Abstract | OBJECTIVE: METHODS: Twenty-six patients with severe rheumatoid arthritis (RA) refractory to treatment with at least one slow acting antirheumatic drug were treated with intravenous fludarabine [20 mg/m2 body surface area (n=12) or 30 mg/m2 body surface area (n=14) per day for 3 consecutive days] given monthly for 6 months. Second line agents with the exception of glucocorticoids were discontinued at least 4 weeks before study entry. Measurements included toxicity and tolerability monitored at monthly intervals: efficacy, by both a 50% reduction in tender or swollen joint count and American College of Rheumatology (ACR) criteria for 20% response; and phenotypic analysis of peripheral blood mononuclear cells and T cell functional assays. RESULTS: Using intention-to-treat analysis, 2 of 12 (17%) patients in the low dose and 7 of 14 (50%) in the high dose groups had 50% or greater reduction in tender and/or swollen joint count after 6 months of therapy compared to baseline (p=0.09). Two of 12 (17%) in the low dose group and 5 of 14 (36%) in the high dose group met ACR criteria for 20% improvement (p=0.28). No immediate toxicity was observed. Several infections occurred, including 4 episodes of limited Herpes zoster, which responded to standard therapy. Significant lymphopenia involving T and B cells was observed in all patients. Both naive (CD4+CD45RA+) and memory CD4+ T cells (CD4+CD45RO+) were reduced (naive > memory). No significant regeneration of naive T cells was observed, which may suggest limited thymic regenerative capacity. Fludarabine decreased the proliferative response of peripheral blood lymphocytes to mitogens, as well as the production of T cell ( interleukin 2 and interferon-gamma) and monocyte derived ( tumor necrosis factor-alpha and IL-10) cytokines. CONCLUSION:
Fludarabine treatment of patients with severe, refractory RA resulted in significant lymphopenia, suppression of lymphocyte function, and clinical improvement in the high dose group. There was no immediate toxicity; however, several infections occurred. Controlled trials are needed to substantiate the clinical improvement observed in this open label trial.
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Authors | J C Davis Jr, B J Fessler, I O Tassiulas, I B McInnes, C H Yarboro, S Pillemer, R Wilder, T A Fleisher, J H Klippel, D T Boumpas |
Journal | The Journal of rheumatology
(J Rheumatol)
Vol. 25
Issue 9
Pg. 1694-704
(Sep 1998)
ISSN: 0315-162X [Print] Canada |
PMID | 9733448
(Publication Type: Clinical Trial, Clinical Trial, Phase I, Clinical Trial, Phase II, Controlled Clinical Trial, Journal Article)
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Chemical References |
- Antigens, CD
- Immunosuppressive Agents
- Vidarabine
- fludarabine
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Topics |
- Antigens, CD
(analysis)
- Arthritis, Rheumatoid
(drug therapy, immunology)
- Dose-Response Relationship, Drug
- Female
- Humans
- Immunosuppressive Agents
(administration & dosage, adverse effects, therapeutic use)
- Leukocytes, Mononuclear
(drug effects, physiology)
- Lymphocyte Count
(drug effects)
- Male
- Middle Aged
- Phenotype
- Platelet Count
(drug effects)
- Time Factors
- Treatment Outcome
- Vidarabine
(administration & dosage, adverse effects, analogs & derivatives, therapeutic use)
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