Le neuropatie disimmuni e la realtà dei trattamenti

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1 Simposio satellite INTEGRATED SYSTEM IN TUSCANY FOR APPROACHING NEUROMUSCOLAR TREATMENT LE RAGIONI DI UN PROGETTO Le neuropatie disimmuni e la realtà dei trattamenti Fabio Giannini Dipartimento Scienze Mediche, Chirurgiche e Neuroscienze Università di Siena

2 Heterogeneous spectrum of conditions with evidence of inflammation originated from autoimmunity (when immunologic tolerance to antigenic targets on myelin or axonal membrane of peripheral nerves is lost) Both humoral and cellular immunity directed against peripheral axons and myelin Molecular mimicry may be triggered at the systemic level (bacterial oligosaccharides for GBS and CJ) Significant associations with specific neuropathic syndromes: Miller-Fisher Syndrome with anti-gq1b, Multifocal Motor Neuropathy with IgM anti-gm1, and Distal Acquired Demyelinating Symmetric neuropathy with anti-mag antibodies The classification of immune neuropathy has been expanded to take into account other specific syndromes that share clinical, electrophysiological, prognostic and serological features

3 Vasculitic neuropathy Polineuropathies in rheumatic diseases Paraproteinemic neuropathies (Bourque, 015)

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5 Peripheral neuropathy is frequently seen in patients with rheumatic disease, but extensive epidemiological data are lacking The causal link between peripheral neuropathy and rheumatic disease mainly includes compression by joint deformation or swelling, vasculitis or drug toxicity The relationship between the two disorders is incompletely understood in many situations (RA, SLES, Sjögren s syndrome) Nerve and/or muscle biopsy might be necessary; Skin biopsy (IENFD) can be helpful to confirm the diagnosis of small-fibre neuropathy

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10 The efficacy of IVIg in IIM is supported by randomized controlled trials, involving DM and PM subjects, in refractory, relapsed, or steroid-dependent disease, as well as part of first-line therapy in elderly dermatomyositis subjects. Other indications for IVIg are supported by uncontrolled evidence only Despite the limited evidence, there is strong biological plausibility for the role of IVIg in IIM (016)

11 SCIg has become a relevant treatment option in autoimmune diseases, including inflammatory myopathies The use of high-dose SCIg is feasible, beneficial and safe in patients with long-standing inflammatory myopathies Patients refractory to steroids or immunosuppressants and receiving SCIg are likely to show improvement in muscle strength and disability at long-term follow-up The use of SCIg reduces the risk of systemic adverse reactions and the cost linked to IVIg treatment

12 Paraproteins are immunoglobulins that are produced in excess by an abnormal clonal proliferation of B- lymphocytes or plasma cells (from subclinical MGUS to malignancies such as MM or WM) These monoclonal proteins exist as heavy chain subtypes (IgG, IgA, IgG, less commonly IgD or IgE) and light chain subtypes (kappa or lambda) 1 % of the general population and rises with age Up to 5. % among individuals over 70 years and up to 10 % in people older than 80 years The prevalence of paraproteinemia in cryptogenic neuropathy is 10 % IgM gammopathy: 48 % (one half reacts with the CD57/HNK-1 carbohydrate, epitope found on Myelin-Associated Glycoprotein anti-mag antibodies) IgG gammopathy : 7 % IgA gammopathy : 15 %

13 IgM paraprotein have been found in sural nerves of patient myelin in a similar distribution to MAG (Takatsu 1985) The binding has been associated with the deposition of activated complement components (Hays 1988; Monaco 1990). Demyelination has also been induced in animal models by transfer of anti-mag Ab (Tatum 199; Willison 1988) Figure 1 Anti-MAG neuropathy with IgM/K Electron Microscopy of sural nerve specimen, showing widely spaced myelin involving central lamellae (Bar = 0.5 lm). Rajabally, 011

14 Phenotype associated with anti-mag antibodies is usually relatively homogeneous: predominantly distal chronic (duration over 6 months) slowly progressive symmetric predominantly sensory impairment relatively mild or no weakness variable degree of ataxia often tremor sometimes painful neurophysiology of demyelination (more slowing of conduction in the distal than the proximal nerve segments) EFNS/PNS Guideline, 010

15 EFNS/PNS Guideline, 010 meet the definite electrophysiological criteria for CIDP (EFNS/PNS, 010) additional specific electrophysiological features in one or more nerves

16 1. ms S MEDIAN - Abd-BrevePollice 5 Polso ms 5mV 49mA 4.7 m/s Gomi to.1 50ms 5mV 49mA 6.6 ms D ULNAR - Abd-V Dito m/s Polso 1 50ms 5mV 54mA Sottogomito 50ms 5mV 100mA Ascella.1 50ms 5mV 100mA Sopragomito 50ms 5mV 100mA Ascella4 50ms 5mV 100mA S COMM PERONEAL - Est-Breve-Dita D TIBIAL (KNEE) - Adduttore Alluce 18. ms m/s Caviglia 1 100ms mv 100mA Sottocapitello 100ms mv 71mA.4 ms m/s Caviglia 1 100ms 1mV 57mA 5 Cavo poplite 100ms 1mV 100mA D SURAL S RADIAL 1 Tendine della 0ms Sura 1µV 1 56 Avambraccio I di to 1 0ms 1µV ms 1µV m/s 1.0 m/s

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18 (Rison, 016)

19 Treatment strategies in Anti-MAG neuropathy: to reduce the IgM paraprotein concentration, by removing the antibody or targeting the monoclonal B-cell clone and reducing its production to interfere with the presumed effector mechanisms such as complement activation or macrophage recruitment Fig. 1 Variazioni di IgM a 6 (T6) e 1 (T1) mesi di follow-up rispetto al basale (T0). Fig. Variazioni dei Linfociti B in valore assoluto a 6 (T6) e 1 (T1) mesi di follow up rispetto al basale (T0).

20 In meta-analysis there is low-quality evidence (two small studies), that rituximab is of benefit in stabilizing or improving anti-mag neuropathy

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22 IgG and IgA paraproteinaemic neuropathy are either demyelinating or axonal/mixed Slowly progressive distal axonal polyneuropathy tend to show a poor response Sensorimotor demyelinating neuropathy frequently respond to immunotherapy The RCT revealed a modest benefit of plasma exchange in the weakness component of the NDS: the mean improvement with PE was 17 points vs. 1 point in the sham group at weeks Observational or open trials provide limited support for the use of treatments such as plasma exchange, cyclophosphamide combined with intravenous immunoglobulin, and corticosteroids

23 Conclusioni (I)

24 Conclusioni (II)

25 Conclusioni (III) LIMITAZIONI ALLE EVIDENZE : Molti studi basati su pochi casi (rarità delle malattie, assenza di dati epidemiologici) Spesso evidenze su singoli pazienti Pochissimi RCT Durata degli studi spesso inadeguata per patologie croniche Misure di outcome spesso inappropriate Casistiche non omogenee, quindi non confrontabili a causa di difficoltà diagnostiche (spesso mancanza di criteri validati), eterogeneità patogenetica e clinica (criteri per definire l attività) DIFFICOLTA OPERATIVE-GESTIONALI: Ruolo diagnostico e di valutazione di outcome del neurologo Necessaria multidisciplinarietà e condivisione decisioni terapeutiche fra specialisti diversi Sovrapposizione competenze specialistiche ( chi fa cosa e quando ) Problemi di prescrivibilità per la gran parte dei farmaci off-label Differenti protocolli terapeutici per medesimi farmaci nelle diverse branche specialistiche (es. Rituximab nella pratica reumatologica o neurologica/ematologica), diversa posologia nell utilizzo cronico delle IVIg