Management and Prognosis of Lupus Nephritis

Transcription

1 Management and Prognosis of Lupus Nephritis Dimitrios T Boumpas National and Kapodistrian University of Athens Special thanks to G Bertsias, University of Crete

2 Key Questions in Lupus Nephritis Is it common? Is it important and why? Who is more likely to develop it? -When should I think of? How could I best document its presence and severity? -Do I need a biopsy and why? Does serology help and how much? What is the prognosis? -How could I tailor therapy so that my treatment best fits the patient? Who is more likely to flare and how could I prevent it? -Can I discontinue therapy?

3 During the last decade, a number of large observational cohort studies and randomized controlled trials have been published, upon which, recommendations can be based Joint EULAR/ERA-EDTA recommendations for the management of adult and paediatric lupus nephritis. Bertsias G., et al. Ann Rheum Dis. 71; 11: (2012) Evidence and experience based Why? Prevent polyphony from turning into cacophony. Ensure homogeneity in care in view of National Data showing same or worsening outcomes.

4 Hippokrates Percepts 7 Evidence-based medicine in the Hippokratic tradition: Tων δ ως λόγου μόνου ξυμπαιρομένων μη είη επαύρασθαι, των δε ως έργου ενδείξιος. Σφαλερή γαρ και εύπαιστος η μετ αδολεσχίης ισχύρισις. Only conclusions based on demonstrated facts (evidence, endeixeis, εργου ενδείξιος ) can be trusted. Empty words and long-winded talk can be deceptive and easily contradicted. For this reason, stick to the facts, this is what we Hellenes call Medicine and listen to the patient relatives if you think this may help for the treatment!

5 Key Questions in Lupus Nephritis Is it common? Is it important and why? Who is more likely to develop it? -When should I think of? How could I best document its presence and severity? -Do I need a biopsy and why? Does serology help and how much? What is the prognosis? -How could I tailor therapy so that my treatment best fits the patient? Who is more likely to flare and how could I prevent it? -Can I discontinue therapy?

6 SLE in Crete (0.65 million): Lupus nephritis is less common in the community but can be severe Prevalence 0.1% (LETO REGISTRY). Only 1/3 moderate to severe LN in the community is less common. -Renal disease 13% Better prognosis only 4.4% with ESRD Earlier onset of lupus nephritis and NPSLE in male than female patients Males have twice the prevalence of LN than females Gergianaki et al Lupus suppl 2015

7 Why lupus nephritis? Most common severe manifestation in SLE In referral centers 15 20% will progress to ESRD within years. Increased mortality PARADOX!!! -ESRD: Data from individual centers improving. No decline, possible increase in USA National Data. (Tektonidou et al ART 2016) -Mortality: Decreased in single centers, BUT increased in National Registries (USA) Tektonidou ART 2015)) Data from centers may be better than National Data. Drug-related toxicity. Increased direct and indirect health care costs

8 Who is at risk to develop lupus nephritis? Childhood-young onset lupus Male patient High-disease activity ie SLEDAI more than 8 Serology: anti-dna, low complement First 2-5 years of the disease IFN-a signature ( in some ethnic groups) Decreased risk: other ENAs (ie Ro/La/Sm/RNP)

9 Key Questions in LN Is it common? Is it important and why? Who is more likely to develop it? When should I think of? How could I best document its presence and severity? -Do I need a biopsy and why? Does serology help and how? What is the prognosis? -How could I tailor therapy so that my treatment best fits the patient? Who is more likely to flare and how could I prevent it? -Can I discontinue therapy?

10 Issues in the management of lupus nephritis When to perform kidney biopsy and how to evaluate the results? Can blood tests and existing biomarkers accurately predict kidney biopsy results? What is the recommended treatment? Does it differ according to the histological class? How are severe forms of lupus nephritis treated? What is the target of treatment? How are patients followed up? Which tests are useful? How are treatment failures treated? Management of co-morbidities in lupus nephritis Pregnancy in LN

11 Pathological assessment of the kidney biopsy International Society of Nephrology/Renal Pathology Society 2003 classification [class I VI] (Grade: C) II Pathology report 1. Acute glomerular lesions («activity») 2. Chronic glomerular lesions («chronicity») 3. Tubulo-interstitial lesions (acute/chronic) 4. Vascular bed lesions (associated with apl) (Grade: Α/C) Rare III V Thrombotic microangiopathy Wu et al. Kidney Int. 2013

12 Indications for immunosuppressive treatment Indications Class III IV A or III IV A/C (Grade: A) Mixed class V + III-IV (Grade: A) Class V with UPCR >1.0 despite optimal use of RAAS blockers (Grade: C Grade A if nephrotic-range proteinuria) Other indications: Class II with UPCR >1.0 (despite RAAS blockers) Class I with podocytopathy (minimal change disease) Interstitial nephritis

13 Prognostic factors-biomarkers Prognostic markers at disease onset Poor prognosis: - childhood-young onset; male - anti-dna, anti-phospholipids (APL), IFN-a signature( in some ethnic groups), - decreased GFR, nephrotic range proteinuria, high activity and chronicity Good: other ENAs (ie Ro/La/Sm/RNP) Biomarkers for early renal response (8 weeks) - improvement in proteinuria by at least 25% - normalization of C3, C4 or both, increase in Hct!!! Intermediate biomarkers for renal response (24 weeks) - remission of proteinuria and normalization of Cr -proteinuria less than 1 gm/24 hour Decrease in anti-dna unreliable alone. Better if combined with C3

14 The management of LN in 2017

15 Initial immunosuppressive treatment in lupus nephritis 24-wk induction phase 36-mo maintenance phase MMF 1.5 g BID IVC g/m 2 Monthly Response or Remission Yes Rerandomization MMF 1 g BID AZA 2 mg/kg/d No ALMS study n=370 patients No further treatment (exit study) *Oral corticosteroids administered in induction and maintenance phases AZA, azathioprine; IVC, intravenous cyclophosphamide; MMF, mycophenolate mofetil

16 Mycophenolate in the treatment of lupus nephritis Appel et al. JASN 2009 Touma et al. J Rheum 2011 Mycophenolate is recommended as initial treatment for most patients with class III IV (± class V) nephritis based on similar efficacy, ease of administration and better toxicity profile than high-dose IV-CY (Grade A) Evidence from post-hoc analysis of two RCTs support mycophenolate for initial treatment of class V nephritis with nephrotic-range proteinuria (Grade B) Recommended dosage of steroids: IV-MP mg 3 days oral prednisone 0.5mg/kg 4 wks (Grade C)

17 Mycophenolate in lupus nephritis: how much and for how long? Evidence from transplantation medicine and therapeutic studies in lupus nephritis suggest that the two MPA formulations seem to be equivalent MMF : target dosage 3 g/day for 6 months empa : target dosage 2160 mg/d for 6 months Higher (>2 g/day MMF) daily doses may not be tolerated (dose adjustments are common) Potent immunosuppressive drug! Monitoring MPA blood levels could be helpful to optimize drug exposure and improve renal response (at present not indicated for routine use)

18 Mycophenolate: panacea for lupus nephritis? More evidence is awaited Long-term (>5 years) efficacy and safety of MPA, especially against hard outcomes (ESRD, death) The superiority over CY in certain ethnic groups requires confirmation Could this account for the increase incidence of ESRD in USA? Austin HA et al. NEJM 1986

19 What is the place of CY in the treatment of lupus nephritis? EuroLupus Trial: low-dose IV-CY (3 g over 3 months) was as efficacious and less toxic than the high-dose IV-CY (monthly pulses g/m 2 6 months) Houssiau et al. ARD 2010 Low-dose IV CY: considered as first-line treatment of class III-IV nephritis in Caucasians (Grade B) Pure membranous nephritis (class V): A single RCT has shown superiority of high-dose IV CY (Grade A) Austin et al. JASN 2009 However, MMF is preferred due to more favorable efficacy/toxicity ratio Cyclosporin: also efficacious but more relapses than CY The low-dose IV CY regimen has not been tested

20 Treatment of severe lupus nephritis If adverse prognostic factors (reduced GFR, crescents or fibrinoid necrosis, or tubular atrophy/interstitial fibrosis ), treatment may also include: High-dose IV-CY (monthly pulses g/m 2 6) (Grade A) or Per os CY(2-2.5 mg/kg 3 months) (Grade B) Points to consider Mycophenolate is efficacious evidence from non-randomized trials, or post-hoc analyses of RCTs with short-term follow-up (Grade B) Walsh. Am J Kidney Dis 2013 Boumpas. Lancet 1992

21 Azathioprine? Grootscholten et al. KI 2006; Arends et al. ARD 2012 CY IVMP / AZA Class III-IV or V: azathioprine (2mg/kg/day) may be considered as an alternative to MPA or CY in selected patients without adverse prognostic factors, or when these drugs are contra-indicated, not tolerated or unavailable (Grade B-C). Azathioprine use is associated with a higher flare risk (Grade B)-increased risk for ESRD

22 Maintenance treatment in lupus nephritis: ALMS trial 24-wk induction phase 36-mo maintenance phase MMF 1.5 g BID IVC g/m 2 Monthly Response or Remission Yes Rerandomization MMF 1 g BID AZA 2 mg/kg/d No No further treatment (exit study) *Oral corticosteroids administered in induction and maintenance phases AZA, azathioprine; IVC, intravenous cyclophosphamide; MMF, mycophenolate mofetil

23 Maintenance treatment in lupus nephritis: ALMS trial Dooley et al. NEJM 2011

24 Maintenance treatment in lupus nephritis: MAINTAIN trial Houssiau et al. ARD year follow-up.annrheum Dis Excellent predictive value of proteinuria less than 500 mg at 3, 6 or 12 months. Confirm NIH studies

25 RENAL RELAPSES No significant difference between MPA and AZA in terms of incidence of ESRD, doubling of SCr, or any adverse event except for leukopenia (RR 6.2).

26 Maintenance treatment in lupus nephritis: the Eular recommendations In patients improving after initial treatment, subsequent immunosuppression is recommended with either MPA at lower doses (initial target MMF dose 2g/day) or AZA (2mg/kg/day) for at least 3 years, in combination with low dose prednisone (5-7.5mg/day) (Grade A) Gradual drug withdrawal, glucocorticoids first, can then be attempted (Grade C) Patients who responded to initial treatment with MPA should remain on MPA unless pregnancy is contemplated, in which case they should switch to AZA (Grade C) Calcineurin inhibitors can be considered (Grade C)

27 Short-follow up Less infections, 10% increase in Cr (reversible), tremor

28 New calcineurin inhibitors : Voclosporine Voclosporine AURA trial PHASE 2 LANDMARK STUDY Voclosporine: new generation CNI, more potent-less toxicity 3- to 5-fold increase in potency compared to CsA. Faster elimination of metabolites There is less diabetes, hirsutism, gum disease and possibly hypertension with voclosporin. Renal toxicity is similar and infection risk probably similar also to ciclosporin/tacrolimus Stucturally similar to CsA (modification on amino acid 1 residue) Binds more tightly to calcineurin Well studied in psoriasis 2 x IV MP mg/d oral pred (5 mg/d at w12) MMF: 2 g/d Press Release AUGUST X2 REMISSIONS, 13 DEATHS Placebo Voclosporin (2 doses) Primary endpoint: up/c ratio 0.5 mg/mg and no decrease egfr of 20%

29 Low prednisone MyLupus trial 24-week, multicenter, open-label study EC mycophenolate sodium Standard vs reduced dose of prednisolone Serum creatinine (µmol/l; mean SD) up/c ratio (g/g; mean ± SD) Time Standard GC 1mg/kg/d N=42 Reduced GC 0.5mg/kg/d N=39 Baseline 74.8± ±27.1 Week ± ±20.7 Baseline 2.0± ±1.5 Week ± ±1.4 CR (%) Week Infections (%) * Herpes zoster (%) ** Zeher M et al. Lupus 2011; 20: 1484 *: **: 0.012

30 STEROID FREE RX!!!! Renal predominantlupus Need confirmation 50 patients. 2 doses of rituximab (1 g) and IV-MP (500 mg) on days 1 and 15;maintenance MMF Exclusions: Patients on maintenance steroids or with life-threatening SLE or requiring dialysis 40%, active class IVor class IV+V LN, 22 (44%) patients had pure class V LN. 58% had extrarenal involvement at presentation. Renal predominant-lupus-need confirmation

31 Treat-to-target in lupus nephritis Targets of immunosuppressive treatment Complete renal response = UPCR <0.5 AND normal or near-normal GFR (±10%) Partial renal response = reduction in UPCR 50% (to sub-nephrotic) AND normal or near-normal GFR (±10%) (Grade B) Chen 2008 PRR should be achieved preferably within the first 6 months and no later than 12 months after treatment initiation PRR worse prognosis than CRR but may be an acceptable outcome when all treatments have been exhausted or cannot be used due to high risks for toxicity Houssiau 2004

32 Proteinuria less than at 12 mo predicts good long-term outcome ELNT Dall Era et al, Arthritis Rheumatol 2015 Dall Era M et al. Arthritis Rheumatol 2015; Epub ahead of print

33 Refractory lupus nephritis 20-30% of patients with lupus nephritis will not respond to initial immunosuppressive treatment ALMS induction phase: <10% of patients achieved complete response during the first 6 months!? Definition Grootscholten. ΚΙ 2006

34 Definitions Eular recommendations for refractory lupus nephritis 3-4 months lack of any improvement (ie, no reduction in UPCR) 6-12 months lack of (at least) partial renal response (50% reduction to subnenhrotic) 24 months lack of complete renal response proteinuria equal or more than 1 gm Management For patients who fail treatment with MPA or CY either because of lack of effect or due to adverse events, we recommend that the treatment is switched From MPA to CY, or From CY to MPA, or From MPA or CY directly to Rituximab (Grade C). Rituximab: better for relapses or as initial treatment? Metanalysis of 300 patients 70% response (40% complete). Poor results in crescentic, flares are common. Additional options: Calcineurin Inhibitors, - IVIG, plasma exchange for rapidly progressive glomerulonephritis, immunoadsorption

35 Adjunct treatments for co-morbidities Agent Indication Evidence RAAS blockers UPCR >0.5 or hypertension Grade Β Statins Dyslipidemia (target LDL-C 100 mg/dl) Grade C Hydroxychloroquine Reduced risk for relapse, damage accrual, cardiovascular events Grade B Aspirin Thromboprophylaxis in apl-positive patients Grade C Calcium and vitamin D Osteoprotection Grade C Immunizations Reduction in risk for infections Grade C Anticoagulation Nephrotic syndrome with severe hypo-albuminaemia (especially if apl-positive) Grade C

36 Monitoring lupus nephritis Active lupus nephritis should be regularly monitored by determining at each visit : body weight Proteinuria (spot UPCR preferred) blood pressure urinary sediment (microscopic evaluation) serum creatinine and egfr serum C3 and C4, anti-dsdna serum albumin complete blood cell count (Grade B/C) apl antibodies and lipid profile: at baseline and monitored intermittently (Grade B) Visits: every 2-4 weeks for the first 2-4 months after diagnosis or flare, then according to the response (Grade C) Monitoring for both renal and extra-renal disease activity: life-long at least every 3-6 months (Grade C)

37 Monitoring lupus nephritis: proteinuria and serology Proteinuria : spot UPCR preferred) Serology: Test LR+ LR- Serum C Serum C Anti-dsDNA Anti-C1q Points to consider: The individual predictive value of clinical and laboratory tests for hard outcomes at particular time points is modest Changes in serological tests are more important predictors of concurrent or impending flare than their absolute levels; Pre-emptive treatment is not indicated

38 Topics not covered in this presentation Biopsy and repeat renal biopsy Optimal histologic examination End-stage renal disease-transplantation APS-association nephropathy Pediatric lupus nephritis: no difference Pregnancy and lupus nephritis (GFR at least 50) Ann Rheum Dis Nov;71(11):

39 Renal disease increases risk for pre-eclampsia

40 EULAR-ERA 2012 LN recommendations in a nutshell Acceptable Goals: -short term (3-4 months): improvement -any reduction in proteinuria, stable renal function -medium term ( 6-12 months): partial response ( 50% reduction in proteinuria to subnephrotic levels). In long standing disease this is a good as someone could go -Long term ( 1-2 years):complete response: less than gm protein Why MMF and low-dose IV-CY? MMF or low dose IV-CY based on ease of administration/gonadal toxicity. Refractory patients: switch to the other drug or directly to rituximab Why? Expert opinion.cni? Maintenance: MMF or AZA. If starting with MMF continue with MMF unless pregnancy is contemplated Risk stratification: for severe LN may use IV-MP with IV-CY or MMF Pediatric lupus: No significant differences

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42 Unresolved issues and questions Better for fresh disease? In patients with disease modified by previous treatment may be more problematic to apply these recommendations. Access to care and adherence maybe more important in the long-run. For instance ESRD nor reduced in USA -as compared to European-centers. Waiting for 12 months before switching : too long?( 6 months if nephrotic range proteinuria?). -Should CNI used in cases of nephrotic syndrome? Probably yes, short term use -Can the cut-off for proteinuria at 12 months be placed at mg/dl? Yes EUROLUPUS, MAINTAIN Dall Era et al, Arthritis Rheumatol 2015 Change in ESRD or just delaying it? -~ up to 30% of patients (NIH,EUROLUPUS ) have GFR less than 60 ml after an average 7-10 years of follow -up ( however ESRD only 4%). After the acute phase, decrease in renal reserves - damage may continue to the kidney because of HTN, proteinuria, hyperlipidemia, obesity, hyperglycemia.

43 Unresolved issues and questions (2) Calcineurin inhibitors such as tacrolimus for proliferative disease? -Iinitial therapy: rapid decrease of proteinuria. Consider in patients with nephrotic syndrome? -Renal dysfunction, high chronicity index at biopsy, and uncontrolled HTN are contraindications to CNI use -Maintenance: Consider in patients after MMF/CY/Rituximab if residual proteinuria more than 1 gm/day. Effects on non renal lupus? Need More Data: a) Steroid sparing: need a trial comparing ie 0.5 mg with 0.25 mg initial dose. b)10 or 15 year data with MMF or Tacrolimus. Is increase in ESRD in USA due to using less CY? Renal biopsy not feasible in many places-reading is problematic. Collaboration with nephrologists not feasible in many places. Care in specialized lupus centers? Co-morbidities especially infections and cardiovascular diseases are still an issue especially for patients with decreased GFR. Concern of cardiorenal syndrome type 4 if

44 New agents: Belimumab any role in the prevention of flares-reduction in proteinuria, steroid reduction? Blisibimod, PEARL-SC study (Phase II), Furie et al ARD 2015 inhibits soluble and membrane bound BAFF; decrease in proteinuria Rituximab: Better for relapses or as initial treatment or both? Metanalysis of 300 patients 70% response (40% complete). Poor results in crescentic, flares are common. Need for longer use than the 6 months?

45 Small increases in Cr are not acceptable. The importance of preserving renal function to GFR above 60ml/min to avoid CardioRenal Syndrome (CRS) type 4 Decreased cardiac function Cardiac hypertrophy Increased cardiovascular events Aggressive control atheromatosis risk factors

46 1 in 5 patients in Europe with significant renal impairment at risk for cardio-rénal syndrome Louvain Lupus Nephritis Inception Cohort Housiau et al 98 last cases LOULUNIC Follow-up: 6.5 years ESRD: 4% egfr <60ml/min/1.73m 2 : 17.5% Aggressive control atheromatosis risk factors Most patients below age 40...

47 Key Questions in LN Is it common? Is it important and why? Who is more likely to develop it? When should I think of? How could I best document its presence and severity? -Do I need a biopsy and why? Does serology help and how? What is the prognosis? -How could I tailor therapy so that my treatment best fits the patient? Who is more likely to flare and how could I prevent it? -Can I discontinue therapy?

48 Which SLE patients are at higher risk to flare? Risk factors Ethnicity (AA, OR 1.8) Young-onset disease ( 25 years) (HR 2.1) Previous disease activity (AMS [OR 1.42 per 1-unit]; CNS [OR 10.9, HR ]; renal [HR ]; vasculitis [HR ]) Need for steroids (OR 2.4) or immunosuppressives (HR 3.2) during the previous year Withdrawal or no use of HCQ (OR 2.5) Immunologic activity ( C3/C4 and/or anti-dsdna, OR ) BlyS 2 ng/ml (HR ) G Bertsias Conti F, et al. PLoS One, 2012; 7:e45934, Nikpour M, et al. Arthritis Rheum, 2009; 61: , Petri M, et al. J Rheumatol, 2009; 36: , Ines L, et al. Rheumatology, 2014; 53:85 89, Petri M, et al. Arthritis Rheum, 2013; 65:

49 SLE flares-especially severe- increase the risk for subsequent active disease, damage accrual, and death Prediction of death or increase in total damage score 5 yr after inclusion (n=135) when the average total number of BILAG A-flares (per visit) was entered as disease activity marker Disease variable Odds ratio 95% CI P value Total number of A-flares (average per encounter) Initial mental health (SF-20+) Initial physical functioning Disease duration Both severe and mild-moderate flares are associated with damage accrual G Bertsias Stoll T. et al. Rheumatology 2004; 43: ; Mok CC. et al. J Rheum. 2003; 30: ; Bandeira M. et al. Lupus 2006; 15: ; Oelzner P. et al. Rheumatol. Int. 1996; 16: , Ugarte-Gil M, et al. doi: /annrheumdis

50 Stop IST in LN? When and how? Less than 20% of LN patients are able to discontinue completely IST after at least 5 years on therapy -Less than 40% of physicians are willing to do this in clinical practice. Withdrawing steroids desirable but in some case extra-renal lupus especially arthritis may not allow this. Belimumab may help to reduce steroids and prevent renal flares but it is expensive Risk to benefit/ratio for azathioprine withdrawal not clearly established. Better be safe rather than risk a flare May consider switching MMF to AZA after remission especially if pregnancy is anticipated. Withdrawing therapy in patients with class III-IV treated with MMF alone and severe disease may not be wise, until long term data MMF become available to document its ability to halt renal disease.

51 ..The most prevalent recent change in this subset of patients has been a shift in treatment away from high-dose cyclophosphamide, raising the question of whether these new treatment approaches result in different long-term outcomes.

52 My own practice: When I may discontinue therapy IST Less than 5% of my patients More eager to discontinue steroids rather than AZA or MMF The 5 year rule : Selected cases, i.e. patients without risk factors (ie history of 1 severe flare or abnormal GFR) who have received maintenance therapy for at least 5 years and who have been in complete renal remission for at least 3 years and have not had a history of severe LN. The rule of 3 strikes and you are out in proliferative LN: -Be cautious with patients with 1 previous severe flare! I do not do that in these patients Gradual tapering very slowly Strict surveillance monthly UA with dipstick at home

53 Less glucocorticoids!!! Key Points in Lupus Nephritis Early proteinuria decrease is critical Induction and switching to less toxic therapies. Prolonged maintenance immunosuppression - Induction by MMF, EUROLUPUS CY, NIH CY (? CNI) - Maintenance by AZA or MMF - RTX for refractory cases Adjunct therapy - Optimal global care makes the difference -Optimal renal protection -Prevention of cardiovascular disease -Prevention of other comorbidities Never forget hydroxycloroquine be aware of high non-compliance rate