Download THE USE OF INTRAVENOUS PULSED METHYLPREDNISOLONE

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
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ADEBAJO AND HALL: PULSE METHYLPREDNISOLONE IN SYSTEMIC-ONSET JCA
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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
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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.
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