Treatment of refractory JIA via pulse therapy using methylprednisolone & cyclophosphamide

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Treatment of refractory juvenile idiopathic arthritis via pulse therapy

using methylprednisolone and cyclophosphamide

Sao o Medical Journal

Print ISSN 1516-3180 Sao o Med. J. vol.121 no.3 São o 2003

http://www.scielo.br/

ABSTRACT

CONTEXT: Patients with refractory juvenile idiopathic arthritis can

benefit from aggressive therapy.

CASE REPORT: We followed the clinical course of 4 patients (2 male, 2

female) aged 9.1-17.8 years (mean of 14.5 years) with polyarticular

onset of juvenile rheumatoid arthritis and one 16-year-old boy with

juvenile spondyloarthropathy associated with inflammatory bowel disease.

All the juvenile rheumatoid arthritis patients fulfilled the diagnostic

criteria established by the American College of Rheumatology. All

patients had unremitting arthritis despite maximum therapy. All patients

began receiving treatment using intravenous cyclophosphamide at 500-750

mg/m2 and intravenous methylprednisolone at 30 mg/kg, for 3 days monthly

(1 g maximum).

The patients received between 3 and 11 monthly treatments, and/or 3-5

treatments every two months for 12 months, according to the severity of

the disease and/or response to the therapy. All but one patient were

evaluated retrospectively at the start (time 0) and 6 months (time 1),

and 12 months (time 2) after the beginning of the treatment.

A rapid and clinically significant suppression of systemic and articular

manifestations was seen in all patients. Our results showed the

favorable effect of this treatment on the clinical and some laboratory

manifestations of juvenile idiopathic arthritis.

Keywords: Rheumatoid athritis. Juvenile rheumatoid arthritis. Arthritis.

Methylprednisolone. Cyclophosphamide. Methotrexate.

INTRODUCTION

Juvenile rheumatoid arthritis is the most common cause of chronic

arthritis in children. It is defined as an arthritis complaint lasting 6

weeks or longer in patients 16 years of age and younger that has no

known etiology. This is a diagnosis of exclusion, so other causes of

chronic arthritis must be ruled out.1,2

Juvenile rheumatoid arthritis has been divided into subtypes, but we are

still unable to identify those children who will progress to poor

outcomes and might benefit from more aggressive therapy.3 Many children

with juvenile rheumatoid arthritis respond to a limited course of

nonsteroidal anti-inflammatory drugs, especially those with

oligoarticular onset. Sometimes, these drugs associated with

intra-articular corticosteroid are often the only treatment needed.4

Most patients with systemic or polyarticular onset need second-line

medication. Hydroxychloroquine or methotrexate is useful as an adjunct

to nonsteroidal anti-inflammatory drugs. Glucocorticoids have been tried

with good results in juvenile rheumatoid arthritis, but their side

effect profile precludes routine use. They should be used for shorter

periods of time. Immunosuppressive drugs are being increasingly utilized

early on in patients with juvenile rheumatoid arthritis who need

aggressive therapy.

Refractory juvenile rheumatoid arthritis should be considered when the

disease does not respond to high doses of methotrexate (1 mg/kg/week

subcutaneously). In such cases, therapies involving combinations of

drugs or more aggressive therapies like intravenous methylprednisolone

and cyclophosphamide can be considered, since the use of biological

agents is not possible for most patients.

Our purpose was to clinically and serologically evaluate the treatment

outcomes from four patients with a severe form of juvenile rheumatoid

arthritis and one with juvenile spondyloarthropathy, treated using

intravenous pulses of cyclophosphamide and methylprednisolone and high

doses of subcutaneous methotrexate over periods ranging from 8 to 11

months.

CASE REPORT

Patient 1

A 9.1-year-old boy had developed rash, fever and polyarthritis in the

large joints of the cervical spine, shoulders, wrists and ankles at the

age of 2.6 years. He presented persistent anemia, leukocytosis and

thrombocytosis, and an elevated erythrocyte sedimentation rate, despite

therapy using prednisone, nonsteroidal anti-inflammatory drugs and

methotrexate. He maintained fever, rash and arthritis when we started a

course of immunoglobulin IV monthly, with cyclosporin and pulse therapy

using methylprednisolone, with no improvement. Because of persistent

active disease, we started pulses of intravenous methylprednisolone with

cyclophosphamide (11 monthly treatments). The patient showed good

response with improvement in the clinical and laboratory parameters.

Patient 2

A 14.3-year-old girl had started fever and polyarthritis at the age of 2

years. She presented small joint disease involving the hands and feet.

The cervical spine, shoulders, elbows, wrists, hips, knees and ankles

were also involved. She presented anemia, leukocytosis, thrombocytosis

and an elevated erythrocyte sedimentation rate. She used prednisone,

nonsteroidal anti-inflammatory drugs, immunoglobulin IV monthly and

methotrexate, with no clinical and laboratory improvement. She developed

toxicity with elevation of hepatic enzyme levels, and methotrexate was

discontinued. Cyclosporin was introduced but the patient persisted with

disease activity. We started pulses of intravenous methylprednisolone

and cyclophosphamide (3 monthly and 3 bimonthly treatments). The patient

showed improvement in the clinical and laboratory activity.

Patient 3

This 15.5-year-old girl had started polyarticular onset disease at the

age of 1.4 years. She presented fever and rash, with small and large

joint disease involving the hands, feet, shoulders, elbows, wrists, hips

and knees. She had unremitting disease despite therapy with prednisone,

nonsteroidal anti-inflammatory drugs, methotrexate, azathioprine and

pulses of methylprednisolone. She was treated using pulse therapy of

intravenous methylprednisolone with cyclophosphamide (5 bimonthly

treatments), with improvement in her joint symptoms and laboratory results.

Patient 4

This 17.8-year-old boy had presented with polyarthritis in the large

joints of the cervical spine, shoulders, elbows, wrists, hips, knees and

ankles at the age of 7 years. He had not obtained improvement with

prednisone, nonsteroidal anti-inflammatory drugs, methotrexate,

hydroxychloroquine and pulses of methylprednisolone. He started a course

of azathioprine because of his unremitting disease. The patient showed

improvement after treatment using pulse therapy of intravenous

methylprednisolone with cyclophosphamide (5 bimonthly treatments).

Patient 5

A 16-year-old boy had developed spondyloarthropathy associated with

inflammatory bowel disease at the age of 2 years. He presented

involvement of elbows, wrists and knees. He was initially treated with

prednisone, nonsteroidal anti-inflammatory drugs and methotrexate and

then with sulfasalazine and azathioprine, with no improvement. He

persisted with active disease until the beginning of pulse therapy of

intravenous methylprednisolone with cyclophosphamide (8 monthly

treatments). He showed improvement in the number of joints with active

disease and the erythrocyte sedimentation rate.

RESULTS

Characteristics of the five patients are shown in Table 1. Disease onset

occurred between the ages of 1.4 and 7.0 years (mean of 3.0 years) and

patient ages at the time of the study were 9.1 to 17.8 years (mean of

14.5 years). Disease duration was considered to be the period of time

from the first clinical manifestations until the beginning of the

therapy (methylprednisolone, cyclophosphamide and methotrexate). It

ranged from 6.5 to 14.1 years (mean of 11.5 years).

All the juvenile rheumatoid arthritis patients presented polyarticular

onset. Each patient received between 3 and 11 monthly treatments of

intravenous methylprednisolone and cyclophosphamide, and 3-5 intravenous

methylprednisolone and cyclophosphamide infusions every two months for

12 months (Table 1). Clinical and serological improvement was noted in

four patients (Table 2). The number of joints with active disease was

reduced in four patients, as was the erythrocyte sedimentation rate in

four patients. Hemoglobin levels increased in four patients. All

patients required lower doses of corticosteroids and two discontinued

this medication (Table 2). During the evaluation period, only one

patient underwent modification of the therapy (azathioprine use), with

no improvement. Two patients took cyclosporin, two patients

azathioprine, one patient intravenous immunoglobulin and one patient

sulfasalazine over the whole follow-up period (Table 1). With regard to

side effects, patient 4 presented nausea and patient 1 hypertension.

Improvement was noted in both patients after symptomatic therapy. No

patients in this study went into remission. All subjects were at or

below the 10th percentile in height for age.

DISCUSSION

The aim in treating juvenile rheumatoid arthritis is to minimize

discomfort, reduce disability, prevent joint destruction, and maximize

physical, social and emotional development. However, successful

management of severe juvenile rheumatoid arthritis remains a challenge

in pediatric rheumatology.5

Pulse therapy using methylprednisolone is an alternative to oral

corticosteroids, in order to reduce the side effects. Job-Deslandre and

Menkes6 retrospectively evaluated the results from methylprednisolone

pulses in 15 children with chronic arthritis (13 cases of juvenile

rheumatoid arthritis and two cases of spondyloarthropathy).

Methylprednisolone succinate was administered at a dosage of 700 mg/m2

by an intravenous infusion pump on 3 consecutive days. A dramatic

clinical improvement was obtained in 12/15 cases by day 4. In seven

cases, multiple pulses (between two and eight courses) were administered

to obtain better control of the disease and a decrease in the daily

dosage of corticosteroids. The authors observed only mild and transient

side effects and a decrease in the previous side effects from the

corticosteroids (especially growth retardation).

Azathioprine and cyclophosphamide have been used in the treatment of

juvenile rheumatoid arthritis but their potential toxicity is greater.

The benefits from pulse cyclophosphamide in comparison with oral

cyclophosphamide include reduction in the total dose and the risk of

side effects. Adequate hydration can be provided, so as to protect the

bladder from hemorrhagic cystitis.7 Other " disease-modifying therapies "

that are being tried in juvenile rheumatoid arthritis include

hydroxychloroquine, sulfasalazine, intravenous immunoglobulin,

cyclosporin, and combination therapy.3,8,9 The most commonly used

disease-modifying antirheumatic drug presently used in juvenile

rheumatoid arthritis is methotrexate, particularly in polyarticular and

systemic juvenile rheumatoid arthritis. It has been shown to be safe and

effective in retrospective studies, clinical practice and controlled

trials.10,11 Serious long-term toxicity appears to be infrequent.10,11

Pulse cyclophosphamide with methylprednisolone has been proposed for the

treatment of severe systemic-onset juvenile rheumatoid arthritis.12

Wallace and Sherry13 studied four children (two male, two female) with

systemic-onset juvenile rheumatoid arthritis, joint destruction and

polyarthritis that remained active despite maximal therapy with

combination of drugs. Intravenous cyclophosphamide (500-1000 mg/m2) and

methylprednisolone 30 mg/kg/day (1 g maximum) were given monthly.

Patients received six to ten monthly treatments followed by two to

thirteen subsequent treatments every two to three months. All patients

showed clinical improvement with 12-20 intravenous pulses. Three

patients achieved disease remission despite the discontinuation of

cyclophosphamide. Shaikov et al.14 evaluated the effectiveness of pulse

therapy consisting of methylprednisolone 30 mg/kg/day for three

consecutive days, cyclophosphamide 400 mg/m2 and methotrexate 10 mg/m2

in 18 patients (10 male, 8 female) with systemic juvenile rheumatoid

arthritis. The children received pulse therapy every three months in an

open trial of 12 months duration. A rapid and clinically significant

suppression of systemic and articular manifestations was seen in all

patients. A significant decrease in laboratory indices of disease

activity was also observed. These studies and ours suggest that the

addition of pulse therapy of cyclophosphamide and methylprednisolone to

the methotrexate treatment is potentially useful in patients with

resistant polyarticular or systemic-onset disease.

In our study, all patients had been using methotrexate prior to this

treatment, with no results. It was only when we associated intravenous

cyclophosphamide and methylprednisolone that we observed a notable

clinical and laboratory improvement. No significant side effects were

observed during the study.

CONCLUSION

Our results showed the favorable effect of this treatment on the

clinical and some laboratory manifestations of juvenile idiopathic

arthritis. The reduction in the daily dose of oral steroids must be

considered one of the most important effects among such patients. These

data support the need for controlled trials using cyclophosphamide,

methylprednisolone and methotrexate in a larger cohort of patients with

juvenile idiopathic arthritis, so as to determine the safety, efficacy,

and disease-modifying effects in this inflammatory condition.

Treatment of refractory juvenile idiopathic arthritis via pulse therapy

using methylprednisolone and cyclophosphamide

Tania Caroline Monteiro de Castro; Terreri; Claudio Len;

Odete Esteves Hilário

Division of Allergy, Clinical Immunology and Rheumatology, Department of

Pediatrics, Universidade Federal de São o – Escola ista de

Medicina, São o, Brazil

Correspondence

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are immunosuppressives appropriate? Arthritis Rheum 1993;36(1):71-4.

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nonrheumatic disorders. Rheum Dis Clin North Am 1997;23(4):811-40.

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pulse in chronic arthritis in children. Clin Exp Rheumatol 1991;9(Suppl

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Rheumatol 1998;10(3):169-73.

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treatment of rheumatoid arthritis. Br J Rheumatol 1998;37(8):824-36.

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Rheumatol 1993;11(2):113-5.

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12. Cron RQ, Sharma S, Sherry DD. Current treatment by United States and

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[ Medline ]

RESUMO

CONTEXTO: Pacientes com artrite idiopática juvenil refratária podem se

beneficiar com uma terapia mais agressiva.

RELATO DE CASO: A artrite reumatóide juvenil é a causa mais comum de

artrite crônica em crianças definida como artrite por mais de seis

semanas em pacientes com idade igual ou inferior a 16 anos. Ela é

considerada refratária quando não responde ao tratamento com metotrexato

em doses elevadas (1 mg/kg/semana subcutâneo). Nesses casos, terapias de

associação de medicamentos ou terapias mais agressivas, como pulso de

solumedrol e ciclofosfamida podem ser indicadas. Quatro pacientes com

artrite reumatóide juvenil e um com espondiloartropatia juvenil

associada a doença inflamatória intestinal foram acompanhados em nosso

serviço. Todos receberam pulsoterapia com ciclofosfamida intravenosa

(500-750 mg/m2) e metilprednisolona intravenosa (30 mg/kg/dia). Todos os

pacientes receberam entre 3 e 11 pulsos mensais e/ou 3 a 5 pulsos a cada

2 meses por um período de 12 meses de acordo com a gravidade da doença

e/ou a resposta à terapia. Todos, exceto um paciente, foram avaliados

retrospectivamente no início (tempo 0), 6 meses (tempo 1) e 12 meses

(tempo 2) após iniciar o tratamento. Uma rápida e significante supressão

das manifestações articulares e sistêmicas foi observada em todos os

pacientes. Nossos resultados mostraram um efeito favorável deste esquema

terapêutico nas manifestações clínicas e laboratoriais da artrite

idiopática juvenil. A redução da dose diária de corticóide oral deve ser

considerada um dos mais importantes efeitos nestes pacientes.

Palavras-chave: Artrite reumatóide. Artrite reumatóide Juvenil. Artrite.

Metilprednisolona. Ciclofosfamida. Metotrexate.

Correspondence to

Terreri

Rua Loefgreen, 2381 – Apto. 141

São o/SP – Brasil – CEP 04040-004

Tel. (+55 11) 5579-1590 – Fax (+55 11) 5579-1590

E-mail: terreri@...

Sources of funding: None

Conflict of interest: None

PUBLISHING INFORMATION:

Tania Caroline Monteiro de Castro, MD. Pediatric rheumatologist,

Division of Allergy, Clinical Immunology and Rheumatology, Department of

Pediatrics, Universidade Federal de São o/Escola ista de

Medicina, São o, Brazil.

Terreri, MD, PhD. Assistant professor, Division of Allergy,

Clinical Immunology and Rheumatology, Department of Pediatrics,

Universidade Federal de São o/Escola ista de Medicina, São

o, Brazil.

Claudio Len, MD, PhD. Assistant professor, Division of Allergy, Clinical

Immunology and Rheumatology, Department of Pediatrics, Universidade

Federal de São o/ Escola ista de Medicina, São o, Brazil.

Odete Esteves Hilário, MD, PhD. Associate professor, Division of

Allergy, Clinical Immunology and Rheumatology, Department of Pediatrics,

Universidade Federal de São o/Escola ista de Medicina, São

o, Brazil.

© 2003 Associação ista de Medicina