Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

2009 Convegno Malattie Rare Nobile Orazio [22 01]

1,394 views

Published on

Le neuropatieimmunomediate: cosa
fare nei pazienti non responsivi alle terapie convenzionali?

Published in: Health & Medicine
  • Be the first to comment

2009 Convegno Malattie Rare Nobile Orazio [22 01]

  1. 1. 12° CONVEGNO PATOLOGIA IMMUNE E MALATTIE ORFANE 2009 Torino, 22-24 gennaio 2009 Le neuropatie immunomediate: cosa fare nei pazienti non responsivi alle terapie convenzionali? Eduardo Nobile-Orazio Dip. Scienze Neurologiche, Università di Milano, Centro Congressi Torino Neurologia 2, IRCCS Istituto Incontra Clinico Humanitas Via Nino Costa, 4 – Torino
  2. 2. IMMUNE-MEDIATED NEUROPATHIES I. 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 polyneuropathy 3 Chronic inflammatory demyelinating polyneuropathy (CIDP) • (?) chronic relapsing axonal form (CIAP) 4 Multifocal demyelinating (motorsensory) neuropathy (Lewis-Sumner) 5 Multifocal motor neuropathy (MMN) II. Neuropathies associated with other disorders 6 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 (?)
  3. 3. 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 may be affected Absent or reduced tendon reflexes in all extremities Elevated cerebrospinal fluid protein with leukocyte count < 10/mm3 Electrophysiological and/or morphological features of a demyelinating neuropathy
  4. 4. List of presumed CIDP variants Clinical • DADS (Distal Acquired Demyelinating Symmetric) • Pure sensory (ataxic) neuropathy • Pure motor 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)
  5. 5. CIDP AND CLINICAL VARIANTS Rotta et al. Cranial Neurop. With CNS J Neurol Sci 2000 5% involv. 8% RLS1% Markedly asymmetric CLASSIC 8% CIDP 46% Pure Sensory 15% Subclassification of chronic dysimmune DADS 17% neuropathies in 102 patients 87 pts. with AAN dem features in > SENSORY 1 motor or > 2 sensory nerves MMN MF S-M ATAXIC 13% (MDN) (SENSORY 6% CIDP) 5% MOTOR MOTOR SENSORY DEMYEL (TYPICAL (MOTOR CIDP) Bushby & Donaghy J CIDP) 70% 6% Neurol 2003
  6. 6. Steroids IVIG better Steroid better Steroid worse IVIg
  7. 7. 1) Clinical Criteria: Inclusion A 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 CIDP One of following but otherwise as in A (DTR may be normal in unaffected limbs) Predominantly distal weakness (distal acquired demyelinating symmetric, DADS) Pure motor or sensory presentations including chronic sensory immune polyradiculoneuropathy affecting the central process of the primary sensory neuron. Asymmetric presentations (multifocal acquired demyelinating sensory and motor, MADSAM, Lewis-Sumner syndrome) Focal presentations (e.g., involvement of the brachial plexus or of one or more peripheral nerves in one upper limb) CNS involvement (may occur in typical or atypical CIDP)
  8. 8. 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) cytokine levels; • Similarity with chronic EAN in Lewis rat (P0, P2; T cell mediated) & rabbit (myelin, GalC; ab. mediated); • Passive transfer studies with serum (α-P0) of CIDP; • Serum antineural reactivity in patients’ sera; • Response to immune therapy (Steroids, PE, IVIg);
  9. 9. JNNP 1999; 66:677-680 • 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) • 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%)
  10. 10. Treatment of CIDP 1. Indication for initiating treatment 2. Therapy for initial management A. Steroids B. Plasma exchange C. IVIG 3. Therapy for long-term management A. Steroids B. Plasma exchange C. IVIG D. Immunosuppressive agents E. Interferons 4. Dosage, regimen, and duration of treatment 5. General treatment 6. Patient’s support group
  11. 11. CORTICOSTEROIDS FOR CIDP Mehndiratta MM & Hughes RAC Cochrane Database of Systematic Reviews 2008 (4) PLASMAEXCHANGE FOR CIDP Mehndiratta MM, Hughes RAC, Agarwal P Cochrane Database of Systematic Reviews 2008 (4) IVIg FOR CIDP van Schaik IN, Winer JB, de Haan R, Vermeulen M Cochrane Database of Systematic Reviews 2008 (4)
  12. 12. 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?
  13. 13. Comparison of effective therapies in CIDP 20 patients; cross-over; IVIg (0,4->0,2g/kg/wk x 6wks) vs. PE (2->1/wk x 6 wks) IVIg = PE Ann Neurol 1994 24 patients; cross-over; IVIg (2g/kg) vs Prednisolone (60->10 mg x 6 wks) IVIg =Prednisolone Ann Neurol 2001 Steroids, PE & IVIg are similarly effective (~60%) as initial therapy in CIDP
  14. 14. 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
  15. 15. Response to initial therapy in CIDP Therapy Responder Non Respond. Side Effect 87 (64%) 49 (36%) 18 (13%)* Steroids 136 (51%) 90 (78%) 25 (22%) 5 (4%)* IVIg 115 (43%) 9 (56%) 7 (44%) 4 (25%) PE 16 (6%) 186 (69%) 81 (31%) TOTAL 267 * Steroids vs IVIg: p= 0.02
  16. 16. Advantage & Disadvantage of Steroids and IVIg in CIDP • Steroids • IVIg – Pros: – Pros: • Low cost • Well tolerated • Easy oral assumption • Few side effects • No need for hospital stay • Less contraindications - Cons: – Cons - Major side effects - High cost especially on the long term - Repeated periodic hospital - More contraindications access (1-2d/month)
  17. 17. EFNS/PNS Recommendations 1) Initial Treatment 1. Patients with very mild symptoms not or slightly interfering with daily activities may be monitored without treatment. 2. IVIg or corticosteroids should be considered in sensory and motor CIDP in presence of troublesome symptoms (Level B 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)
  18. 18. What to do in CIDP patients not responsive to conventional therapy? Review the therapy regimen prescribed
  19. 19. Dosage, Regimen & Duration of Treatment: Steroids 1. Common initial doses of corticosteroids are prednisone or predniso(lo)ne 1 mg/kg or 60 mg daily but 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 monthly intravenous or oral regimens. 2. For patients starting on corticosteroids a 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.
  20. 20. Dosage, Regimen & Duration of Treatment: IVIg 1. 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. 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 before the frequency of administration is lowered
  21. 21. 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). 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)
  22. 22. Response to second therapy in CIDP patients NR to initial treatment 1st Treat. 2nd Treat. No. Treated Responsive Intolerant Steroids -> –> IVIg 38 0 21 (56%) (N=43 ) –> PE 5 0 1 (20%) IVIg -> –> STE 14 1 (7%) 6 (43%) (N=14 ) PE - > –> STE 5 0 2 (40%) (5 pt)
  23. 23. Risultati: pazienti NR 250 200 89 % 81 % 150 66% NR R 100 50 34% 19% 11% 0 I SCELTA SWITCH OL
  24. 24. 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
  25. 25. Immunosuppressant and immunomodula- tory drugs reported to be beneficial in CIDP Class IV evidence (see Hughes et al. 2004) 1. Azathioprine 2. Cyclophosphamide 3. Ciclosporin 4. Etanercept 5. Interferon alpha 6. Interferon beta1a 7. Mycophenolate mofetil 8. Rituximab (anti-CD20)
  26. 26. Cytotoxic and Interferons for CIDP Hughes RAC, Swan AV, van Doorn PA Cochrane Database of Systematic Reviews 2004 (4) • Reviewers’ conclusion: • Only two RCT assessing the effect of azathioprine or 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.
  27. 27. RCT OF AZATHIOPRINE IN CIDP Dyck 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 • No significant difference in any of the 16 parameters examined between the two groups BUT 1. Azathioprine Dose & duration insufficient 2. Only analyzed the adjunctive effect and not the steroid-sparing effect of Azathioprine
  28. 28. AZATHIOPRINE IN CIDP Open or retrospective studies • Dalakas et al 1981: 3 mg/kg, improvement in 3/4 steroid resistant CIDP patients • McCombe et al 1987: improvement observed in 4/7 CIDP patients 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
  29. 29. CYCLOSPORINE IN CIDP Open or retrospective studies Hodgkinson et al 1990 & Barnett et al 1998: • 14/14 CIDP 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. Matsuda et al 2004: • 7/7 CIDP patients poorly responsive to conventional therapy improved in disability and grip strength within 3 months of Cys-A 5mg/kg/d. None had side effects Odaka et al 2005: • 4/5 CIDP patients improved with Cys-A 3mg/kg/d. Visudtibhan et al 2005: • 2/2 steroid resistant CIDP children markedly improved in strength and/or reduced relapses with Cys-A 5mg/kg/d. Total responder to Cyclosporine 30/36 (83%)
  30. 30. CYCLOPHOSPHAMIDE (CTX) IN CIDP Open 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: 4/5 patients improved with CTX (dose & route ?) • Bouchard et al 1999: 0/2 patients 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 mos effective in 11/15 (73%) patients not responding to other therapies • Branagan et al 2002 & Gladstone et al 2005: 200mg/kg in 4d effective in 4/5 (80%) patients unresponsive to other therapies Total responder to Cyclophosphamide 24/32 (75%)
  31. 31. 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 * 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
  32. 32. MYCOPHENOLATE MOFETIL IN CIDP Open or retrospective studies • Chaudhry et al 2001: 1/3 patients treated with MMF 2g/d improved in strength and reduced steroids. • Mowzon et al 2001: 2/2 patients improved in strength & sensation, 1 relapsed at MMF suspension & improved at restart • Benedetti et al 2004: 2/2 patients reduced IVIg by 50% without deterioration and could suspend concomitant azathioprine • Umapathi et al 2002: 0/4 patients 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 4/7 patients (in 1 only on pain) • Total responder to Mycophenolate 12/31 (39%)
  33. 33. RCT OF INTERFERON β−1a IN CIDP Hadden 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 -> 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
  34. 34. INTERFERON β−1a IN CIDP Vallat 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. • 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.
  35. 35. INTERFERON β−1a ADJUNCTIVE TO IVIg IN CIDP Gorson 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). • 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.
  36. 36. OTHER IMMUNESUPPRESANT IN CIDP Uncontrolled 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 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)
  37. 37. RMC Trial A 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. 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.
  38. 38. Methotrexate (n=27) Placebo (n=32) 10 14/27 (52%) responders 14/32 (44%) responders 8 Frequency 6 4 2 0 -100 -50 0 50 100 -100 -50 0 50 100 Percentage Change Graphs by Treatment Group Adjusted odds ratio 1.21 (95% CI 0.40 to 3.70).
  39. 39. Immunosuppressant and immunomodulatory drugs in CIDP A literature overview A bunch of experts’ view 1. Cyclosporin (83%) 1. Azathioprine 10 2. Azathioprine (64%) 2. Methotrexate 6 3. Cyclosporin 4 3. Cyclophosphamide (75%) 4. Mycophenolate mofetil 1 4. Methotrexate (70%) 5. Cyclophosphamide 1 5. Interferon α (64%) 6. Rituximab (anti-CD20) 6. Mycophenolate mofetil (39%) Interferon α 7. Interferon β 1a 7. (35%) Interferon β 1a 8. 8. Rituximab (anti-CD20) (?%) 9. Etanercept 9. Etanercept (30%) RMC Trial Meeting, London, April 2008 10. Autologous hematopoietic stem cell transplantation
  40. 40. Multifocal Motor Neuropathy • Rare disorder characterized by: • progressive, predominantly distal, multineuropathic limb weakness, usually more 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
  41. 41. 1) Clinical Criteria for MMN A) Core criteria (both must be present) 1. Slowly progressive or stepwise progressive, asymmetric limb weakness, or motor involvement having a motor nerve distribution in at least two nerves, for more than one month# 2. No objective sensory abnormalities except for minor vibration sense abnormalities in the lower limbs. B) Supportive clinical criteria 3. Predominant upper limb involvement 4. Decreased or absent tendon reflexes in the affected limb 5. Absence of cranial nerve involvement 6. Cramps and fasciculations in the affected limb C) Exclusion criteria 7. Upper motor neuron signs 8. Marked bulbar involvement 9. Sensory impairment beside for minor vibration loss in the legs 10. Diffuse symmetric weakness during the initial weeks 11. Laboratory: CSF protein > 1 g/l
  42. 42. EVIDENCES FOR IMMUNE PATHOGENESIS IN MMN • IgM antibodies to GM1 or other gangliosides are present in 30-50% of MMN patients (but may be also found in other PN and MND) and often though not always decrease 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).
  43. 43. 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 isab p tie ts le a n 80 60 42% 40 33% 17.5% %d 20 9.5% 0 5 10 15 20 Years from onset neuropathy
  44. 44. IMMUNE THERAPIES IN MMN No. No. (%) No. (%) Therapy treated improved worsened ________________________________________________ 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%)
  45. 45. IVIg for Multifocal Motor Neuropathy Van 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 assessing the effect of IVIg in MMN have been performed including a total of 34 patients. • Strength improved in 78% pts treated with IVIg vs 4% with placebo; disability improved in 39% treated and 11% untreated patients • IVIg has beneficial effect on strength in MMN and provide a non-significant trends toward improvement in disability • More research is needed to discover whether IVIg improves disability and is cost-effective.
  46. 46. LONG-TERM IVIg THERAPY IN MMN • 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. Periodic IVIg are necessary in most MMN patients
  47. 47. Neurology 2004 10 MMN patients responding to Summed dCMAP IVIg treated with periodic IVIg infusions for 5-12 yrs (mean 8.2) Mean MRC Summed pCMAP
  48. 48. Disability progression in MMN Years of neuropathy 5 10 15 20 Treated patients 6 5 7 4 Rankin > 3 0 0 1 (14%) 1 (25%) Untreated patients 15 12 5 3 Rankin > 3 2 (12%) 3 (25%) 3 (60%) 2 (66%) 100 ts le atien 80 p< 0.01 ) (R k > 3 p< 0.01 isab p 60 an in Treated 40 Not treated %d 20 0 5 10 15 20 Years from onset neuropathy
  49. 49. Neurology 2005; 63: 1264 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 radial peroneal
  50. 50. OTHER IMMUNE THERAPIES IN MMN • To treat patients not responsive to IVIg • To treat patients progressively less responsive or unresponsive to IVIg • To reduce the cost of IVIg use • To reduce patients’ dependency from IVIg and Hospital admission
  51. 51. OTHER IMMUNE THERAPIES IN MMN No. No. (%) Therapy treated improved _______________________________________________ Cyclophoshamide i.v. 40 30 (75%) “ “ oral 6 3 (50%) β Interferon-β1a 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+)
  52. 52. INTERFERON-β1a IN MULTIFOCAL 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. • 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. β INF-β1a may be effective in some MMN patients
  53. 53. 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. • 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.
  54. 54. • 14 MN (11+CB) & α- GM1 IgM; 7 with PN & α- ΜAG IgM; 13 untreated • 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
  55. 55. Adjunctive Rituximab to IVIg in MMN 2 pats (1 MMN) No effect Neurology 2003 1 pat: Ig every 12 instead of 7 days Neurology 2004 2 pats: 1Ig+24% 1Ig- 43% Tot: 2/4 Muscle Nerve 2007
  56. 56. An open-label trial of Rituximab in MMN Chaudhry & 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, 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
  57. 57. JNNP 1997 Pts. treated: 6 Follow-up: 47 mos (37-61) Remission after 1-4 yrs of IVIg+CTX: 3 (50%) Requiring reduced doses of IVIg: 3 (50%) Pts. with severe side effects: 2 (33%)
  58. 58. • 28 pts randomized • 1 pt with MMF ↓↓ IVIg by 50%. • 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
  59. 59. 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-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
  60. 60. 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 • 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
  61. 61. Adjunctive MTX in MMN: Summary Terenghi 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 (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)
  62. 62. 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 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 effective immunosup- pression may be considered. Cyclophosphamide, cyclosporin, azathioprine, interferon β1a, or rituximab are possible agents (GPP). 5. Toxicity makes cyclophosphamide less desirable (GPP)
  63. 63. Fabrizia Terenghi Department of Gianluca Ardolino Neurological Sciences, Chiara Casellato IRCCS Humanitas Clinical Institute Barbara Bossi Milan University, Francesca Gallia Rozzano, Milan, Claudia Giannotta
  64. 64. Immunosuppressant & Immunomodulatory treatments for MMN Umapathi T, Hughes RAC, Nobile-Orazio E, Leger JM Cochrane Database of Systematic Reviews 2008 update Reviewers’ conclusion: • In the only RCT, mycophenolate mofetil did 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. • 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 response to 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.
  65. 65. Acta Neurol Scand. 2008 Jun;117(6):432-4. Epub 2007 Dec 12 No 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.
  66. 66. Neurology 2007
  67. 67. IVIg m 0 10 20 30 40 50 60 70 80 ar -0 6 ap r-0 m6 ag 7.5 mg -0 6 gi u- 06 lu g- 06 ag o- 06 15 mg se t- 0 6/ 6 10 / -10% 25 06 /1 0/ 16 0 6 /1 1/ -20% 12 0 6 - /1 2/ 06 4/ 1/ 0 -30% 25 7 /1 /0 * 15 7 /2 /0 7 8/ 3/ 0 28 7 /3 /0 19 7 /4 /0 17 7 Patient 1 (CP) /5 /0 7 MTX x 18 months gi u- 07 gi u- 0 '1 5/ 7 07 ' 0 /07 2/ 08 ' 2 /07 7/ 08 /0 7 se t- 0 7 ot IVIg * t-0 7 MRC 60 65 70 75 80 85 MRC
  68. 68. OTHER INTERFERONS IN CIDP Uncontrolled studies β INF-β 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) α INF-α 2a: • 2 patients unresponsive to Steroids, AZT, Cys-A & short 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) α µ PEG INF-α 2b (1µg/kg/wk) + Ribavirine (1200mg/d): • 1 patient with HCV, improved after 7 wks (Corcia et al 2004)
  69. 69. 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
  70. 70. 1) Diagnostic Categories in MMN A) Definite MMN Core criteria and exclusion criteria AND definite CB with normal sensory NCS in > 1 nerve B) Probable MMN Core criteria and exclusion criteria AND probable CB with normal sensory NCS in > 2 nerve Or Core criteria and exclusion criteria AND probable CB with normal sensory NCS in one nerve AND at least one supportive criteria. Supportive criteria 1. Elevated IgM anti-GM1 antibodies 2. MRI Gad enhancement/hypertrophy of the brachial plexuses 3. Clinical improvement following IVIg treatment
  71. 71. 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%) β Interferone-β1a 12 5 (42%) IVIg 383 303/373 (81%) impair. 91/123 (74%) disability
  72. 72. 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 - _______________________________________________________
  73. 73. JNNP 2008; 79: 93-96 • Retrospective analysis of response to IVIg in 40 MMN patients including 22 treated de novo. • 14/20 (70%) de novo patients improved by 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)
  74. 74. 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, 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)
  75. 75. Immunosuppressive treatment for MMN Umapathi T, Hughes RAC, Nobile-Orazio E, Leger JM Cochrane Database of Systematic Reviews 2005 (3) 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. • 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.
  76. 76. 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 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 effective immu- nosuppression may be considered. Cyclophosphamide, cyclosporin, azathioprine, interferon β1a, or rituximab are possible agents (Good Practice Point). 5. Toxicity makes cyclophosphamide less desirable (GPP)
  77. 77. Neuropathy and Monoclonal Gammopathy • Malignant monoclonal gammopathies – Multiple myeloma (overt, smoldering, etc) Plasmocitoma (solitary, extramedullary) – Malignant lymphoproliferative diseases: • Waldenström’s macroglobulinemia • Malignant lymphoma • Chronic lymphocytic leukemia – Heavy chain diseases – Amyloidosis (AL) (Primary, +myeloma) • Monoclonal gammopathy of undetermined significance (MGUS)
  78. 78. Prevalence of clinical neuropathy in different monoclonal gammopathies Osteosclerotic myeloma (POEMS) 50-85% WM 30-50% MGUS 5-37% Amyloidosis (AL) 10-20% Cryoglobulinemia 7-15% Multiple myeloma 3-14% Lymphoma 2-8%
  79. 79. Prevalence of PN in MGUS in relation to isotype No. of Clinical Subclinical Total PN patients PN PN Total MGUS 74 8% 8% 16% IgG 34 3% 3% 6% IgA 14 7% 7% 14% IgM 26 15% 15% 31% IgM vs IgG+IgA: p < 0.025 Nobile-Orazio et al. 1991 PN+MG at our Institute (1984-2000) PN+IgM 95 (83%) PN+IgG 15 (13%) PN+IgA 5 (5%)
  80. 80. Anti-neural reactivities of IgM M-proteins in PN Antigens % PN type Pathology Authors MAG/SGPG/P0 50% S>>M Dem Latov et al 1980 (DADS-M) (Katz et al 2000) 6% S; S>M; SM Ax or Dem Pestronk et al 1991 Sulfatide 2% S>M Dem Ilyas et al 1986 GQ1b+Disyalo (CANOMAD) (Willison et al 2000) 3% M; M>S Dem Bollensen et al 1989 GD1a 2% M; M>S Dem Ilyas 1988 GM2 <2% M; LMNS Focal Dem Latov et al 1988 GM1 (MMN) (Pestronk et al 1988) <2% SM Axonal Sherman et al 1983 ChS-C
  81. 81. NEUROPATHY ASSOCIATED WITH ANTI- MAG IgM MONOCLONAL GAMMOPATHY • Slowly progressive Distal, Acquired, Demyelinating Symmetric (DADS) predominantly sensory, ataxic, PN often associated with arm tremor; • Estimated prevalence of 20/100,000, mostly affecting men aged 50-70 yo; • Electrophysiologically characterized by signs of a demyelinating PN with disproportionately increased DL compared to CV (reduced TLI); CB rare • Pathologically characterized by demyelination, abnormally spaced myelin lamellae by EM and IgM & complement deposits in nerve by IF
  82. 82. PN ASSOCIATED WITH ANTI-MAG IgM Homogeneous clinical and electrophysiological features consistent with a chronic, slowly progressive, predominantly sensory, demyelinating neuropathy p MAG + (42) MAG - (26) Type of PN S or S>M 62% 31% < 0.025 SM 31% 38% n.s. M>S 7% 31% < 0.01 NCS Peroneal Mean MCV 22.9 m/s 39.6 m/s < 0.000001 < 35 m/s 90% 23% < 0.0001 81%/19% 27%/73% < 0.0005 MGUS/WM-NHL Nobile-Orazio et al 1994
  83. 83. 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): 26 (22/4) 25 (96%) 73.3 (58-84) Mean age at PN onset: 61.2 (42-78) Years of follow-up: 8.5 (2-13) Mean years from PN onset : 3.4 (0-10) 11.8 (3-18) Median Rankin score 1 (0-3) 2 (1-5) Walk+support/or unable/tremor 2/0/0 6/1/5 Total disabled (Rankin>2): 2 (8%) 11 (44%) (24%at 10 yrs; 50%at 15 yrs) Patients deceased: 8(32%) 6% at 10,33% at 15 yr)
  84. 84. 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 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
  85. 85. 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%) 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 1 Other therapies 7 1 (14%) ________________________________ Total patients 378 150 (40%)
  86. 86. 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 difference between Ch and Ch+PE • Dalakas et al 1996: IVIg vs placebo x 3 mos; double-blind, cross-over 11 PN+IgM (9 MAG); IVIg effective in 2 IgM (18%) (1 MAG, 11%) • Comi et al 2002: IVIg vs placebo x 1 mos; double-blind, cross-over 22 PN+IgM (11/19 MAG); IVIg slightly better (p=0.05) than placebo • Mariette et al 1997: IFN-a vs IVIg x 12 mos; open 20 PN+MAG; Sensory improvement in 8/10 IFN-a and 1/10 IVIg • Mariette et al 2000: IFN-a vs placebo x 6 mos; double blind 24 PN+MAG; No difference between IFN-a and placebo. • Niermejier et al 2007: Oral CTX+ Prednisone (16) vs Placebo (19) x 6 mos double-blind; 35 PN+IgM (17 MAG); No difference in functional scales (33% better vs 21%); MRC, sensory & DL better at 6 mos.
  87. 87. RITUXIMAB (α-CD20 MAB) IN PN AND ANTI-MAG IgM Renaud et al 2003 Muscle Nerve • 9 pts with PN & anti−ΜAG • Rituximab 375mg/m2/wk x 4 • B cells decreased 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
  88. 88. JPNS 2007, 12:102-7 • 13 patients with PN & anti-MAG IgM-M-protein. • Anti-MAG IgM significantly reduced after 1 year. • 8 patients (62%) improved in INCAT sensory & MRC score and 7 (54%) in disability too. • Improvement in INCAT sensory sumscore correlated with lower anti-MAG titres at entry and at follow-up. Antibody reduction below a critical level may be necessary to achieve clinical improvement
  89. 89. Worsening of neuropathy under Rituximab • 1 patient with WM had acute worsening of pre-existing neuropathy consistent with GBS during therapy with Rituximab and fludarabine (Noronha et al 2006) • 1 patient with NHL in complete remission developed GBS during Rituximab maintenance therapy(Carmona et al 2006) • 1 patient with NHL developed GBS soon after combined CHOP and Rituximab therapy (Terenghi et al 2007) • 3 patients with 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 multiplex with conversion of type I to II cryoglobulin during Rituximab (Mauermann et al 2007)
  90. 90. Ongoing or unpublished trials of Rituximab in anti-MAG PN 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 . 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
  91. 91. 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 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.
  92. 92. EFNS/PNS PDN GUIDELINES Good 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. 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.
  93. 93. Fabrizia Terenghi Department of Gianluca Ardolino Neurological Sciences, Chiara Casellato IRCCS Humanitas Clinical Institute Barbara Bossi Milan University, Francesca Gallia Rozzano, Milan, Claudia Giannotta
  94. 94. Type and mechanisms of neuropathy in plasma cell dyscrasias • Mono-, multi-, cranial neuropathy & radiculopathy (MM, WM, LL, lymphoma) – direct infiltration – nerve/root compression – hyperviscosity – 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)
  95. 95. Mycophenolate Mofetil in Dysimmune Neuropathies: a preliminary study Benedetti et al. Muscle & Nerve 2004; 29:748-749 MMN Pts. treated: 4 Follow-up: 9 mos (6-12) 2 (50%)1* Suspension of IVIg after 4 -> 12 mos: 1 (25%)1* IVIg reduced by 50% after 4 -> 6 mos: IVIg reduced by 25% only for 4 mos: 1 (25%) *Pts. Suspending MM for side effects:2 (50%)
  96. 96. 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)
  97. 97. Results: MTX efficacy in MMN (2) 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 more than 50% 1 patient suspended Ig without worsening The mean maximal Ig reduction obtained without deterioration was 32% (range 0 to 100%)
  98. 98. MTX in MMN: effect on MRC & Ig dose Pt. Time 0 4m -10/15% -20/25% -30/40% -40/50% - 55+% Max eff Last visit MRC(Ig (Igdose)(mos) MTX (5-6 m) (6-7 m) (8-9 m) (10-12m (>12m Red. CP 71 72 72 71 69 nd nd 20% 72 (60g, +10%) (18) (55g) (45g) (40g) CT 66 69 68 63 nd nd nd 10% 66 (120g -10%) (18) (135) (120) (105) NU 97 97 98 99 98 97 95 50% 97 (40g, -50%) (12) (80) (40g) (35g) FA 73 69 nd nd nd nd nd 0 69 (80g =) (4) (80g) (80g) SG 70 70 73 70 69 nd nd 25% 67 (80g =) (11) (80g) (60g) (50g) GM 87 89 88 89 89 92 97 100% 97 (0g -100%) (16) (60g) (0g) (35) (15gr) CR 79 79 85 86 94 84 nd 30% 84 (60g, -25%) (15) (80g) (65g) (55g) (45gr) SA 50 64 60 58 55 nd nd 20% 55 (80g =) (7) (80g) (65g) (65g) MRC 74 76 76 76 76 75 75 76 32% M Ig 81g 60
  99. 99. 5) CIDP: Diagnostic Categories Definite CIDP 1) Clinical Criteria I A or B & II with Electrodiagn. criteria Def. 2) or Probable CIDP + at least 1 Supportive Criterion 3) or Possible CIDP + at least 2 Supportive Criteria Probable CIDP 1) Clinical criteria I A or B & II with Electrodiagn. criteria Prob. 2) or Possible CIDP + at least 1 Supportive Criterion Possible CIDP 1) 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
  100. 100. 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 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)
  101. 101. CORTICOSTEROIDS FOR CIDP Mehndiratta MM & Hughes RAC The Cochrane Library 2002, Issue 4 Reviewers’ conclusion: • A single randomised, controlled trial with 35 partecipants provided weak evidence to 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.
  102. 102. PLASMA EXCHANGE IN CIDP 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 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
  103. 103. IVIg IN CIDP Randomized, 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 d on 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) 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 IVIg vs 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
  104. 104. IVIg IN CIDP Van Schaik et al, Cochrane library, 2002, Issue 2 IVIg is effective for at least 2-6 weeks in CIDP
  105. 105. 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 courses for 8-60 mos • 14/22 patients (64%) improved with IVIg: 50% of responders required repeated courses for 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
  106. 106. IMMUNESUPPRESSIVE THERAPIES IN CIDP • Azathioprine+ Prednisone no better than Prednisone in a RCT. Dose & duration unsuffcient (Dyck et al, 1985); • Cyclosporin A effective 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 mos effective 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 (Branagan et al 2002) • Mycophenolate effective in 6/22 (27%)(Chaudhry et al 2001; Mowzon et al 2001;Umapathi et al 2002;Gorson et al 2004) therapy res/dep α • INF-α 2a effective 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 β−1a 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).
  107. 107. Etanercept (soluble TNF-α receptor) in CIDP Chin 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 • 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
  108. 108. Mycophenolate mofetil in CIDP Gorson 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 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
  109. 109. 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 and safe 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
  110. 110. Italian Register for response to treatment in CIDP patients Cumulative response to IS of NRs DRUG N R Azatioprina 11 6 (54%) Rituximab 8 4 (50%) Cyclophosphamide 6 4 (66%) Methotrexate 4 3 (75%) Mycophenolate 3 2 (66%) 1 1 α-IFN Cyclosporine A 1 0 Cocito et al 2008
  111. 111. Italian Register for response to treatment in CIDP patients Risposta cumulativa a IS DRUG N R SE Azatioprina 65 41 (63%) 8 (12%) 13 3 (23%) 3 (23%) α-IFN Rituximab 11 6 (54%) 0 8 5 (62%) 2 (25%) Cyclophosph. Cyclosporine A 8 4 (50%) 4 (50%) Methotrexate 6 3 (50%) 2 (33%) Mycophenolate 6 4 (66%) 0 Cocito et al 2008
  112. 112. Distinguishing features between CIDP and MMN Features CIDP MMN Distribution Symmetric Asymmetric (MN) Arms >legs no Yes (80%) Sensory loss yes no Gen. Areflexia yes no Reduced CV no yes Reduced SNAP no yes ↑ CSF proteins Rare (1/3) yes ↑ GM1 IgM yes (30-40%) no S. Nerve biopsy Often normal demyelination Steroid effective No (1/10) yes (2/3) IVIg effective yes (4/5) yes (2/3) Modified from Van den Berg-Vos et al Neurology 2000;
  113. 113. Electrodiagnostic Criteria in MMN 1. Definite motor CB: proximal vs distal neg. CMAP area reduction > 50% whatever the nerve segment length. Negative distal CMAP amp. must be >20% of lower NL & > 1 mV & increase of proximal CMAP duration (temporal dispersion: TD) ≤ 30%. 2. Probable motor CB: negative CMAP area reduction of > 30% over a long segment of an UL nerve with TD ≤ 30%; OR negative CMAP area reduction of > 50% with TD > 30%. 3. Normal sensory nerve conduction in upper limb segments with CB and normal SNAP amplitudes.
  114. 114. IVIg IN MMN Randomized 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, crossover trial; 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
  115. 115. Mean MRC score in 10 MMN patients under chronic IVIg therapy Terenghi et al, Neurology 2004
  116. 116. Brain 2002; 125: 1875-86
  117. 117. Patient 3 (NU) 100 100 MTX x 13 mos 96 7.5 mg 15 mg 92 88 84 80 76 * 72 68 -12% 64 60 56 -25% 52 90 48 -37.5% 44 40 36 -50% -50% 32 -55% 28 24 20 16 IVIg 12 MRC 8 4 0 80 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
  118. 118. 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%)
  119. 119. EFFECTS OF CYTOSTATIC-IMMUNE THERAPIES IN PN & ANTI-MAG IgM Pts. treated for >6 mos: 19 (15) (for the PN) Mean yrs of therapy: 4 (0.5-11) Patients improved: 9 (47%) Patients with therapy- 10 (53%) related complications: 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
  120. 120. Terenghi et al, JPNS 2007

×