Treatment options and Treatment optimizationBCL me mere demyelinating polyneuropathy “When” the treatment should be initiated? * Patients with very mild symptoms that do not or only slightly interfere with activities of daily living may be monitored without treatment. * Wait and see !! * Sensory CIDP * Mild motor disability : INCAT 0 or 1 Spontaneous remission about 10%INCAT Disability Scale INCAT, inflammatory neuropathy cause and treatment ‘No upper limb problems Symp not aectng ably to perform: dong allppers and buttons, washing or Brushing hale ing ke and fork together handling smallcoins Symptoms affecting But not preventing functions sted above ‘Symptoms preventing 1 or 2 functions listed above ‘Symptoms preventing 3 oF ail functions listed above, but some purposeful movements still possible inability to use either arm for any purposeful movement Walking not affected Walking affected, but walks independently outdoors Usually uses unilateral support (stick, single crutch, 1 arm) to walk outdoors Usually uses bilateral support (sticks, crutches, frame, 2 arms) to walk outdoors Usually uses wheelchair to travel outdoors, but able to stand and walk few steps Restricted to wheelchaig unable to stand and walk few steps with help SyObjective clinical severity measuring Bedside mae * INCAT disability score _graded 0 (no movement) to 5 (normal * MRC sum score 3 arm and 3 leg muscles on both body sides 0 60 ee ‘ (paralysis strength, » + Deltoid (shoulder abduction) _- ‘Iliopsoas (hip flexion) * Biceps (elbow flexion) * Quadriceps femoris (knee extension) + Wrist extensor * Tibialis anterior (ankle dorsiflexion)Objective clinical severity measuring * Bedside * INCAT disability score * MRC sum score * Grip strength -> Jamar Dynamometer * Vibration sensation -> Rydel-Seiffer tuning forkBI mem CLT Lele, demyelinating polyneuropathy “What” the treatment should be initiated? Proven efficacy * Corticosteroid * Intravenous immunoglobulin * Plasma exchange b Unproven efficacy + Azathioprine, mycophenolate mofetil, cyclophosphamide, methotrexate, ciclosporin, Tacrolimus + Interferon-alpha, beta, Rituximab, Etanercept, Alemtuzumab year tal 207 2966 2 Vn be Pgh Pr 8 204-8 Sota ical oanatite scone her sionaseieoe SansoneClinical trials and reports of CIDP treatment Response rate * Prednisolone 86 % * Intravenous immunoglobulin 54 - 100% * Plasma exchange 33-80% b Muscle & Nerve 2009;39:563-78Corticosteroid "Uncertain whether daily oral prednisone improved weakness _ and sensation compared to no treatment (Cochrane 2017) * Oral prednisolone + 60-80 mg/kg/day * Improvement can be anticipated to start within 2 months but may not be evident until 3 — 5 months (Van Schaik 2010) > Dose is too low or Treatment is too short eg. Prednisolone 20 mg/day for 6 months Prednisolone 60 mg/day for 2 weeksCorticosteroid Uncertain whether daily oral prednisone improved weakness * Oral prednisolone and sensation compared to no treatment (Cochrane 2017) + 60-80 mg/kg/day * Improvement can be anticipated to start within 2 months but may not be evident until 3-5 months (Van Schaik 2010) > Dose is too low or Treatment is too short eg. Prednisolone 20 mg/day for 6 months Prednisolone 60 mg/day for 2 weeks Use the “proper dose” for the “proper duration” and “assess for objective change”Corticosteroid Prednisolone Pulse oral dexamethasone Pulse intravenous methylprednisolone * No differences between treatment modalities in terms of efficacy and safetyCorticosteroid * Pulse IV methylprednisolone - 1000 mg 3-5 days, followed by 1000 mg weekly (tapered over a period of 2 months to 2 years) - 500 mg 4 days monthly for 6 months (Nobile-Orazio E 2010) * weight gain and cushingoid features are less than oral prednisolone (Lopate 2005, Muley 2008) * Pulse oral dexamethasone - 40 mg/day for 4 days, repeated every 4 weeks for 24 weeks * Similar side effect as oral prednisolone * But the patient improved twice as fast ( PREDICT study 2010)Corticosteroid — The Down side Short. Term AE Long-Term AE + weight gain + osteoporosis + Coumati side effect + Aseptic necrosis + Hypertension + Gi bleeding + Highblood sugar + Susceptibility to infection + Gastritis + Glaucoma * Insomnia + cataract + Mood lability “Tremor + Easy bruisingCorticosteraid — Pure motor CIDP Pure motor CIDP * Severe weakness with proximal involved as much as distal one * Slight asymmetrical * EMG : clear cut motor conduction block with normal distal CMAP amplitude + Negative GM1 IgM antibody A pure motor CIDP patient deteriorated dramatically after dexamethasone and intravenous immunoglobulin -> but improved after IVIg __ (D S Molenaar 1997) A four patient in the study were steroid unresponsive, whereas improved after being treated with Vig (Sabatelli M 2001)Corticosteroid ise tm Colm cal cllela) * Corticosteroids lead to improvement in 60% of patients and to remission in 61% of treatment responders (van Lieverloo GGA 2018) ° * However, when effective, steroid were more likely to induce remission (at 6 months) and less frequently associated with deterioration after therapy discontinuation than IVIG (Nobile-Orazio 2012)Intravenous immunoglobulin “VIG as a first choice of treatment” Wiciocurchoaieaue uence cua [7] [contraindication for coricosterois | Pure motor phenotype Mm J Neurol, 2018 Sep;265(9):2052-2059Intravenous immunoglobulin van Doorn PA 1990 + High-dose intravenous immunoglobulin treatment in chronic inflammatory demyelinating polyneuropathy: a double-blind, placebo-controlled, crossover study. Vermeulen M 1993 + Intravenous immunoglobulin treatment in patients with chronic inflammatory demyelinating polyneuropathy: a double blind, placebo controlled study. Hahn AF 1996 + Intravenous immunoglobulin treatment (IVIg) in chronic inflammatory demyelinating polyneuropathy (CIDP): a double-blind placebo-controlled cross-over study. Mendell JR 2001 *+ Randomized controlled trial of IVig in untreated chronic inflammatory demyelinating, polyradiculoneuropathy.Intravenous immunoglobulin Hughes RA 2008 * Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomized placebo-controlled trial. * Largest (117 patients) and longest (up to 48 weeks) IVIG trial in CIDPIntravenous immunoglobulin * ICE study GAMUNEX-C (10%) * Loading dose (at week 0) *+ 2.g/kg (20 ml/kg) over 2-4 days(up to 80 g/day) * Maintenance dose (every 3 weeks) * 1. g/kg (10 ml/kg) over 1-2 days (up to 80 g) + Improvement of disability, grip strength, MRC sum score and health-related quality of life * > 87% of patients given maintenance dose every 3 weeks did not relapse during the extension phaseICE Study: Important and Sustained Improvements Efficacy Period ‘Maintenance Period e- GAMUNEX-C ro 09 os as Change From Baseline in Adjusted INCAT Score 20 0 4 8 2 we 20 mM mw 2 3 0 mH OB Week ‘Among responders, maximal improvement achieved by weeks 12-24 and maintained through week 48 Latov N, et al. Agch Neurol. 2010;67(7):802-807.INCAT Disability Scale INCAT, inflammatory neuropathy cause and treatment © | Nopper imb problems © Walking not affected 1 Symptoms not aiecting abiity to 1 (Wateng afeces, but wats perform: doing al zipers and independently outdoors buttons, washing or brushing hal, using kil and fork togete handling small coins 2 symptoms affecting but not 2 preventing functions sted above (stick, single crutch, 1 arm) to walk outdoors 3 Symptoms preventing Tor? "3 Uwally uses blatenl suppor (atic, functions listed above crutehes, frame, 2 arms) to walk outdoors 4 Symptoms preventing 3 or all 4 3 r functions listed above, but some outdoors, but able to stand and walk purposeful movements stil possible few steps 5 inability to use either am for 5S Resticted to wheeichaig unabie to any purposeful movement stand and walk few steps with help SIRs EnerTiming and Course of Clinical response to IVIg in CIDP (Data extracted from the ICE trial) Arch Neurol 2010;67:802-7tuwamariiunstte intravenous human normal immunoglobulin, Fousl¥ Tan Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP)avamadaiunrsttion ir Gani 1 intravenous humar care n normal immunogl mmatory Demyelinating menace cca IDP) = ——_——— i ] — a cts cc ne ES a savclud ‘an Wtuendhurin 1 ou un ‘2 Werte 3 ou wet a3 duatrahusTquuntusey 6 Jauftuennngit INCAT Score > 6 INCAT Score 2 2 sade 3 vio 4 wrnnatt coticosteroid wie CorticosteroidIntravenous immunoglobulin How to taper IVIG * No protocols from clinical trials * Option 1 Lengthen the interval between infusion * Option 2 Reduce the dose for each subsequent infusion (maintain the 3 week interval) * Option 3 Just stop after pre-specified interval o stability ( ?? 3 months)When to stop IVIG - No “cycling” relapse before next infusion Unequivocal improvement, stable over multiple infusionContraindications and Precautions fim... Warnings and Precautions * Individuals with acute hypersensitivity eee ee tren ineeuneobin * aot nme red ty pt + gAideficient patients with antibodies + Renal fare ‘gaint IgA and a history of ealtincon swine tt sh be entre pay pen Iypersenstity + Hyperpoteineraa, increased serum viscosity and hyponatremia + Ascptic meningitis syndrome + Hemolsis: "anspor tnenss we eet et utr apenas «anno egy “ie ~SS Stine ec pn ee me a sae + ten in * tube tnt ere ‘stool etl rsh, wih te pote er mclendingmcerpreaiICE Study: Most Frequently Reported Drug-Related Adverse Events ‘any. 62(55), a7 16(17) 43 Headache 3127) 40 616) 12 Pyrexia 35(3) 2a ° o chile a0) om 0 o Hypertension 716) 15 30) os, Rash 6s) 07 30) 02 Nausea 605) 06 30) 05, ‘asthenia 605) as 0 ° Latov N, et al, Arch Neurol. 2010;67(7):802-807.ICE Study: Safety and Adverse Event Profile Most common dusted eadache, fv chil hypertension, (25% incidence) ‘rash, nausea, and asthveniat Mos serious Pn patient ith istry of PE who rectved GAMUNEXC: associated wih event 301113 GAMUNEXC patients: nonein eterson ce aCe phase* 2 of 95 placebo patients! Latov N, et al. Arch Neurol, 2010;67(7):802-807..Subcutaneous immunoglobulin (SClg) * IgG peak/trough levels that occur with intravenous administration can be avoided by administration of SClg * Administration represents a therapeutic alternative for patients who suffer wear-off phenomena with cyclic deterioration at an interval following an Miginfusion. PATH study -> SClg is efficacious and well tolerated in CIDP The Danish CIDP study group -> SClg = IVig Eur J Neurol 2017;24:412-8. Lancet Neurol 2018;17:35-46,Plasma exchange * Three exchanges of 50 ml/kg weekly for the first 2 weeks, followed by or two exchanges per week from the third through the sixth week * Three controlled studies have confirmed the benefit of therapeutic plasma exchange for CIDP of both chronic progressive and relapsing course °How to deal with treatment non-responder * Misdiagnosed cases of CIDP are reported in 15-89% of patients * Better when diagnosis was made with the use of CIDP diagnostic criteriaTreatment of chronic inflammatory demyelinating polyneuropathy How to deal with treatment non-responder * CIDP mimics * Diabetic neuropathy with demyelination = POEMS syndrome + Nodal-paranodal neuroapathies + Inherited demyelinating neuroapthies (CMT1A, CMTX®) * Poorly performed or misinterpretation EMG studiesTreatment of chronic inflammatory demyelinating polyneuropathy How to deal with treatment non-responder If still be CIDP * 67% of IVig non-responders get improved with plasma exchange 59% of IVig non-responders get improved with corticosteroid * 75% of first two treatment non-responder get improved with the 3 treatment Bunschoten C 2019Alternative forms of immunosuppressive treatment * Limited for those who are refractory or contraindicate to corticosteroid, IVig and Plasma exchange ! None of the alternative agents have proven efficacy in controlled trialsAlternative forms of immunosuppressive treatment * Azathioprine 2-3 mg/kg/day * Mycophenolate mofetil 1000 mg bid * Intravenous cyclophosphamide 1 g/m2 monthly for 2-6 months * Rituximab 375 mg/m2 each week for 4 weeksTreatment of chronic inflammatory demyelinating polyneuropathy CIDP tends to be associated with prolonged neurological disability and is less likely to have spontaneous remission * About 50% of patient are severely disabled * 10% of patients remain disabled in spite of treatment (axonal loss correlated with poorer outcome ; Bouchard 1999) * Despite the initial responsiveness, only 40% of patient remained in partial or complete remission without receiving any medication oOSupportive and symptomatic treatment * Advice about foot care, exercise, diet, driving and life style management * Neuropathic pain should be treated * Physiotherapy, Occupational therapy, Orthoses, Psychological * Depending on the needs of the patient* Journal of Neurology (2019) 266:461-467Individualized immunoglobulin protocol Intiaton Wg 2 pg of OW oe * it detenoration blared weeks ‘couse Wie whe OW = Mig REsPonsive IMgReeRAcTORY Further courses of 247g DW every 4 wees, Lngtded unt! complete /near complete provement or Bateau Suspend Mg treatment to determine dosing interval even ‘Aéminster one sabiang course at? g/g of OW on deterioration Re-treat a the estabished dosing interval Rece Mig dose by 15-258 at each review every 2-3 courses) nti owesigctine dase teaced Remislon and wean of Mg Lite Deterioration Restabiled at higher doe (25.25%) Reaterpt wean of Vg yearly Journal of Neurology (2019) 266:461—467.‘Number of patients os 10 20 3 4 §& 6 7 8 9 10 Frequency of immunoglobulin dosing interval in inflammatory neuropathy patients following treatment optimization. Journal of the Peripheral Nervous System 21:33-37 (2016)Table3 Mean savings achieved during IVIg weatment in 29 paticats using standard dosing at 1 pkg every 3 weeks using dosing weight ‘with CIDP on log term treatment wsing an ouicome-measured reat and recoded weight ‘ment protocol with cuts defining response vs. hypothetical costs ‘Mean Vig Mean Vig Rounded Num- Rounded Num- Mean IVIg dose saved in / dose saved inp/ ber of avoided her of woided Drug Costs faticuweck putienlyear infusions sex-—lafushoadays/saved/patical slonvyear year yer Gar © ‘Savings a 9 6 1 ‘72 (€6753)‘oma aTCLE aoe Dramatic clinical response to ultra-high dose IVig in otherwise treatment resistant inflammatory neuropathies ime Kapocr* Mary Mii Hu Mp Michel PL Asing Sad Car =a mm Dane Dr rons oe, a Sut ata ae (i etond nga @ ecy ashen De Laon rpm hears ne Same ona ew tenn Ue 0 oH ar Tae aan Fa ao ‘Dae OOF Tene bee cP ee oan ‘base owl ont s > o . ° = etome Ate Grae Orne fee Coe rie oven meer: wees Peal and Sok'p a cr saan GEM cmt ominous MU BSC Pa EE tga eo) yet ope ‘on eeu Copenh Sgtgmont Segment Cart ‘wou Seromenmaypinh Let masa Teer montane "macnn 43949 Sau Seinen \gnwmoe ireland pabey me Satie eaten ute re sate 7 ae m suite wes * 6 @ o » « ae own % o 6 Mesmgcou Se 3 ‘= 2 i 3 to EA It rapes stan PC paraphenny Ween CC cranes GR qcipenpn, AA aap DU bu wanton MH mean OC apres RET map BrAL that influences Thi7 and Treg —§ Cytokines e@- e@ a Antibodies (via Tht/Th2) Ny aon alll tes 1.17, BAFF 3° IgG-AcnR. ot > a Dalakas MC. Curr Opin Neurol 2020Pharmacokinetics of IVIG Click to add textof serum immunoglobulin GBS patients Proportion of patients who walk unaided iti fed preteaiment weeks — 4weeks — 3months — Smanths (N=174)—(=t74)— (M=ot) (M86) (NEB) 2 Kuitwaard K. Ann Neuro! 2009RESEARCH REPORT Efficacy and safety of Privigen® in patients with chronic inflammatory demyelinating polyneuropathy: results of a prospective, single-arm, open-label Phase Ill study (the PRIMA study) Induction dose (2 g/kg bw) over 2-5 days Responder rate (%) eos88S S838 88 —Allpatients —MG-naive - Maintenance 1 g/kg bw at 3-week —— MG pretreated intervals ; up to seven infusions | 14 (63.6%)of 22 patients were responders 1 4 7 wo 13 16 9 22 3 Study time frame (Week) Adpatients 0/28 9/19 4/14 16/12 16/12 16/12 18/10 18/10 18/10(27/11) ‘Monave 0/715 2/13 6/9 8 6/9 6/9 6/9B/T BT BT (7/8) Le’ger JM. JPNS 2013. MG-pretreated 0/13 7/6 8/5 10/3 10/3 10/3 10/3 10/3 :10/3 ESLSerum IgG concentration — wG =~ Average daily IgG level with IVIG — sag WEEK — IMIG loading + SCG maintenance — Loading with sig [Gi Higher risk zone between two IVIG infusionsSubcutaneous immunoglobulin for maintenance treatment in chronic inflammatory demyelinating polyneuropathy Subcutaneous dose (PATH): a randomised, double-blind, placebo-controlled, en reas Od phase 3 trial Ino van Shai, Vero rl, Non van Geloven, Hans-Peter Hartung Richard A Lewis, Gn Sabu, ohn Philip Bille Dum Dovid Comblath, Ingemar Meds, on behalf ofthe PATH study group” £084 vigh-dose placebo Ht 038 (9561022-067; 04005 t f °*| (ercucisesonacmest reer Veo 2 06 5 Sos Less headache, nausea, 5 and hemolytic anemia = 02 PyHuwonswpwhwhhgas Tine (vets) Number at ik (oumber cerned) Mghdnwescly 58) 510) OBO) OGD) Lowaesescly 570) $010) 7} 60) Placebo 57(0) 42(0) 31(0) 24(0) 210) oanThe importance of FcRn in neuro- immunotherapies: From IgG catabolism, FCGRT gene polymorphisms, IVIg dosing and efficiency to specific FcRn inhibitors Wily i Senna isinane Procyon fa se ! ‘ eS Maturation 4% BW (Gf neonatal Fe receptor (FeRn) in protecting IgG from degradation Call surface (pH7-4) /FeRn inhibitors to reduce | pathogenic IgG antibodies cell surtace (pH 7.4) a Endosome ) ences 7 ae jest ty Maturation and sorting Lysosome at low pH (want ¥ Dalakas MC. Ther Adv Neurol Disord 2021VNTR2/VNTR3 genotype in the FCGRT gene is associated with reduced effectiveness of intravenous immunoglobulin in patients with myasthenia gravis 5 s = z 5 8 2 5 8 ° 2 © 3 o £ 2 © o ° © 9 ° oO fod | VNTR2/3 genotypes reduce effectiveness of IgG therapy VNTR3/3_ VNTR2/3. Su S. Ther Adv Neurol Disord 2021ay nfusion rate calculations in mL (cc) per hour es Infusion Rate wo) fw | of) | wm fo ) wo | wm ] to | mbfkghmin imblkg/h 2 44 6 88 110 132, 154 176 198 20 202 264 0.005 03 3 6 9 w 15 18 a 24 Eu 30 33 3% 010 06 e[u2l]elu i» | «| else | s« | «| « | 2 0's 8 o> |» [| # > [|e [= [= | «| «|e om 2 vfw | «| #« | « | na |» | % | we | mw | om | iw os 5 [a (0030 18 18 36 Ey n 90 108 126 144 162 180 198 26 | 0035 nu aH a a u 105 16 17 | 168 Teo io Bi m) 0.040 24 um 8 n % 120 144 168 192 216 7240 264 22 | 08 2 a [oe [aoe [se |e ae [eae 0050 30 30 0 90 vo | 150 | 10 | 20 | 20 | 270 300 330 360 | 6 3B Ea 6 36 % [| 2 | 1 | 1 | to | ve | 2 | mm | ae | 90 | 6 | an ra 2 = [oe [ow [sae [en an) eae 007 e @ [ow | we | we | mw | | om | se | me | ao | a | sot os 5 6 |» [15 | | as | am | as | oo | as | eof as | se 0.080 48 48 6 14 i | |e 336 384 82 480 528 576 ‘Treating patients at risk of thrombosis, renal dysfunction, ‘or renal failure ‘Adrinister Prvigen at the minimum dose {and infusion rate practicable,