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