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An Open-label, Phase I/II Study of 5-Fluorouracil Plus Leucovorin in the Treatment of Rheumatoid Arthritis

To the Editor:

Anecdotal experience in treating patients with metastatic colorectal cancer who coincidentally had rheumatoid arthritis (RA) suggests that 5-fluorouracil (5-FU) plus leucovorin (LCV) leads to improvement in patients' symptoms of RA. This observation led us to study the combination of 5-FU plus LCV in patients with active RA. We followed a treatment protocol similar to that used successfully and with acceptable toxicity in patients with metastatic colorectal cancer¹. The goals of this 24 week, open label pilot study were to determine the maximum tolerated dose of 5-FU, define the toxicity of this combination, and document any clinical benefit in patients with RA.

Study inclusion criteria included RA according to the 1987 classification criteria, positive rheumatoid factor, and active disease defined as ³ 9 swollen joints plus ³ 6 tender joints plus a Westergren sedimentation rate > 27 mm/h². A total of 9 patients (4 male, 5 female; mean age 55.1 yrs, range 48-62) were treated; 6 patients were in American College of Rheumatology (ACR) functional class 2, and 3 in functional class 3³. Mean disease duration was 12.8 years (range 1.5-24). Patients had taken a mean of 3.5 disease modifying antirheumatic drugs (DMARD), 7/9 were taking prednisone at a dose of £ 15 mg/day, and all were receiving, but failing, conventional solo DMARD therapy with methotrexate (MTX) at the screening visit for this study. MTX was discontinued 2 weeks prior to the first dose of the study drug. The prednisone dose was held constant during the study. An SGOT and complete blood count were obtained prior to each dose of the study drug.

Treatment consisted of intravenous LCV plus 5-FU given 5 consecutive days every 4 weeks for 24 weeks. Leucovorin dosage was constant at 20 mg/m² given as an intravenous bolus. The first 6 patients received 200 mg/m² of 5-FU. Because there was no appreciable toxicity at that dosage, the next 6 patients were to receive 300 mg/m² of 5-FU plus LCV. Because of the striking and consistent observations by each patient that their maximum benefit from treatment was at about 14 days after each treatment sequence, with marked worsening thereafter, we did not feel we could ethically continue the study as designed. The study was therefore terminated after 3 patients received the increased 5-FU dosage of 300 mg/m².

At baseline, the mean tender joint count was 28.2 (range 8-49), mean swollen joint count 26.1 (range 10-41), and mean Westergren sedimentation rate 44.7 mm/h (range 27-74). Swollen joint scores improved dramatically in 5/9 patients, decreasing from a mean of 32.4 to a mean of 11 (66%) by the end of the followup period at 24 weeks. However, the mean swollen joint count for all patients was 26.1 at entry, and 28 at the end of the study, while the mean tender joint count was 28.2 at entry and 23.2 by week 24. Only 3/9 patients had improvement by ACR20 criteria⁴. Westergren sedimentation rates did not mirror clinical improvement and were unchanged at 24 weeks (mean 42.4 mm/h).

Because most patients came from some distance, only monthly clinical observation by the study physician was possible. All patients reported feeling best at about 14 days after each treatment sequence but we have no clinical observation data from those intervals. As an example of the swollen joint count in a patient with good response, the initial count was 29; 12 at week 4, 10 at week 8, 2 at week 12, 7 at week 16, 5 at week 20, and 7 at week 24.

No serious toxicity requiring discontinuation or alteration of dosage schedules was noted in any patient. One patient fell and suffered a hip fracture requiring surgery and completed only 4 of 6 treatments. Another had transient blue fingertips at 8 weeks into the study that resolved spontaneously. Six patients had minor transient nausea or diarrhea during drug infusions; one of these patients developed transient minor mouth ulcers after 2 treatment sequences, and another had minor headaches briefly during 2 treatments. No treatment related hepatotoxic or hematologic toxicities occurred.

MTX has proven to be a very useful drug in RA, yet only about 19% of patients improve by ACR50 criteria, and only 39% improve by ACR20, although in early disease improvement by ACR20 may be seen in about two-thirds of patients^5-8. 5-FU, like MTX, is an anti-metabolite and much of its effects are due to inhibition of DNA synthesis⁹. This inhibition can be enhanced by increasing levels of reduced folate in target cells, an effect of LCV¹⁰. In addition to its anti-tumor activity, 5-FU has immunosuppressive properties^11,12. It also increases apoptosis, which may be relevant to disease activity in RA¹³.

This open label study, with the shortcomings inherent in this design, suggested the possibility of a beneficial treatment effect of 5-FU, with an acceptable side effect profile for some patients, but the results were not compelling. Intravenous treatment for 5 consecutive days is cumbersome. While 5-FU may hold some promise for improving disease control in some patients with RA, the temporary improvement noted by many patients at 2 weeks following drug administration suggests that a more prolonging dosing approach would be beneficial. Since the completion of this pilot trial, capecitabine, an oral formulation of 5-FU has been approved for treatment of patients with metastatic breast and colorectal cancer. This treatment, which is commonly given for 2 out of every 3 weeks, may be reasonable to evaluate in patients with RA that are resistant to conventional therapy.

THOMAS W. BUNCH, MD; CHARLES ERLICHMAN, MD; HARVINDER S. LUTHRA, MD; ERIC L. MATTESON, MD, MPH, Mayo Clinic and Mayo Graduate School of Medicine, Rochester, Minnesota 55905, USA.

REFERENCES

1. O'Connell MJ, Mailliard JA, Kahn MJ, et al. Controlled trial of fluorouracil and low-dose leucovorin given for six months as postoperative adjuvant therapy for colon cancer. J Clin Oncol 1997;15:246-50.

2. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315-24.

3. Hochberg MC, Chang RW, Dwosh I, Lindsey S, Pincus T, Wolfe F. The American College of Rheumatology 1991 revised criteria for the classification of global functional status in rheumatoid arthritis. Arthritis Rheum 1992;35:498-502.

4. Felson DT, Anderson JJ, Boers M, et al. The American College of Rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trials. Arthritis Rheum 1993;36:729-40.

5. Bathon JM, Martin RW, Fleischmann RM, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 2000;343;1586-93.

6. Cohen S, Cannon GW, Schiff MH, et al. Two-year, blinded, randomized controlled trial of treatment of active rheumatoid arthritis with leflunomide compared with methotrexate. Arthritis Rheum 2001;44:1984-92.

7. Tugwell P, Bennett K, Gent M. Methotrexate in rheumatoid arthritis: indications, contributions, efficacy, and safety. Ann Intern Med 1987;197:358-66.

8. Fries JF, Williams CA, Morfeld D, Singh G, Sibley J. Reduction in long-term disability in patients with rheumatoid arthritis by disease-modifying anti-rheumatic drug-based treatment strategies. Arthritis Rheum 1996;39:616-22.

9. Schalhorn A, Kuhl M. Clinical pharmokinetics of fluorouracil and folinic acid. Semin Oncol 1992;19:82-92.

10. Park J, Collins JM, Gazdar AF, et al. Enhancement of fluorinated pyrimidine-induced cytotoxicity by leucovorin in human colorectal carcinoma cell lines. J Nat Cancer Inst 1988;80:1560-4.

11. Vetvicka V, Vetvicka J, Sonnenfeld G. Effect of cytokines on 5-fluorouracil-mediated immunosuppression. Immunol Lett 1995;47:103-6.

12. El-Assouli SM. The molecular basis for the differential sensitivity of B and T lymphocytes to growth inhibition by thymidine and 5-fluorouracil. Leukemia Res 1985;9:391-8.

13. Sakaguchi Y, Stephens LC, Makino M, et al. Apoptosis in normal tissues induced by 5-fluorouracil: comparison between bolus injection and prolonged infusion. Anticancer Res 1994;14:1489-92.

Bisphosphonate Addition to Stable Hormone Replacement Therapy Increases Bone Mineral Density in Postmenopausal Women

To the Editor:

Numerous studies have described the efficacy of hormone replacement therapy (HRT) in preventing the progression of osteoporosis, increasing bone mineral density (BMD)^1,2, and decreasing incidence of fracture^3,4. On the other hand, Komulainen, et al⁵ found between 11 and 26% of women after 5 years of HRT were densitometric nonresponders at both the lumbar spine and femoral neck. We investigated if the addition of a bisphosphonate, either alendronate or etidronate, would increase BMD at the lumbar spine, greater trochanter, or femoral neck in postmenopausal women undergoing stable HRT.

Patients were chosen from the Canadian Database of Osteoporosis and Osteopenia (CANDOO)⁶. This database is accumulated from standardized forms completed prospectively for each patient with osteopenia or osteoporosis seen in consultation and followup at a tertiary care bone disease referral center.

All women who presented with BMD evidence of osteopenia (T score < -1 to ³ -2.5) or osteoporosis (T score < -2.5) from 1990 until 1998 were identified. BMD was measured at the lumbar spine, femoral neck, and greater trochanter by dual x-ray absorptiometry. From this cohort of 5066 patients, we selected postmenopausal women who had been undergoing continual estrogen therapy as a single agent, or with a progestin (for those with a uterus), for at least 2 years, with documented BMD data in our database after 2 consecutive years of HRT. This timepoint was denoted the baseline. Further, to qualify for the study, this cohort of women had to have taken HRT with or without a bisphosphonate (alendronate 10 mg or cyclical etidronate) for the following year from their baseline, with a followup BMD at the end of the one year.

Women were classified into 3 groups depending on the type of treatment they received the following year. The groups included: (1) continuing hormone replacement (HRT) alone (n = 249), (2) hormone replacement with the addition of alendronate (HRT + A) (n = 30), or (3) hormone replacement with the addition of intermittent cyclical etidronate (HRT + E) (n = 37). Patients were excluded if they had taken medications known to affect bone metabolism such as calcitonin, fluoride, corticosteroids, or anticonvulsants during the stable estrogen or followup phase of the study.

Baseline characteristics and BMD at one year followup of the 3 groups were compared using one-way analysis of variance and Tukey's honestly significant difference for pairwise comparisons. Baseline differences between groups were seen in age, years in menopause, calcium and vitamin D intake per day, and baseline BMD at the lumbar spine, femoral neck and greater trochanter (Table 1).

Table 1. Baseline characteristics of the 3 treatment groups. All values represent mean (standard deviation).

The multiple regression technique of analysis of covariance was subsequently used to analyze the BMD at one year followup, to take into account these baseline differences between groups, with the Bonferroni test to adjust for multiple comparisons. The analysis revealed that treatment with a bisphosphonate in addition to HRT led to an increase in BMD, compared with HRT alone. Differences between treatment groups in BMD at the lumbar spine: HRT + A vs HRT: +3.7% (p < 0.001), HRT + E vs HRT: +3.9% (p < 0.001), and HRT + E vs HRT + A: +0.2% (p = 1.0); at the femoral neck: HRT + A vs HRT: +2.6% (p = 0.088), HRT + E vs HRT: +0.9% (p = 1.0), and HRT + A vs HRT + E: +1.7% (p = 0.808); and at the greater trochanter: HRT + A vs HRT: +2.1% (p = 0.129), HRT + E vs HRT: +3.2% (p = 0.012), and HRT + E vs HRT + A: +1.1% (p = 1.0) (Figure 1). There were no differences in the occurrence of new fractures.

Although this was not a randomized study, our results are closely comparable to 2 randomized controlled trials showing that both etidronate⁷ and alendronate⁸ were effective in increasing BMD when added to ongoing HRT. The CANDOO database, as evident in this study, is useful for direct comparisons between multiple drugs. Ours is the first study to directly compare the effectiveness of adding etidronate or alendronate, following the use of HRT alone, on BMD. It is also the first to describe the effectiveness of combination therapy, whose efficacy has been shown under clinical trial conditions, in clinical practice. Additional features of our cohort study design include the ability to analyze endpoints at lesser expense and within a shorter time than is possible in a randomized controlled trial. Such results could be used to generate hypotheses for future randomized controlled trials.

Thus, the addition of either intermittent cyclical etidronate or alendronate to stable estrogen therapy can significantly increase a postmenopausal woman's trabecular BMD. Both alendronate and etidronate were effective at the lumbar spine. Etidronate was also effective in increasing BMD at the greater trochanter. No statistically significant differences were observed between the effectiveness of the 2 bisphosphonates compared to each other.

PAULINE BOULOS, MD, FRCPC, Department of Medicine, St. Joseph's Healthcare; ROLF J. SEBALDT, MD, FRCPC; CHARLIE H. GOLDSMITH, PhD, Department of Clinical Epidemiology and Biostatistics, McMaster University, Centre for Evaluation of Medicines, Hamilton, Ontario, Canada.

Dr. Boulos' research fellowship is funded by a joint grant from
The Arthritis Society/Canadian Institutes of Health Research.

REFERENCES

1. Harris ST, Genant HK, Baylink DJ, et al. The effects of estrone (Ogen) on spinal bone density of postmenopausal women. Arch Intern Med 1991;151:1980-4.

2. Stevenson JC, Cust MP, Gangar KF, Hillard TC, Lees B, Whitehead MI. Effects of transdermal versus oral hormone replacement therapy on bone density in spine and proximal femur in postmenopausal women. Lancet 1990;336:265-9.

3. Lindsay R, Hart DM, Forrest C, Baird C. Prevention of spinal osteoporosis in oophorectomised women. Lancet 1980;2:1151-4.

4. Kiel DP, Felson DT, Anderson JJ, Wilson PW, Moskowitz MA. Hip fracture and the use of estrogens in postmenopausal women. The Framingham Study. N Engl J Med 1987;317:1169-74.

5. Komulainen M, Kroger H, Tuppurainen MT, Heikkinen A-M, Honkanen R, Saarikoski S. Identification of early postmenopausal women with no bone response to HRT: Results of a five-year clinical trial. Osteoporosis Int 2000;11:211-8.

6. Sebaldt RJ, Adachi JD. Canadian Database of Osteoporosis and Osteopenia Patients (CANDOO). COACH Conference Proceedings. Edmonton: Healthcare Computing and Communications Canada Inc.; 1996:36-9.

7. Wimalawansa SJ. A four-year randomized controlled trial of hormone replacement and bisphosphonate, alone or in combination, in women with postmenopausal osteoporosis. Am J Med 1998;104:219-26.

8. Lindsay R, Cosman F, Lobo RA, et al. Addition of alendronate to ongoing hormone replacement therapy in the treatment of osteoporosis: a randomized controlled clinical trial. J Clin Endocrinol Metab 1999;84:3076-81.

Infliximab for Systemic Onset Juvenile Idiopathic Arthritis: Experience in 3 Children

To the Editor:

The tumor necrosis factor-a (TNF-a) blockers infliximab and etanercept are now licensed for the treatment of refractory rheumatoid arthritis, but experience with TNF-a blockade in juvenile idiopathic arthritis (JIA) is limited^1-4. The heterogeneity of JIA disease phenotypes indicates that the pathogenesis — and the role of TNF-a — may be different. We describe 3 patients treated with infliximab for systemic onset JIA.

Patient A (girl age 18 yrs), Patient B (girl age 11 yrs), and Patient C (boy age 10 yrs) were diagnosed with systemic onset JIA at the ages of 11, 3, and 5, respectively. They received combined treatment with nonsteroidal antiinflammatory drugs (NSAID), corticosteroids, high dose methotrexate (MTX) (25 mg/m² once weekly, discontinued in Patient A because of gastrointestinal side effects), and cyclosporin A (CsA, Patients B and C). Both girls' systemic features remitted 2 years after onset, but destructive polyarthritis persisted. Patient C experienced a continuing systemic and polyarticular course. All patients experienced growth retardation and osteoporosis. Infliximab was started at 3 mg/kg at Weeks 0, 2, and 6, followed by infusion every 8 weeks. NSAID, CsA, and MTX were continued throughout treatment. Each clinical visit included assessment of active joint number (AJN, joints with swelling not due to deformity or with limited motion and with pain, tenderness, or both), joints with limited motion (LJN), visual analog scale measurement (parent assessment) for global well being (VASg) and pain (VASp) (scale 0-100 mm), Childhood Health Assessment Questionnaire (CHAQ), and serum C-reactive protein (CRP) and interleukin 6 (IL-6) (Patient C).

Infliximab induced rapid and sustained control of polyarthritis in Patients A and B, as evidenced by decreasing clinical, biochemical, and functional scores (Figure 1). In Patient A, steroid dose (0.2 mg/kg/day) was reduced by 50%; it was unchanged in Patient B (0.2 mg/kg/day). Strikingly, in Patient B, infliximab treatment resulted in an apparent repair process of the damaged hip joints. Six months before infliximab treatment, the hip radiograph showed severe joint space narrowing and erosions; reevaluation at Week 37 showed improvement in joint space, indicating gain of articular cartilage (Figure 2). During infliximab therapy, the girl, who was wheelchair-bound, regained the ability to walk independently.

In Patient A, LJN changed minimally, suggesting irreversible joint damage; the decrease in CRP lagged behind the clinical improvement. A self-limited rhinitis in Patient B (Figure 1) was associated with an increased CHAQ score but not with arthritis relapse, suggesting that infection related malaise, rather than arthritis, was the major determinant of the CHAQ score. This is in accord with the report by Ruperto, et al, who found the LJN, CHAQ, and biochemical measures to be less sensitive for assessment of disease activity in JIA⁵. A slightly modified definition of improvement, proposed by Giannini, et al⁶, was used: we considered patients as responders when 30% or greater improvement was noted in at least 3 of 5 variables, with no more than one variable worsening by 30% or more. Accordingly, Patients A and B were considered to be responders.

A similar favorable response of polyarthritis was observed in Patient C. However, systemic features failed to respond to 3 and 5 mg/kg infliximab (Figure 1). Elliott, et al reported temporary control of systemic disease but not of polyarthritis by 2 doses of 10 mg/kg infliximab in a similar patient¹. An abstract on the use of etanercept in systemic JIA notes remission of systemic features in 23 out of 36 patients (survey by questionnaire)³; a variable response to etanercept was reported in another abstract⁴. In our patient, systemic disease seemed to remit following a dose increase to 10 mg/kg, but at Week 67 high fever recurred, paralleled by high CRP and IL-6 levels, and arthritis reappeared. The CsA dose (0.5 mg/kg/day), which had been reduced by 40%, was increased again. Systemic disease and — since functional scores improved only with intensive physiotherapy — mechanical joint damage may have affected subjective and functional scoring. Overall, Patient C was found to be a nonresponder.

Possible adverse reactions of infliximab therapy were self-limited upper airway infections (Patient B one, Patient C 3).

Numerous investigators have reported on the expression of pro- and antiinflammatory cytokines in synovial fluid and serum of patients with JIA, and have tried to characterize cytokine profiles in different JIA subtypes that may be related to their pathogenesis^7-9. Increasing evidence suggests IL-6 is largely responsible for the extraarticular features of systemic JIA¹⁰. The fluctuating levels of both CRP and IL-6 in Patient C support this hypothesis and reflect failure of chronic pulsed TNF-a antagonism to control the acute phase response typical of systemic JIA.

Our experience suggests infliximab may be effective for polyarthritis in systemic onset JIA when systemic symptoms are controlled or absent, whereas it may not control systemic disease activity at doses up to 10 mg/kg. Discordance of the articular compared to the systemic disease response suggests that different cytokine networks may operate in these disease components and supports the view that several cytokines, such as TNF-a and IL-6, may be potential targets for immunotherapy in JIA.

AN D. BILLIAU, MD, Pediatric Rheumatology, University Hospital Gasthuisberg; FREDDY CORNILLIE, PhD, Centocor BV, Leuven; CARINE WOUTERS, MD, PhD, Pediatric Rheumatology, University Hospital Gasthuisberg, Leuven, Belgium.

ACKNOWLEDGMENT

We thank Anne Goossens and Dr. Francis de Halleux, Schering Plough, Belgium, for supplying infliximab. We thank Martine Adé for excellent technical assistance in IL-6 measurement by ELISA, and Dr. Gregory Keenan for critical revision of the manuscript.

REFERENCES

1. Elliott MJ, Woo P, Charles P, Long-Fox A, Woody JN, Maini RN. Suppression of fever and the acute-phase response in a patient with juvenile chronic arthritis treated with monoclonal antibody to tumor necrosis factor-alpha (cA2). Br J Rheumatol 1997;36:589-93.

2. Lovell DJ, Giannini EH, Reiff A, et al. Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group. N Engl J Med 2000;342:763-9.

3. Kimura Y, Li Z, Ebner-Lyon L, Imundo L. Treatment of systemic JIA with etanercept: Results of a survey [abstract]. Arthritis Rheum 2000;43 Suppl:S257.

4. Higgins GC, Jones K, Rennebohm RM. Variable response of systemic juvenile rheumatoid arthritis to etanercept [abstract]. Arthritis Rheum 2000;43 Suppl:S257.

5. Ruperto N, Ravelli A, Migliavacca D, et al. Responsiveness of clinical measures in children with oligoarticular juvenile chronic arthritis. J Rheumatol 1999;26:1827-30.

6. Giannini EH, Ruperto N, Ravelli A, Lovell DJ, Felson DT, Martini A. Preliminary definition of improvement in juvenile arthritis. Arthritis Rheum 1997;40:1202-9.

7. Woo P. Cytokines in juvenile chronic arthritis. Baillieres Clin Rheumatol 1998;12:219-28.

8. Prieur AM, Kaufmann MT, Griscelli C, Dayer JM. Specific interleukin-1 inhibitor in serum and urine of children with systemic juvenile chronic arthritis. Lancet 1987;2:1240-2.

9. Rooney M, Varsani H, Martin K, Lombard PR, Dayer JM, Woo P. Tumor necrosis factor alpha and its soluble receptors in juvenile chronic arthritis. Rheumatology 2000;39:432-8.

10. De Benedetti F, Martini A. Is systemic juvenile rheumatoid arthritis an interleukin 6 mediated disease? J Rheumatol 1998;25:203-7.