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Trial of intravenous pulse cyclophosphamide and methylprednisolone in the treatment of severe systemic-onset juvenile rheumatoid arthritis.

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ARTHRITIS XC RHEUMATISM
Vol 40, No 10, October 1997, pp 1852-1855
0 1997, American College ot Rheumdtology
1852
TRIAL OF INTRAVENOUS PULSE CYCLOPHOSPHAMIDE AND
METHYLPREDNISOLONE IN THE TREATMENT OF
SEVERE SYSTEMIC-ONSET JUVENILE RHEUMATOID ARTHRITIS
CAROL A. WALLACE and DAVID D. SHERRY
Objective. Not uncommonly, some children with
systemic-onset juvenile rheumatoid arthritis (JRA) have
persistently active disease with joint destruction and
profound growth delay despite maximum treatment with
known medications. Based on previous observations of
improvement in synovitis following intravenous (IV)
cyclophosphamide (CYC) and methylprednisolone
(MP) treatments, a group of children with severe
systemic-onset JRA was treated in an attempt to control
active synovitis and to allow tapering of corticosteroids.
Methods. Four patients with systemic-onset JRA
were continued on a daily regimen of nonsteroidal
antiinflammatory agents and prednisone, with a weekly
subcutaneous dose of methotrexate (1 mg/kg). In addition, 1 patient continued receiving sulfasalazine and 1
patient remained on a regimen of sulfasalazine and
hydroxychloroquine. Patients received 6-10 monthly
treatments of IV CYC (500-1,000 mg/m2) and MP (30
mg/kg; 1 gm maximum) accompanied by IV mesna and
large amounts of IV fluids. Subsequent treatments were
given once every 2-3 months.
Results. After 12-20 IV pulses of CYC, all patients
showed improvement, and 3 achieved remission of disease. All were able to discontinue corticosteroid use and
all had a n increase in linear growth.
Conclusion. Monthly IV pulse CYC treatments
can be useful to control disease in selected children with
severe, destructive JRA.
Children with the systemic-onset subtype of juvenile rheumatoid arthritis (JRA) can have the most
severe, persistent, and destructive disease of all JRA
Carol A. Wallace, MD, David D. Sherry, MD: Children’s
Hospital and Medical Center, University of Washington, Seattle.
Address reprint requests to Carol A. Wallace, MD, Pediatric
Rheumatology, Children’s Hospital, 4800 Sandpoint Way, NE, Seattle,
WA 98105.
Submittcd for publication February 24, 1997; accepted in
revised form May 4, 1997.
patients. In published outcome series, the majority of
children who become disabled (Steinbrocker functional
class 111 or IV) (1) have had systemic-onset JRA (2). In
addition to the increased risk of disability, children with
systemic-onset JRA face a higher risk of mortality than
other children with arthritis (2). Not uncommonly, some
children with systemic JRA have persistently active
disease with joint destruction and profound growth delay
despite maximum treatment with known medications. A
report by Shaikov et a1 ( 3 ) documented improvement in
synovitis following intravenous (IV) pulse cyclophosphamide (CYC) and methylprednisolone (MP)
treatments every 3 months. Based on the findings of that
report, we treated a group of patients with severe
systemic-onset JRA with IV pulse CYC and MP in an
attempt to control active synovitis and to allow tapering
of corticosteroids.
PATIENTS AND METHODS
Patients. Four patients fulfilling the American College
of Rheumatology (ACR) criteria for systemic-onset JRA (4)
were treated in this study. All had joint destruction, were
corticosteroid dependent, had severe growth retardation, and
had unremitting polyarthritis despite maximum therapy. Previous treatment included the combinations of methotrexate
(MTX) (1 magiweek subcutaneously) (n = 4), sulfasalazine
(50-60 mglkgiday) (n = 3), nonsteroidal antiinflammatory
drugs (NSAIDs) (n = 4), hydroxychloroquine (4-6 mgikgiday)
(n = 2), weekly IV pulse MP (30 mgikg) (n = l),and multiple
joint injections (n = 4). In addition, 2 patients had been
unsuccessfully treated with gold sodium thiomalate, azathioprine, and IV IgG.
Before treatment with CYC, patients had severe active
disease for a range of 2.7-4.8 years. Disease onset occurred at
between 1.8 and 5.8 years of age (Table 1). The duration of
daily treatment with prednisone for each patient varied from
2.1 to 4.0 years, with the lowest amount of prednisone tolerable
being 0.2-0.6 mgikgiday.
Disease remission following treatment was defined as
morning stiffness of <15 minutes, no fatigue, no joint swelling,
1853
IV PULSE CYC AND MP IN SYSTEMIC-ONSET JRA
Table 1. Characteristics of 4 patients with systemic-onset juvenile
rheumatoid arthritis before treatment with intravenous cyclophosphamide and methylprednisolone
Patient
1
Patient
2
Patient
3
Patient
4
M
1.8
2.7
2.1
0.2
F
3.8
3.8
3.7
0.4
M
5.8
3.8
3.4
0.6
F
4.5
4.8
4.0
0.4
Sex
Age at onset, years
Duration of disease, years
Duration of prednisone, years
Lowest prednisone dose, mgikg
and no joint pain for 2 consecutive months (based on the ACR
criteria for remission of adult RA) (5).
Treatment. All patients were continued on a daily
regimen of oral prednisone and NSAIDs, and received MTX 1
mgikgiweek subcutaneously. In addition, 1 patient continued
to take sulfasalazine, and another patient remained on a
regimen of sulfasalazine and hydroxychloroquine. One patient
who was receiving weekly IV M P discontinued it. The daily
dose of prednisone was decreased according to individual
tolerance.
After lengthy discussions of risks, and when verbal
consent was obtained, the patients began receiving monthly
treatment with IV CYC at 500-1,000 mgim’ and M P at 30
mg/kg (1 gm maximum). The CYC was given during a 12-hour
hospital stay, combined with IV fluids at a rate known to
produce urine output of 2 mlikglhour. Mesna (total dose equal
to the dose of CYC) was administered in 5 equal doses, during
and after the CYC treatment, for 12 hours. M P was given -5
hours after the CYC dose (Appendix 1).Followup white blood
cell (WBC) counts with differential were obtained on postCYC days 7, 10, 14, and 21, to detect each patient’s WBC nadir
and rebound levels. The CYC dose was adjusted to obtain a
WBC nadir level between 3,500 and 4,500/cm2, with absolute
neutrophil counts >1,500/cm2. The majority of treatments for
these 4 patients were at the 1,000-mg/m2 dose. Each patient
received between 6 and 10 monthly treatments, and 2-13
subsequent treatments every other, or every third, month. The
time between each dose of CYC was increased based on the
judgment of individual physicians. In all cases, the joint count
Table 3. Laboratory parameters at the firstilast treatments*
Patient 1 Patient 2
30138
Hct, %
7.715.8
WBC, X 1,000/cm2
ESR, mmihour
711.5
7.8/<0.8
CRP, mgidl
Platelets, X 1,000/cm2 5921237
34/43
11.0118.4
76117
8.510.8
6651293
Patient 3
Patient 4
36/37
2315.0
78110
10.61ND
4161251
37/38
12.614.9
56121
8.414.5
5881278
* Hct = hematocrit; WBC = white blood cell count; ESR = Westergren erythrocyte sedimentation rate; CRP = C-reactive protein; ND =
not determined.
showed 250% improvement, and in 3 patients, the prednisone
dose had been decreased by 225%.
RESULTS
All 4 patients improved with 12-20 IV pulses of
CYC and MP (Table 2). Improvement was first noted
after the third or fifth treatment in all patients, and 3
patients achieved remission of disease. In addition, all
patients required significantly lower daily doses of corticosteroid, and corticosteroids were eventually discontinued in all (Table 2). All patients showed improvement
in their laboratory parameters from the start of treat-
Table 2. Results of treatment of 4 patients with syqtemic-onset
juvenile rheumatoid arthritis with intravenous (IV) pulse cyclophosphamide and methylprednisolone
Patient 1 Patient 2 Patient 3 Patient 4
IV cyclophosphamide, no.
of treatments
Monthly
Total
Joint count
Before treatment
At last dose
Daily prednisone dose,
m&&
Before
At last dose
At last followup
7
20
10
12
10
14
6
12
32
2
34
0
7
0
7
0
0.2
0
0
0.4
0.05
0
0.6
0.1
0
0.4
0.1
0
Figure 1. Growth charts before and after cyclophosphamide (cyc) and
methylprednisolone administration. JG = patient 1; BL = patient 2;
JR = patient 3; AS = patient 4.
WALLACE AND SHERRY
1854
ment to the last dose of CYC and MP (Table 3). Moreover, all patients had an increase in their linear growth
velocity (Figure 1).
The clinical status of each patient has been
followed up over the long term. Patient 1 continues to
receive CYC, but has just increased the duration between doses to every 4 months. He is no longer taking
prednisone daily. He ha5 2 finger joints with active
disease and continues to receive NSAIDs, MTX, and
sulfasalazine. Patient 2 was in remission for 21 months
after treatment with CYC in conjunction with NSAIDs
and MTX. Six weeks after abrupt discontinuation of
MTX, her synovitis flared. Thirteen months after his last
dose of CYC, patient 3 was in remission while continuing to receive MTX, sulfasalazine, and plaquenil, but
required a right total hip replacement for joint destruction that had been severe before treatment with CYC
was started. Seventeen months after her last dose of
CYC, patient 4 continues to be in remission and remains
on a regimen of NSAIDs, plaquenil, and decreasing
doses of MTX. Due to previous joint destruction, she
has undergone right subtalar fusion.
very severe, destructive, persistent systemic-onset JRA.
The risk of possible malignancy and gonadal dysfunction
in later years is an important issue of unknown magnitude and cannot be answered by this study. The risk of
later gonadal dysfunction may possibly be lessened by
using testosterone in sexually mature males (6), keeping
total CYC dose to <20 gm (or 540 mgikg) (7), treating
prepubertally (6), or using pulse IV treatment rather
than daily doses of CYC (8). The risk:benefit ratio of
this treatment must be considered for each individual
patient. This aggressive therapy is not to be undertaken
lightly. In these 4 patients, the risks of continued joint
destruction, future disability, potentially shortened life
span, and tremendous growth retardation were considered to outweigh the potential unknown risks of later
cancer and gonadal dysfunction, in favor of treatment.
DISCUSSION
REFERENCES
The response to CYC and MP treatment in all 4
patients was a marked reduction in synovitis, and the
corticosteroid dosage was decreased. Moreover, 3 of the
4 patients achieved clinical remission. In addition to the
reduction in corticosteroid use, all patients benefited
from improved linear growth. This may be the most
long-lasting effect of this treatment.
We were surprised at the number of monthly
pulse CYC treatments that were required to control this
disease. The response in our patients was not as dramatic as that reported by Shaikov et al (3). There are
several possible reasons for this difference. Our patients
had been treated with significant doses of MTX prior to
starting the pulse therapy, and were treated primarily to
gain control of their severe arthritis (their systemic
features were controlled). In addition, the protocol used
by Shaikov et a1 included 3 days of IV MP with each
treatment, whereas our patients received only a single
dose.
These patient cases are reported not for the
purpose of promoting this particular therapy, but to
offer another possible treatment for select patients with
1. Steinbrocker 0, Traeger CH, Batterman RC: Therapeutic criteria
in rheumatoid arthritis. JAMA 140:659-662, 1949
2. Wallace CA, Levinson JE: Juvenile rheumatoid arthritis: outcome
and treatment for the 1990s. Rhcum Dis Clin North Am 17:891905. 1991
3. Shaikov AV, Maximov AA, Speranslq Al, Lovell DJ, Giannini EH,
Solovyev S K Repetitive use of pulse therapy with methylprednisolone and cyclophosphamide in addition to oral mcthotrexdte in
children with systemic juvenile rheumatoid arthritis: preliminary
results of a long-term study. J Rheumatol 19:612-616, 1992
4. Cassidy JT, Levinson JE, Bass JC, Baum J, Brewer EJ Jr, Fink CW,
Hanson V, Jacobs JC, Masi AT, Schallcr JG, Fries JF, McShane D,
Young D: A study of classification criteria for a diagnosis of juvenile
rheumatoid arthritis. Arthritis Rheum 29:274-281, 1986
5. Pinals RS, Masi AT, Larsen RA, and The Subcommittee for
Criteria of Remission in Rhcumatoid Arthritis of thc Amcrican
Rheumatism Association Diagnostic and Therapeutic Criteria
Committee: Preliminary criteria for clinical remission in rheumatoid arthritis. Arthritis Rheum 24:1308-3315, 1981
6. Masala A, Faedda K.Alagna S, Satta A, Chiarelli G, Rovasio PP.
Ivaldi R, Taras MS, Lai E, Bartoli E: Use of testosterone to prevent
cyclophosphamidc-induced azoospermia. Ann Intern Med 126:292295, 1997
7. Bogdanovic R, Banicevic M, Cvoric A: Tcsticular function following
cyclophosphamide treatment for childhood nephrotic syndrome:
long-term follow-up study. Pediatr Nephrol 4:45 1-454, 1990
8. Langevitz P, Klein L, Pras M, Many A The Effect of cyclophosphamide pulses on fertility in patients with lupus nephritis.
Am J Reprod Immunol 28:157-158, 1992
ACKNOWLEDGMENTS
We thank Drs. P. Boehm, M. Boyd, C. Plonsky, and K.
Rioradin for their help in managing these patients, and
Rachelle Binder for help in manuscript preparation.
IV PULSE CYC AND MP IN SYSTEMIC-ONSET JRA
1855
APPENDIX 1: PROTOCOL FOR CYCLOPHOSPHAMIDE TREATMENT IN SYSTEMIC-ONSET JUVENILE RHEUMATOID ARTHRITIS*
-
00 Mon 1997 Height
- hours
000000
LAST, First
00/00/00
= - cm;
weight
=
kg; M2 =
Admit to: -; allergies: -.
Diagnosis: -, for cytoxan #.
Blood pressure (BP) every 4 hours.
Call house officer (HO) if diastolic BP >05 mm Hg.
Regular diet.
Isolation not required.
Activity: ad libitum.
8. Have patient void every 2 hours; dipstick all voids for heme, unless initial
urine heme test is large or greater, then do not dipstick.
9. Start intravenous (IV) line immediatcly upon arrival:
Ds 114 normal saline with 20 mEq KCliliter at __ ccihour and adjust rate to
keep urine output >2 cckgihour.
10. Medications:
0.0 hours: decadron, ~-mg orally.
0.5 hours: ondansetron, - mg diluted in 50 cc IV fluid; give over 15 minutes
1V.i
1.0 hours: cyclophosphamide,
mg (500-1,000 mgim’) with mesna, - mg,
together over 30 minutes (dilute in IV maintenance fluid if needed).$
1.5 hours: mesna, - mg over 3 hours in 3 hours’ worth of 1V maintenance.
mg IV (0.5 mgikg).
2.0 hours: furosemide,
4.5 hours: mesna, - mg; infuse over 15 minutes.
5.0 hours: methylprednisolone, - mg IV (30 mgikg, with 1 gm maximum)
over 1 hour; BP every 15 minutcs X 2, then cvery 30 minutes during
infusion.
mg over 15 minules.
7.5 hours: mesna,
- mg over 15 minutes.
11. Other medications
mg IV (0.5-1 mgikg, with 50
a) For nausea a5 nccded: diphenhydramine,
mg maximum) and thcn every 4-6 hours.
b) May take own oral medications.
c) Diphenhydramine and epinephrine at nursing station in case of
anaphylaxis from methylprednisolone.
mg IV (0.15 mgikg) at hour 10 or later as needed for
d) Ondansetron,
nausea.
12 Admission laboratory tests: complete blood cell (CBC) count with differential
and platelets, erythrocyte sedimcntation rate. clectrolytes, blood urea
nitrogen, creatinine, C-reactive protein, aspartatc aminotransferase, and
urinalysis.
13 Call HO if patient unable to take oral medications or if urine becomes grossly
bloody or increases >2 grades in hemc.
14 Before discharge, obtain clean catch of urine for urinalysis.
15 May discharge home at hour 11, if no vomiting.
16 Followup laboratory measures: CBC with differential on days 7, 10, 14,
and 21.
1.
2.
3.
4.
5.
6.
7.
* This is our protocol, reproduced for example only. It is not necessarily the best or only method for administration.
7 0.45 mgikg loading dose, 24 mg maximum.
3 Total mesna dose equals that of total cyclophosphamide; each dose is 115 of total.
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