Management of SLE patients with nephritis

and CNS involvement

George Bertsias

Rheumatology, Clinical Immunology and Allergy

University of Crete Medical School

Larissa, 20/03/2015

Disclosures / potential conflicts of interest: none

Renal and CNS involvement contribute to significant

morbidity & mortality in SLE

Predictors of mortality in SLE (meta-regression analysis)

Mak A, et al. Semin Arthritis Rheum. 2012; 41:830-839

Renal and CNS involvement are major drivers of direct and

indirect medical cost in SLE

Average annual total costs per SLE patient

Zhu T, et al. Rheumatology. 2009;48: 564-8

Neuropsychiatric

damageClarke et al. Rheumatology. 2008;47(3), Pelletier et al. Clin Ther. 2009;31(11)

Renal and CNS lupus – Outline

• Diagnosis & attribution

• Principles of therapy – indications for immunosuppression (1st line

treatment) & therapeutic goals

• Monitoring

EULAR recommendations for the management of systemic lupus

erythematosus with neuropsychiatric manifestations: report of a task

force of the EULAR standing committee for clinical affairs.

Ann Rheum Dis. 2010;69(12): 2074-82

Joint EULAR/ERA-EDTA recommendations for the management of adult

and paediatric lupus nephritis.

Ann Rheum Dis. 2012;71(11): 1771-82

Diagnosis of lupus nephritis and the role of kidney biopsy

• Urine abnormalities are frequently encountered

in SLE patients. ‘Low threshold’ to perform

kidney biopsy

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

Normal Hematuria or pyuria hematuria or casts hematuria or casts

<0.5 g/24hr <0.5 g/24hr >0.5-1 g/24hr >3 g/24hr

Active proliferative nephritis (renal biopsy)

Urinalysis

Proteinuria

• Any sign of renal involvement (in particular,

reproducible UPCR ≥0.5 especially with

glomerular hematuria and/or cellular casts)

should be an indication for renal biopsy

(EULAR Recommendation)

Points to consider

• Clinical, serological, or other biomarkers do not accurately predict biopsy findings

• Low GFR correlates (r = 0.27-0.46) with chronic histological lesions

• Biopsy should be performed within the first month after disease onset, preferably before the institution of

immunosuppressive treatment, unless contraindicated

Diagnosis of lupus nephritis and the role of kidney biopsy

• Classification of lupus nephritis lesions according to the International Society of

Nephrology/Renal Pathology Society 2003 system [class I → class VI]

Class II

Class III Class V

• Immunofluorescence (or immunohistochemistry)

is recommended: IgG, IgA, IgM, C3, C1q, κ and λ

light chains deposits

• Electron microscopy may be used

Class I - Minimal mesangial LN

Class II - Mesangial Proliferative LN

Class III - Focal Proliferative LN

Class IV - Diffuse Proliferative LN

Class V - Membranous LN

Class VI - Advanced sclerosing LN

Diagnosis of lupus nephritis and the role of kidney biopsy

• Pathology report & prognostic significance

1. Acute glomerular lesions («activity»)

2. Chronic glomerular lesions («chronicity»)

3. Tubulo-interstitial lesions (acute/chronic)

4. Vascular bed lesions (associated with antiphospholipid

antibodies)

Thrombotic

microangiopathy

Wu et al. Kidney Int. 2013

Immunosuppressive treatment in lupus nephritis

Indications

Class III–IVA or III–IVA/C (Grade: A)

Mixed class V + class 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

Immunosuppressive treatment in lupus nephritis

INDUCTION

MAINTENANCE

Halt immunological insult

Reduce inflammation-injury

Restore function

Consolidate response

Prevent flare-ups

Immunosuppressive treatment in class III-IV lupus nephritis

‘National Institutes of Health’ regimen1

High-dose IV-Cyclophosphamide (0.75-1

g/m2) qm x6 mo for I

q3m x2 yrs for M

50% ovarian failure

infectious side effects

I: Induction treatment

M: Maintenance treatment

Mycophenolate (MMF)

MMF for I3 (x6 mo) and M4

1: Austin NEJM 1986; Boumpas Lancet 1992; Gourley Ann Int Med 19962: Houssiau A&R 2002; Houssiau A&R 2004; Houssiau Ann Rheum Dis 2010

3: Ginzler NEJM 2005; Appel JASN 2009; 4: Dooley NEJM 2011

Euro-Lupus regimen2

Low-dose IV-CY

6 x 500 mg q2w (=3 mo) for I

azathioprine for M

EULAR/ERA-EDTA Recommendations

for initial (induction) treatment of class III-IV LN

• Mycophenolic acid (Grade: A) or low-dose IV-CY (Grade: B) in combination

with glucocorticoids

• Glucocorticoids dosage: pulses IV methyl-prednisolone 500-750mg ×3 days

→ oral prednisone 0.5mg/kg ×4 weeks , taper to ≤10 mg/day by 4–6 months

• If adverse prognostic factors (reduced GFR, substantial crescents or fibrinoid

necrosis in biopsy), consider high-dose IV CY (Grade A) or oral CY (2-2.5

mg/kg ×3 months) (Grade B), or MMF (Grade B)

• Azathioprine: 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). Risk for flares (Grade B).

Bertsias G, et al. Ann Rheum Dis. 2012;71(11): 1771-82

EULAR/ERA-EDTA Recommendations

for initial (induction) treatment of pure class V LN

• Mycophenolic acid (Grade: B) in combination with glucocorticoids, based

on more favorable efficacy/toxicity ratio 1

• Alternative options: CY (Grade A), calcineurin inhibitors (ciclosporin [Grade

A 2], tacrolimus [Grade B]), or rituximab (Grade C)

1 Post-hoc analysis of 2 RCTs showing equivalent efficacy of MMF and high-dose IV-CY

2 Increased risk for relapse after CsA discontinuation

Austin HA 3rd, et al. J Am Soc Nephrol. 2009;20:901; Radhakrishnan J, et al. Kidney Int. 2010; 77:152

Liu Z, et al. Ann Intern Med. 2015;162(1):18-26

• Low-dose MMF (1 g/day) +

tacrolimus (4 mg/day) versus IV-

CY (0.5-1 g/m2/month) x6 months

• Both regimens received pulses

IV-MP, followed by oral steroids

• At 6 months, renal remission

rates were 46% with ΜΤ versus

26% with IV-CY (hazard ratio 2.03)

‘Multi-target’ treatment in lupus nephritis?

Either azathioprine or mycophenolate are recommended for

chronic maintenance treatment in lupus nephritis

Dooley MA, et al. N Eng J Med. 2011; 365(20):1886-95

ALMS trial MAINTAIN trial

Houssiau F, et al. Ann Rheum Dis. 2015 doi:

10.1136/annrheumdis-2014-206897.

In chronic management of SLE (including lupus nephritis), the

acceptable dose of steroids is ≤ 7.5 mg prednisone!

Complete withdrawal of steroids should be attempted

1.0 1.7

5.4

0

1

2

3

4

5

6

Νo steroids ≤7.5 mg/day >7.5 mg/day

Risk for irreversile organ damage (year 5)

Ruiz-Arruza I, et al. Rheumatology. 2014; 53(8): 1470-6

average dose of steroids: years 0-4

Monitoring of patients with lupus nephritis

EULAR recommendations

Active lupus nephritis should be regularly monitored by determining at each visit :

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)

• body weight • proteinuria (spot UPCR preferred)

• blood pressure • urinalysis / urinary sediment (microscopic evaluation)

• serum creatinine and eGFR • serum C3 and C4, anti-dsDNA

• serum albumin • complete blood cell count (Grade B/C)

Therapeutic targets in lupus nephritis

Chen M, et al. Kidney Int. 2008

• Achievement of complete renal response (remission) (at any time point) (ie,

near-normal GFR with UPCR <0.5) is associated with favorable patient and

renal long-term outcome

• Prognostic role both in proliferative and membranous LN

Fre

e o

f C

RI

or

de

ath

CR

PR/NR

Moroni G, et al. Lupus. 2013

Membranous LN Proliferative LN

CR

PR

NR

Reduction of UPCR to <0.8 at 12 months after

treatment is strong predictor of good long-term

renal function (sensitivity=81%, specificity=78%)

Dall’Era M, et al. Arthritis Rheumatol. 2015; doi:10.1002/art.39026

Do not overlook adjunctive treatments and comorbidities!

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

CNS lupus

Neuropsychiatric events are common in SLE, are a frequent source of

anxiety, and often pose a diagnostic and therapeutic challenge

Focal manifestations Diffuse manifestations

Central nervous system

Cerebrovascular disease Aseptic meningitis

Seizure Demyelination

Chorea Headache

Myelopathy Confusion

Psychosis

Depression

Anxiety

Cognitive dysfunction

Peripheral nervous system

Mononeuropathy

Polyneuropathy

Cranial neuropathy

Autonomous neuropathy

Guillain-Barre syndrome

Myasthenia gravis

Neuropsychiatric SLE

“Primary”

(caused by lupus)

“Secondary”

(not caused lupus)

Infections (CNS or systemic)

Metabolic disturbances (uremia,

electrolytes, glycemic disorders)

Vitamin-nutrients deficiency

Endocrine disorders

Drug-related

‘ Idiopathic ’

Less than 30–40% of

neuropsychiatric events

are attributed to underlying

active CNS lupus!

SLE patient with neuropsychiatric manifestation: Is it lupus?

Who is at risk for (primary) NPSLE?

• Most (50–60%) SLE-related neuropsychiatric events occur at disease

onset or within the first 1-2 years after diagnosis, usually and in the

presence of generalized (extra-CNS) lupus activity

• ‘Mild’ manifestations such as headache / lightheadedness, anxiety,

mild depression, dizziness, mild cognitive impairment, neuropathy

without electrophysiology confirmation, are common but only rarely

correlate with underlying lupus CNS activity

EULAR recommendations. Ann Rheum Dis. 2010; 69: 2074-82

(Evidence: 2/B)Bertsias G, Boumpas D. Nat Rev Rheumatol. 2010;6:358-67, Zirkzee E, et al. J Rheumatol. 2014;

41:1720-1, Sciascia S, et al. J Neurol. 2014; 261: 1706-14, Morrison E, et al. Lupus. 2015; 23: 370-7

Who is at risk for (primary) NPSLE?

In SLE patients with symptoms or signs suggestive of NP disease,

initial diagnostic work-up should be similar to that in non-SLE

patients presenting with the same manifestation(s)

• Depending on the type of NP manifestation, this may include:

Lumbar puncture & CSF analysis (primarily to exclude CNS infection),

EEG (primary to diagnose seizure disorder),

Neuropsychological (cognitive function) & psychiatric assessment,

Nerve conduction studies & EMG (peripheral NS disorders)

Neuroimaging (MRI) to assess brain structure and function

EULAR Recommendations (Evidence: 2/B)

Diagnostic work-up in suspected NPSLE: points to consider

• CSF analysis

– Mild abnormalities (↑ WBCs, protein, ↓ gluc) can be found in 30–40% of

active NPSLE; low specificity

– ↑ IgG index: common (≤75%) in diffuse NP; cannot ddx from MS

– Promising biomarkers (IL-6, anti-NR2) not yet in clinical practice

– Useful to rule out CNS infection

• EEG studies

– Seizure disorder: abnormal in 70-80% during the active phase;

epileptiform activity predictive for seizure recurrence (PPV 73%, NPV 79%)

– Lower sensitivity-specificity (50–60%) for other NP syndromes

Fragoso-Loyo H, et al. Rheumatology. 2013; 52: 2218-22

MRI in suspected NPSLE:

conventional T1/T2 FLAIR, diffusion-weighted imaging (DWI), and

gadolinium-enhanced T1 sequences

• 40-50% of NPSLE patients have normal

MRI scan!

• Various MRI abnormalities…NOT

specific to SLE!

• White-matter T2/FLAIR hyper-

intensities represent the most frequent

abnormality (↑ sensitivity in focal versus

diffuse NPSLE)

Luyendijk. Arthritis Rheum. 2011; 63:722; Zivadinov R, et al. Lupus. 2013; 22: 675-683;

Sarbu N, et al. Autoimmun Rev. 2015; 14: 153-9

Features with higher specificity for SLE:

Absence of CVD risk factors

Younger age

Multiple (≥5), ≥6-8 mm, amphi-hemispheric T2 lesions

T1 hypo-intense lesions

Cortical/brain atrophy

Treatment of SLE–related neuropsychiatric events

EULAR Recommendations for the Management of Neuropsychiatric SLE

Therapy Indications Evidence

Symptomatic

(analgesic, anti-depressive, anti-anxiety)

Headache, anxiety, mood disorders /

depression

C/D

Control of aggravating factors

(cardiovascular risk factors, metabolic

disturbances, infection)

CVA, cognitive impairment, confusion /

delirium

D

Immunosuppressive treatment

(GC ± AZA or CY)

* After exclusion of non-SLE causes

Inflammatory-type events (e.g. optic

neuritis, PNS, myelitis, recurrent seizure,

confusion, severe psychosis)

Extra-CNS lupus activity

A

Anti-platelet/thrombotic treatment

(warfarin, heparin, aspirin, clopidogrel)

High titre anti-phospholipid Abs or APS &

associated thrombotic mechanism (CVD,

chorea, ischaemic optic neuropathy)

B/C

Monitoring patients with NPSLE

• Clinical presentation

• Repeat of diagnostic tests

– Guided by the type of manifestation

• Repeat MRI

– ? consider if no improvement or definitive clinical

worsening

– ? guidance of immunosuppressive treatment

Conclusions

• Renal and CNS lupus represent the two most frequent, severe

manifestations in patients with SLE, associated with increased

morbidity, mortality and medical costs

• To facilitate physicians, the EULAR has issued evidence- and

eminence-based recommendations for the diagnosis, treatment and

monitoring of these patients.

• For the future, we anticipate the discovery of accurate biomarkers to

assist the diagnosis/attribution and immunosuppressive treatment in

lupus nephritis and CNS lupus

• SLE has entered into the ‘era’ of biologic therapies, several of which

are currently being tested and hopefully, could be added to the

therapeutic armamentarium and enable personalized care of the

disease