Lymphocyte depletion with fludarabine in patients with psoriatic arthritis: clinical and immunological effects.

OBJECTIVE: To obtain preliminary information on the safety and efficacy of fludarabine in PsA and analyse its immunomodulatory effects in peripheral blood and synovial tissue. METHODS: 15 patients with active PsA who did not respond to DMARDs were randomly allocated to receive fludarabine every four weeks or placebo. Primary outcomes were the proportion of patients who met the ACR20 and the psoriatic arthritis response criteria (PsARC) at 16 weeks. Secondary outcomes were changes in tender or swollen joint counts and scores of the psoriasis area and severity index (PASI). Phenotypic analysis of peripheral blood mononuclear cells (PBMC), synovial immunohistochemistry, and functional analysis of PBMC were used to determine the immunomodulatory effects of fludarabine. RESULTS: At 16 weeks the ACR20 criteria were met by 3/7 (43%) fludarabine treated v 0/8 placebo treated patients (p=0.08); the PsARC was achieved by 4/7 (57%) fludarabine treated v 2/8 (25%) placebo treated patients; and 3/7 (43%) fludarabine treated v 0/7 placebo treated patients had > or =20% improvement in the PASI. Marked peripheral lymphopenia involving naive (CD4(+) CD45RA(+)) and memory (CD4(+) CD45RO(+)) T cells, CD8(+) T cells, and B cells was seen in fludarabine treated patients. CONCLUSIONS: In PsA fludarabine induces significant peripheral, but modest, synovial lymphopenia, and a trend towards improved clinical response.

A pilot study of low-dose fludarabine in membranous nephropathy refractory to therapy.

BACKGROUND: Lymphocytes are believed to play a role in the induction and perpetuation of membranous nephropathy. Fludarabine is a purine nucleoside analog with selective activity against both dividing and resting lymphocytes. We evaluated the tolerance, toxicity, pharmacokinetics, immunologic, and clinical effects of fludarabine in patients with membranous nephropathy in an single arm pilot study. PATIENTS AND METHODS: Eight patients with idiopathic (n = 7) or lupus (n = 1) membranous nephropathy who had failed high-dose prednisone (n = 8) and/or alkylating agents (n = 2), or cyclosporine (n = 1) were treated with 6-monthly cycles of fludarabine (cycles 1-2, 20 mg/m2/day x 2 days, cycles 3-6, 20 mg/m2/day x 3 days). Mean proteinuria was 9 g/day with a mean duration of disease of 25 months (range 12-48). Proteinuria, GFR and effective renal plasma flow were compared before and after completing the treatment. RESULTS: Seven patients completed the protocol. CD3, CD4, CD8 and B cell counts decreased by 53%, 46%, 61% and 84%, respectively, at the end of treatment and remained at lower than pretreatment levels 6 months after completing the trial. Despite lymphopenia, serum immunoglobulin levels remained unchanged. Both naive (CD45RA+) and memory CD4+ T cells (CD45RO+) were reduced (naive > memory). Proteinuria decreased by > or = 50% in 5 out of 7 patients (p = 0.11). Filtration fraction improved in all patients with decreased filtration fraction at baseline. The only side-effect observed was one episode of acute bacterial sinusitis that responded promptly to antibiotic therapy. CONCLUSION: We conclude that low-dose fludarabine treatment in patients with membranous nephropathy is well tolerated and results in significant lymphopenia involving B more than T cells. In this pilot study improvement in proteinuria and filtration rate were observed. Additional studies are required to determine the optimal dose and clinical efficacy of fludarabine.

High dose versus low dose fludarabine in the treatment of patients with severe refractory rheumatoid arthritis.

OBJECTIVE: Fludarabine, a nucleoside analog that targets both resting and proliferating lymphocytes, is a promising drug for the treatment of autoimmune diseases. We conducted a 2 dose, open label clinical trial to evaluate the toxicity/safety of the fludarabine treatment and its clinical and immunological effects. 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.

Angiotensin I converting enzyme gene polymorphisms in systemic lupus erythematosus: decreased prevalence of DD genotype in African American patients.

The presence of the D (deletion) allele at the angiotensin converting enzyme (ACE) gene has been associated with a) adverse vascular events contributing to early mortality and b) progressive deterioration of renal function in a variety of chronic glomerular diseases. We investigated the potential role of ACE polymorphisms in patients with systemic lupus erythematosus (SLE). Two hundred and sixteen (216) SLE patients (121 Caucasians; 78 African Americans; and 17 other) and 200 normal controls were studied; 134 patients had evidence of renal disease. ACE genotypes were determined by a polymerase chain reaction based assay. The frequency of genotype DD was increased in African American normal controls compared to Caucasians (55% vs. 37%, p = 0.017) and in African American normal controls vs. African American lupus patients (55% vs. 30%, p = 0.008). Trend analysis of the genotype distribution across the three African American groups (renal, non-renal, controls) revealed a trend of increased frequency of I and decreased frequency of D as likelihood of renal disease increases (p = 0.008). No association between any ACE genotype with parameters of renal disease and/or response to therapy was identified. African American patients with lupus have a lower frequency of DD genotype as compared to African American normal controls. Further studies will be necessary to address whether this is due to decreased survival of these patients, a protective effect of DD genotype from developing the disease or a chance sample effect.

Lupus nephritis.

Both immune and nonimmune mechanisms are operant in lupus nephritis. Recent findings have begun to elucidate fundamental questions in the pathogenesis of the disease. Genetic linkage studies have identified susceptibility loci contributing to nephritis in lupus-prone mice. Polymorphisms of the Fc gamma Rlla gene have been found to correlate with the development of renal disease in black Americans and white Europeans. Genetic factors are important in determining both predisposition to nephritis and outcome (and likely response to therapy). In lupus nephritis, prevention of tissue injury involves effective immunosuppressive therapy and aggressive management of hypertension and hyperlipidemia. Although with intensive immunosuppressive therapy most lupus patients achieve remission, a substantial number of these patients either do not respond, respond partially, or relapse after discontinuation of therapy. Moreover, the toxicity of available immunosuppressive drugs is substantial, suggesting that alternative therapeutic regimens are needed. In the future, other inhibitors of inflammatory, immune, vasoactive, proteolytic, and growth-promoting mediators are likely to play a role in the management of lupus nephritis.