THERAPY IN LUPUS NEPHRITIS

1. THERAPY IN LUPUS NEPHRITIS

2. Approximately 25% to 60% of unselected patients with • SLE have renal involvement as assessed by urinalysis or impairment • of renal function, but often the disease is mild.

3. the spectrum of lupus nephritis is wide, encompassing the • acute nephritic syndrome, nephrotic syndrome, acute or chronic renal failure, and isolated abnormalities of the urinary sediment. • proteinuria is the most constant feature, being present in almost every patient with clinical lupus nephritis

4. The large majority of patients with lupus nephritis will have SLE at the time of diagnosis of the renal disease. • Exception to this is membranous lupus nephropathy, which may predate the development of extrarenal and serologic features of SLE.

5. Question IS why some patients with lupus develop nephritis whereas • others do not, and what accounts for the marked heterogeneity?

6. Brief pathogenesis • Loss of self tolerance • Amplification and sustained loss of tolerance and activation of t cells and b cells • many of these perturbations can be classified either into those directly or indirectly increasing the activation state or survival of T or B lymphocytes or • those impairing the clearance of apoptotic cells or chromatin fragments.

7. Increased circulating levels of DNA and nucleosomes also have been shown in patients with SLE • consistent with the model of impaired self-antigen clearance as a critical factor in the pathogenesis of human SLE.

8. a central role for plasmacytoid dendritic cells also has been proposed • These various components of the immune system interact, leading to the activationof a number of additional downstream effector cells and soluble • proinflammatory mediators, including cytokines and chemokines, to cause end-organ disease

9. Possible pathogenic mechanisms, in addition to their role in DNA–anti-DNA immune complex formation, include cross-reactivity with structural renal antigens such as alpha-actinin • and direct penetration of glomerular cells with nuclear binding and consequent induction of cellular dysfunction.

10. In addition to the immune complex–induced inflammatory responses, direct T-cell cytotoxicity may contribute importantly to renal injury, in particular to tubulointerstitial nephritis. • Vasculitis and arteriolar thrombi also may coexist and aggravate disease. • Antiphospholipid antibodies in patients with lupus nephritis have been reported to increase the long-term risk for developing chronic renal failure.

11. Tubuloreticular inclusions are structures composed of ribonucleoprotein and membrane that are seen frequently • within glomerular endothelial cells in lupus nephritis. They can be induced experimentally in B-cell lines by • IFN-alfa, and therefore are believed to constitute an IFN footprint

12. the expression of IFN-alfa–inducible genes in peripheral blood mononuclear cells as an indicator of an effect of IFNalfa • (the interferon signature), • this IFN signature has been found to correlate with nephritis and with other aspects of disease activity

13. DNA–anti-DNA immune complexes in the sera of patients with SLE could induce • IFN-alfa production by plasmacytoid dendritic cells, • the major cell type in the body specifically dedicated to IFNalfa production. • The interferogenic activity was dependent • completely on the DNA within the complex.

14. This shows an important concept that has emerged in recent years, namely • that mammalian nucleic acids have important immunostimulatory capacities once endocytosed,

15. Renal biopsy ? • Renal biopsy examination is valuable in patients with SLE, and is indicated in nearly all cases involving abnormalities of • the urine sediment or impaired renal function.

16. There are 2 main reasons for this. • First, it is not possible in an individual patient to predict the renal histology with any accuracy from the clinical manifestations of renal disease although, • in general, more severe histology tends to correlate with more severe clinical disease.

17. Second, in untreated patients, the renal • histology as classified by the World Health Organization WHO) is a powerful predictor of eventual outcome, and • thus helps guide initial therapeutic decisions.

18. Evidence?

19. Significance of histological patterns of glomerular injury uponlong-term prognosis in severe lupus glomerulonephritis Kidney International, Vol. 59 (2001), pp. 2156–2163 LNCS

25. In conclusion, histopathologic categorization among patients with severe lupus glomerulonephritis does follow a clinical course relevant to their long-term outcome.

26. Including all patients into a single category of severe DPGN would ignore the long term prediction of prognosis and treatment response

27. Patients with diffuse proliferative glomerulonephritis (category IV) were more likely to enter a remission compared with patients with • focal and segmental glomerulonephritis or membranous glomerulonephritis with category III and category IV superimposed proliferation • indicating a superior response to therapy

28. The presence of category III or Vc Vd lesion was predictive of progression to End stage renal disease • The accurate pathological stratification of renal biopsies is essential to the ultimate definition of the optimal therapy for patients

31. Therapeutic options - why treat? • A delay between the onset of renal disease and initiation of treatment has been linked to the subsequent development of renal insufficiency.

32. Prognostic factors • factors including increased serum creatinine levels, anemia, black race, and hypertension have been associated with a poor prognosis • However, at the present time, renal histology in untreated patients is the best predictor of eventual outcome, and treatment decisions are based largely on the renal biopsy examination result.

33. Severe Lupus Nephritis: Racial Differences in Presentationand Outcome J Am Soc Nephrol 18: 244–254, 2007

44. Patients with class II lupus nephritis generally have an excellent renal prognosis, although occasionally the disease may transform into class III or IV. • Some physicians will treat class II with a course of corticosteroid monotherapy, although there is no good evidence that this prevents the subsequent evolution of severe disease • in those patients in whom class III or IV proliferative nephritis coexists with class V, treatment is directed toward the class III or IV disease. • Gradations of disease severity exist within class III ranging from mild to severe, which complicates prognosis in this class

45. Most patients with class IV and severe class III will develop progressive renal failure, and in these groups of patients immunosuppressive treatment clearly is indicated

46. The goals of immunosuppression • (1) induction of renal remission, • (2) avoiding renal flares, • (3) preventing chronic kidney disease, and • (4) accomplishing these goals with minimal toxicity to the patient.

47. Overall outcomes • with current treatment protocols only about 80% of patients achieve renal remission with initial therapy, • Approximately 30% experience renal flares, • 5% to 20% of patients progress to end-stage kidney disease, • and treatmentrelated toxicity is appreciable

48. Choice of immunosuppression • Steroid • Steroid + CTX pulse or oral • MMF induction and maintainence • Sequential therapy • Others • Novel agents and future directions

49. Hit early and hit hard • Induction and maintenance strategy • Until recently, the majority of nephrologists and rheumatologists relied on one ‘standard’ approach to the treatment of severe LN based upon a series of trials at the National Institutes of Health

50. NIH studies • National Institutes of Health trials proved the efficacy of a • regimen consisting of six monthly pulses of intravenous (i.v.) cyclophosphamide (CYC) (0.5–1 g/m2) followed by subsequent i.v. CYC pulses every 3 months for 2 years. • This regimen was shown to have fewer flares and relapses and better renal survival than a shorter regimen of six monthly treatments without follow-up doses.