Management of Neuropsychiatric lupus

Dr. D. ChellapandianThanjavurTamil Nadu

Classification of Neuropsychiatric SystemicLupus Erythematosus (NPSLE)

•No gold standard •Diagnosis – exercise of exclusion•No formal system – to guide therapy decisions

Diagnosis - NPSLE

Management pathway

1. Exclusion of other causes and attribution of symptoms to SLE

2. Assessment of severity of symptoms, disease activity, other organ system involvement & prognosis

3. Elucidation of underlying patho-physiological process (inflammatory or thrombotic or both)

4. Formulating treatment strategy – tailor made to the patient

Evaluation1) Careful & thorough history, Physical examination ( including complete neurological and mental status evaluation ) 2) Laboratory: (to rule out secondary causes and to assess disease activity)A) CBC, ESR, CRP, peripheral smearB) Chemistries: Electrolytes, urea, creatinine, glucose, transaminases, C3, C4 C) UrinanalysisD) Antibodies: anti dsDNA, anti ribosomal P, anti neuronal, antiphospholipid (ACL, anti 2 glycoprotein I, lupus anti coagulant)E) CSF: Cell count, protein, glucose, Q albumin, IgG index, anti neuronal anti bodies gram stain and India Ink, VDRL, cultures, viral PCRsF) Neuro imagingG) EEG (when required)H) Others when needed: a) Tests for hypercoagulability b) CT or MR angiogram c) Cerebral angiography d) Echocardiogram

Two separate main pathogenic mechanisms are hypothesized to lead to NPSLE

1. Autoimmune or inflammation characterized by brain dysfunction due to autoantibodies or inflammatory mediators with either a disrupted blood–brain barrier (BBB) or intrathecal formation of immune complexes and the presence of inflammatory mediators. Neuronal dysfunction may be induced directly by these mediators or indirectly through activation of other neural cells.

2. Vascular injury and occlusion characterized by a thrombotic process of the large and small (microangiopathy) intracranial vessels due to auto-antibody mediated vascular injury, immune complexes, complement deposition, leukoagglutination, and accelerated atherosclerosis.

Therapeutic options in NPSLE

Primary prevention - Antimalarials

• ↓ mortality & ↓ accrual of damage• Improvement of dyslipidaemias, prevention of

Primary prevention - diabetes and reducing aPL titers

• Protective effect on metabolic syndrome• Antithrombotic effect• Protective effect against seizures

Primary prevention - Statins

• Immunomodulating effects improve the inflammatory process involved in atherosclerosis

• No studies demonstrate efficacy in primary or secondary cardiovascular protection in SLE

• Recommended in SLE patients with hyperlipidaemia who meet criteria for statin use based on standard CVD guidelines

Non pharmacologic intervention

Cognitive dysfunction• Most cases are mild – immunosuppressive

therapy not indicated• Psychosocial factors (fatigue, sleep deprivation,

pain, depression & anxiety) operate• Psycho educational group intervention -

improve memory self-efficacy, memory function & ability to perform daily activities

Pharmacologic Intervention

Symptomatic therapy

• Mood disorders, psychosis, seizure disorders, movement disorders, headaches

• Antiepileptics: 2nd seizure (>24 hours after first event), serious brain injury, brain structural abnormalities (MRI), focal neurological signs, partial seizure as the 1st seizure, epileptiform discharges

• Dopamine agonists – movement disorders• NSAIDs – symptomatic pain relief & migraine

treatment• Antidepressives, anxiolytics, antipsychotics

MANAGEMENT OFINFLAMMATORY NPSLE

Corticosteroids

• Most effective immediate therapy available• In most NPSLE manifestations when

associated with high SLE activity • Severe symptoms – IV pulse oral

prednisolone 1mg/kg• Less severe – 0.5-1 mg/kg

Cyclophosphamide

• Severe NPSLE mainly CNS involvement• RCT (Fabris etal) – significant benefit over methyl

prednisolone alone• Cochrane review – this RCT quoted as evidence

CYC is more effective compared with methyl prednisolone

• Induction regimen – 500-750 mg/m2/month IV + steroids for 6 months.

• After 6 months, every 3 months for 18 months1) Barile-Fabris L et al. Annals of Rheumatic Diseases. 2005;64(4):620-52) Fernandes Moca Trevisani V et al. Cochrane Database Syst Rev. 2013;(2):CD002265

Azathioprine

• Ginzler et al – effective in maintenance of clinical remission & inhibition of further deterioration

• Hahn et al – no short term benefit in life threatening SLE

• Current use – as maintenance after CYC induction in severe NPSLE and as first option in mild NPSLE as steroid sparing agent

1) Ginzler E et al. Arthritis Rheumatism. 1975;18(1):27-342) Hahn BH et al. Annals of Internal Medicine. 1975;83(5):597-605

Mycophenolate mofetil

• Not effective as first option in inducing remission in NPSLE (contrary to lupus nephritis)

• Efficacy in NPSLE - modest • Role in maintenance therapy following

induction therapy with CYC.

Cesar Magro-Checa et al. Management of Neuropsychiatric Systemic Lupus Erythematosus: Current Approaches and Future Perspectives. Drugs (2016) 76:459-483

Methotrexate

• Rarely used in NPSLE• Intrathecal MTX + steroids positive outcome• Intrathecal – not a common clinical practice

Cesar Magro-Checa et al. Management of Neuropsychiatric Systemic Lupus Erythematosus: Current Approaches and Future Perspectives. Drugs (2016) 76:459-483

Cyclosporin

• No studies explicitly describe it’s effect on neuropsychiatric symptoms

• Studied mostly in combination with other measures real efficacy is not known

Cesar Magro-Checa et al. Management of Neuropsychiatric Systemic Lupus Erythematosus: Current Approaches and Future Perspectives. Drugs (2016) 76:459-483

Rituximab

• Systematic review – safe & effective in non renal SLE(Cobo-Ibanez et al)

• Good efficacy in refractory NPSLE• Current data – as second line therapy in

severe refractory NPSLE • Additional trials needed to define the exact

place in the therapeutic regimen for NPSLE

Cobo-Ibanez T et al. Efficacy and safety of Rituximab in the treatment of non-renal systemic Lupus Erythematosus: A systematic review. Seminars in Arthritis and Rheumatism: 2014;44(2):175-85

Intravenous immunoglobulins (IVIG)

• No response after corticosteroid pulses• Failure of (or) contraindication for standard

immunosuppressive therapy• As the first choice, 1) When patients are pregnant 2) Presence of a concomitant infection

Cesar Magro-Checa et al. Management of Neuropsychiatric Systemic Lupus Erythematosus: Current Approaches and Future Perspectives. Drugs (2016) 76:459-483

Intravenous immunoglobulins (IVIG)

• CNS manifestations – ACS, seizures, headache, chorea, psychosis

• PNS – CIDP,GBS, peripheral neuropathy associated with vasculitis

• Psychiatric – psychosis, depression, mood disorder

1) Hum Immunol. 2005;66(4):395-4022) Autoimmun Rev. 2007;6(4):257-93) Clin Exp Rheumatol. 2014;32(1):41-7

Therapeutic plasma exchange

• Use in clinical practice – limited• In combination with other immuno

suppressive therapy – acceptable toxicity• Good alternative in severe NPSLE• Controlled trials needed to better define the

role

Cesar Magro-Checa et al. Management of Neuropsychiatric Systemic Lupus Erythematosus: Current Approaches and Future Perspectives. Drugs (2016) 76:459-483

Autologous hematopoieticstem cell transplantation

• Emerged as an effective treatment modality in intractable SLE patients

• Used to control lupus refractory to aggressive standard immunosuppressive therapy

• Successful remission reported• Salvage therapy for severe NPSLE refractory to

aggressive standard immunosuppressive therapy• More trials are needed to establish criteria for

patient selection and the exact role of this therapy

Management of ischemic NPSLE

Antiplatelet treatment• Low dose aspirin In patients without aPL In patients with aPL who do not fulfill the criteria for APS• In patients who have had a 2nd CV event while receiving ASA,

alternative agents like clopidogrel• In patients with stroke and APS Sole Antiplatelet treatment? Antiplatelet with low intensity anticoagulation (INR 2-3)? Antiplatelet with high intensity anticoagulation (INR>3)?

Anticoagulation • EULAR – anticoagulation superior to antiplatelet therapy for secondary

prevention (stroke/TIA) in APS• In definite APS and arterial thrombosis Warfarin therapy (INR >3.0) or Antiaggregant with anticoagulant (INR 2.0-3.0)• In cerebral venous and sinus thrombosis – INR (2.0-3.0)• aPL + with myelopathy• Chorea or seizure – when aPL + or suspected ischemia• aPL related ischemic optic neuropathy• aPL + cranial neuropathy not responding to immunosuppressive therapy• APS with cognitive dysfunction

Potential future therapies

Drugs in development

• Anti B cell therapies – Belimumab, Tabalumab, Blisibimod, Atacicept, Epratuzumab (anti CD22)

• Anti cytokines – Sifalimumab, Rontalizumab (anti-IFN- α), Tocilizumab (anti-IL6), AMG 811 (anti IFN-γ)

• New generation direct oral anticoagulants – Dabigatran (thrombin inhibitor), rivaroxaban, apixaban & edoxaban (direct Xa inhibitors)

Potential future targets

• Disruption of BBB – important role in pathogenesis

• Targeting cytokines involved in this – control of NPSLE

• TWEAK – member of TNF superfamily• Alternate compliment cascade Eculizumab – blocks generation of terminal

compliment components C5a and C5b-9

Conclusion

• Management of NPSLE – not evolved substantially & characterized by lack of good evidence and use of empirical therapies to date

• More biomarkers needed for diagnosis & follow up

• Role of new imaging modalities MRS,SPECT – clearly defined

• More trials needed to define exact place of each therapy

The presence of which cytokine in CSF is reported to have the most robust positive association with NPSLE and can be used as potential biomarker in NPSLE in future?

1)IL-12)IL-23)CX3CL1 (Fractalkine)4)IL-65)TNF

Answer:4) IL-6

1) Fragoso-Loyo H et al. Arthritis and rheumatism. 56. 1242-1250 (2007)2) Hirohata S et al. Clinical Rheumatology. 28. 1319-1323 (2009)

Which of the following biologics in the pipe linefor NPSLE targets IFN- γ

1) Sifalimumab2) Rontalizumab3) Eculizumab4) Fontolizumab

Answer:4) Fontolizumab

Fontolizumab targets interferon-γ

Thank you