Specialist Working Group for Neurology Proposed changes to the Criteria for the clinical use of intravenous immunoglobulin in Australia, Second Edition ITEM CRITERIA FOR THE CLINICAL USE OF INTRAVENOUS IMMUNOGLOBULIN IN AUSTRALIA, SECOND EDITION (CRITERIA) PROPOSED REVISIONS TO THE CRITERIA (INCLUDING ADAPTATION TO THE IG SYSTEM) SWG RATIONALE FOR PROPOSED CHANGE Condition Name Guillain–Barré Syndrome (GBS) Guillain–Barré Syndrome (GBS), including variants Addition: the inclusion of variants in the title. Variants were already included within the condition. Specialty Neurology Neurology Chapter 5 5 Specific Conditions GBS GBS GBS variants GBS variants Level of Evidence Clear evidence of benefit (Category 1). Clear evidence of benefit (Category 1). Justification for Evidence Category One systematic review of nine RCTs of moderate quality found IVIg hastened recovery in adults with GBS to the same degree as plasma exchange (Biotext 2004). One systematic review of nine randomised controlled trial (RCTs) of moderate quality found intravenous immunoglobulin (IVIg) hastened recovery in adults with GBS to the same degree as plasma exchange (Biotext 2004). This conclusion was confirmed in a 2014 Cochrane review. In severe disease, IVIg started within two weeks One low-quality RCT with a small sample from onset hastens recovery as much as plasma size (n=21), in which the randomisation of exchange. Three studies, including a total of 75 children, patients to the IVIg treatment group was suggested that IVIg significantly hastens recovery skewed, was identified. Children who compared with supportive care. One low-quality RCT received IVIg treatment showed earlier with 21 mildly affected children showed ealier signs of signs of improvement, and disability This section has been updated ITEM Description and Diagnostic Criteria CRITERIA FOR THE CLINICAL USE OF INTRAVENOUS IMMUNOGLOBULIN IN AUSTRALIA, SECOND EDITION (CRITERIA) PROPOSED REVISIONS TO THE CRITERIA (INCLUDING ADAPTATION TO THE IG SYSTEM) scores were lower at four weeks than the placebo group (Frommer and Madronio 2006). improvement and lower disability grades after four weeks with IVIg than supportive treatment alone. (Frommer and Madronio 2006). GBS is the commonest cause of acute flaccid paralysis in the West. The syndrome typically presents with rapidly progressive, relatively symmetrical ascending limb weakness consistent with a polyradiculoneuropathy and often with associated cranial nerve involvement. GBS is the commonest cause of acute flaccid paralysis in the West. The syndrome typically presents with rapidly progressive, relatively symmetrical ascending limb weakness consistent with a polyradiculoneuropathy and often with associated cranial nerve involvement. Motor signs and symptoms usually predominate over sensory signs and symptoms. Loss of tendon reflexes occurs in most cases. Major complications include respiratory failure and autonomic dysfunction. The disease is monophasic, reaching its nadir usually within two weeks, although arbitrary definition accepts a limit of four weeks. A plateau phase of variable duration follows the nadir before gradual recovery. Although recovery is generally good or complete in the majority of patients, persistent disability has been reported to occur in about 20% and death in 4 to 15% of patients. National Blood Authority SWG RATIONALE FOR PROPOSED CHANGE Motor signs and symptoms usually predominate over sensory signs and symptoms. Loss of tendon reflexes occurs in most cases. Major complications include respiratory failure and autonomic dysfunction. The disease is monophasic, reaching its nadir usually within two weeks, although arbitrary definition accepts a limit of four weeks. A plateau phase of variable duration follows the nadir before gradual recovery. Although recovery is generally good or complete in the majority of patients, persistent disability has been reported to occur in about 20% and death in 4 to 15% of patients. IVIg has been shown to have the same efficacy as plasma exchange. The choice is based on availability, practicality, convenience, cost, and ease or safety of administration (Asia–Pacific IVIg Advisory Group). pg. 2 ITEM CRITERIA FOR THE CLINICAL USE OF INTRAVENOUS IMMUNOGLOBULIN IN AUSTRALIA, SECOND EDITION (CRITERIA) PROPOSED REVISIONS TO THE CRITERIA (INCLUDING ADAPTATION TO THE IG SYSTEM) IVIg has been shown to have the same efficacy as plasma exchange. The choice is based on availability, practicality, convenience, cost, and ease or safety of administration (Asia–Pacific IVIg Advisory Group). Investigations There is no biological marker for GBS. It is diagnosed by clinical recognition of rapidly evolving paralysis with areflexia. Investigations include the following: Investigations There is no biological marker for GBS. It is diagnosed by clinical recognition of rapidly evolving paralysis with areflexia. Investigations include the following: SWG RATIONALE FOR PROPOSED CHANGE Cerebrospinal fluid (CSF) protein elevation, although the level may be normal in the first two weeks of illness. The CSF white cell count may rise transiently, but a sustained pleocytosis suggests an alternative diagnosis or association with an underlying illness (e.g. HIV). Cerebrospinal fluid (CSF) protein elevation, although the level may be normal in the first two weeks of illness. The CSF white cell count may rise transiently, but a sustained pleocytosis suggests an alternative diagnosis or association with an underlying illness (e.g. HIV). Electrophysiological studies may show changes after the first or second week of the illness, including conduction block, conduction slowing or abnormalities in F waves. Electrophysiological studies may show changes after the first or second week of the illness, including conduction block, conduction slowing or abnormalities in F waves. Diagnosis is required Yes National Blood Authority By which specialty General physician or Yes By which specialty Neurologist SWG has recommended that diagnosis is limited to neurologists, if Ig is to be used. This is already pg. 3 ITEM CRITERIA FOR THE CLINICAL USE OF INTRAVENOUS IMMUNOGLOBULIN IN AUSTRALIA, SECOND EDITION (CRITERIA) PROPOSED REVISIONS TO THE CRITERIA (INCLUDING ADAPTATION TO THE IG SYSTEM) Neurologist By which specialty Neurologist (if neurologist did not make original diagnosis) SWG RATIONALE FOR PROPOSED CHANGE required for the second dose, and is now extended to all eligible patients because of the requirement for assessment against formal neurological scoring methods. Diagnosis must be verified Yes No By which specialty Exclusion Criteria - - No exclusion criteria required. Indications GBS and its variants with significant disability and progression Initial therapy for GBS with significant disability and progression. The addition of a second indication is required as there is a requirement in the original Criteria for mandatory assessment by a neurologist if a second dose is required, (noting that a second dose is not continuing treatment but has been created as a new authorisation). Data will be collected on response to initial dose. Relapse in GBS treatment-related fluctuation with initial improvement and subsequent deterioration post IVIg treatment (neurologist review required). Qualifying Criteria Patients with GBS (or variant) with significant disability and disease progression National Blood Authority Initial therapy for GBS with significant disability and progression. SWG agreed that the GBS Disability Score be used to assess elibility all patients except some GBS variants with bulbar or autonomic features rather than motor weakness. The GBS Disability Score has pg. 4 ITEM CRITERIA FOR THE CLINICAL USE OF INTRAVENOUS IMMUNOGLOBULIN IN AUSTRALIA, SECOND EDITION (CRITERIA) PROPOSED REVISIONS TO THE CRITERIA (INCLUDING ADAPTATION TO THE IG SYSTEM) SWG RATIONALE FOR PROPOSED CHANGE Assessment by a neurologist is recommended. But not mandatory. [Group 1] been updated since the last version. Disability Grade 0 - A healthy state Patient with GBS demonstrates significant disability as objectively measured by the GBS Disability Score of greater than one point (adapted from Hughes et al 1978). 1 – Minor symptoms or signs of neuropathy but capable of manual work 0 - A healthy state 1 – Minor symptoms and capable of running 2 – Able to walk without the support of a stick but incapable of manual work 2 – Able to walk 10 metres or more without assistance but unable to run 3 – Able to walk 10 metres across an open space with help 3 – Able to walk with a stick, appliance or support 4 – Bedridden or chairbound 4 – Confined to bed or chair bound 5 – Requiring assisted ventilation for at least part of the day 5 – Requiring assisted ventilation 6 – Dead Qualification score is defined as > 1. Revised values for the GBS disability score are shown opposite and endorsed by the SWG (Lancet 1978;2:750-753). 6 – Dead Progressive weakness is being used as a criterion to require that disease progression has a trajectory to significant disability. Text comments will be used to capture this information. Patients with GBS variants may be able to walk yet still have significant disability and risk of progression, not measured by GBS Disability Score. In this instance, description of symptoms will be used. OR Patient with GBS variant demonstrates bulbar or autonomic features and significant disability. It was noted that disease progression is difficult to measure or set parameters for a rate, therefore a textual description would be best way to assess. AND New indication [Group 2] The progressive nature of the weakness indicates a trajectory to significant disability. Relapse in GBS treatment-related fluctuation with National Blood Authority Evidence supports a second dose for treatmentrelated fluctuations as allowed under the current Criteria. It was noted that the Disability Grade may not improve even when patient has responded to pg. 5 ITEM CRITERIA FOR THE CLINICAL USE OF INTRAVENOUS IMMUNOGLOBULIN IN AUSTRALIA, SECOND EDITION (CRITERIA) Approximately 10% of patients relapse, which may require a second treatment with Ig. A second dose of IVIg must only be on the advice of and after assessment by a neurologist. PROPOSED REVISIONS TO THE CRITERIA (INCLUDING ADAPTATION TO THE IG SYSTEM) SWG RATIONALE FOR PROPOSED CHANGE initial improvement and subsequent deterioration post IVIg treatment (neurologist review required). IVIg, when GBS is very severe. The Ig request is made by a neurologist. AND Patient has demonstrated an Initial response followed by recurrent weakness with no alternative explanation as demonstrated by deterioration in a recent Medical Research Council (MRC) Sum (12) Score compared to the MRC Sum (12) Score post Ig treatment (Kleyweg et al 1991). It was agreed that deterioration would be better measured by MRC score as it would be more sensitive than INCAT. There is currently no data to support a second dose of IVIg if first dose was ineffective unless delta IgG levels are being measured which are not widely available. Any further deterioration would be expected to occur within 1-2 weeks if Ig treatment. The MRC Sum (12) Score will be used to assess and document the deterioration. Detail regarding the MRC Sum (12) Score Range 0 (total paralysis) – 60 (normal strength) Sum of 6 muscle pairs examined bilaterally: Kleyweg, RP, van der Meché, FGA, Schmitz, PIM 1991, ‘Interobserver agreement in the assessment of muscle strength and functional abilities in Guillain-Barré syndrome’, Muscle Nerve, vol. 14, pp. 1103–1109. Arm: shoulder abductors, elbow flexors, wrist extensors Leg: hip flexors, knee extensors, foot dorsiflexors MRC grade 0-5 (full numbers ie. 4+=4, 4- =3) References to MRC Sum Score (12) are provided and will link to a reference page containing detail of the measurements required. Review Criteria Initial therapy for GBS with significant disability and progression Review Preamble Given that Ig treatment for GBS is one-off, no review will be required however, clinicians can submit outcome data. Review criteria for assessing the efficacy of IVIg use: National Blood Authority pg. 6 ITEM CRITERIA FOR THE CLINICAL USE OF INTRAVENOUS IMMUNOGLOBULIN IN AUSTRALIA, SECOND EDITION (CRITERIA) PROPOSED REVISIONS TO THE CRITERIA (INCLUDING ADAPTATION TO THE IG SYSTEM) SWG RATIONALE FOR PROPOSED CHANGE Improvement in disability at four weeks after Ig treatment. GBS Disability Score + Date of Assessment 0 - A healthy state Review 1 – Minor symptoms and capable of running Review criteria for assessing effectiveness of IVIg use 2 – Able to walk 10 metres or more without assistance but unable to run i Primary outcome measures: 3 – Able to walk 10 metres across an open space with help improvement in disability grade four weeks after treatment 4 – Bedridden or chairbound 5 – Requiring assisted ventilation for at least part of the day Disability Grade 0 - A healthy state 1 – Minor symptoms or signs of neuropathy but capable of manual work 2 – Able to walk without the support of a stick but incapable of manual work The updated GBS Disability Score is more detailed in defining the disability eg defined walking distances for assessment. 6 – Dead OR Improvement in bulbar or autonomic symptoms in patient with GBS variant. (Large Text*) & (Date) of Assessment 3 – Able to walk with a stick, appliance or support 4 – Confined to bed or chair bound • Time until walking unaided 5 – Requiring assisted ventilation • Time until recovery of walking with aid 6 – Dead • Time until off ventilation ( for those ventilated) Secondary outcome measures National Blood Authority Optional secondary outcome measures • Treatment-related fluctuation pg. 7 ITEM CRITERIA FOR THE CLINICAL USE OF INTRAVENOUS IMMUNOGLOBULIN IN AUSTRALIA, SECOND EDITION (CRITERIA) PROPOSED REVISIONS TO THE CRITERIA (INCLUDING ADAPTATION TO THE IG SYSTEM) • Time until walking unaided • Time until recovery of walking with aid • Time until off ventilation ( for those ventilated) • Treatment related fluctuation SWG RATIONALE FOR PROPOSED CHANGE • Death or disability [Review Postscript] Relapse in GBS (treatment-related fluctuation) with recurrent weakness after initial improvement may require a second treatment with IVIg. A second dose of IVIg must only be on the advice of and after assessment by a neurologist. • Death or disability Approximately 10% of patients relapse, which may require a second treatment with Ig. A second dose of IVIg must only be on the advice of and after assessment by a neurologist. Relapse in GBS treatment-related fluctuation with initial improvement and subsequent deterioration post IVIg treatment (neurologist review required). Review Preamble Review criteria for assessing the efficacy of IVIg use are: Improvement in GBS Disability Score at four weeks after Ig treatment and date of assessment. OR Improvement in bulbar or autonomic symptoms in patient with GBS variant & Date of Assessment. Optional secondary outcome measures • Time until walking unaided • Time until recovery of walking with aid • Time until off ventilation ( for those ventilated) • Treatment-related fluctuation National Blood Authority pg. 8 ITEM CRITERIA FOR THE CLINICAL USE OF INTRAVENOUS IMMUNOGLOBULIN IN AUSTRALIA, SECOND EDITION (CRITERIA) PROPOSED REVISIONS TO THE CRITERIA (INCLUDING ADAPTATION TO THE IG SYSTEM) SWG RATIONALE FOR PROPOSED CHANGE • Death or disability [Review Postscript] Relapse in GBS (treatment-related fluctuation) with recurrent weakness after initial improvement may require a second treatment with IVIg. A second dose of IVIg must only be on the advice of, and after assessment by, a neurologist. Dose Induction - 2 g/kg in 2 to 5 divided doses. Initial therapy for GBS with significant disability and progression. The dosing approach is the same for both indications. Induction dose is unchanged. Aim for minimum dose to maintain optimal functional status. Refer to the current product information sheet for further information. The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient. Initial - 2 g/kg in 2 to 5 divided doses. System Controls for Dosing The amount per dose should be titrated to the Individual’s response. Refer to the current product information sheet for further information. This script was deleted as inappropriate for this condition - the dose is standard for all patients ( unless lean body mass is being used). Relapse in GBS with significant disability and progression post IVIg treatment (neurologist review required) National Blood Authority pg. 9 ITEM CRITERIA FOR THE CLINICAL USE OF INTRAVENOUS IMMUNOGLOBULIN IN AUSTRALIA, SECOND EDITION (CRITERIA) PROPOSED REVISIONS TO THE CRITERIA (INCLUDING ADAPTATION TO THE IG SYSTEM) SWG RATIONALE FOR PROPOSED CHANGE Initial - 2 g/kg in 2 to 5 divided doses. Refer to the current product information sheet for further information. As above - standard dosing applies. POTENTIAL OPERATIONAL IMPACT Diagnosis and Ig ordering can only be made by a neurologist so this will require the referral of patients where initial care is being provided by General Physicians. Request for authorisation for a second dose of Ig can only be made by a neurologist under current Criteria requiring the referral of patients where initial care is being provided by General Physicians. This will now be required for any Ig treatment. POTENTIAL IMPACT ON DEMAND Patient numbers in 2013-14 Usage 2013-14 663 patients treated Some potential for reduction in use by: 3% System requirement for moderate to severe level of disease severity at qualifying (cease use in mild cases that was reported during IVIg Review) No impact on demand is expected due to GBS variants but improved data will be available regarding clinical outcome for future analysis. Given that these changes effect up to 3% usage, the savings estimate is minor. POTENTIAL COST Cost Anticipated reduction in cost, if any Minor Marginal = borderline or unchanged from current cost Minor = decrease by $500K - $1.99M from current cost Major = decrease $2M+ from current cost BIBLIOGRAPHY Association of British Neurologists 2005, Guidelines for the use of intravenous immunoglobulin in neurological diseases, The Association, London. Available from: National Blood Authority pg. 10 www.theabn.org/ documents/IVIg-Guidelines-2005.pdf [cited 7 Dec 2007] Biotext 2004, ‘Summary data on conditions and papers’, in A systematic literature review and report on the efficacy of intravenous immunoglobulin therapy and its risks, commissioned by the National Blood Authority on behalf of all Australian Governments, pp.149–50. Available from: http://www.nba.gov.au/pubs/pdf/report-lit-rev.pdf. Frommer, M & Madronio, C 2006, The use of intravenous immunoglobulin in Australia. A report for the National Blood Authority, Part B: systematic literature review, Sydney Health Projects Group, University of Sydney, Sydney, pp. 32–4. Hughes, RAC, Raphaël, J-C, Swan, AV, et al 2006, ‘Intravenous immunoglobulin for Guillain Barré syndrome (Cochrane Review)’, in The Cochrane Library, Issue 1, John Wiley & Sons, Ltd, Chichester, UK. Kleyweg, RP, van der Meché, FGA, Schmitz, PIM 1991, ‘Interobserver agreement in the assessment of muscle strength and functional abilities in Guillain-Barré syndrome’, Muscle Nerve, vol. 14, pp. 1103–1109. Korinthenberg, R, Schessl, J, Kirschner, J, et al 2005, 'Intravenously administered immunoglobulin in the treatment of childhood Guillain-Barré syndrome: a randomized trial’, Paediatrics, vol. 116, no. 1, pp. 8–14. Kornberg, AJ, for the Asia–Pacific IVIg Advisory Board 2004, Bringing consensus to the use of IVIg in neurology. Expert consensus statements on the use of IVIg in neurology, 1st edn, Asia–Pacific IVIg Advisory Board, Melbourne, pp. 14–20. END OF DOCUMENT National Blood Authority pg. 11