2009 Convegno Malattie Rare Nobile Orazio [22 01]

Le neuropatie immunomediate: cosa fare nei pazienti non

responsivi alle terapie convenzionali?

12° CONVEGNO

PATOLOGIA IMMUNE E

MALATTIE ORFANE 2009

Torino, 22-24 gennaio 2009

convenzionali?

Eduardo Nobile-Orazio

Dip. Scienze Neurologiche, Università di Milano,

Neurologia 2, IRCCS Istituto Clinico Humanitas

Centro Congressi Torino Incontra

Via Nino Costa, 4 – Torino

IMMUNE-MEDIATED NEUROPATHIESI. Idiopathic neuropathies

1 Guillain Barré Syndrome (GBS):• Acute inflammatory demyelinating polyneuropathy (AIDP) • Acute motor (-sensory) axonal neuropathy (AMAN & AMSAN)• (Miller) Fisher Syndrome and other regional or functional variants

2 Subacute inflammatory demyelinating polyneuropathy3 Chronic inflammatory demyelinating polyneuropathy (CIDP)

• (?) chronic relapsing axonal form (CIAP)

4 Multifocal demyelinating (motorsensory) neuropathy (Lewis-Sumner)4 Multifocal demyelinating (motorsensory) neuropathy (Lewis-Sumner)5 Multifocal motor neuropathy (MMN)

II. Neuropathies associated with other disorders6 Neuropathies associated with monoclonal gammopathies:

- IgG & IgA (?) - IgM: anti-MAG; anti-sulfatides, -GM1, -GD1a, -GD1b, -ChSC,; antigen unknown

7 Paraneoplastic neuropathies: - subacute sensory neuronopathy: anti-Hu (mostly in lung carcinoma);- not anti-Hu- subacute motor neuronopathy in lymphoma (?)

8 Vasculitic neuropathies (?)

CHRONIC INFLAMMATORY DEMYELINATING POLYRADICULO-

NEUROPATHY (CIDP)

� Chronically progressive, stepwise, or recurrent symmetric proximal and distal weakness and sensory dysfunction of two or more extremities, developing over at least 2 months; cranial nerves developing over at least 2 months; cranial nerves may be affected

� Absent or reduced tendon reflexesin all extremities

� Elevated cerebrospinal fluid proteinwith leukocyte count < 10/mm3

� Electrophysiological and/or morphological features of a demyelinating neuropathy

List of presumed CIDP variantsClinical• DADS (Distal Acquired Demyelinating Symmetric)• Pure sensory (ataxic) neuropathy • Pure motor neuropathy• Focal or multifocal neuropathy• Focal or multifocal neuropathy• Lewis-Sumner syndrome (MDN; MADSAM)• MMN (Multifocal Motor Neuropathy)

Pathological• Axonal CIDP

Adapted from: Hahn et al (Dyck & Thomas, Peripheral Neuropathy 2005; Said (Neuromusc Dis 2006) & Koller et al (NEJM 2005)

With CNS involv.

8%Markedly

asymmetric8%

Pure Sensory 15%

DADS 17%

Cranial Neurop.5%

RLS1%

CLASSIC CIDP 46%

Subclassification of chronic dysimmune

Rotta et al. J Neurol Sci 2000

CIDP AND CLINICAL VARIANTS

Bushby & Donaghy J Neurol 2003

DADS 17% Subclassification of chronic dysimmune neuropathies in 102 patients

MOTOR DEMYEL(MOTOR

CIDP) 6%

MF S-M(MDN)

6%

MMN 13%

SENSORY ATAXIC

(SENSORY CIDP)

5%

MOTOR SENSORY (TYPICAL

CIDP)70%

87 pts. with AAN dem features in >1 motor or >2 sensory nerves

Steroid better IVIG better

Steroids

Steroid worse

IVIg

1) Clinical Criteria: InclusionA Typical CIDP

� Chronically progressive, stepwise, or recurrent symmetric proximal and distal weakness and sensory dysfunction of all extremities, developing over at least 2 months; cranial nerves may be affected

� Absent or reduced tendon reflexes in all extremities

B Atypical CIDPOne of following but otherwise as in A (DTR may be normal in unaffected limbs)

� Predominantly distal weakness (distal acquired demyelinatingsymmetric,DADS)

� Pure motor or sensory presentationsincluding chronic sensoryimmune polyradiculoneuropathy affecting the central process of theprimary sensory neuron.

� Asymmetric presentations (multifocal acquired demyelinatingsensory and motor, MADSAM,Lewis-Sumner syndrome)

� Focal presentations(e.g., involvement of the brachial plexus or ofone or more peripheral nerves in one upper limb)

� CNS involvement(may occur in typical or atypical CIDP)

EVIDENCES FOR IMMUNE PATHOGENESIS IN CIDP

• Pathological evidence of demyelination with macro-phage and T cell infiltrates and Ig deposits in nerve;

• Association with HLA-B8 (HLA-CW7 & HLA-DR2);

• Increased circulating (Th1) cytokinelevels;• Increased circulating (Th1) cytokinelevels;

• Similarity with chronic EANin Lewis rat (P0, P2;T cell mediated) & rabbit (myelin, GalC; ab. mediated);

• Passive transfer studieswith serum (α-P0) of CIDP;

• Serum antineural reactivityin patients’ sera;

• Response toimmune therapy(Steroids, PE, IVIg);

• Prevalence of CIDP in SE England: 1.32/100.000 on 1/1/95 (3.5/100,000 in Piemonte on 31/12/2001; Chiò et al, JNNP 2007)

• On the prevalence date:• Mean age: 54.4 years (range 10-95)

JNNP 1999; 66:677-680

• Mean age: 54.4 years (range 10-95)• Mean age of onset: 45.6 years (41.8 for RR, 50 for CP) (59.6)• Mean duration of CIDP: 8.9 years (range 2-490 months) (7.3)• 13% of patients required aid to walk (11.6%)• 54% were still on treatment

• The average Rankin score at the worse relapse was 3.5• 54% of patients had been severely disabled (Rankin

score 4 or 5) at some time during the illness (8.5%)

Treatment of CIDP1. Indication for initiating treatment2. Therapy for initial management

A. SteroidsB. Plasma exchangeC. IVIG

3. Therapy for long-term managementA. SteroidsB. Plasma exchangeC. IVIG D. Immunosuppressive agentsE. Interferons

4. Dosage, regimen, and duration of treatment5. General treatment6. Patient’s support group

CORTICOSTEROIDS FOR CIDPMehndiratta MM & Hughes RAC

Cochrane Database of Systematic Reviews 2008 (4)

IVIg FOR CIDPvan Schaik IN, Winer JB, de Haan R, Vermeulen M


PLASMAEXCHANGE FOR CIDPMehndiratta MM, Hughes RAC, Agarwal P


OPEN ISSUES IN CIDP TREATMENT

What therapy should we first use in CIDP (IVIg, steroids or PE)?

� Which is the most effective therapy?

�Which is the best tolerated therapy?

�Which is the most convenient therapy?

Comparison of effective therapies in CIDP

20 patients; cross-over; IVIg (0,4->0,2g/kg/wk x 6wks)

vs. PE (2->1/wk x6 wks)

IVIg = PEAnn Neurol 1994

24 patients; cross-over; IVIg (2g/kg)vs Prednisolone

(60->10 mg x6 wks)

IVIg =PrednisoloneAnn Neurol 2001

Steroids, PE & IVIg are similarly effective (~60%) as initial therapy in CIDP

Italian Register for response to treatment in CIDP patients

Cocito D, Paolasso I, Jann S, Benedetti L, Briani C, Comi C, Fazio R, Mazzeo A, Sabatelli M, Nobile-Orazio E.

Torino, Milano, Genova, Padova, Novara, Messina, Roma.

Italian PNS meeting, Alba, April, 2008

Response to initial therapy in CIDP

5 (4%) *25 (22%) 90 (78%) IVIg

18 (13%)*49 (36%) 87 (64%) Steroids 136 (51%)

Side EffectNon Respond.ResponderTherapy

81 (31%) 186 (69%) TOTAL267

4 (25%) 7 (44%) 9 (56%) PE16 (6%)

5 (4%) *25 (22%) 90 (78%) IVIg115 (43%)

* Steroids vs IVIg: p= 0.02

Advantage & Disadvantage of Steroids and IVIg in CIDP

• Steroids– Pros:

• Low cost

• Easy oral assumption

• IVIg– Pros:

• Well tolerated

• Few side effects• Easy oral assumption

• No need for hospital stay

- Cons:- Major side effects

especially on the long term

- More contraindications

• Few side effects

• Less contraindications

– Cons- High cost

- Repeated periodic hospital access (1-2d/month)

EFNS/PNS Recommendations 1) Initial Treatment

1. Patients with very mild symptomsnot or slightly interfering with daily activities may be monitored without treatment.

2. IVIg or corticosteroidsshould be considered in sensory and motor CIDP in presence of troublesome symptoms (Level B recommend.). The presence of contraindications to either recommend.). The presence of contraindications to either treatment should influence the choice (Good Practice Point)

3. The advantages and disadvantages should be explained to the patient who should be involved in the decision making (Good Practice Point).

4. In pure motor CIDP IVIg should be considered as the initial treatment (Good Practice Point)

5. If IVIg and corticosteroids are ineffective PE should be considered(Level A recommendation)

What to do in CIDP patients not responsive to conventional therapy?

Review the therapy regimen prescribedregimen prescribed

Dosage, Regimen & Duration of Treatment:

Steroids

1. Common initial doses of corticosteroids are prednisone or predniso(lo)ne 1 mg/kg or 60 mg dailybut there is a wide variation in practice. There is no evidence and no consensus about whether to use daily or alternate day prednisone or prednisolone or intermittent high dose prednisone or prednisolone or intermittent high dose monthly intravenous or oral regimens.

2. For patients starting on corticosteroidsa course of up to 12 weeks on their starting dose should be considered before deciding whether there is no treatment response. If there is a response, tapering the dose to a low maintenance level over one or two years and eventual withdrawal should be considered.

Dosage, Regimen & Duration of Treatment:

IVIg1. The usual first dose of IVIg is 2.0 g/kg (0.4 g/kg on 5

consecutive days). For patients starting on IVIg, observation to discover the occurrence and duration of any response to the first course should be considered before embarking on further treatment. Between 15 and 30% of patients do not need further treatment. and 30% of patients do not need further treatment.

2. If patients respond to IVIg and then worsen,repeated doses should be considered. Repeated doses may be given over one or two days. The amount per course needs to be titrated according to individual response. Repeated courses may be needed every 2 – 6 weeks.

3. If a patient becomes stable on a regime of intermittent IVIg, the dose per course should be reduced beforethe frequency of administration is lowered

Recommendations for Treatment 2) Maintenance Treatment

1. If the first line treatment is effective continuation should considered until maximum benefit, then dose reduced to the lowest effective maintenance dose (Good Practice Point).

2. If response is inadequate or maintenance doses are high, combination treatments or adding immunosuppressant/ modulatory drug may be considered(Good Practice Point).modulatory drug may be considered(Good Practice Point).

3. Advice about foot care, exercise, diet, driving and life style management should be considered. Neuropathic pain should be treated with drugs according to EFNS guideline (Attal et al 2005, in preparation). Depending on patients’ needs, orthoses, physiotherapy, occupational therapy, psychological support and referral to a rehabilitation specialist should be considered (Good Practice Points)

4. Information about patient support groups should be offered to those who would like it (Good Practice Point)

Steroids ->(N=43 )

–> IVIg 38 21 (56%) 0

–> PE 5 1 (20%) 0

1st Treat. 2nd Treat. No. Treated Responsive Intolerant

Response to second therapy in CIDP patients NR to initial treatment

–> PE 5 1 (20%) 0

IVIg ->(N=14 )

–> STE 14 6 (43%) 1 (7%)

PE - >(5 pt)

–> STE 5 2 (40%) 0

Risultati: pazienti NR

150

200

250

81 %

89 %

0

50

100

150

I SCELTA SWITCH OL

NRR

34%19%

11%

66%

What to do in unresponsive CIDP patients?Reconsider the Diagnosis

1. POEMS

2. Osteosclerotic myeloma

3. Neural B-cell lymphoma

4. Amyloidosis

5. PN+ IgM anti-MAG

6. CMT1

Immunosuppressant and immunomodula-tory drugs reported to be beneficial in CIDP

Class IV evidence (see Hughes et al. 2004)

1. Azathioprine

2. Cyclophosphamide

3. Ciclosporin3. Ciclosporin

4. Etanercept

5. Interferon alpha

6. Interferon beta1a

7. Mycophenolate mofetil

8. Rituximab (anti-CD20)

Cytotoxic and Interferons for CIDPHughes RAC, Swan AV, van Doorn PA


• Reviewers’ conclusion: • Only two RCT assessing the effect of azathioprine or

interferon beta have been performed in CIDP.interferon beta have been performed in CIDP.

• The evidence is inadequate to decide whether azathioprine, interferon beta or any other immuno-suppressive drug or interferon is beneficial in CIDP.

• More research is needed to determine whether immunosuppressive drugs or interferon are beneficial for CIDP.

RCT OF AZATHIOPRINEIN CIDPDyck et al, Neurology 1985; 35: 1173-6

• 27 CIDP patients • Randomized open controlled trial (not blind)• Azatioprine (2mg/kg) + Prednisone (120mg/alt day

→ 0) versus Prednisone alone for 9 months → 0) versus Prednisone alone for 9 months • No significant difference in any of the 16 parameters

examined between the two groups

BUT1. Azathioprine Dose & duration insufficient

2. Only analyzed the adjunctive effect and not the steroid-sparing effect of Azathioprine

AZATHIOPRINE IN CIDPOpen or retrospective studies

• Dalakas et al 1981: 3 mg/kg, improvement in 3/4steroid resistant CIDP patients

• McCombe et al 1987: improvement observed in 4/7CIDP patients

Total responder to Azathioprine 7/11 (64%)Total responder to Azathioprine 7/11 (64%)� Barohn et al 1989: 56/59 (95%) CIDP patients responded to

prednisone followed by azathioprine in case of relapse or poor response: number treated with azathioprine not mentioned.

� Simmons et al 1995: 8 of 50 treated patients with CIDP received Azathioprine, results not mentioned

� Monaco et al 2004: low dose azathioprine (1 mg/kg) and Prednisolone (0.25-05 mg/kg) were mentioned to prevent relapse in CIDP particularly in poor responders to IVIg but data not reported

CYCLOSPORINE IN CIDPOpen or retrospective studies

� Hodgkinson et al 1990 & Barnett et al 1998: • 14/14CIDP patients treated with 10mg/kg (3-7)→5mg (2-3)

improved in disability or relapse rate; 11/19 (including 5 with paraproteinemia) had side effects (4 nephrotoxicity & 4HBP)

� Mahattanakul et al 1996:• 3/8 (37%)CIDP patients poorly responsive or intolerant to

conventional therapy improved with Cys-A 3-5 mg/kg/d, and could reduce or suspend PE or steroids.could reduce or suspend PE or steroids.

� Matsuda et al 2004:• 7/7CIDP patients poorly responsive to conventional therapy

improved in disability and grip strength within 3 monthsof Cys-A 5mg/kg/d. None had side effects

� Odaka et al 2005:• 4/5CIDP patients improved with Cys-A 3mg/kg/d.

� Visudtibhan et al 2005:• 2/2steroid resistant CIDP children markedly improved in

strength and/or reduced relapses with Cys-A 5mg/kg/d.Total responder to Cyclosporine 30/36 (83%)

CYCLOPHOSPHAMIDE (CTX)IN CIDPOpen or retrospective studies

• Oral:• Prineas et al 1976: 4 patients had sustained improvement with

oral CTX 50-150 mg/d• Dalakas et al 1981: 1 patient improved with oral CTX 2mg/kg• McCombe et al 1987: 4/5patients improved with CTX (dose

& route ?)• Bouchard et al 1999: 0/2patients unresponsive to Steroid,

IVIg & PE respond to oral CTX 2mg/kg x 6-12 months• pulsed i.v.:

• Good et al, 1995: 1g/m2/mo x 6 moseffective in 11/15(73%)patients not responding to other therapies

• Branagan et al 2002 & Gladstone et al 2005: 200mg/kg in 4deffective in 4/5 (80%)patients unresponsive to other therapies

Total responder to Cyclophosphamide 24/32 (75%)

MAJOR SIDE EFFECTS OF CYCLOPHOSPHAMIDE

High Dose Low Dose Side effect (>6mg/kg/die,i.v.) (<3mgKg/die,oral) ____________________________________________________________ Nausea and vomit severe * mild Hemorragic cystitis severe * microscopic hematuria Leucopenia rapid onset * slow onset Thromocytopenia severe but rare * Hair loss alopecia * moderate Mucosal ulceration severe * Mucosal ulceration severe * Infection HZV & bacterial Cardiotoxicity rare Amenorrea rare, can be permanent same Azoospermia rare, can be permanent same Remote bladder cancer yes yes Remote leukemia & lymphoma yes yes SIADH rare Liver toxicity, Pulmonar fibrosis rare ____________________________________________________________ With low CTX dose, most side effect are reversible

MYCOPHENOLATE MOFETIL IN CIDPOpen or retrospective studies

• Chaudhry et al 2001:1/3patients treated with MMF 2g/d improved in strength and reduced steroids.

• Mowzon et al 2001: 2/2patients improved in strength & sensation, 1 relapsed at MMF suspension & improved at restart

• Benedetti et al 2004:2/2patients reduced IVIg by 50% without deterioration and could suspend concomitant azathioprinedeterioration and could suspend concomitant azathioprine

• Umapathi et al 2002:0/4patients improved in or could reduce concomitant steroids, PE or IVIg

• Gorson et al 2004: 3/13 (23%)patients failing or relapsing after conventional therapy improved with MMF (1gx2/d x 2-36 mos).No significant improvement in Rankin, sensory & MRC scores; 5 patients (24%) had one or more side effects.

• Radziwill et al 2006: effective in 4/7patients (in 1 only on pain)

• Total responder to Mycophenolate 12/31 (39%)

RCT OF INTERFERON β−1a IN CIDPHadden et al, Neurology1999; 53: 57-61

• 10 consecutive treatment-resistant CIDP patients.

• Randomized, double-blind, cross-over.

• Interferon β−1a (Rebif), s.c. (3 MIU 3 x wk x 2 wks -> • Interferon β−1a (Rebif), s.c. (3 MIU 3 x wk x 2 wks -> 6MIU 3 x wk x 10 wks), vs. placebo, 4 wks washout.

• Clinically important improvement in 1 patient with INF-β and 2 with placebo.

• No significant clinical or neurophysiologic effect.

INF-β is not effective in treatment-resistant CIDP

INTERFERON β−1a IN CIDPVallat et al (Neurology 2003; 60(suppl3) S23-8

• 20 IVIg resistant, deteriorating CIDP patients.

• Prospective, open label, baseline versus treatment study.

• Interferon β−1α (Avonex) im, 30 µg 1 x week x 6 mos. 30 µg 1 x week x 6 mos.

• 7 (35%) improved, 10 (50%) stable,3 (15%) deteriorated

• Significant improvement in NDS score(IT/PP, p: .0005), clinical grading(PP, p: .05) but not grip strength.

• Improvement of CMAP areas.

INTERFERON β−1a ADJUNCTIVE TO IVIg IN CIDPGorson et al (AAN 2008, in preparation)

• 67 IVIg dependent CIDP patients.• Multicenter RCT, IFNβ-1a, 30 or 60 ug (45 pts) vs

placebo (22 pts) once or twice weekly• After 16 wks IVIg discontinued and restarted upon

worsening by 2 or more MRC points (0-60). worsening by 2 or more MRC points (0-60). • The mean IVIg dose in week 16-32 (1g/kg) in IFNβ-1a

treated did not differ from placebo (1.9g/kg)• In both groups 47% of patients did not relapse by 32

weeks• Patients more severe (MRC <51) or more intensely

treated with IVIg (>0.95g/kg/mo) treated with IFNβ-1a required less IVIg than placebo treated patients.

OTHER IMMUNESUPPRESANTIN CIDPUncontrolled studies

�Rituximab• Beneficial in 5 patients (Briani et al 2004;Knecht et al 2004;

Bodley Scott et al 2005; Gono et al 2006; Munch et al. 2007)�Methotrexate

• 7/10 (70%)patients improved by at least 2 MRC point and 2 also in disability with MTX 10-15 mg/wk alone (1) or in association with steroids or IVIg or both. 3 patients worsened association with steroids or IVIg or both. 3 patients worsened including 1 who died. None suspended concomitant therapy (Fialho et al 2006)

�Etanercept (soluble TNF-α receptor)• 3/10 (30%)therapy refractory or intolerant patients signifi-

cantly improved and 3 possibly improved. (Chin et al 2003)�Tacrolimus(FK506)

• 1 patient improved (Ahlmen et al 1998)�Campath 1 H

• 1 patient improved (Hirst et al.2006)

RMC TrialA Pilot Randomised controlled trial of Methotrexate for

Chronic Inflammatory Demyelinating Polyradiculoneuropathy EudraCT Number – 2005-003382-16

Co-Sponsors: King’s College London, Guy’s & St Thomas’ NHS

Principal investigator: Professor Richard A C Hughes

Centres: 26 in 5 European countries (6 centres in Italy)

Patients: 60 patients randomised. Patients: 60 patients randomised.

Trial design: oral methotrexate or placebo (7.5 mg/wk increasing to 10 mg weekly after 4 weeks and 15 mg weekly after 8 weeks) and folic acid 5 mg twice weekly for 40 weeks. After 16 weeks corticosteroids or IVIg were reduced, subject to satisfactory progress, at a rate of 20% of the baseline dose every 4 weeks.

Primary outcome: At least 20% reduction in mean weekly dose of steroids or IVIg from week 37-40 compared with week 1– 4.

Secondary outcome:change in disability and impairment from baseline to week 16 and to week 40.

68

10

Methotrexate (n=27) Placebo (n=32)

Fre

quen

cy14/27 (52%) responders 14/32 (44%) responders

02

4

-100 -50 0 50 100 -100 -50 0 50 100

Fre

quen

cy

Percentage ChangeGraphs by Treatment Group

Adjusted odds ratio 1.21 (95% CI 0.40 to 3.70).

Immunosuppressant and immunomodulatory drugs in CIDP

1. Cyclosporin (83%)

2. Azathioprine (64%)

3. Cyclophosphamide (75%)

1. Azathioprine 10

2. Methotrexate 63. Cyclosporin 4

A literature overview A bunch of experts’ view

4. Methotrexate (70%)

5. Interferon α (64%)6. Mycophenolate mofetil (39%)7. Interferon β 1a (35%)

8. Rituximab (anti-CD20) (?%)

9. Etanercept (30%)

10. Autologous hematopoietic stem cell transplantation

4. Mycophenolate mofetil 1

5. Cyclophosphamide 1

6. Rituximab (anti-CD20)

7. Interferon α8. Interferon β 1a

9. Etanercept

RMC Trial Meeting, London, April 2008

Multifocal Motor Neuropathy

• Rare disordercharacterized by:• progressive, predominantly

distal, multineuropathic limb weakness, usually more pronounced in the arms;pronounced in the arms;

• minimal or no sensory loss;• multifocal persistent partial

motor conduction block. • Frequent (30-50%) association

with anti-GM1 IgM antibodies• Frequent (80%) response to IVIg

1) Clinical Criteria for MMNA) Core criteria (both must be present)1. Slowly progressive or stepwise progressive, asymmetric limb

weakness, ormotor involvement having a motor nervedistribution in at least two nerves, for more than one month#

2. No objective sensory abnormalitiesexcept for minor vibrationsense abnormalities in the lower limbs.

B) Supportive clinical criteria3. Predominantupperlimb involvement3. Predominantupperlimb involvement4. Decreased or absent tendon reflexes in the affected limb5. Absence of cranial nerve involvement6. Cramps and fasciculations in the affected limbC) Exclusion criteria7. Upper motor neuron signs8. Marked bulbar involvement9. Sensory impairment beside for minor vibration loss in the legs10. Diffuse symmetric weakness during the initial weeks11. Laboratory: CSF protein > 1 g/l

EVIDENCES FOR IMMUNE PATHOGENESIS IN MMN

• IgM antibodies to GM1or other gangliosides are present in 30-50% of MMN patients (but may be also found in other PN and MND) and often though not alwaysdecrease during clinical improvement;

• Deposits of IgM were found at the nodes of Ranvier of sural nerves in a patient with CB (and MND);

• CB can be induced in vitro & vivo by serum from MMN patients with and without anti-GM1 IgM;

• Most patients with MMN respond to immune therapies(IVIg and CTX).

Disability progression in MMN

Years of neuropathy 5 10 15 20• N° pts 21 17 12 7• N° pts Rankin 2 3 4 3

score >3

100

0

20

40

60

80

5 10 15 20

Years from onset neuropathy

% disable patients

9.5%17.5%

33%42%

IMMUNE THERAPIES IN MMN

No. No. (%) No. (%)Therapy treated improved worsened________________________________________________

Steroids (alone) 64 (62) 7 (11%) 14(22%)Steroids (alone) 64 (62) 7 (11%) 14(22%)

Plasmaexch.(alone) 21 (20) 4 (20%) 2 (10%)

IVIg: 383 ↓↓↓↓↓↓↓↓ impairment: 303/373 (81%) ↓↓↓↓↓↓↓↓ disability: 91/123 (74%)

IVIg for Multifocal Motor NeuropathyVan Schaik I, van den Berg L, de Haan R, Vermeulen M

Cochrane Database of Systematic Review, 2005, April 18

• Reviewers’ summary and conclusion:

• Four RCT assessingthe effect of IVIg in MMN have been performed including a total of 34 patients.

• Strength improved in 78% pts treated with IVIgvs 4% with placebo; disability improved in 39% treated and 11% untreated patients

• IVIg has beneficial effect on strength in MMNand provide a non-significant trends toward improvement in disability

• More research is needed to discover whether IVIg improves disability and is cost-effective.

• Azulay et al., J Neurol Neurosurg Psychiatry 1997• 8/12 (66%) responding pts required repeated Ig x 9-48 mos,

uneffective in 3 after 3 mos; 2 (11%) in remission after 1 yr.

• Van den Berg et al., Brain 1998• 6/7 (86%) responding pts required weekly Ig (0.4g/kg/wk) x

2-4 yrs (follow-up); 3 (43%) had some deterioration.

LONG-TERM IVIg THERAPY IN MMN

2-4 yrs (follow-up); 3 (43%) had some deterioration.

Periodic IVIg are necessary in most MMN patients

Neurology 2004

10 MMN patients responding to IVIg treated with periodic IVIg infusions for 5-12 yrs (mean 8.2)

Summed dCMAP

Mean MRC

Summed pCMAP

Disability progression in MMNYears of neuropathy 5 10 15 20Treated patients 6 5 7 4

Rankin >3 0 0 1 (14%) 1 (25%)

Untreated patients 15 12 5 3Rankin > 3 2 (12%) 3 (25%) 3 (60%) 2 (66%)

0

20

40

60

80

100

5 10 15 20

Years from onset neuropathy

% disable patients

(Rankin > 3)

Treated

Nottreated

p< 0.01 p< 0.01

10 MMN patients responding to IVIg treated with periodic IVIg infusions for

3.5-12 yrs (mean 7.2) Mean monthly dose 1.6g/kg+/-0.8 vs 0.5-1g/kg

Neurology 2005; 63: 1264

dose 1.6g/kg+/-0.8 vs 0.5-1g/kg

radialperoneal

OTHER IMMUNE THERAPIES IN MMN

• To treat patients not responsive to IVIg

• To treat patients progressively less responsive or unresponsive to IVIgresponsive or unresponsive to IVIg

• To reduce the cost of IVIg use

• To reduce patients’ dependency from IVIg and Hospital admission

OTHER IMMUNE THERAPIES IN MMN

No. No. (%)

Therapy treated improved _______________________________________________Cyclophoshamide i.v. 40 30 (75%)

“ “ oral 6 3 (50%)“ “ oral 6 3 (50%)

Interferon- ββββ1a 12 6 (50%)Azathioprine, (alone) 10 (4) 5 (2) (50%)

Mycophenolate 1 0

Cyclosporine 2 2

Rituximab 14 11 (?)(81% of 21, incl. 7 MAG+)

INTERFERON-β1a INMULTIFOCAL MOTOR NEUROPATHY

• Martina et al 1999 (JNNP,1999)• 3 MMN, 1 Motor CIDP, resistant to IVIg, steroid or CTX

• 6MIU sc , 3 x wk, x 6-12 mos;

• All improved in MRC sumscore, ambulation & dexterity, but only 2 improved in Rankin score.but only 2 improved in Rankin score.

• Van den Berg-Vos et al 1999 (Neurology, 2000)• 9 MMN pts IVIg responsive;6MIU sc, 3 x wk, x 6 mos;

• No effect in 6 patients (67%), 4 of whom deteriorated and returned to IVIg; 3 patients (33%)with shorter & less severe disease improved on INF-β more than on IVIg.

INF- ββββ1a may be effective in some MMN patients

Interferon β-1a in IVIg responsive MMN Radziwill AJ et al, INC , Paris 2008

• 3 MMN patients receiving IVIg infusions every 2nd to 6th week prior to study entry.

• A prospective 9-month pilot trial of s.c. INF b-1a, 12 MIU, 3 times a week; IVIg therapy maintained. maintained.

• Intervals of IVIg prolonged from 6 to 8 weeks in 1 patient and from 5 to 6 weeks in 1 patient.They both observed a quicker recovery after IVIg and a slower relapse before IVIg. The third patient had no change.

• No major changes in the strength disability, quality of life or a reduction of combined treatment costs.

• 14 MN (11+CB) & αααα-GM1 IgM ; 7 with PN & αααα-ΜΜΜΜAG IgM; 13 untreated

• Rituximab: 375mg/ m2/ • Rituximab: 375mg/ m2/ wk x 4 -> (16) 1/wk x 2-> 1/10 wks- > 2yrs

• Strength ↑↑↑↑ 23% after 2 years (81% pts ↑↑↑↑ 12%)

• IgM ↓↓↓↓ to 55%; Abs ↓↓↓↓ to 43%

• No major side effects

Neurology 2003

2 pats (1 MMN) No effect

Adjunctive Rituximab to IVIg in MMN

1 pat: Ig every

2 pats: 1Ig+24%1Ig- 43%

Neurology 2004

Muscle Nerve 2007

Ig every 12 instead of 7 days

Tot: 2/4

An open-label trial of Rituximab in MMNChaudhry & Cornblath, INC , Paris 2008

• 6 patients with MMN under chronic IVIg therapy treated with 2 doses of Rituximab 1g iv, 2 weeks apart.

• Primary outcome total amount of IVIg used during 12-month study compared to 12 months prior.

• Secondary outcomes: changes in MRC sumscores, • Secondary outcomes: changes in MRC sumscores, grip strength, disability & handicap scores, & safety.

• No significant change in IVIg use in the group over the 12-month study. 2 able to reduce their IVIg use by 11%.

• No significant change in any score (MRC, grip strength, overall disability, Rotterdam handicap scale), although some improved on these measures.

• Rituximab can be safely given to people with MMN but in this pilot study was unable to reduce the

Pts. treated: 6

Follow-up: 47 mos (37-61)

JNNP 1997

Remission after 1-4 yrs of IVIg+CTX: 3 (50%)

Requiring reduced doses of IVIg: 3 (50%)

Pts. with severe side effects: 2 (33%)

• 28 pts randomized

• 1 pt with MMF ↓↓ IVIg by 50%.

• No signif. ↓↓ of IVIg after 12 mo.• No signif. ↓↓ of IVIg after 12 mo.

• Pts did not have drug toxicity.

•No signif. progression after 12 mo

• Muscle strength, FS unchanged after 3 months & GMI-IgM after 12 months.

Adjunctive MMF was safe but did not alter MMN course or allow IVIg reduction

Oral methotrexate in multifocal motor neuropathy patients treated with IVIg: preliminary results of

an open pilot study

Fabrizia Terenghi, Chiara Casellato, Francesca Gallia, Eduardo Nobile-OrazioGallia, Eduardo Nobile-Orazio

Department of Neurological Science, Milan University

2nd Neurology, IRCCS Istituto Clinico Humanitas, Rozzano, Milan

Dario Cocito, Serena Grimaldi

Department of Neuroscience, Turin University, Turin

Patients

We reviewed the effect of MTX in 8 patients with

MMN diagnosed according to EFNS/PNS criteria

(2006) who were clinically stable under chronic

maintenance IVIg therapy which had not been

modified during the previous 3 IVIg courses modified during the previous 3 IVIg courses

• Gender: 7M/1F

• Mean age at onset: 42.6 yrs (22-63)

• Mean years of MMN: 7.6 yrs (2-15)

• Mean duration of IVIg: 5.5 yrs (1-13)

• Mean current IVIg dose: 81g (55-135)/3-4wks

Adjunctive MTX in MMN: SummaryTerenghi et al, INC , Paris 2008

• MTX was well or moderately well tolerated by 5/8 patients with MMN.

• In 7/8 patients the association of MTX to IVIg was followed by mild to moderate (1-15 MRC) improvement and in 1 by some deterioration (4 MRC) in muscle strength MRC) improvement and in 1 by some deterioration (4 MRC) in muscle strength (mean improvement: 5.5; p: 0.0543).

• In 5/7 pts IVIg were reduced by up to 10% to 30% without clinical worsening while more consistent Ig reduction (50%) or suspension could be achieved in only 2 pts(mean Ig reduction 32%; p: 0,0253)

EFNS/PNS TREATMENT RECOMMENDATIONS

1. IVIg (2 g/kg over 2 to 5 days) should be considered as first line treatment(Level A recommendation) when disability is sufficiently severe to warrant treatment.

2. Steroids are not recommended(Good Practice Point).

3. If IVIg is initially effective, repeated IVIg should be considered(Level C) and its frequency guided by the considered(Level C) and its frequency guided by the response (Good Practice Point). Typical treatment regimens are 1 g/kg every 2 to 4 weeks, or 2 g/kg every 1 to 2 months (Good Practice Point).

4. Only if IVIg is not sufficiently effectiveimmunosup-pression may be considered.Cyclophosphamide, cyclosporin, azathioprine, interferon β1a, or rituximab are possible agents(GPP).

5. Toxicity makes cyclophosphamide less desirable (GPP)

Department of Neurological Sciences,

IRCCS Humanitas Clinical Institute Milan University, Rozzano, Milan,

Fabrizia Terenghi

Gianluca Ardolino

Chiara Casellato

Barbara Bossi

Francesca Gallia

Claudia Giannotta

Immunosuppressant & Immunomodulatorytreatments for MMN

Umapathi T, Hughes RAC, Nobile-Orazio E, Leger JMCochrane Database of Systematic Reviews 2008 update

Reviewers’ conclusion: • In the only RCT, mycophenolate mofetildid not significantly

improve strength or function or reduce the need for IVIg• The use of corticosteroids,and occasionally plasma exchange,

has been associated with deterioration. • The use of corticosteroids,and occasionally plasma exchange,

has been associated with deterioration. • There are some reports of benefit but also of serious adverse

events from cyclophosphamide either as a primary agent or for patients who do not respond or lose their responseto IVIg or require frequent infusions

• There is still little or no evidence about azathioprine, β interferon, rituximab or ciclosporin,

• Trials of IS should be undertaken but non-randomised studies do not suggest a particular favourite candidate.

Acta Neurol Scand. 2008 Jun;117(6):432-4. Epub 2007 Dec 12No benefit of treatment with cyclophosphamide and autologous blood stem cell transplantation in multifocal motor neuropathy.Axelson HW, Oberg G, Askmark H.

We report on a patient who responded to IVIG, but temporarily deterio-rated dramatically after treatment with high-dose cyclophosphamide and autologous blood stem cell transplantation. Today the situation is the same as before the treatment with cyclophosphamide and blood stem cell transplantation, i.e. IVIG is given every 4 weeks.

Neurology 2007

Patient 1 (CP)

40

50

60

70

80

IVIg

75

80

85

MR

C

MTX x 18 months7.5 mg 15 mg

-20%-10%

-

0

10

20

30

mar

-06

apr-0

6m

ag-0

6giu

-06

lug-0

6ag

o-06

set-0

66/

10/0

625

/10/0

616

/11/0

612

/12/0

64/

1/07

25/1/

0715

/2/07

8/3/

0728

/3/07

19/4/

0717

/5/07

giu-0

7giu

-07

'15/0

7/07

'02/0

8/07

'27/0

8/07

set-0

7ot

t-07

IVIg

60

65

70

MR

C

IVIgMRC

**

-20%-30%

OTHER INTERFERONSIN CIDPUncontrolled studies

� INF- ββββ 1b:• 1 patient with relapsing CIDP poorly or transiently responsive

to IVIg or PE had no further relapse after INF-β 1b (Betaferon) 8 M IU/alt. d, s.c. (Cocco et al, 2005)

� INF- αααα 2a:• 2 patients unresponsive to Steroids, AZT, Cys-A & short

benefit from IVIg made a complete & sustained recovery with benefit from IVIg made a complete & sustained recovery with INF-α 2a (Roferon-A) 2-3m IU x2/wk (Sabatelli et al 1995)

• 9/14 (64%)patients unresponsive to other therapy improved with 3 mil IU x 3/wk x 6 wks including 6 with a sustained improvement (Gorson et al, 1998)

• 1 patient with CIDP unresponsive to steroids, IVIg, PE, AZT and CTX made a complete & sustained recovery 6 mos after INF-α 2a (Roferon-A) 3 M IU x2/wk (Pavesi et al, 2002)

� PEG INF-αααα 2b (1µµµµg/kg/wk) + Ribavirine (1200mg/d):• 1 patient with HCV, improved after 7 wks (Corcia et al 2004)

P07.101 Efficacy of Interferon Beta-1a in Patients

POSTER SESSION VII: THURSDAY, APRIL 17 / 11:30 A.M.–2:30 P.M.

P07.101 Efficacy of Interferon Beta-1a in Patients with Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP)

Kenneth Gorson, Richard Hughes, Didier Cros, John Pollard, Jean Vallat, Katherine Riester, Gudarz Davar, Katherine Dawson,Alfred Sandrock

1) Diagnostic Categories in MMNA) Definite MMN

Core criteria and exclusion criteria AND definite CB with normal sensory NCS in >1 nerve

B) Probable MMNCore criteria and exclusion criteria AND probable CB with normal sensory NCS in >2 nerve

OrOrCore criteria and exclusion criteria AND probable CB with normal sensory NCS in one nerve AND at least one supportive criteria.

Supportive criteria1. Elevated IgM anti-GM1 antibodies 2. MRI Gad enhancement/hypertrophy of the brachial plexuses 3. Clinical improvement following IVIg treatment

IMMUNE THERAPIES IN MMN

No. No. (%) No. (%)

Therapy treated improved worsened________________________________________________Steroids (alone) 64 (62) 7 (11%) 14 (22%)Plasmaexchange, (alone) 21 (20) 4 (20%) 2 (10%)Azathioprine, (alone) 4 (3) 3 (75%)Cyclophoshamide (iv) 42 (34) 20 (48%)(iv 53%)

Interferone-ββββ1a 12 5 (42%)

IVIg 383 303/373 (81%) impair.91/123 (74%) disability

SIDE EFFECTS OF CTX IN MMN PATIENTS _____________ORAL CTX_____________ Pat. mg/ period total Side No. day months dose(g) effects _______________________________________________________

1. 100→→→→75 23 63.0 -

2. 150→→→→50 41 129.0 Haemorrhagic cystitis & Amenorrhea

3. 25→→→→50 43 33.0 -

4. 200→→→→100 13 58.3 Haemorrhagic cystitis & Azoospermia

5. 150→→→→50 37 67.5 -

6. 150→→→→50 37 90.0 - _______________________________________________________

JNNP 2008; 79: 93-96

• Retrospective analysis of response to IVIg in 40 MMN patientsincluding 22 treated de novo.

• 14/20 (70%) de novo patients improvedby at least 1 MRC point in • 14/20 (70%) de novo patients improvedby at least 1 MRC point in 2 affected muscles after 6 months

• At the end of follow up (2.2+-2 years):

• 8/40 (22%) had stable remission after 6 months of IVIg for > 6 months without additional therapy

• 25/45 (68%) were IVIg dependent including 8 receiving additional IS

• Non significant predictive factor for IVIg response (including GM1 abs and NCS)

MTX treatment

� Oral methotrexate as 2.5 mg tablets starting at 7.5 mg and increasing at 4 weekly

intervals to 10 then to 15 mg once weekly

� Oral folic acid 10 mg weekly

After 4 months of combined therapy, � After 4 months of combined therapy, patients who were stable or improving were planned to reduce their IVIg doses by ~10% of their baseline dose every 2-3 IVIg courses

until suspension

Mean duration of MTX treatment: 12.6 mos (4-18)

Immunosuppressive treatment for MMNUmapathi T, Hughes RAC, Nobile-Orazio E, Leger JM


Reviewers’ conclusion: • There are no randomised controlled trials of immuno-

suppressive agents as primary or adjunctive or second-line therapy in MMN on which to base practice.line therapy in MMN on which to base practice.

• Non-randomised study suggest a possible therapeutic role of CTX in primary treatment and moderate effect as adjunctive or second-line therapy in MMN.

• Randomised controlled trials are needed to establish the value of immunosuppressive agents in MMN.

IVIg is the gold standard of treatment for MMN.

EFNS/PNS TREATMENT RECOMMENDATIONS

1. IVIg (2 g/kg over 2 to 5 days) should be considered as first line treatment(Level A recommendation) when disability is sufficiently severe to warrant treatment.

2. Steroids are not recommended(Good Practice Point).

3. If IVIg is initially effective, repeated IVIg should be considered(Level C) and its frequency guided by the considered(Level C) and its frequency guided by the response (Good Practice Point). Typical treatment regimens are 1 g/kg every 2 to 4 weeks, or 2 g/kg every 1 to 2 months (Good Practice Point).

4. ONLY(ENO) If IVIg is not sufficiently effectiveimmu-nosuppression may be considered.Cyclophosphamide, cyclosporin, azathioprine, interferon β1a, or rituximabare possible agents(Good Practice Point).

5. Toxicity makes cyclophosphamide less desirable (GPP)

Neuropathy and Monoclonal Gammopathy

• Malignant monoclonal gammopathies

– Multiple myeloma (overt, smoldering, etc) Plasmocitoma (solitary, extramedullary)

– Malignant lymphoproliferative diseases:– Malignant lymphoproliferative diseases:

• Waldenström’s macroglobulinemia

• Malignant lymphoma

• Chronic lymphocytic leukemia

– Heavy chain diseases

– Amyloidosis (AL) (Primary, +myeloma)

• Monoclonal gammopathy of undetermined significance (MGUS)

Prevalence of clinical neuropathy in different monoclonal gammopathies

Osteosclerotic myeloma (POEMS) 50-85%

WM 30-50%

MGUS 5-37% MGUS 5-37%

Amyloidosis (AL) 10-20%

Cryoglobulinemia 7-15%

Multiple myeloma 3-14%

Lymphoma 2-8%

Prevalence of PN in MGUS in relation to isotype

16%8%8%74Total MGUS

14%7%7%14IgA

6%3%3%34IgG

Total PNSubclinical PN

Clinical PN

No. of patients

31%15%15%26IgM

IgM vs IgG+IgA: p < 0.025 Nobile-Orazio et al. 1991

5 (5%)PN+IgA

15 (13%)PN+IgG

95 (83%)PN+IgM

PN+MG at our Institute (1984-2000)

Anti-neural reactivities of IgM M-proteins in PN

Antigens % PN type Pathology Authors

MAG/SGPG/P0 50% S>>M

(DADS-M)

Dem Latov et al 1980

(Katz et al 2000)

Sulfatide 6% S; S>M; SM Ax or Dem Pestronk et al 1991

GQ1b+Disyalo 2% S>M Dem Ilyas et al 1986 GQ1b+Disyalo 2% S>M (CANOMAD)

Dem Ilyas et al 1986 (Willison et al 2000)

GD1a 3% M; M>S Dem Bollensen et al 1989

GM2 2% M; M>S Dem Ilyas 1988

GM1 <2% M; LMNS

(MMN)

Focal Dem Latov et al 1988

(Pestronk et al 1988)

ChS-C <2% SM Axonal Sherman et al 1983

NEUROPATHY ASSOCIATED WITH ANTI-MAG IgM MONOCLONAL GAMMOPATHY

• Slowly progressive Distal, Acquired, Demyelinating Symmetric (DADS) predominantly sensory, ataxic, PNoften associated with arm tremor;

• Estimated prevalence of 20/100,000,mostly affecting men aged 50-70 yo;mostly affecting men aged 50-70 yo;

• Electrophysiologicallycharacterized by signs of a demyelinating PNwith disproportionately increased DL compared to CV (reduced TLI); CB rare

• Pathologicallycharacterized by demyelination,abnormally spaced myelin lamellae by EM and IgM & complement deposits in nerveby IF

Homogeneous clinical and electrophysiological features consistent with a chronic, slowly progressive,

predominantly sensory, demyelinating neuropathy

Type of PN

< 0.02531%62%S or S>M

p MAG - (26)MAG + (42)

PN ASSOCIATED WITH ANTI-MAG IgM

< 0.000527%/73%81%/19%MGUS/WM-NHL

< 0.000123%90%< 35 m/s

< 0.00000139.6 m/s22.9 m/sMean MCV

NCS Peroneal

< 0.0131%7%M>S

n.s.38%31%SM

< 0.02531%62%S or S>M

Nobile-Orazio et al 1994

LONG-TERM PROGNOSIS OF PN & ANTI-MAG IgM(Nobile-Orazio et al, Brain 2000)

At entry At last follow-up

No. of patients (M/F):

Mean age at PN onset:

Years of follow-up:

26 (22/4)

61.2 (42-78)

25 (96%)

73.3 (58-84)

8.5 (2-13)

Mean years from PN onset :

Median Rankin score

Walk+support/or unable/tremor

Total disabled (Rankin>2):

Patients deceased:

3.4 (0-10)

1 (0-3)

2/0/0

2 (8%)

11.8 (3-18)

2 (1-5)

6/1/5

11 (44%)(24%at 10 yrs;50%at 15 yrs)

8(32%) 6% at 10,33% at 15 yr)

Pathogenetic role of anti-MAG IgM 1. Anti-MAG IgM are almost

invariably associated with PN or predict its onset

2. Clinical & electrophysiological homogeneous features of the neuropathy;

3. Pathological evidence of 3. Pathological evidence of demyelination and IgM & complement deposits in nerve;

4. Complement mediated nerve demyelination induced in animals by anti MAG IgM;

5. Improvement correlates with reduction of anti-MAG IgM

THERAPY OF NEUROPATHY AND ANTI-MAG IgM

No. No (%) Therapy treated improved________________________________Plasmaexchange 80 36 (45%)Chlorambucil 78 31 (40%)Steroids 46 18 (39%) Cyclophosphamide 38 18 (47%)IVIg 45 8 (18%)IVIg 45 8 (18%)Interferon α 32 9 (27%)Fludarabine 27 14 (52%)

5/16 (31%) in one trial

Rituximab 16 10 (62%)double dose 8 4 (50%)

Cladribine 1 1Other therapies 7 1 (14%)________________________________Total patients 378 150 (40%)

RCT in PN & anti-MAG IgM • Dyck et al. 1991: PE (2/wk x 3 wks)vs sham exchange; double-blind

39 PN+MGUS (21 IgM); PE effective in IgG/IgA, not IgM MGUS• Oksenhendler et al.1995: Chloranbucil (Ch) +/- PE (15 in 4 mos);open

44 PN+IgM (33 MAG);No differencebetween Ch and Ch+PE

• Dalakas et al 1996: IVIg vs placebo x 3 mos; double-blind, cross-over11 PN+IgM (9 MAG); IVIgeffective in 2 IgM (18%) (1 MAG, 11%)

• Comi et al 2002: IVIg vsplacebox 1 mos; double-blind, cross-over• Comi et al 2002: IVIg vsplacebox 1 mos; double-blind, cross-over22 PN+IgM (11/19 MAG); IVIg slightly better (p=0.05) than placebo

• Mariette et al 1997: IFN-a vs IVIg x 12 mos; open20 PN+MAG; Sensory improvement in 8/10 IFN-aand 1/10 IVIg

• Mariette et al 2000: IFN-a vs placebo x 6 mos; double blind24 PN+MAG; No differencebetween IFN-a and placebo.

• Niermejier et al 2007: Oral CTX+ Prednisone (16) vs Placebo (19) x 6 mosdouble-blind; 35 PN+IgM (17 MAG); No difference in functional scales (33% better vs 21%); MRC, sensory & DL better at 6 mos.

RITUXIMAB ( α-CD20 MAB) IN PN AND ANTI-MAG IgMRenaud et al 2003 Muscle Nerve

• 9 ptswith PN & anti−ΜAG

• Rituximab375mg/m2/wk x 4

• B cellsdecreased in all • B cellsdecreased in all

• IgM ↓ in all by 35% to 82 %

• Anti-MAG ↓ by > 50% in 8/9

• NDS ↑ in 6 (<5 in 4, >10 in 2) . 1 ↓ (16) , 2 =

• Ulnar MCV ↑ by >10% in 7

• 13 patientswith PN & anti-MAG IgM-M-protein.

• Anti -MAG IgM significantly reduced after 1 year.

JPNS 2007,

12:102-7

• Anti -MAG IgM significantly reduced after 1 year.

• 8 patients (62%) improvedin INCAT sensory & MRC score and 7 (54%) in disability too.

• Improvement in INCAT sensory sumscorecorrelated with lower anti-MAG titres at entry and at follow-up.

Antibody reduction below a critical level may be necessary to achieve clinical improvement

Worsening of neuropathy under Rituximab

• 1 patient with WM had acute worsening of pre-existing neuropathy consistent with GBSduring therapy with Rituximab and fludarabine (Noronha et al 2006)

• 1 patient with NHL in complete remission developedGBSduringRituximab maintenance therapy(Carmona et al 2006)

• 1 patient with NHL developed GBSsoon after combined • 1 patient with NHL developed GBSsoon after combined CHOP and Rituximab therapy (Terenghi et al 2007)

• 3 patientswith neuropathy with anti-MAG (Broglio et al 2005; Renaud et al 2003)or -ganglioside (Rojas-García et al 2003)IgM M-protein had severe worsening of neuropathy within one month after treatment with Rituximab .

• 1 patient with WM & mild sensory PN evolved into severe vasculitic mononeuritis multiplexwith conversion of type I to II cryoglobulin duringRituximab (Mauermann et al 2007)

A Double-Blind, Placebo-Controlled Study of Rituximab in Patients with Anti-MAG Antibody-Demyelinating Polyneuropathy (A-MAG-DP)Dalakas MC, et al; Bethesda, MD

1. Placebo-controlled study on 26 patients randomized to 4 weekly infusions of . 375 mg/m2 Rituximab or placebo. 2. The INCAT scores of patients with baseline disability >1, significantly

Ongoing or unpublished trials of Rituximab in anti-MAG PN

2. The INCAT scores of patients with baseline disability >1, significantly . improved (p < 0.05) 8 months after Rituximab compared to placebo. 3. We conclude that Rituximab is an effective treatment in 75% of patients . with A-MAG-DP with disability > 1 INCAT scores.

Presented at 2006 ANA meeting, Ann Neurol 2006; 60, Suppl. 10: S91

French- Suisse Double-Blind, Placebo-Controlled Study of Rituximab in Patients with Anti-MAG Polyneuropathy Leger JM, Steck A

Immunetherapy for anti- MAG PN Lunn MPT & Nobile-Orazio E

The Cochrane Library 2006, Issue 1

Reviewers’ conclusion: • There is inadequate reliable evidence from trials of

immunotherapies in anti-MAG neuropathy to immunotherapies in anti-MAG neuropathy to recommend any particular immunotherapy.

• IVIg is relatively safe a may produce some short-term benefit.

• Large randomised trials of at least 12 months duration are required to assess the efficacy of existing or novel therapies.

EFNS/PNS PDN GUIDELINESGood practice points for treatment of IgM PDN

1. In patients without significant disability, consideration should be given to withholding immunosuppressive or immunomodulatory treatment, providing symptomatic

treatment for tremor and paraesthesiae, and giving reassurance that symptoms are unlikely to worsen

significantly for several years. significantly for several years.

2. In patients with significant disability or rapid worsening, IVIg or PE should be considered as initial treatment,

although their efficacy is unproven.

3. In patients with moderate or severe disability, immunosuppressive treatment should be considered, although its long term efficacy remains unproven.

Preliminary reports suggest that Rituximab may be a promising therapy.

Department of Neurological Sciences,

IRCCS Humanitas Clinical Institute Milan University, Rozzano, Milan,

Fabrizia Terenghi

Gianluca Ardolino

Chiara Casellato

Barbara Bossi

Francesca Gallia

Claudia Giannotta

• Mono-, multi-, cranial neuropathy &radiculopathy(MM, WM, LL, lymphoma)– direct infiltration– nerve/root compression– hyperviscosity– bleeding diathesis

Type and mechanisms of neuropathy in plasma cell dyscrasias

– bleeding diathesis– cryoglobulinemia (also )

• Symmetric polyneuropathy– Amyloidosis (AL) (+MM)– Activation of VEGF (POEMS)– Drug related toxicity (often painful)

– M-protein reactivity with nerve (IgM PCD)– Unknown (MGUS, mostly IgG & IgA)

MMN Pts. treated: 4


Mycophenolate Mofetil in Dysimmune Neuropathies: a preliminary study

Benedetti et al. Muscle & Nerve 2004; 29:748-749


Suspension of IVIg after 4 -> 12 mos: 2 (50%)1*

IVIg reduced by 50% after 4 -> 6 mos: 1 (25%)1*

IVIg reduced by 25% only for 4 mos: 1 (25%)

*Pts. Suspending MM for side effects:2 (50%)

Results: MTX efficacy in MMN (1)

During combined MTX & IVIg therapy,

before or during IVIg reduction:

� 7/8 patients improved by > 1 MRC point (mean 6.8, range1-15)(4 pts before, 3 during Ig reduction)

� 1/8 patient had clinical worsening and relevant side effects and suspended MTX after 4 months

The improvement in muscle strength (mean 5.5, range: -4+15) achieved at any time during therapy was not significant

(p: 0.0543)

During IVIg reduction in 7 patients:

� 5 pats worsened or started to lose the

improvement after reducing Ig by more

than 10-30% of baseline dose

� 1 patient deteriorated after reducing Ig by

Results: MTX efficacy in MMN (2)

� 1 patient deteriorated after reducing Ig by

more than 50%

� 1 patient suspended Ig without worsening

The mean maximal Ig reduction

obtained without deterioration was 32%

(range 0 to 100%)

MTX in MMN: effect on MRC & Ig dosePt. Time 0

MRC(Ig4 m MTX

-10/15% (5-6 m)

-20/25% (6-7 m)

-30/40% (8-9 m)

-40/50% (10-12m

- 55+% (>12m

Max eff Red.

Last visit (Igdose)(mos)

CP 71 (55g)

72 72 71 (45g)

69 (40g)

nd nd 20% 72 (60g,+10%) (18)

CT 66 (135)

69 68 (120)

63 (105)

nd nd nd 10% 66 (120g -10%) (18)

NU 97 (80)

97 98 99 98 97 (40g)

95 (35g)

50% 97 (40g, -50%) (12)

FA 73 (80g)

69 (80g)

nd nd nd nd nd 0 69 (80g =) (4)(80g) (80g) =) (4)

SG 70 (80g)

70 73 70 (60g)

69 (50g)

nd nd 25% 67 (80g =) (11)

GM 87 (60g)

89 88 89 89(35)

92(15gr)

97 (0g)

100% 97 (0g -100%) (16)

CR 79 (80g)

79 85 86 (65g)

94 (55g)

84 (45gr)

nd 30% 84 (60g, -25%) (15)

SA 50 (80g)

64 60 58 (65g)

55 (65g)

nd nd 20% 55 (80g =) (7)

MRC M Ig

7481g

76 76 76 76 75 75 32% 7660

5) CIDP: Diagnostic CategoriesDefinite CIDP

1) Clinical Criteria I A or B & II with Electrodiagn. criteria Def.2) or Probable CIDP + at least 1 Supportive Criterion3) or Possible CIDP + at least 2 Supportive Criteria

Probable CIDP1) Clinical criteria I A or B & II with Electrodiagn. criteria Prob.1) Clinical criteria I A or B & II with Electrodiagn. criteria Prob.2) or Possible CIDP + at least 1 Supportive Criterion

Possible CIDP1) Clinical criteria I A or B & II with Electrodiagn. criteria Poss.

CIDP (definite, probable, possible) with concomitant dis.

I: Inclusion A: Typical CIDP; B: Atypical CIDP; II: Exclusion

STEROIDS IN CIDP

• McCombe et al 1987: Steroids* effective in 65%of 49 patients(*undefined steroid and dosage);

• Barohn et al 1989: Prednisone* initially effective in 95%of 59 patients (*100/d x 2-4wks -> alternate day);

• Molenaar et al 1997: Pulsed dexamethasone* effective • Molenaar et al 1997: Pulsed dexamethasone* effective in 70%of 10 patients (*40mg/d x 4d every 28d x 6 times);

• Dyck et al 1982: Oral Prednisone significantly effec-tive in a open RCT on 35 previously untreated CIDP patients (*120->100->...->2.5mg/d, each for 1wk, total 3 mos)

Steroids (oral or iv) effective in CIDP (~ 60% pts)

CORTICOSTEROIDS FOR CIDPMehndiratta MM & Hughes RAC

The Cochrane Library 2002, Issue 4

Reviewers’ conclusion: • A single randomised, controlled trial with 35

partecipants provided weak evidenceto support partecipants provided weak evidenceto support the conclusions from non-randomised studies that oral corticosteroids reduce impairment in CIDP.

• Corticosteroids are known to have serious long term-side effects. The long-term risk and benefits have not been adequately studied.

I) Randomized Controlled Trials:1. Dyck et al. N Eng J Med 1986

• 29 stable or worsening pts; double-blind, Plasma (15 pts) vs sham exchange (14 pts) (6 each in 3 wks)

• 5/15 PE patients improved in NDS more than any control Plasma exchange superior to sham exchange

2. Hahn et al. Brain 1996• 18 untreated pts; double-blind, cross-over, Plasma vs sham

PLASMA EXCHANGE IN CIDP

• 18 untreated pts; double-blind, cross-over, Plasma vs sham exchange (10 in 4 wks, 5 wks wash-out)

• 12/15 (80%) completing (66% treated) improved with PE; 8/12 (66%) PE responders relapsed 7-14d after stopping PE

PE significantly though transiently effective

II) Cochrane Review 2004, Issue 3 (Mehndiratta et al):

PE provide short term benefit in 2/3 of CIDP pts often followed by rapid deterioration. Adverse effects are not uncommon

IVIg IN CIDPRandomized, placebo-controlled trials

1) Hahn et al. Brain 1996• 30 CIDP patients; randomized, double-blind, cross-over; IVIg

(0.4g/kg x 5d) vs placebo• 19/30(63%) pts improved at 28 don IVIg vs 5/30 (17%) on PL• 8/9 CP CIDP responders steadily recovered while 10/10 R

CIDP relapsed 3-22 wks after IVIg (all improved again)CIDP relapsed 3-22 wks after IVIg (all improved again)

IVIg significantly effective in CIDP

2) Mendell et al. Neurology 2001• 33 untreated CIDP patients; randomized, double-blind, cross-

over; IVIg (1g/kg days 1, 2 & 21) vs placebo (PL)

• 11/33 (33%) improved on IVIgvs 2/23 (9%) on PL (p: .019);

• ↑↑ in muscle strength by day 10-> 42 (p:.006) after IVIg vs PL

IVIg is effective as initial treatment in CIDP

IVIg IN CIDPVan Schaik et al, Cochrane library, 2002, Issue 2

IVIg is effective for at least 2-6 weeks in CIDP

PLASMA EXCHANGE VS IVIg IN CIDP(Effect of long-term treatment)

Choudhary et al. QJM 1995

• Retrospective study of 105 CIDP patients

• 23/33 patients (70%) improved with PE: 30% of responders required repeated coursesfor 8-60 mos

• 14/22 patients (64%) improved with IVIg: 50% of responders required repeated coursesfor 6-51 mos

• More complications after PE (10) than IVIg (0)

Similar long-term efficacy of PE & IVIg in CIDP but PE has more side effects

IMMUNESUPPRESSIVE THERAPIES IN CIDP• Azathioprine+ Prednisone no better than Prednisone in a

RCT. Dose & duration unsuffcient (Dyck et al, 1985);• Cyclosporin Aeffective in 37%pts not responding to other therapies.

(Hodgkinson et al 1990; Mahattanakul et al 1996);• Cyclophosphamide pulsed i.v.:

• 1g/m2/mo x 6 moseffective in 11/15(73%)pats not responding to other therapies (Good et al, 1995)

• 200mg/kg x4d effective in 4 pats not responding to other therapies • 200mg/kg x4d effective in 4 pats not responding to other therapies (Branagan et al 2002)

• Mycophenolateeffective in 6/22 (27%)(Chaudhry et al 2001; Mowzon et al 2001;Umapathi et al 2002;Gorson et al 2004) therapy res/dep

• INF- αααα 2aeffective in 56%unresponsive pats (Gorson et al, 1998)• Etanercept (soluble TNF-α receptor)effective in 3(+3?)/10 (30%)

therapy refractory or intolerant patients (Chin et al 2003)

• INF ββββ−−−−1111a not effective in RCT on 10 therapy-resistant pats (Hadden et al . 1999),effective in open trail on 20 IVIg resistant patients (Vallat et al 2003).

Etanercept (soluble TNF-α receptor) in CIDPChin et al, J Neurol Sci 2003; 210: 19-21

• 10 CIDP patients refractory or intolerant to standard immune therapy.

• Open study.

• Etanercept (Enbrel) 25 mg x 2/week 4-6 mos • Etanercept (Enbrel) 25 mg x 2/week 4-6 mos

• Muscle strength, sensory thresholds & functional abilities

• 3 significantly improved and 3 possibly improved

Etanercept may be effective in CIDP but its efficacy needs to be confirmed in RCT

Mycophenolate mofetil in CIDPGorson et al, Neurology 2004; 63: 715-717

• 13 CIDP patients, 8 with PN+IgM, failing or relapsing after conventional immune therapy.

• Retrospective study.

• Mycophenolate mofetil 1gx2/d x 2-36 mos (Mean 15)

• No significant improvement in Rankin, sensory & MRC • No significant improvement in Rankin, sensory & MRC scores

• 3 (23%) with CIDP and 1 PN+IgM (13%) improved

• 5 patients (24%) had one or more side effects (3 nausea, 2 malaise, 2 headache, 1 diarrhea); 1 suspended x nausea

MM had a modest effect on 20% of patients

IMMUNE THERAPY FOR CIDP

• IVIg, PE & steroids are similarly effective as initial therapy in CIDP;

• PE is unsuitable for the long term treatment of CIDP;

• Steroids have more contraindications than IVIg especially in aged people (diabetes, cardiac disease, hypertension,)

• IVIg is better tolerated but more expensive than steroids;

• Studies are needed to establish the most effective andsafe therapy for the long-term treatment of CIDP.

Steroids are probably the first option in CIDP while the efficacy of IVIg should be balanced by its cost. IVIg is

the first option in children and in pts with contraindications to steroids


Cumulative response to IS of NRs DRUG N R

Azatioprina 11 6 (54%)

Rituximab 8 4 (50%)

Cocito et al 2008

Rituximab 8 4 (50%)

Cyclophosphamide 6 4 (66%)

Methotrexate 4 3 (75%)

Mycophenolate 3 2 (66%)

α-IFN 1 1

Cyclosporine A 1 0


Risposta cumulativa a ISDRUG N R SE

Azatioprina 65 41 (63%) 8 (12%)

α-IFN 13 3 (23%) 3 (23%)α-IFN 13 3 (23%) 3 (23%)

Rituximab 11 6 (54%) 0

Cyclophosph. 8 5 (62%) 2 (25%)

Cyclosporine A 8 4 (50%) 4 (50%)

Methotrexate 6 3 (50%) 2 (33%)

Mycophenolate 6 4 (66%) 0

Cocito et al 2008

Distinguishing features between CIDP and MMN

Features CIDP MMNDistribution Symmetric Asymmetric (MN)

Arms >legs no Yes (80%)

Sensory loss yes no

Gen. Areflexia yes no

Reduced CV yes noReduced CV yes no

Reduced SNAP yes no

↑ CSF proteins yes Rare (1/3)

↑ GM1 IgM no yes (30-40%)

S. Nerve biopsy demyelination Often normal

Steroid effective yes (2/3) No (1/10)

IVIg effective yes (2/3) yes (4/5)

Modified from Van den Berg-Vos et al Neurology 2000;

Electrodiagnostic Criteria in MMN1. Definite motor CB:

proximal vs distal neg. CMAP area reduction >50% whatever the nerve segment length. Negativedistal CMAP amp. must be >20% of lower NL & > 1mV & increase of proximal CMAP duration(temporal dispersion:TD) ≤ 30%.

2. Probablemotor CB:2. Probablemotor CB:negative CMAP area reduction of > 30% over along segment of an UL nerve withTD ≤ 30%;

ORnegative CMAP area reduction of >50% with TD> 30%.

3. Normal sensory nerve conduction in upper limbsegments with CB and normal SNAP amplitudes.

IVIg IN MMNRandomized controlled trials

• Federico et al., Neurology 2000• 16 MMN patients; double-blind, placebo-controlled,

crossover, trial; IVIg 0.4g/kg/day x 5 days

• 11/16 (69%) improved after IVIg, none after placebo; signifi-cant improvement in disadbility, strength & CB after IVIg

• Leger et al., Brain 2001• 19 MMN patients, 10 never treated with IVIg, 9 relapsing

after previous response to IVIg; double -blind, placebo-controlled, crossovertrial; IVIg 0.5g/kg/day x 5 days

• 12/18 (67%) improved after IVIg, 2/18 (11%) after placebo;significant improvement in daily activities but not MRC score.

IVIg significantly better than placebo in MMN

Mean MRC score in 10 MMN patients under chronic IVIg therapy

Terenghi et al, Neurology 2004

Brain 2002; 125: 1875-86

Patient 3 (NU)

52

56

60

64

68

72

76

80

84

88

92

96

100

90

100

7.5 mg 15 mg

-12%

-25%

MTX x 13 mos

*

0

4

8

12

16

20

24

28

32

36

40

44

48

52

gen-07 feb-07 mar-07 apr-07 mag-07 giu-07 lug-07 ago-07 '30/08/07 '27/09/07 '25/10/07 '23/11/07 '20/12/07 '22/01/08 '21/02/08

80

90

IVIgMRC

-25%

-50%

-37.5%

-55%-50%

Summary

• MTX was well or moderately well tolerated by all but one patient with MMN.

• In 6/7 patients the association of MTX to IVIg was followed by a variable (1-18 MRC, mean 7) improvement in muscle strength.

• In four patients monthly IVIg dose could be reduced by 10% to 35% without clinical deterioration whereas a more consistent Ig reduction (50%) or complete suspension could be only achieved in 2 patients (33%)

• A mean Ig reduction of 34% could be reached without deterioration (range 0-100%)

EFFECTS OF CYTOSTATIC-IMMUNETHERAPIES IN PN & ANTI-MAG IgM

Pts. treated for >6 mos:(for the PN)

Mean yrs of therapy:

19 (15)

4 (0.5-11)

Patients improved: 9 (47%)

Patients with therapy-related complications:

10 (53%)

2 piastrinopenia (CTX) 4 H.Zoster (Chlor) 1 hepatitis (Chlor)

1 severe hypotension (PE) 2 ac. leukemia (dec.)(Chlor)

1 pulm. edema (dec)(Steroids)

Nobile-Orazio et al 2000

Terenghi et al, JPNS 2007

2009 Convegno Malattie Rare Nobile Orazio [22 01]

Health & Medicine

Transcript of 2009 Convegno Malattie Rare Nobile Orazio [22 01]