Boumpas Dt

The history of glucocorticosteroid therapy and modern rheumatology are inseparable. Glucocorticosteroids exert profound effects on the inflammatory and immune responses. They affect the growth, differentiation and function of monocytes and lymphocytes, the distribution of cellular subsets, and the production of cytokines. Glucocorticosteroid-induced lipocortins inhibit eicosanoid production and release by suppressing phospholipase A2. The principal mechanism whereby they exert their powerful effects is through modulation of the transcription of specific sets of genes. Recently, post-transcriptional mechanisms have also been recognized to be affected by glucocorticosteroids. In this review we discuss the molecular and cellular aspects of glucocorticosteroid action on the immune system.

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.

Atherosclerosis may be more prevalent and more extensive in individuals with rheumatoid arthritis (RA) compared with the general population. Despite the fact that traditional and novel cardiovascular disease (CVD) risk factors are clinically important in these patients, it seems that inflammation--a key feature of RA--plays a crucial role in atherogenesis. Reducing the CVD burden in patients with RA is a more complex process than in the general population, mostly due to inadequate inflammation suppression as well as multiple concomitant drug therapy. Furthermore, there is no current consensus on whether RA patients should be treated as individuals at high-risk for vascular events. Statins have proved their efficacy in reducing CVD events in the general population. Despite the fact that they are not specifically indicated in RA, there is evidence supporting a beneficial effect on CVD risk factors as well as disease activity and progression. The present review considers the traditional and novel as well as the RA-specific CVD risk factors. The current evidence supporting the use of statins in this patient population is also discussed.

Two patients developed drug induced lupus secondary to sulfasalazine (SSZ). One patient was receiving SSZ for Crohn's disease and was subsequently treated with olsalazine, which lacks the sulfapyridine component of SSZ. Her inflammatory bowel disease (IBD) remained controlled and she did not develop a recurrence of lupus, suggesting that olsalazine is safe in patients with IBD and a history of SSZ induced lupus. The SSZ induced antibodies were predominantly IgG against the (H2A-H2B)-DNA complex. Since lupus induced by 7 other drugs was associated with a similar antibody response, our findings support the existence of a common pathway for autoantibody induction.