Treatment of Severe Lupus Nephritis:The

new horizonMuhammad Azhar,MD

Assistant Consultant Nephrology

common and severe manifestation of systemic lupus erythematosus.

important cause of both acute kidney injury and end-stage renal disease.

amenable to treatment in the majority of patients

Lupus Nephritis

corticosteroids alone  corticosteroids plus cyclophosphamide

MMF has emerged as a standard of care option for both induction and maintenance treatment.

multiple novel therapeutic options, such as calcineurin inhibitors and biologic agents 

Evolution of treatment

evidence in support of current standard of care immunosuppressive treatments

and emerging therapies. roles and relative merits in the

management of patients with lupus nephritis.

This review-includes

Corticosteroids plus cyclophosphamide standard therapy for severe lupus nephritis

novel treatments have been compared since the 1980s

  cyclophosphamide and corticosteroids more effective

than corticosteroids alone.

Increased adverse events significantly greater mortality (18.2%, versus 3.7%)

Cyclophosphamide

leukopenia, alopecia, vulnerability to infections, gonadal toxicity, haemorrhagic cystitis, uroepithelial tumours increased incidence of other malignancies.

cyclophosphamide

rate of renal remission with lupus nephritis (defined as proteinuria <0.33 g daily and serum creatinine <124 µmol/l) corticosteroids with 8 weeks of oral cyclophosphamide was 41%.  corticosteroids and oral or intravenous cyclophosphamide for 6 months switch to azathioprine maintenance therapy stable renal function in 80%

10 years of follow-up.

Collaborative Study Group trial

six monthly pulses plus two quarterly pulses  six 500 mg pulses every 2 weeks

initial pulse methylprednisolone (750 mg daily for 3 days) followed by oral corticosteroids

 followed by azathioprine maintenance

Euro-Lupus Nephritis Trial 

similar rates of treatment failure (20% and 16%)

renal flare (29% and 27%)

chronic kidney disease (11% versus 5%), death (4% versus 11%), serum creatinine doubling (11% versus 14%) and ESRD (9% versus 5%) .

Euro-Lupus Nephritis Trial

Table 1 Key trials of induction treatment for severe lupus nephritis

Chan, T. M. (2014) Treatment of severe lupus nephritis: the new horizonNat. Rev. Nephrol. doi:10.1038/nrneph.2014.215

cyclophosphamide,MMF,Azathioprine 59 patients Corticosteroids plus iv cyclophosphamide induction

treatment. Mortality and renal-failure-free survival inferior with

prednisolone plus cyclophosphamide;

relapse-free survival better with prednisolone plus mycophenolate mofetil than with prednisolone plus cyclophosphamide

N Engl J Med 2004; 350:971-980March 4, 2004DOI: 10.1056/NEJMoa031855

Cyclophosphamide as maintanance

cyclophosphamide as maintenance has decreased.

The latest KDIGO guidelines - lifetime exposure not > 36 g

Cyclophosphamide as maintanance

greater efficacy than azathioprine well tolerated in most patients. gastrointestinal irritation leukopenia anaemia predisposition to infections. attractive candidate for the treatment of

lupus nephritis.

Mycophenolate mofetil

randomized controlled trial

compared mycophenolate mofetil for 12 months with oral cyclophosphamide for 6 months followed by azathioprine for 6 months

42 Chinese patients

active class IV lupus nephritis. 

12 months, response rates in the two groups were similar

80% and 15% complete and partial remission respectively

Mycophenolate as Induction

largest trial of treatment for lupus nephritis to date 

 industry-sponsored, multinational prospective study. 

The first phase compared mycophenolate mofetil and intravenous cyclophosphamide as induction therapy

second phase compared mycophenolate mofetil and azathioprine as maintenance therapy.

The Aspreva Lupus Management Study (ALMS)

induction phase of ALMS to demonstrate the superiority of mycophenolate mofetil over cyclophosphamide,

the results confirmed earlier reports that mycophenolate

mofetil was no worse than cyclophosphamide as an induction

  could be the preferred induction choice for black and

Hispanic patients - inferior outcome of cyclophosphamide therapy in these groups.

ethnicity, geographic factors, dose and overall immunosuppressive potency might contribute to determining the optimal balance between efficacy and risk.

The Aspreva Lupus Management Study (ALMS)

Mycophenolate mofetil was superior to azathioprine

maintaining a renal response to treatment and

preventing relapse

ALMS-Maintenance phase

Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial 

the MAINTAIN Nephritis Trial Group

MMF as Maintenance

Trial profile and patient disposition.

Frédéric A Houssiau et al. Ann Rheum Dis 2010;69:2083-2089

©2010 by BMJ Publishing Group Ltd and European League Against Rheumatism

Kaplan–Meier probability analysis of renal flare.

Frédéric A Houssiau et al. Ann Rheum Dis 2010;69:2083-2089

©2010 by BMJ Publishing Group Ltd and European League Against Rheumatism

Relapse-free survival and the impact of MMF treatment duration in 65 proliferative LN patients.

Desmond Y. H. Yap et al. Rheumatology 2013;52:480-486

© The Author 2012. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Preliminary data- combined calcineurin inhibitor and corticosteroid therapy is effective in the treatment of class III, IV or V lupus nephritis,

data on tacrolimus is largely from patients of Asian ethnicity.

Calcineurin inhibitors

Ciclosporin given continuously as both initial and maintenance therapy was as effective as cyclophosphamide (both in combination with corticosteroids) in 19 patients with lupus nephritis.

Calcineurin inhibitors

In Chinese and Japanese patients, various small observational studies  randomized controlled trials efficacy of ciclosporin and corticosteroids in

induction treatment of lupus nephritis. satisfactory response rates, a potential alternative as induction therapy

for proliferative lupus nephritis. 

Calcineurin inhibitors

Acute and chronic nephrotoxicity

Higher incidence of rebound after treatment discontinuation

Concerns with CNIs

Commonly used with low dose steroids as maintenance

Good tolerability and safety in pregnancy

A study by the Dutch Working Party compared azathioprine plus intravenous methylprednisolone versus intravenous cyclophosphamide plus oral prednisone as induction treatment in 87 patients with proliferative lupus nephritis

Azathioprine

response rates in the first 2 years were comparable between the two regimens

repeat renal biopsy in 39 patients greater increase in chronicity index in the azathioprine group.

At follow-up (median 5.7 years), azathioprine group more disease flares ,higher incidence of infections cyclophosphamide group.

Azathioprine

azathioprine, even when combined with methylprednisolone pulses, might not be sufficient to ensure sustained remission and prevent renal scarring in patients with aggressive disease.

might have a role in patients with mild to

moderate lupus nephritis.

Azathioprine

Table 2 Key trials of maintenance treatment for lupus nephritis

Chan, T. M. (2014) Treatment of severe lupus nephritis: the new horizonNat. Rev. Nephrol. doi:10.1038/nrneph.2014.215

Monoclonal antibodies Fusion proteins Target cell surface molecules Signalling pathways critical to pathogenesis Increased specificity Reduced interference to physiological

processes

Biological agents

Overall well tolerated Clinical role inclusive Small scale,open label case series of anti

CD 20 Large scale,multicenter,placebo contrlloed

trials LUNAR &BELONG Unable to demonstrate significant superior

results

Biological agents

Table 3 Key trials of biologic therapies for severe lupus nephritis

Chan, T. M. (2014) Treatment of severe lupus nephritis: the new horizonNat. Rev. Nephrol. doi:10.1038/nrneph.2014.215

should not be used as add-on therapy routinely.

could benefit who do not respond to conventional treatments

minimize exposure to conventional medications

reduce treatment-associated adverse effects

Biological agents

Inhibits purine synthesis similar to MMF Selective action on lymphocytes Less oncogenic than azathioprine Well tolerated Studies mostly from japan Low immunosupressive potential

mizoribine

Inhibits pyrimidine biosynthesis Treatment of non renal manifestation 110 Chinese patients with class III or IV ± V

lupus nephritis response rates of 70–80% after 6 months with

either corticosteroids and leflunomide, or corticosteroids and monthly intravenous cyclophosphamide

effective treatment for lupus nephritis no obvious advantages over other

immunosuppressive medications.

leflunomide

absence of nephrotoxicity and

reduced occurrence of malignancies.

aphthous oral ulcers, dyslipidaemia, impaired wound healing and interstitial pneumonitis.

  Data from animal experiments and

preliminary studies in patients with lupus nephritis suggest potential therapeutic role.

mTOR inhibitors

Recommended in long term maintenance Reduced renal and nonrenal flares Reduced accural of organ damage Improved survival Canadian Hydroxychloroquine Study

discontinuation of hydroxychloroquine was associated with a sixfold increase in the relative risk of a severe nonrenal or renal disease flare requiring study withdrawal, versus continued hydroxychloroquine treatment

Antimalarial drugs

74% reduction in renal flares versus the placebo group.

LUMINA and GLADEL studies reduced occurrence of severe lupus nephritis and

improved patient survival with prolonged hydroxychloroquine or chloroquine treatment.

antimalarial treatment is associated with reduced accrual of renal damage

reduced levels of LDL-cholesterol and apolipoprotein B and increased HDL-cholesterol level

Antimalarial drugs

Figure 3 Treatment algorithm for severe (class III–V) lupus nephritis

Chan, T. M. (2014) Treatment of severe lupus nephritis: the new horizonNat. Rev. Nephrol. doi:10.1038/nrneph.2014.215

Progress over the past 50 years has brought about new paradigms in the management of lupus nephritis.

treatment has greatly improved increased efficacy reduced adverse effects improved quality of life increased range of therapeutic options enabling treatment regimens to be tailored

to the needs of individual patients.

conclusions

effective in a high proportion of patients renal survival and patient survival have

improved considerably.

treatment-related complication rates are still excessive

reliance on corticosteroids is still considerable.

conclusions

high-risk groups, such as black individuals, do not respond adequately

discontinuation of immunosuppression an elusive target

A number of new treatments have become available ,many are still being evaluated.

conclusions

CNI use is likely to increase -immunosuppressive and proteinuria-reducing actions.

B‑cell depletion or T‑cell co-stimulatory blockade, have a biological effect on the disease process.

magnitude of their clinical efficacy

role in the current therapeutic options for lupus nephritis require clarification.

conclusions

Strategies to identify patients who will benefit from treatment with biologic agents are critically needed.

The management of patients with multiple relapses, and the potential for minimizing steroid use, are other currently unmet needs that warrant further investigation

conclusions

Thank you very much