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British Journal of Rheumatology 1998;37:1240–1242 PAEDIATRIC RHEUMATOLOGY SERIES EDITOR: P. WOO THE USE OF INTRAVENOUS PULSED METHYLPREDNISOLONE IN THE TREATMENT OF SYSTEMIC-ONSET JUVENILE CHRONIC ARTHRITIS A. O. ADEBAJO and M. A. HALL Department of Paediatric Rheumatology, Wexham Park Hospital, Slough SUMMARY An open prospective study using i.v. methylprednisolone in children with juvenile chronic arthritis (JCA) who had had a systemic exacerbation of disease is described. Eighteen children aged from 3 to 14 yr and 9 months (mean 9.7 yr) were treated. Ten patients (55%) had a loss of all systemic features 1 month after the pulse, and eight (45%) had a reduction in the active joint count. At this time, five of the patients on oral prednisolone had achieved a reduction in dosage. Also at 1 month, a reduction in erythrocyte sedimentation rate was observed in 11 patients (61%) and of C-reactive protein in 11 of 16 (72%). Altogether, 13 patients (72%) had a good response, while a further three (16%) went into remission. Our conclusions are that pulse methylprednisolone provides good short-term benefit in patients with systemic-onset JCA; no serious side-effects were noted. Further long-term studies are warranted. K : Intravenous pulse methylprednisolone, Paediatric, Systemic onset, Juvenile chronic arthritis. I pulse methylprednisolone is a recognized and accepted form of treatment for inflammatory arthritides. In adult rheumatoid arthritis, pulses of methylprednisolone have been used in patients refractory to other treatments, as well as during initiation of a remittive agent or during a relapse [1–4]. Furthermore, it has been suggested that corticosteroids given in this manner show a more favourable risk/ benefit ratio than when oral corticosteroids are used [1, 3, 5, 6 ]. These studies have shown that there are significant short-term beneficial clinical effects of pulse methylprednisolone, such as reduction in the articular index, morning stiffness and pain score [2, 7], accompanied by a reduction in erythrocyte sedimentation rate ( ESR), C-reactive protein (CRP), circulating immune complexes and rheumatoid factor levels [8]. Osteoblast and osteoclast inhibition, reduction in calcium absorption, serum calcium and renal calcium excretion, an increase in 125 hydroxy vitamin D level and an increase in parathyroid hormone after 24 h, have all been noted, but are short lived [8]. In two studies using pulse methylprednisolone in children with juvenile chronic arthritis (JCA), a beneficial effect has been noted [9, 10]. However, these studies have included all the different subgroups of disease [11], with small numbers in each subgroup. Our experience with methylprednisolone pulses in JCA suggests that children with systemic-onset disease are those most likely to benefit. As the systemic features of the disease are usually the most difficult to control, and some disease-modifying anti-rheumatic drugs (DMARDs) are harmful as well as ineffective in the systemic state [12], it seemed sensible to look at the effect of this form of therapy in such children. MATERIALS AND METHODS The open study was carried out prospectively with ethical approval. Eighteen children with a systemic flare of their disease were studied. Assessments as described below were not made blind. The characteristics of these patients are shown in Table I. Of the 18 patients, 13 were male; at the time of pulsing, the age of these patients ranged from 3 to 14 yr and 9 months (mean 9.7 yrs). The mean age at disease onset was 5.6 yr (1–14). The duration of the disease was from 6 months to 11 yr and 1 month (mean 6.2 yrs). All patients were taking a nonsteroidal anti-inflammatory drug, 12 patients were on DMARDs and 13 on oral steroids (Table I ). Systemic features, defined as the presence of at least two of the following—fever, rash, hepatosplenomegaly, lymphadenopathy, serositis and myocarditis—were documented, as were the duration of morning stiffness in minutes, active (tender) joint count and functional status using Steinbrocker’s grade [13]. Prior to the administration of the methylprednisolone i.v. pulse, a physical examination and a throat swab and urine culture were performed, to exclude any occult infection. Haemoglobin, white count, platelet count, ESR and CRP were measured prior to the pulse and at 1 month post-pulse. The pulse and blood pressure were measured immediately before and every 15 min during the infusion, and continued for 1 h postinfusion. The dosage of methylprednisolone was 30 mg/kg to a maximum of 1 g [10]. The drug was administered in normal saline over 1 h and repeated as necessary when the systemic manifestations of the disease recurred [10], but not more frequently than every fourth day. Eight patients had one pulse, seven patients had two and four patients had three. Submitted 9 December 1996; revised version accepted 19 May 1998. Correspondence to: M. A. Hall, Department of Paediatric Rheumatology, Wexham Park Hospital, Slough SL2 4HL. RESULTS One month after the first pulse of methylprednisolone, 10 patients (55%) had a loss of all systemic © 1998 British Society for Rheumatology 1240 ADEBAJO AND HALL: PULSE METHYLPREDNISOLONE IN SYSTEMIC-ONSET JCA 1241 TABLE I Characteristics of patients Age at disease onset (yr) Age at pulse (yr) Mean 5.6 (1–14) Medication at time of systemic flare NSAIDs 18 features, eight had a reduction in active joint count ( Table II ). Ten patients showed improvement in Steinbrocker’s functional grade. Among the 16 patients with morning stiffness, nine patients (56%) had a reduction at 1 month. Of the 11 patients on oral prednisolone, a reduction in the prednisolone dosage had been achieved in five (45%). At 1 month, the laboratory variables measured showed a rise in haemoglobin of 1 g or greater in 12 patients (60%). Similarly, a reduction in thrombocytosis was observed in 11 patients (61%), with a similar trend in the white blood count. A reduction in ESR at 1 month was observed in 11 patients (61%), while a reduction in CRP was also observed in 11 of the 16 patients (72%) in whom it was measured ( Table II ). The reduction in prednisolone dosage is shown in Table III. A good response was defined as an improvement in >50% of measured variables at 1 month, and was observed in 13 patients (72%). The duration of the response lasted from 1 month to remission, this latter being defined as the absence of systemic features and active synovitis, and the return of all laboratory parameters to normal. Three patients (16%) went into TABLE II Changes in the measured variables 1 month after pulse Total no. Loss of systemic features Reduction in active joint count Reduction in morning stiffness Improvement in functional grade Rise in haemoglobin concentration 1 g Reduction in thrombocytosis Reduction in ESR 30% Reduction in CRP 18 18 16 18 18 18 18 16 No. of responses (%) 10 8 9 10 12 11 11 11 (55) (45) (56) (55) (66) (61) (61) (72) TABLE III Reduction in prednisolone dose (shown as alternate daily doses in milligrams) Patient 1 2 3 4 5 Pre-pulse dose Post-pulse dose 30/20 20/2.5 20/5 20/5 20/5 30/12.5 20/0 17.5/5 20/1 17.5/5 Duration of systemic flare (weeks) 9.7 (3–14.9) 6.5 (15–26) Oral steroid 13 (5 daily) (8 alternate day) DMARDs 10 Hydroxycloroquine Methotrexate Sulphasalazine Penicillamine 7 1 1 1 remission and all have remained in remission for at least 2 yr. There were no short-term side-effects recorded. One patient had avascular necrosis of the hips before the pulse therapy and another had already had bilateral hip replacements. Over the 12 month follow-up period none of the others developed increased hip pain, suggestive of avascular necrosis, but routine radiographs and MRI of the hips were not performed. DISCUSSION In this open study, there was improvement in the majority of children with beneficial short-term effects in both clinical and laboratory parameters. Our results are in common with findings in adults with rheumatoid arthritis when this treatment has been compared with placebo [2, 7]. The mechanism of action of i.v. megadose methylprednisolone pulse is unknown. Our study did not compare oral, i.m. or intraarticular steroid pulses with i.v. pulses of methylprednisolone, nor did it compare differing doses of methylprednisolone. Both comparisons are of interest and need to be studied. Similarly, the effect of pulse therapy on growth was not addressed because of the short length of the study period. One suggested advantage of pulse methylprednisolone over oral daily steroid is the reduction in the incidence of corticosteroid sideeffects. There were no significant side-effects among our patients, although in adults myocardial ischaemia and arrhythmias, gastrointestinal haemorrhage and perforation, infection and avascular necrosis have all been recorded. In a study of methylprednisolone in JCA, JobDeslandre and Menkes [9] observed a dramatic response among 80% of children studied, with a maximum response on the fourth day after the pulse therapy and improvement maintained at 1 month in 60%. They also found that 80% of the children studied were able to switch from a daily to an alternate-day corticosteroid regime. The use of the pulse enabled us to reduce the dose of oral corticosteroid in almost half of the patients who were on oral prednisolone. Among children treated with pulse prednisolone in a variety of rheumatic diseases, Miller [10] observed few side-effects. He also observed improvement in 85% of the children studied, and in 25% of his patients oral corticosteroids 1242 BRITISH JOURNAL OF RHEUMATOLOGY VOL. 37 NO. 11 were discontinued following the treatment. The frequency of avascular necrosis following methylprednisolone pulse is unknown [14], but is of concern. JobDeslandre and Menkes [9] found no evidence of this complication at 1 yr on standard radiographs. We did not perform routine hip X-rays on our patients, but none developed symptoms in the year following pulse therapy to suggest this complication. One child had radiological evidence of asvascular necrosis and one had had bilateral total hip replacements prior to the pulse therapy. It is possible that early changes might have been detected had we performed MRI on our patients. Clearly, longer term placebo-controlled studies are required, and it would be useful to compare the effects of methylprednisolone with those of intraarticular and i.m. steroids. This pilot study, however, suggests that pulse methylprednisolone provides significant short-term benefit in the treatment of systemiconset JCA. 5. 6. 7. 8. 9. R 1. Forster PJG, Grindulis KA, Neumann V, Hubbal S, McConkey B. High-dose intravenous methylprednisone in rheumatoid arthritis. Ann Rheum Dis 1982;41:444–6. 2. Williams JA, Baylis EM, Shipley ME. A double-blind placebo controlled trial of methylprednisolone pulse therapy in active rheumatoid disease. Lancet 1982;ii:237–40. 3. Neumann V, Hopkins R, Dixon J, Watkins A, Bird H, Wright V. Combination therapy with pulsed methylprednisolone in rheumatoid arthritis. Ann Rheum Dis 1985;44:747–51. 4. Hansen TM, Dickneiss E, Jans H, Hansen TI, Ingemann- 10. 11. 12. 13. Nielsen N, Lorenzen IB. Combination of methylprednisolone pulse therapy and remission inducing drugs in rheumatoid arthritis. Ann Rheum Dis 1987;46:290–5. Walters MT, Cawley MID. Combined suppressive drug treatment in severe refractory rheumatoid disease: an analysis of the relative effects of parenteral methylprednisolone, cyclophosphamide and sodium aurothiomalate. Ann Rheum Dis 1988;47:924–9. Williams IA, Mitchell AD, Rothman W, Tallett P, Williams K, Pitt P. Survey of the long term incidence of osteonecrosis of the hip and adverse medical events in rheumatoid arthritis after high dose intravenous methylprednisolone. Ann Rheum Dis 1988;47:930–3. Lieling MR, Leib E, McLaughlin K et al. Pulse methylprednisolone in rheumatoid arthritis. A double-blind crossover trial. Ann Intern Med 1981;94:21–6. Smith MD, Ahern MJ, Brooks PM, Roberts-Thomson PJ. The clinical and immunological effects of pulse methylprednisolone therapy in rheumatoid arthritis II. Effects on immune and inflammatory indices in peripheral blood. J Rheumatol 1988;15:233–7. Job-Deslandre C, Menkes CJ. Administration of methylprednisolone pulse in chronic arthritis in children. Clin Exp Rheumatol 1991;9:15–8. Miller JJ. Prolonged use of large intravenous steroid pulses in the rheumatic diseases in children. Paediatrics 1980;65:989–94. Wood PH. Nomenclature and classification of arthritis. In: Munthe E, ed. The care of rheumatic children. Basel: EULAR, 1978:47–50. Manners PS, Ansell BM. Slow-acting antirheumatic drug use in systemic onset juvenile chronic arthritis. Paediatrics 1986;77:99–103. Steinbrocker O, Traeger CH, Batterman EC. Therapeutics criteria in rheumatoid arthritis. J Am Med Assoc 1949;140:659–62.