Treatment of Neuropsychiatric lupus - sums.ac.irira7congress.sums.ac.ir/editor_file/Dr_ Haj Alilo.pdf · T Cell pathway Co-stimulatory blockaed Cytokine blockade Kinase Inhibitor

Treatment of

Neuropsychiatric lupus

Dr HAJIALILO

Treatment strategy

Diagnosis TreatmentPathogenesis

Signs

symptoms

Treatment Strategy

Before NP-SLE

Treatment strategy


Signs

symptoms

Treatment Strategy

Before NP-SLE

Treatment strategy

HLA-DRB104 genotype and STAT4 rs10181656 were

associated with ischemic CVD

Mutations in TREX1

On of expression quantitative trait loci (eQTL) was IRF5

cis-SNP rs4728142 with cognitive dysfunction

Prediction of NPSLE

1- Ann Rheum Dis 2010; 69:1886–1887. 2-Genes Immun 2011; 12:270–279.

3-PLoS Genet 2012; 8:e1002707

.

Treatment strategy

Arthritis Rheum 2001; 45:419–423

Include : generalized (nonneurological) SLE activity

or damage, history of previous or concurrent other

major NPSLE, aPL antibodies (persistently positive

moderate-to-high aCL or anti ß2 GPI Ig titers, LAC)

Assessment for risk factors for SLE-related events

Treatment strategy


Include: Increasing age, atherosclerotic risk factors

(hypertension, diabetes, dyslipidemia), heart ((valvular

disease, chronic atrial fibrillation), High cumulative dose

of glucocorticoids

Assessment for risk factors for SLE-unrelated events

Treatment strategy


Signs

symptoms

Treatment Strategy

Before NP-SLE

Treatment strategy


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

onset or within the first 1–2 years after diagnosis;

events occurring >6 months before the onset of

SLE are less likely to be attributed to SLE

Timing of event

Treatment strategy

40–50% of NPSLE are primary and remaining are

secondary

Exclusion of infection, hormonal/metabolic

disturbances, vitamin deficiencies, drug effects,

and association factors reported in the ACR

nomenclature and case definitions for NPSLE

Exclusion of secondary causes

1-Rheumatology (Oxford) 2012; 51:157–168 2-Ann Rheum Dis 2010; 69:2074–2082.

Treatment strategy


Minor events : (headache, anxiety, mild forms of depression

, and cognitive dysfunction, polyneuropathy without

electrophysiological confirmation ) are less likely to be

attributed to SLE

Major events : seizures, cerebrovascular disease (CVD)

myelopathy, optic neuritis, aseptic meningitis, and

psychosis, acute confusional state

Type of event: Minor versus Major

Treatment strategy

Pathogenesis of the underlying process

Antiphospholipid antibodies

Accelerated atherosclerosis

Antineuronal antibodies.Antiribosomal-P

Anti-N-methyl-D-aspartate receptor (NMDA)

Anti-RO

Antiphospholipid antibodies

Vasculopathy- Thrombotic

Inflammatory/neurotoxic

Treatment strategy


Vasculopathy-Thrombotic Inflammatory/neurotoxic

Can we separate these process definitely ?

Treatment strategy


Vasculopathy-Thrombotic Inflammatory/neurotoxic

Some times it is difficult and impossible

Treatment strategy


Thrombotic CVD, has also been used in antiphospholipid-associated ischaemic

optic neuropathy and chorea , as well as in myelopathy refractory to

immunosuppressive therapy

Aseptic meningitis, optic neuritis, transverse myelitis, peripheral neuropathy,

refractory seizures, psychosis, acute confusional state; ACS

Vasculopathy- Thrombotic

Inflammatory/neurotoxic

Antiplatelet/anticoagulation

Glucocorticoids alone or in

combination CTX or AZA

Plasmapheresis,Rituximab,IVIg

Innate Immunity

Adaptive Immunity

Novel target therapy in LUPUS

Innate Immunity

Targeting IFN pathway

Sifalimumab

Rontalizumab

TNF a signaling

Infliximab

Adaptive Immunity



Adaptive immunityB cell pathwayB cell depletion

Inhibition f Bcell activation

Plasma cell depltion

Induction of B-Cell tolerance

T Cell pathwayCo-stimulatory blockaed

Cytokine blockade

Kinase Inhibitor

StatusStudy PhaseDrugTarget

This study on going but not

recuritment participant

Phase 3 RCT,multicenterOcrezulimabAntiCD20

This study has been completedPhase IIb RCT,multicenterEpratuzumabAnti-CD22

This study currently recruiting

participants

Phase III,belimumab

versus placebo in

treatment SLE located

northeast Asia

BelimumabBAFF Inhibitor


participants

Phase Ib RCTOmalizumabIgG 1 k

monoclonal

antibody that binds

to IgG E


participants

Phase 2 open labelTamibaroteneRetinobanzoic acid

This study on going but not

recuritment participant

Phase II RCTRontalizumabAntiinerfron a

monoclonal

antibody


participants

Phase II RCTN-AcetylsysteinAntioxidant

New therapies in SLE Current opinion 2013

Treatment strategy


Signs

symptoms

Treatment Strategy

Before NP-SLE

Treatment strategy


NeuroImaging : MRI(small punctuate hyperintense T2-weighted

focal lesions in subcortical and periventricular WM, diffuse

cortical GM lesions , cerebral atrophy, infarcts)

CTScan , MRS, SPECT

CSF Analysis

EEG (Abnormalities has 50–60% sensitivity and specificity for

active Primary NPSLE)

Serology ( Anti-DsDNA,C3,C4, Anti-Ribosomal-P,aPL,…)

Echo, Doppler,

Diagnostic Approach

Treatment strategy


Signs

symptoms

Treatment Strategy

Before NP-SLE

Headache

In patients with lupus all headache types was not different from controls .

Usually it does not require further investigation and it should be classified according to IHS criteria and managed as a primary headache .

Headache might be the heralding symptom of a more complex CNS syndrome.

Brain127,1200–1209 (2004).

Headache

Cases of acute occurrence or modification of an existing chronic headache associated with high-risk factors :

must be viewed cautiously, and must be managed and treated accordingly.

Severe headache refractory to analgesic drugs,

sudden onset, vomiting, fever, immunosuppression ,

aPL positivity and alarm signs (sign of infection,

meningeal signs, papilledema, focal neurologic signs,

decreased level of consciousness

Headache

Acute : Metoclopramide IV(10 mg)or Prochlorperazine

IV(10mg) or Dihydroergotamine plus diphenhydramine IV

(12.5-25 mg)

Preventation : TCA, Valoproate,Topiromate,Calcium channel

blockers

Migraine

headache

Acute : ASA, NSAIDS(Naproxen,ibuprofen,..)

Acetaminophen Triptans, muscle relaxants,

Preventation: TCA,Tizanidin, some time

anticonvulsant agents

Tension-type

headache

Sumatriptan (6mg), Inhaled oxygen, Octerotide,Intra nasal

lidocaine,Oral ErgotamineCluster

headache

Headache in SLE often responds to the same

interventions as non-SLE headache.

Seizure

Most seizures in SLE represent single isolated events;

recurrent seizures (epilepsy) are less common (12–22%)

Some points

Epilepsy typically is not associated with current active

SLE and responds to anticonvulsants

Isolated seizures are most often associated with active

SLE and respond to therapy for SLE .

Seizure

Control acute phase like as other patients

Be sure to be open airway

IV line and taking blood sample

Drug for acute attack (diazepam)

Management

Seizure

The diagnostic work-up aims to exclude :

Structural brain disease , metabolic disturbances

infections, hypoxemia, hypertension, uremia,

medication effects ,tumor,…

Management

Seizure

The diagnostic work-up aims to exclude :

Structural brain disease , metabolic disturbances

infections, hypoxemia, hypertension, uremia,

medication effects ,tumor,…

Evaluation of disease activity

and

Management

Seizure

The diagnostic work-up

Brain MRI

EEG

LP (if suspicious to infection)

Blood sample(BS,Na,Ca,…,and lab date for lupus activity)

Management

Seizure

Are glucocorticoid useful of seizure in lupus

patients ?

If seizures are thought to reflect an acute inflammatory

event or if a concomitant lupus flare is present,

glucocorticoids alone or in combination with

immunosuppressive therapy may be given.

The combination of pulse methylprednisolone and

cyclophosphamide has shown effectiveness in refractory

seizures in the context of generalized lupus activity.

Ann Rheum Dis 2005,64:620

Management

1

2

3

4

5

6

7

8

Basal 6 th month 12 th month Basal 6 th month 12 th month

1

2

3

4

5

6

7

8

1

2

3

4

1

2

3

4

Mean number of seizures/ month

in (A) MP group; (B) Cy group

A B

MeanMean

Ann Rheum Dis 2005;64:620–625.

Induction treatment with 3 g of IV methylprednisolone (MP) followed

by either IV monthly cyclophosphamide (Cy) versus IV MP

bimonthly every 4 months for 1 year and then IV Cy or IV MP every

3 months for another year for severe NP manifestations

Seizure

Correlation with APS :

The mechanism for seizures in SLE patients with aPL has

been related to focal cerebral ischemia or to a direct

aPL-mediated effect on neurons, and this may explain

why antiplatelet and anticoagulation therapy has been

anecdotally reported to be effective in recurrent

refractory unprovoked seizures.

Curr Pharm Des 2008,14(13) :1261-9

Management

Seizure

When we need to anticonvulsant therapy for

seizure in SLE ?

After a single episode of unprovoked seizures

prescription of chronic therapy with an

anticonvulsant should be delayed unless high-

risk features for recurrence are present.

Management

Risk features for recurrence of seizure in

SLE

Two or more unprovoked seizures occurring within 24 h

Serious brain injury

Brain MRI structural abnormalities causally linked to seizures

Focal neurological signs

Partial seizure

Epileptiform EEG

Previous stroke (HR: 2.4)

persistently positive Moderate-to-high titers of

anticardiolipin IgG (HR: 2.2)

Ann Rheum Dis 2010;69:2074–2082

Myelitis

Diagnosis :

With clinical evaluation and confirmed with contracted

enhanced MRI

Are there co-exist other NPSLE symptoms or signs

If there are perform brain MRI

R/O other causes of myelopathy :

Tumor, Abscess , Vertebral compression fracture, Anterior

spinal artery syndrome , Infection With MRI and CSF

analysis

Myelitis

Types of Myelitis:Patients may present with signs of grey matter (lower motor neuron) dysfunction (flaccidity and hyporeflexia) or withe matter (upper motor neuron) dysfunction (spasticity and hyperreflexia); the latter can be associated more with neuromyelitis optica (NMO)

and antiphospholipid and correlation with Anti-RO.

Transverse or longitudinal (more than three sections) myelitis

Gray matter signs have more disability (2)

1-Arthritis& Rheumatism. Vol. 60, No. 11, November 2009, pp 3378–3387

2-Arthritis Rheum Vol. 60, No. 11, November 2009, pp 3378–3387

Myelitis

Transverse MyelitisLongitudinal Myelitis

Myelitis

The combination of intravenous methylprednisolone and

intravenous cyclophosphamide (for 3–6 months

according to severity and clinical response) quickly

added in association with oral prednisone. Because of

the high risk of relapses cyclophosphamide therapy

should be followed by treatment with

immunosuppressants such as azathioprine. (1)

Plasma exchange therapy has been used in severe cases(2),(3)

1-Ann Rheum Dis 2000, 59,120 2-Ther Apher Dial 2003; 7 : 173 – 82

3-.Lupus 2007; 16 : 817 – 22

Myelitis

Anticoagulant :

Some dates support use of anticoagulant with

glucocorticoids in the presence of antiphospholipid

antibodies.(1) but a recent systematic review concluded

anticoagulation no additional benefit over standard

immunosuppression. (2) but may be considered in focal

myelitis and refractory cases. (3)

1- J Rheumatol 2004, 31:280 2-European Journal of Neurology April 2011

3-Clinical Rheumatology 2011 volume 30 981-986

Myelitis

Rituximab :

Recently an observational study in six SLE patients

suggested that a treatment regimen of rituximab and

methylprednisolone pulses could be beneficial in

preventing permanent neurological damage in severe

lupus myelopathy.In this study 4 of 6 patients showed

complete response within 12 months.

Clinical Rheumatology 2011 volume 30 981-986

Rituximab in SLE

EXPLORARE

LUNAR

LESIMAB

BIOGAS registry

Arthritis Rheum 2010 62:222-233

LUPUS 2012 , 21:1036-1076

Autoimmunity REV 2006 11:357-364

Arthritis Rheum 2012,64:1215-1226

Psychosis

Consult with psychiatric

R/O Other etiologies for psychosis

Management

Psychosis

Consult with psychiatric

R/O Other etiologies for psychosis

Neurologic problems:(Infections, Neoplasms ,..)

Endocrine and metabolic dysfunctions (Thyroid, Parathyroid, or

Adrenal abnormalities, Hypoxia, Hypoglycemia,..)

Hepatic and Renal disorders

Toxin

Management

Drug( corticosteroid , anti-malaria)

Psychosis

Psychosis due to (active )organic involvement by SLE usually responds to steroids.

Treatment should be initiated as soon as possible to prevent permanent damage(1-2mg/kg) given for a few weeks in divided doses is usually sufficient

If no improvement is seen within two to three weeks, a trial of cytotoxic therapy (eg, pulse cyclophosphamide)

is warranted followed by maintenance with azathioprine is recommended)

1-Ann Rheum Dis 64,620-625(2005) 2-Rheumatology (Oxford) 47,1498–1502 (2008).

Treatment

PsychosisTreatment

In psychosis refractory to conventional

immunosuppressive treatment :

Plasma exchange or rituximab may be effective

options. (1),(2)

Electroconvulsive therapy (refractory cases )

Antipsychotics ( Chlorpromazine- Trifluoperazine-

Haloperidol ,..) should be prescribed according to

guidelines, especially in relapsing cases.

1-Ther .Apher. Dial 7,173-182(2003) 2- Ann Rheum Dis 66,470-475 (2007)

3- J ECT 2013 Sep;29(3):243-6.

Cerebrovascular Disease(CVD)

Ischemic stroke

TIA

Multifocal

disease

ICH

Sinus

Thrombosis Vasculitis

Types of CVD

Strokes have been reported in up to 19 percent of patients

with SLE and a cause of increased mortality and disability.

Cerebrovascular Disease

History and physical examination :

Neuro Imaging ( CTscan, MRI/DWI ,CT or MR

angiography )Assessment other sites and risk factors for

thrombosis (Echo, Doppler sonography.lipid and glucose level,hypercoagulation state,…)

Evaluation of SLE activity

Work up

SLEDAI >6 has HR: 2.1 for CVD

1-Nat. Rev. Rheumatol.6,358–367 (2010)

2-Rheumatology (Oxford)43,1555–1560 (2004)


The acute management of SLE stroke or TIA is

similar to that in the general population.

A stroke specialist consultation is necessary

to identify patients who are candidates for

thombolytic or surgical therapy; unless

contraindicated .

Treatment

Exclusion criteria Inclusion criteria

Significant stroke or head trauma in the

previous three months

Previous intracranial hemorrhageIntracranial

neoplasm, arteriovenous malformation, or

aneurysm, Recent intracranial or intraspinal

surgery

Persistent blood pressure elevation (systolic

≥185 mmHg or diastolic ≥110 mmHg

Platelet count <100,000/mm

Current anticoagulant use with an

INR>1.7 Evidence of a multilobar

infarction with hypodensity involving >33

percent of the cerebral hemisphere

Pregnancy, Age >80 years

Clinical diagnosis of ischemic stroke

causing measurable neurologic deficit

Onset of symptoms <4.5 hours before

beginning treatment; if the exact time

of stroke onset is not known, it is

defined as the last time the patient

was known to be normal

Age ≥18 years

Strok 2013 , 44 :870

Criteria for treating acute stroke with tPA


Chronic anticoagulation therapy with warfarin or

asprin is indicated in most patients with stroke

syndromes due to aPL or thrombosis if they are

stable and if there is no evidence of hemorrhage.

Treatment

What are recommendations?


For the patient with SLE and an ischemic stroke who has no

other identifiable risk factors (eg, does not have atrial

fibrillation, has no vegetations by echocardiography, has no

significant extracranial arterial stenosis, has no aPL) and for

whom MRI suggests small vessel thrombosis

Treatment

Recommendations for anticoagulation

Low dose Asprin 81mg

Ann. Rheum. Dis.69,2074–2082 (2010).


For the patient with SLE and ischemic stroke and

moderate or high levels of aPL,

The level of anticoagulation is still debated

Treatment


Warfarin with INR 2-3 or 3-4 ?


It has been suggested that the international

normalized ratio should be titrated to 2.0–3.0 in the

absence of risk factors

and 3.0 and 4.0 in patients with risk factors. (1),(2)

Treatment


previous arterial thrombosis, including ischemic stroke,

severe venous or recurrent thrombosis.

1-J. Autoimmun.33,92–98 (2009).

2-J. Thromb. Haemost.3,844–845 (2005).


CVD due to vasculitits is extremely rare, therefore

immunosuppression is not recommended unless

there is an associated lupus flare .

All the modifiable risk factors must be carefully

assessed and managed according to the existing

guidelines .

Treatment

Acute confusional state

Patients should be extensively evaluated for underlying precipitating conditions, especially infections and metabolic disturbances.

CSF examination is recommended to exclude CNS infection

EEG may help diagnose underlying seizure disorder.

Brain imaging is indicated if the patient has focal neurological signs, history of head trauma or malignancy, fever, or when the initial diagnostic work-up has failed to reveal any obvious cause of the ACS.

Brain SPECT is sensitive (93%) and may help monitor response to treatment.

Acute confusional state

Addressing and correcting the underlying causes.

Drug treatment with haloperidol or atypical antipsychotics is used only when other interventions are ineffective in controlling agitation and an underlying cause of ACS has been excluded.

A combination of glucocorticoids with immunosuppressive agents is effective in most patients (response rates up to 70%).

Plasma exchange therapy (synchronised with intravenous cyclophosphamide) and rituximab have been used in refractory cases

Management

1-Ther Apher Dial 2003; 7 : 173 – 82 2-Lupus 2007; 16 : 817 – 22 .

3-J Neurol Neurosurg Psychiatr 1992; 55 : 1157 – 61

Cognitive Dysfunction

Identification and treatment of any associated (e.g., metabolic disturbances, drug abuse or withdrawal) or aggravating (e.g., hypertension or dyslipidemia anxiety and depression) causes of impairment.

Corticosteroid use must be considered only in patients with high disease activity . There has been only one double-blind, paired, placebo-controlled study published . Treatment with 0.5 mg/kg/day prednisone for 21 days, followed by steroid tapering, has been reported to improve cognition in five out of eight patients (n=8 patients)

Management

Arthritis Rheum.37,1311–1320 (1994).

Cognitive Dysfunction

Antiplatelet and anticoagulation therapy :

Might be helpful in patients with persistent positively for aPL and progressive cognitive impairment mostly in the presence of MRI abnormalities and other vascular risk factors. (1), (2)

The result of a prospective study suggests that regular use of asprin may help prevent a decline in cognitive function, particularly in older patients (2)

Symptomatic treatment and Cognitive rehabilitation is an alternative or complementary therapeutic approach

1-Arthritis Rheum.42,728–734 (1999) 2- Neurology64,297–303 (2005).

Management

Peripheral polyneuropathies

Sensory or sensory motor poly neuropathy

Patients with significant paresthesia and abnormal

Nerve Conduction Study (NCS), are treated

with prednisolon 1mg/kg with gabapentin

100mg TDS or TCA .

If either of these approaches is ineffective or

causes intolerable side effects, we would next

utilize carbamazepine .

Treatment


Patients with mild symptoms or normal NCS or

both are treated symptomatically with

neuroleptic medications because 67% will not

deteriorate on follow-up .

Acta Neurol Scand 103:386-391,2001

Treatment


Mononeuritis multiplex

It is typically occurs in the setting of active SLE.

It is belived to be a vasculitic of vasa nervorum.

Use prednisolon 1to 2mg/kg or pulse

methylprednisolone with cyclophosphamid (either

oral daily or monthly pulse) with or without plasma

exchange for a six months period.

IVIg or rituximab are others alternative.

Lupus 1996, 5:74

Treatment


Acute polyradiculoneuropathy (Guillain-Barre like)

Such patients respond to glucocorticoids with in

weeks if there has been no neuronal damage .

but in some cases the addition of IVIg or

plasmapheresis might be necessary .

Am J Emerg 2009 sep ,27(7);900

Rev Neurol 2003 Mar;159(3:)300-6


Chronic demyelinating polyradiculopathy like chronic

inflammatory demyelinating polyneuropathy(CIPD)

Therapy with glucocorticoids and intravenous gamma globulin

or plasmapheresis may be indicated .If there is evidence of

axonal damage on electrodiagnostic studies or vasculitis on

nerve biopsy, then more potent immunosuppressive therapy

is indicated(cyclophosphamide).

Lupus 2012 Sep;21(10:)1119-23

Cranial Neuropathies

R/O other neurological conditions,

such as brainstem stroke

and meningitis,

Funduscopy

Fluoroangiography

Contrast-enhanced MRI

Optic neuropathy


Pulse intravenous methylprednisolone in combination

with intravenous cyclophosphamide is recommended

Anticoagulation may be considered in antiphospholipid-

positive patients not responding to immunosuppressive

therapy.

SLE-related optic neuritis is associated with poor visual

outcome and only 30% of patients maintain a visual

acuity greater than 20/25

Ann Rheum Dis 2005; 64 : 620 – 5 .

Optic neuropathy


0.9

0.1

0.5

0 5 10 15 20

Received cyclophosphamide

Received IV methylprednisolone

Hospitalised for hypotension, pneumonit

Month

Visual

acuity

Prednisolon

Daily

dose

British Journal of Ophthalmology 1997

60

10

Meningitis (Aseptic)

CSF analysis :

WBC > 1000 microL , glucose <20 mg/dl ,

pr>250 mg/dl and positive Gram stain

Treatment

Antibiotics should be initiated promptly

Empiric : Vancomycin +Ampicillin + Cefepime or Meropenem

Septic meningitis

Meningitis (Aseptic)

CSF analysis :

Cell count <500/microL, >50 percent CSF

lymphocytes, protein <80 to 100 mg/dl

normal glucose, and negative Gram stain.

Treatment

R/O other etiology for aseptic meningitis

especially viral etiology

Aseptic meningitis

CSF analysis :

Cell count <500/microL, >50 percent CSF

lymphocytes, protein <80 to 100 mg/dl

normal glucose, and negative Gram stain.

Treatment

R/O other etiology for aseptic meningitis

especially viral etiology

High dose Glucocorticoid

Movement disorders

Most patients (55–65%) experience a single episode

of chorea that subsides within days to a few

months.

Symptomatic therapy with dopamine antagonists is

usually effective.

Glucocorticoids in combination with

immunosuppressive agents may be used to control

NPSLE disease activity.1- Ann Rheum Dis 2010, 69:2074 2- Stroke 2000, 31:3079

Chorea

Movement disorders

Chorea

Antiplatelet and/ or anticoagulation therapy is

administered in antiphospholipidpositive patients,

especially when other antiphospholipid/

APSrelated manifestations are present

1- Medicine (Baltimore) 1997; 76 : 203 – 12

2-Neurology 2007; 69 : 644 – 54

3- J Rheumatol 2008; 35 : 2165 – 70

Thank you

Demyelinating Syndrome

Reports of therapy in SLE-related demyelinating syndromes are anecdotal.

In patients with active brain MRI lesions and progressive and relapsing syndromes:

Methylprednisolone (500–1000 mg daily for 3 days), cyclophosphamide pulses (500 mg every 2 weeks for 3 months or 750 mg/m2 body surface monthly for 3–6 months) and plasma exchange, if available, followed by oral prednisone and immunosuppressants as steroid-sparing agents

Documents

Treatment of Neuropsychiatric lupus - sums.ac.irira7congress.sums.ac.ir/editor_file/Dr_ Haj Alilo.pdf · T Cell pathway Co-stimulatory blockaed Cytokine blockade Kinase Inhibitor