IN CHILDHOOD LUPUS
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This page is provided by Thomas J. A. Lehman MD
Delivering the best care - with great care
Dr. Lehman is the
author of many textbook chapters and articles on the care of children and young
adults with SLE. He practices in New York City. Click
here for more information about Dr. Lehman or
the Hospital for Special Surgery.
Over the past ten years
intravenous cyclophosphamide has been demonstrated to be a safe and effective
therapy for childhood systemic lupus erythematosus over the intermediate term when
used by physicians experienced in the use of immunosuppressive agents. Its use has been associated with both improved survival and an improved
quality of life for children with diffuse proliferative glomerulonephritis
(DPGN) and other life threatening manifestations of systemic lupus
erythematosus [1,2,3]. Before the routine use of
intravenous cyclophosphamide the prognosis for children with continuing active
renal disease was extremely poor . Even now recent publications (2002) indicate 70% long term
survival for children with DPGN secondary to lupus treated with azathioprine
compared to greater than 95% long term survival for children with DPGN treated
at the Hospital for Special Surgery with intravenous cyclophosphamide. The adult experience compiled by the NIH
suggests that the intermediate term improvement in survival for children with
systemic lupus erythematosus receiving cyclophosphamide will be associated with
dramatic long term improvement as well. However, it is not yet possible to
provide follow-up data on significant numbers of patients followed for more
than three years.
At the Hospital for Special Surgery children
with SLE complicated by DPGN are now routinely entered into a protocol calling
for the use of monthly intravenous cyclophosphamide for seven months, followed
by every three month cyclophosphamide for a total of thirty six months. The standard regimen consists of the monthly intravenous infusion of 500
to 1000 mg/m2. In comparison with daily oral therapy, the immunosuppressive
effects of this single large dose appear to be greater, but its toxicity
appears to be less [5,6]. The initial dosage of
cyclophosphamide should be 750 mg/m2 in patients free of significant renal or hepatic
compromise and 500 mg/m2 (or less) if significant compromise is present. The
dose is progressively adjusted upward to the maximum dose of 1 gm/m2 in
increments of 250 mg/m2. There must be careful monitoring of the white blood
cell nadir ten to fourteen days following cyclophosphamide administration. If
the patient experiences a white blood cell nadir of less than 2000 total white
blood cells/mm3 or less than 1000 granulocytes/mm3 the dosage should be reduced
by 125 mg/m2. In small children even though the calculated surface area may
indicate a higher dosage, the dosage of cyclophosphamide should not exceed 40
mg/kg because of potential cardiotoxicity. Once a
child has completed six months of therapy continued administration of
intravenous cyclophosphamide at three month intervals for a total of thirty-six
months appears to offer optimal benefit. Following the completion of this
protocol most children have remained well off cyclophosphamide. A small number
have required repeat treatment with cyclophosphamide (for three months) because
of disease flares occurring 6 to 24 months following cessation of the original
treatment course . In contrast to the few children who have flared after
completing this regimen, a substantial proportion of children who were
withdrawn from cyclophosphamide after a shorter duration of therapy have flared
In reviewing our earliest results it was apparent
that a significant number of patients were dropped from the study because they
became leukopenic during the first few months of
intravenous cyclophosphamide therapy and further doses were withheld. Since
many of these patients ultimately went on to renal failure with active disease,
it was clear that a better approach was needed. At this time children admitted
for intravenous cyclophosphamide who are found to have total WBC less than 4000
or absolute neutrophil counts less than 2500 are
given intravenous methylprednisolone (30 mg/kg up to
a maximum of 1 gram). Interestingly their WBC is usually lower the next day.
They then receive a second dose of intravenous methylprednisolone
and almost invariably their WBC rises to 6 or 7,000. This demonstrates that the
patient can mount a WBC response and I have not had any patient develop
profound neutropenia or septic complications when I then gave them
cyclophosphamide. If the patient does not respond to three doses of methylprednisolone 24 hours apart, I would not give
cyclophosphamide. That's only happened to me once. That patient was discharged
on a higher daily dose of prednisone and ultimately responded with an increased
WBC. This regimen has the advantage of giving additional methylprednisolone
therapy to children with active disease manifested by continuing leukopenia.
Don't forget to observe for the usual complications of 'bolus' methylprednisolone therapy including hypertension,
hypotension, and pancreatitis.
Nausea, vomiting, alopecia, and moderate degrees of myelosuppression, are common side effects of intravenous
cyclophosphamide. Infection during the period of immunosuppression with the
risk of sepsis and death remains an ever present concern, but can be minimized
by careful inpatient observation during the 12 hours before and 24 hours after
administering the cytoxan. The more worrisome
complications of sterility, pulmonary fibrosis, hemorrhagic cystitis, and
secondary oncogenesis have not been reported in
childhood. However they remain potential complications [8-13]. Outpatient
administration of intravenous cyclophosphamide is utilized by some centers.
However, it is impossible to assure adequate hydration and appropriate
electrolyte status for a child who has received a 'central acting' emetic with
out parenteral fluids. Hospitalization allows assured
hydration with careful monitoring of blood pressure and electrolyte status
coupled with superior control of emesis using intravenous anti-emetic agents
and the administration of MESNA . In addition, we have recognized children
with occult infections because they became febrile in the hospital during the
night prior to planned administration of cyclophosphamide. In our hands
hospitalization clearly results in both reduced toxicity and improved patient
Children with diffuse proliferative
glomerulonephritis (even if complicated by nephrotic
syndrome) generally respond well to intravenous cyclophosphamide as do children
with membranoproliferative glomerulonephritis.
However, children with 'pure' membranous nephritis respond
has been less satisfactorily . Cyclosporine or other agents may
ultimately prove superior therapy for this group [15-17]. Children with
significant renal compromise for a prolonged period prior to the initiation of
therapy may continue to deteriorate during the initial six months of
cyclophosphamide therapy. The risks of continued treatment with
cyclophosphamide probably outweigh the potential benefits for these patients.
Similarly, if significant 'chronicity' without
activity is found on the initial renal biopsy, cyclophosphamide therapy is
unlikely to succeed.
Some children with aggressive SLE do not tolerate
the transition to every three month intravenous cyclophosphamide therapy. Many
of these children can be controlled by an additional three months of monthly
therapy. However, a few children continue to experience disease flares whenever
the interval between cyclophosphamide doses is extended. Combinations of
multiple immunosuppressive agents (e.g. cyclophosphamide and methotrexate) have
been useful for these children in pilot studies, but definitive safety and
efficacy data are not available.
Intermittent intravenous cyclophosphamide also has
been used successfully in corticosteroid resistant lupus cerebritis,
recurrent digital infarction, and in pneumonitis but
no 'series' describing its use for these indications in childhood have been published. Seven months of monthly intravenous
therapy appears to be sufficient for these indications.
I have written a very
extensive chapter on childhood SLE which is contained in Dubois textbook of
you would like to order a copy of this text (from amazon.com) click here.
For a more detailed discussion of SLE
in childhood, the diagnosis, the lab tests, the medicine and how to cope with
book –click here to order at a discount from Amazon.com!!
“Dr. Tom Lehman’s experience and compassion are evident on every page of this
book, and they help guide the reader—child, parent,
and healthcare professional alike – through the
world of childhood arthritis. This book
is an absolute gem written with a single goal in mind: improve the lives of kids with arthritis.” -- Jack Klippel, M.D. President and
CEO of the Arthritis Foundation
“Dr. Lehman has given parents and families of children with
arthritis the first book that speaks to the parent and child as equals. His book explains the illnesses, the
medications, the lab tests, and the disease course in simple, understandable
lay language and givens them valuable insight into how a pediatric
rheumatologist thinks. Bravo!”-- Charles Spencer, M.D.,
Professor of Clinical Pediatrics, University
of Chicago, La Rabida
It’s not just
A guide to childhood muscle, bone, and joint pain,
rheumatic diseases and the latest treatments
Click here to see the table of contents
has always been a frustration trying to answer the many questions I have
received from people over the web. I can’t
take the time and give them the detail I would like to. I have to take care of my patients. This book is a distillation of my experience
answering questions for parents and health professionals over 25 years of
practice. If you want to know about the
diseases, the tests, the medications, or how to be sure you are getting the
best care– If you are the family member of a child with joint pains, this book will give you the answers. If you are a general physician, a
pediatrician, or a nurse who cares for children with these diseases it will
answer many of the questions families ask you, and you can recommend it to
them. It will also answer many of your
questions about what shots to give, what precautions to take, and the other
questions families, pediatricians, and other health care providers have asked
me over the years.
Dr. Lehman is
the author of many textbook chapters and articles on the care of children and
young adults with rheumatic diseases including SLE, JRA, dermatomyositis,
scleroderma, Kawasaki disease and related
conditions. He practices in New York City. Click
here for more information about Dr. Lehman or the
Hospital for Special Surgery.
is the author of many textbook chapters and articles on the care of children
and young adults with SLE. He practices
in New York City. Click
here for more information about Dr. Lehman or the
Hospital for Special Surgery.
for The Lupus Foundation web page
The Arthritis Foundation also works with
children with lupus.
Click for BOOKS dealing with SLE
This site provided by Thomas J. A. Lehman MD
Chief, Division of Pediatric Rheumatology
The Hospital for Special
535 E 70 St, New York,
212-606-1151, fax 212-606-1938, e-mail firstname.lastname@example.org
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1. Lehman TJA, Sherry
DD, Wagner-Weiner L, McCurdy DK, Emery HM, Magilavy
DB, Kovalesky A. Intermittent intravenous
cyclophosphamide therapy for lupus nephritis. J Pediatr
2. Lehman TJA. Long term outcome of systemic lupus erythematosus in childhood.
What is the prognosis? Rheum Dis Clin
3. Lehman TJA. Current concepts in immunosuppressive drug therapy of systemic
lupus erythematosus. J Rheum 1992:19(s33);20-22.
4. McCurdy DK, Lehman
TJA, Bernstein B, Hanson V, King KK, Nadorra R,
Landing BH. Lupus Nephritis: Prognostic factors in children. Pediatrics 1992;89:240-246.
5. McCune WJ, Golbus J, Zeldes W, Bohlke P, Dunne R, Fox DA. Clinical and
immunologic effects of monthly administration of intravenous cyclophosphamide
in severe systemic lupus erythematosus. N Engl J Med
6. Austin HA, Klippel JH, Balow JE, LeRiche NG, Steinberg AD, Plotz PH,
Decker JL. Therapy of lupus nephritis. N Engl
J Med 1986;314:614-9.
7. Wagner-Weiner L, Magilavy DB, Emery HM. Flare of childhood lupus nephritis
after discontinuing treatment with intravenous pulse cyclophosphamide. (abstract) Arthritis Rheum 1988;31:s117.
8. Clements PJ, Davis J. Cytotoxic drugs: their
clinical application to the rheumatic diseases. Semin
Arthritis Rheum 1986;15:231-54.
9. Stentoft J. Progressive pulmonary fibrosis complicating
cyclophosphamide therapy. Acta Med Scand 1987;221:403-7.
Sen RP, Walsh TE, Fisher W, Brock N. Pulmonary
complications of combination therapy with cyclophosphamide and prednisone. Chest 1991;99:143-6.
11. Stillwell TJ,
Benson RC Jr, DeRemee RA,
McDonald TJ, Weiland L H. Cyclophosphamide induced
bladder toxicity in Wegener's granulomatosis. Arthritis Rheum 1988;31:465-70.
12. Clamon GH. Alkylating Agents. In
The Chemotherapy Source Book, Perry MC ed, Baltimore, Williams and Wilkins, 1991.
13. Finn GP, Sidau RNB. Protecting the bladder from
cyclophosphamide with mesna. N Engl J Med 1986;314:61.
14. Urizar RE, Tinglof B, McIntosh R,
Litman N, Barnett E, Wilkerson J, Smith F, Vernier RL. Immunosuppressive therapy of
proliferative glomerulonephritis in children. Am J Dis
15. ter Borg EJ, Tegzess AM, Kallenberg CG. Unexpected severe
reversible cyclosporine A-induced nephrotoxicity in a
patient with systemic lupus erythematosus and tubulointerstitial
renal disease. Clin Nephrol
16. Feutren G, Querin S, Noel LH, Chatenoud L, Beaurain G, Tran F, Lesavre P, Bach JF. Effects of
cyclosporine in severe systemic lupus erythematosus. J Pediatr 1987;111:1063-1068.
17. Makover D, Freundlich B, Zurier RB. Relapse of systemic lupus
erythematosus in a patient receiving cyclosporine A. J Rheumatol
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