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