute of Child Health/Great Ormond Street Research and Development office.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
Twelve children were treated with CYP for severe or resistant JDM. During the 6 yr that these 12 patients were treated, 60 cases of JDM were referred to the unit. The demographic and clinical data of these patients are shown in Table 2. There was an equal sex distribution in the cohort, of whom nine were Caucasian and three were Afro-Caribbean. The median age at diagnosis was 5 yr (range 2–10 yr) and median disease duration before initiation of CYP was 11 months (range 2 months to 3 yr). All of the patients had received high-dose steroids (oral or IV) and 9 had been treated with at least one DMARD or IV immunoglobulin (IV Ig). Major systemic manifestations included CNS vasculitis, GI vasculitis and pleural effusion. During this period all eight patients who presented with ulcerative skin disease were treated with CYP. The two patients treated after only 2 months of disease (patients 4 and 5, Table 2) both had severe ulcerative skin disease. Patient 1 presented to our unit from another country, after 8 months of disease, but had been untreated previously. She had severe dysphagia as well as severe weakness and was given CYP after only 3 days of IV MP (MP).


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TABLE 2. Demographic and clinical data of the 12 patients treated with CYP

 
Therapeutic efficacy
Two of the 12 patients given CYP died before the drug could be effective. At the time of administration they were both ventilated. Their ages at disease onset were 4.3 and 2 yr and their disease duration was 1 and 2.5 yr respectively. Both patients were suffering from pulmonary insufficiency. The first of these was from interstitial lung disease and the second had brainstem vasculitis causing central respiratory depression. Both had ulcerative skin disease for a prolonged period.

The median cumulative dose of the 10 surviving patients was 4.6 g/m2 (mean 5.4 g/m2) (range 3–9 g/m2). Between 6 and 14 doses were given, with a median and mean of 8.5 doses. Nine of these 10 patients treated with a full CYP course received concurrent DMARD medication. Of these, eight were treated with methotrexate and one with cyclosporin. The doses of methotrexate and cyclosporin were not reduced during the CYP course. Eight patients received IV MP in the first 2–3 weeks of treatment due to severe disease. One patient who had persistently active skin disease received IV MP before the fourth dose of CYP. Seven of the 10 surviving patients received their second CYP dose early, 3 weeks after their initial dose.

The laboratory and outcome measure data from these 10 patients are shown in Table 3. An excellent response was seen in all 10 patients, who showed improvements 6 months after CYP initiation, which included significant gains in muscle function (CMAS) (P = 0.012) and strength (P = 0.008), significant improvement in skin (P = 0.015), and a significant reduction in the extramuscular disease activity score (P = 0.008). The main persisting extramuscular feature after 6 months was skin disease, but in all patients the ulcerative disease had been successfully treated. A significant decrease in LDH was noted (P = 0.028), as was a marked reduction in CK, which did not reach significance because of the initial wide variation in range (P = 0.093). The ESR and ALT were also decreased, but not significantly during the 6-month treatment period. There was also an apparent reduction in maintenance oral steroid requirements, but this did not reach statistical significance (P = 0.079).


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TABLE 3. Comparison of clinical and laboratory data in the 10 surviving patients before CYP treatment and 6 months after treatment initiation

 
Since completing the CYP course, all of the 10 surviving patients have at least maintained their improved clinical states, and most have continued to improve. Clinical scores at CYP initiation, 6 months after initiation, and at last follow-up are shown in Table 4. Some patients, such as patients 2 and 6, have recently completed their course, but some patients, such as patient 10, have been followed up for almost 7 yr.


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TABLE 4. Clinical and laboratory parameters showing individual patient data at time of CYP initiation: 6 months after treatment initiation and at last follow-up

 
Patients 8 and 6, though improved with CYP, still had active disease and were subsequently treated with an anti-TNF drug (infliximab). Patient 8 had received 14 doses and CYP was discontinued as no further improvement was noted.

Calcinosis was present in one of the children who died. It was unchanged in three others by the end of the treatment, but no worsening was noted.

Side-effects
Side-effects included one episode of febrile neutropenia. This was treated without complication with IV broad-spectrum antibiotics. Another episode of neutropenia occurred at first dose whilst patient 10 was in intensive care following laparotomy for severe gut vasculitis and pancreatitis. This was covered prospectively with broad-spectrum antibiotics. Macroscopic haematuria was not seen in our study patients. Microscopic haematuria was rare, with only two recorded instances (both 3 plus on urinalysis) during all the CYP infusions. Three children had localized herpes zoster infections treated with aciclovir, and four had alopecia, which resolved completely after cessation of the CYP course. Three local cellulitic infections occurred at sites of calcinosis. Nine of the 10 surviving patients developed lymphopenia during the CYP course; however, recent data show that this recovered between 3 and 12 months after completion of the therapy.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
At present there are only small case report series dealing with severe or refractory JDM. Drugs used in this situation have included cyclosporin, immunoglobulin and CYP [1417]. Patients 12 and 9 [5] and 10 [6] have been reported previously. To our knowledge this is the largest reported series of JDM patients treated with CYP.

In this retrospective analysis of patients with severe or refractory JDM, treatment with IV CYP appears to have resulted in major clinical benefit with no evidence of serious short-term toxicity. The skin (especially ulcerative), muscular and extramuscular features of the disease improved, and this improvement was maintained following discontinuation of treatment. A feature of some reports concerning cyclosporin and immunoglobulin is the relapse of a number of patients after stopping the therapy.

In patients 1, 4 and 5, CYP has been used early on in disease treatment due to the severity of presentation. The improvement in the patients’ condition could be attributed to other medications started concomitantly. However, the other nine patients had all been treated for a prolonged period with steroids and DMARDs and any improvements in these patients can be attributed to the initiation of CYP. Evidence has shown that over 35% of JDM patients are still on treatment 3 yr after diagnosis [1]. This study is not able to determine if CYP use shortens the duration of the disease.

The two children who died had received CYP in the last week of a prolonged and severe disease course, and were thought to have died as a result of their disease process, and too early for clinical benefit to be obtained from the drug. Both had been suffering from ulcerative disease for a prolonged period. An earlier use of CYP when this skin sign presented may have prevented the significant worsening of their disease. The two patients (patients 8 and 6) who had a good but incomplete clinical response were also treated late in their disease course. Delay in starting effective treatment in children with JDM may result in inadequate response to treatments. Cronin et al reported on the failure of IV CYP in 12 adults with idiopathic inflammatory myopathy [18]. Although only two of these patients had dermatomyositis, the others suffered from overlap, polymyositis or inclusion body myositis, it is interesting to note that the CYP was given late in their disease course.

CYP is used in our unit as a third-line treatment for remission induction in severe or refractory JDM. Eight of the 10 surviving CYP patients were treated with methotrexate (MTX) and prednisolone concomitantly. Therefore, it was not possible to analyse data from those children receiving steroids and MTX, with CYP, compared with those who did not.

If, in our future practice, a patient were to have evidence of a severe flare after the cessation of CYP we would consider reinduction with CYP. There would be obvious concerns, as a greater cumulative dose would increase the risk of long-term side-effects, but this is balanced against the risk of the short-term complications of a severe flare. In moderate activity resistant to DMARDs we would now consider the use of an anti-TNF drug, as in the case of patients 8 and 6 (both infliximab).

There were no major short-term side-effects resulting from treatment with CYP. Problems experienced by our patients are similar to those reported in the children who received CYP for lupus nephritis, and who have generally received a higher cumulative dose than the JDM patients in our cohort (8–16 g/m2 compared with 3–9 g/m2). There have now been multiple studies of short-term effects in adult and paediatric SLE, with a similar low side-effect profile [12, 13, 19, 20].

The three main long-term concerns for any patient after CYP are malignancy, infertility and gonadal failure. Reported malignancies (skin, bladder and haematological) have most commonly been in adult patients receiving oral CYP at cumulative doses higher than 50 g [21, 22]. The peak incidence for these malignancies is 7 yr after CYP initiation. There are no reports of malignancy in children receiving low cumulative doses of IV CYP. A reassuring consideration is that this treatment has been common practice in children with SLE for over 10 yr. The youngest case report of malignancy in the SLE paediatric group that we could find is of a 17-yr-old girl given over 20 g oral CYP [23]. In the adult literature there are again only isolated case reports of malignancy after starting CYP in SLE. Most of these were associated with prolonged oral CYP [2426].

Three studies have shown infertility to be rare in boys receiving a cumulative dose lower than 7.5 g of CYP or 4 g/m2. The higher risk is felt to be at doses above 9 g/m2 or 25 g. Between these two boundaries oligospermia has been reported, some of which has been reversible. These studies do not agree on whether prepubertal boys have protection against this side-effect [2730].

Although testosterone was found to be normal in these patients, they were found to have raised luteinizing hormone/follicle-stimulating hormone, both basal and stimulated. This implies a possibility of compensatory Leydig cell failure. However, there were neither reports of failure to attain secondary sexual characteristics nor any problems with libido or impotence. The only theoretical concern is that these individuals may experience a premature andropause.

Premature ovarian failure (POF) is relatively common when CYP is administered to women over 30 yr, but very rare in those under 20 yr and only with very high doses. Wang et al. reported that only 4% of younger (<21 yr) female SLE patients receiving oral CYP suffered POF. These patients had received a cumulative dose over 40 g [31]. Boumpas et al. reported 12% of SLE patients <25 yr suffering POF on IV CYP; again, both had received higher cumulative doses (between 10 and 20 g/m2) [32].

There has been some success in adult patients who are about to be treated with CYP, aimed at inducing temporary chemical castration in males and females, with testosterone and gonadotropin-releasing hormone agonists respectively [33, 34]. However, there are obvious problems with this approach in the paediatric age range. Other methods that could be considered include sperm and oocyte cryopreservation, but these require sensitive handling in children.

In our study, relatively low cumulative doses of IV CYP significantly improved the skin, muscle and extramuscular disease in severe or treatment-resistant JDM, with minor reversible side-effects. Other reports show a similar short-term side-effect profile with IV CYP. The available evidence suggests that, with these relatively low doses, the risks of malignancy, infertility and gonadal failure should be low, but only long-term follow-up studies can determine this with complete confidence. Larger and prospective studies are required to fully assess the effect of CYP on JDM.

The authors have declared no conflicts of interest.


    Acknowledgments
 
The Juvenile Dermatomyositis Research Centre (JDRC) (Institute of Child Health) is supported by grants from the Cathal Hayes Research Foundation. We thank Dr Joyce Davidson for careful reading of the manuscript and Ms Elizabeth Halkon and Ms Virginia Brown for their work as research coordinators at the JDRC.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Submitted 27 June 2003; Accepted 22 October 2003





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