INTRAVENOUS CYCLOPHOSPHAMIDE
IN CHILDHOOD LUPUS

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 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 [4].  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 [3]. 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 [7].
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 [14]. 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 compliance.
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 [14]. 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 SLE. If 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 it see….

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    Dr. Tom Lehmans experience and compassion are evident on every page of this book, and they help guide the readerchild, 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 growing pains.
A guide to childhood muscle, bone, and joint pain,
rheumatic diseases and the latest treatments

 

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It 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.

 

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.

Click here 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 Surgery
535 E 70 St,
New York, NY 10021
212-606-1151, fax 212-606-1938, e-mail goldscout@aol.com

 

 

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References

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 1989;114:1055-1060.

2. Lehman TJA. Long term outcome of systemic lupus erythematosus in childhood. What is the prognosis? Rheum Dis Clin NA 1991:17:921-930.

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 1988;318.1423-31.

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.

10. 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 Child 1969;118:411-425.

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 1988;29:93-5.

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 1988;15:117-9.

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