2017 (v3.0) Proposed changes to v2.1 of the Criteria for ...



2017 (v3.0) Proposed changes to v2.1 of the Criteria for the clinical use of intravenous immunoglobulin in Australiav2.1 CONDITION NAME: Sjogren’s syndromev3.0 CONDITION NAME: Sjogren’s syndrome associated neuropathyPROPOSED APPROACH:To retain Sjogren’s syndrome associated neuropathy in Exceptional circumstances only with the changes as outlined. SUMMARY OF RATIONALE: The recommendation is supported by factors including that:Neurological manifestations in Sjogren’s syndrome are rare, and the only indication for Ig therapy for patients with Sjogren’s syndrome is neuropathy. There are a number of neuropathy subtypes which can occur including: sensory ataxic neuropathy, painful sensory neuropathy without ataxia, multiple mononeuropathies, cranial neuropathies including trigeminal neuropathy and autonomic neuropathy.While the evidence base for use of Ig in this condition is weak, some response has been reported in small case series of patients with some forms of sensory neuropathy. Approximately 20 patients have received maintenance therapy nationally over the last 2 years, and it is understood that some are receiving demonstrable benefit from this treatment that is being regularly assessed. Alternative, more effective therapies are available for vasculitic neuropathy. As such, this neuropathy subtype is excluded. It is proposed to formally consult with Australian and New Zealand Association of Neurologists (ANZAN), Australasian Society for Clinical Immunology & Allergy (ASCIA) and the Australian Rheumatology Association (ARA) regarding the proposed criteria during the Public Consultation period. As a result, these proposed criteria may change. Sjogren’s neuropathy is not listed in the Guidelines for IVIg use in Canada (Ontario Regional Blood Coordinating Network, 2016), or the United Kingdom (UK Department of Health, 2011). v2.1 CONDITION CATEGORY: Condition for which Ig use is in exceptional circumstances only (Chapter 7)v3.0 CONDITION CATEGORY: Condition for which Ig use is in exceptional circumstances only (Chapter 7)Role of Ig therapy: Multiple treatments have been trialled for treatment of Sjogren’s syndrome associated neuropathy, with corticosteroids in association with immunosuppressant medications demonstrating the best outcomes. However, where patients are refractory to or unable to tolerate first-line therapy, Ig has been reported to be effective in a few patient series with a variety of neuropathy subtypes and in one study, the majority successfully achieved a 30% reduction in steroid therapy dose (Rist, 2011). The exact mechanism of action of Ig in the context of Sjogren’s syndrome associated sensory neuropathy is unknown. ITEMCRITERIA v2.1PROPOSED REVISIONS TO THE CRITERIASPECIALIST WORKING GROUP RATIONALE FOR ADDITIONS/CLARIFICATIONSCondition NameSj?gren’s syndromeSjogren’s syndrome associated neuropathyCondition name revised to more appropriately reflect the specific diagnosis where evidence suggests some benefit of Ig therapy and is consistent with use in exceptional circumstances. SpecialtyImmunology NeurologyThe specialty is more appropriately Neurology given that the indication for Ig therapy will only be for Sjogren’s syndrome associated neuopathy and not other manifestations of Sjogren’s diseaseCategoryExceptional circumstances only Exceptional circumstances onlyUnchangedSpecific ConditionsSj?gren’s syndromeSmall fibre neuropathyAutonomic neuropathySensory neuropathy/neuronopathyRelevant specific conditions are defined to support data analysisLevel of EvidenceInsufficient data (Category 4a) Insufficient data (Category 4a)UnchangedJustification for Evidence CategorySjogren’s syndrome associated neuropathy comprises a heterogeneous group of neuropathies. There is a very low level of evidence for IVIg use in this condition, with conflicting reports of efficacy. Improvement has been reported in small case series of patients with some forms of sensory neuropathy (Pereira 2016, Rist 2011, Yamashita 2013). Conflicting reports exist for patients with ataxic sensory neuronopathy, with one study reporting benefit (Takahashi 2003) but most studies (Rist 2011, Pereira 2016) and clinical experience suggesting it is ineffective for this patient group.Approximately twenty patients have received maintenance therapy nationally over the last five years, and it is understood that some are receiving demonstrable benefit from this treatment that is being regularly assessed. The Specialist Working Groups (Immunology and Neurology) of the Immunoglobulin Governance Program recommend to retain the condition within the Criteria as an interim measure, in order to better understand the exact nature of the clinical benefit and collect data on the existing patients. However, if no demonstrable benefit can be identified, patients will not be eligible to remain on Ig therapy under these criteria. This section has been developed following consultation of recent literature and by SWG consensus. It is proposed to formally consult with Australian and New Zealand Association of Neurologists, ASCIA and the Australian Rheumatology Association regarding the proposed criteria during the Public Consultation period. Indications Severe, primary Sjogren’s syndrome associated neuropathy that is unresponsive to corticosteroid and immunosuppressant therapy.Relapse of Sjogren’s syndrome associated neuropathy within six months of trial off Ig therapyTwo indications have been developed, the second to manage treatment of responding patients that relapse on a trial of weaning from Ig therapy. Description and Diagnostic CriteriaIVIg may be indicated in patients with some forms of neuropathy associated with Sjogren’s syndrome that is not caused by necrotising vasculitis where other treatments have not been effective.Script developed to reflect the limitation of Ig therapy to patients with autonomic, small fibre or sensory neuropathy/neuronopathy.Diagnosis is required YesBy which specialtyClinical ImmunologyNeurologyRheumatologyPatients are most likely to be treated by any of the listed specialists. Diagnosis must be verifiedNoBy which specialtyExclusion Criteria Sjogren’s syndrome associated vasculitic neuropathyVasculitic neuropathy in association with Sjogren’s syndrome is excluded as there is no evidence of benefit and alternative treatments are available.Qualifying Criteria Severe, primary Sjogren’s syndrome associated neuropathy that is unresponsive to corticosteroid and immunosuppressant therapy.Primary Sjogren’s syndrome with proven sensory or autonomic neuropathy AND Significant disability due to neuropathy as measured by Modified Rankin Score (MRS) of at least 4 pointsANDNo response to an appropriate trial of corticosteroidsORCorticosteroids are contraindicated ANDNo response to at least one immunosuppressant agentORImmunosuppressant medication is contraindicated.Relapse of Sjogren’s syndrome associated neuropathy within six months of trial off Ig therapyDeterioration of neuropathy (formally assessed) and Modified Rankin Score (by at least one point) in a previously stable patient as compared to the previous review scoreANDRelapse occurs within six months of the last immunoglobulin dose Qualifying criteria have been developed and evidence items will capture the type of neuropathy (proven diagnosis) and the formal method of assessment that will be used to measure the clinical response and level of neuropathy at qualifying (and that will be applied for comparison at the initial and continuing reviews). The types of assessment methods expected to be used in new and existing patients include clinical examination together with investigations including nerve conduction studies, nerve biopsy, skin biopsy (IENFD), quantitative sensory testing, autonomic function tests or gastric emptying studies. It is recognised that a Modified Rankin Score (MRS) is an insensitive scale for measurement of disability in this condition and alternative methods will be considered during the consultation process. If the MRS is used, a drop down menu will display a description of the rating levels. The immunosuppressant agents might include: CyclophosphamideAzathiaprineChlorambucilMethotraxateCyclosporinRituximabPreviously responding patients are eligible to recommence Ig therapy if they relapse within 6 months of a trial of weaning. Review Criteria Severe, primary Sjogren’s syndrome associated neuropathy that is unresponsive to corticosteroid and immunosuppressant therapy. IVIg should be used for a maximum period of four months (induction plus 3 maintenance cycles) before determining whether the patient has responded. If there is no benefit after this treatment, IVIg therapy should be abandoned. Review by a Neurologist, Rheumatologist or Clinical Immunologist is required within 4 months of treatment to determine whether the patient has responded, and annually thereafter. Documentation of clinical effectiveness is necessary for continuation of IVIg therapy. On review of the initial authorisation periodClinical effectiveness of Ig therapy can be demonstrated by: Improvement of neuropathy (formally assessed) compared to the qualifying assessmentANDImprovement in disability as measured by a decrease of at least 1 point or no deterioration in the Modified Rankin Score compared to the qualifying assessmentOn review of a continuing authorisation period For stable patients on maintenance treatment, review by a Neurologist, Rheumatologist or Clinical Immunologist is required at least annually.Clinical effectiveness of Ig therapy can be demonstrated by:Improvement in or stabilisation of neuropathy (formally assessed) compared to the previous review assessmentANDImprovement in or stabilisation of the degree of disability as measured by the Modified Rankin Score compared to the previous review assessmentANDA trial of Ig weaning should be attempted after a year of therapy unless there is a contraindication to doing so. Relapse of Sjogren’s syndrome associated neuropathy within six months of trial off Ig therapyIVIg should be used for a maximum period of four months (induction plus 3 maintenance cycles) before determining whether the patient has responded. If there is no benefit after this treatment, IVIg therapy should be abandoned. Review by a Neurologist, Rheumatologist or Clinical Immunologist is required within 4 months of treatment to determine whether the patient has responded, and annually thereafter. Documentation of clinical effectiveness is necessary for continuation of IVIg therapy. Once a patient has relapsed when trialled off Ig treatment, a second line immunomodulatory agent should be strongly considered as additional therapy. IVIg should be used for a maximum period of four months (induction plus 3 maintenance cycles) before determining whether the patient has responded. If there is no benefit after this treatment, IVIg therapy should be abandoned. Review by a Neurologist, Rheumatologist or Clinical Immunologist is required within 4 months of treatment to determine whether the patient has responded, and annually thereafter. Documentation of clinical effectiveness is necessary for continuation of IVIg therapy. On review of the initial authorisation periodClinical effectiveness of Ig therapy can be demonstrated by: Improvement of neuropathy (formally assessed) compared to the qualifying assessmentANDImprovement in disability as measured by a decrease of at least 1 point or no deterioration in the Modified Rankin Score compared to the qualifying assessmentOn review of a continuing authorisation period For stable patients on maintenance treatment, review by a Neurologist, Rheumatologist or Clinical Immunologist is required at least annually.Clinical effectiveness of Ig therapy can be demonstrated by:Improvement in or stabilisation of neuropathy (formally assessed) compared to the previous review assessmentANDImprovement in or stabilisation of the degree of disability as measured by the Modified Rankin Score compared to the previous review assessmentANDA trial of Ig weaning should be attempted after two years of therapy in patients that have previously relapsed after an earlier trial of withdrawal of IVIg, unless there is a contraindication to doing so. Once a patient has relapsed in the first six months of a trial off therapy, a further trial might be considered after at least two years. Review criteria have been developed by SWG consensus. Clinical review of patients will require documentation of the assessment method and a description of the improvement after at least 4 months of Ig therapy. A text description of the improvement in disability will be captured. It is recognised that the Modified Rankin Score may not be sufficiently sensitive to measure a change. A text description of the improvement in disability will be captured. It is recognised that the Modified Rankin Score may not be sufficiently sensitive to measure a change. A trial of weaning should be undertaken after 12 months treatment in most patients. If a patient relapses following a trial of weaning, a second line immunosuppressant agent is recommended as additional therapy. The formal assessment method being used to assess response is required to be documented together with the improvement in symptoms following Ig therapy. A text description of the improvement in disability will be captured. It is recognised that the Modified Rankin Score may not be sufficiently sensitive to measure a change. Two years after relapse, a trial of weaning from Ig therapy should be commenced in most patients. Dose Severe, primary Sjogren’s syndrome associated neuropathy that is unresponsive to corticosteroid and immunosuppressant therapy.Induction Dose – 1- 2 g/kg in 2-5 divided dosesMaintenance Dose – 0.4 -1 g/kg, 4-6 weekly. The amount per dose should be titrated to the individual’s response. A maximum dose of 1 g/kg may be given in any 4 week period. This might be small doses more frequently than fortnightly.The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.Refer to the current product information sheet for further information on dose, administration and contraindications.Relapse of Sjogren’s syndrome associated neuropathy within six months of trial off Ig therapyInduction Dose – 1- 2 g/kg in 2-5 divided dosesMaintenance Dose – 0.4 -1 g/kg, 4-6 weekly. The amount per dose should be titrated to the individual’s response. A maximum dose of 1 g/kg may be given in any 4 week period. This might be small doses more frequently than fortnightly.The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.Refer to the current product information sheet for further information on dose, administration and contraindicationsDosing has been developed by consultation of the literature and by SWG consensus. Some flexibility in dosing has been supported to enable weaning from Ig therapy. References(most recent update: February 2016)Brito-Zeron P, Akasbi A, Bosch X, et al (2013) Classification and characterisation of peripheral neuropathies in 102 patients with primary Sjogren’s syndrome. Clinical and Experimental Rheumatology, 31(1):103-110. M, Pettinari L, Morariu R, et al (2012) Intravenous immunoglobulin and mycophenolate mofetil for long-standing sensory neuropathy in Sjogren’s syndrome. Case reports in immunology, 10:1155-1158. J. A, Benito-Leon J, Bermejo F, et al (1996) Intravenous immunoglobulin therapy in sensory neuropathy associated with Sjogren’s syndrome. J Neurol Neurosurg Psychiatry, 60:699. A, Kawagahira Y, Iijima M, et al (2009) Intravenous immunoglobulin treatment for painful sensory neuropathy associated with Sjogren’s syndrome. Journal of the Neurological Sciences, 279:57-61. Regional Blood Coordinating Network (2016). Ontario Intravenous Immune Globulin (IVIG) Utilization Management Guidelines, Version 3.0. [online]. Available at: R, Viala K. et al (2016) Sjogren Sensory Neuropathy – Long-tern outcome and treatment Response in a series of 13 cases. Medicine (Baltimore), 95(19):e3632. S, Sellam J, Hachulla E, et al (2011) Experience of intravenous immunoglobulin therapy in neuropathy associated with primary Sjogren’s syndrome: A national, multicentric retrospective study. Arthritis Care Res, 63(9):1339-1344. Y, Takata T, Hoshino M, et al (2003) Benefit of IVIg for long-standing ataxic sensory neuronopathy with Sjogren’s syndrome. Neurology, 60:503-505. D, Kato T, Gono T, et al (2009) Extreme efficacy of intravenous immunoglobulin therapy for severe burning pain in a patient with small fiber neuropathy associated with primary Sjogren’s syndrome. Mod Rheumatol, 19: 437-440. A, Jackson M, Wang F, et al (2005) Neutralisation of muscarinic receptor autoantibodies by intravenous immunoglobulin in Sj?gren’s syndrome, Human Immunology, 66(4):411–6. UK Department of Health (2011) Clinical Guidelines for Immunoglobulin Use: Second Edition Update. Available at: Department of Health (2011) Clinical Guidelines for Immunoglobulin Use: Second Edition Update: Summary Poster. Available at: H, Ueda Y, Ozaki T, et al (2013) Diagnosis and treatment of primary Sjogren Syndrome-associated peripheral neuropathy: a six-case series. Modern Rheumatology, 23:925. OPERATIONAL IMPACTIt is recognised that the further consultation to be undertaken with ANZAN, ARA and ACSIA may result in changes to these criteria. The formal access criteria currently proposed require that Ig therapy will only be authorised for treatment of patients with Sjogren’s syndrome associated peripheral neuropathy, and no other manifestations of Sjogren’s syndrome. A neurologist, clinical immunologist or rheumatologist must make the diagnosis and manage patient treatment. The requirement for applying formal assessment methods to the measurement of the clinical response to Ig therapy may be a new requirement for some prescribers (and patients) and may result in additional investigations being undertaken. There will be an increase in the amount of data entry required compared to the current request process for this condition. For new patients, if no response is demonstrated at the initial review, patients will not be eligible to continue Ig therapy. For those patients with stabilised disease, a trial off Ig therapy will need to be undertaken to identify those in remission. It is expected that prescribers will undertake a trial off therapy as relapsing patients may be eligible to recommence treatment, should relapse occur. If patients have subtypes of neuropathy that are recommended to be excluded from this condition, Ig therapy will cease. In order to support doctors to provide optimal patient management and transition to alternative treatment approaches, if required, advice will be provided to prescribers well prior to the date of implementation of this change. POTENTIAL IMPACT ON PATIENTS, DEMAND AND EXPENDITUREDescription of impact on patients:The review that has been undertaken has identified that the only potential role for Ig therapy in Sjogren’s syndrome is for the treatment of Sjogren’s syndrome associated peripheral neuropathy when patients have failed to respond to treatment with a number of alternative medications. Whilst the results are variable, some benefit has been demonstrated in some patients in small studies and case reports. The formal access criteria currently proposed require that a neurologist, clinical immunologist or rheumatologist make the diagnosis and manage the treatment. There will be further consultation undertaken during the public consultation period with the expert groups of the Australian and New Zealand Association of Neurologists, the Australasian Rheumatology Association and the Australasian Society of Clinical Immunology and Allergy and, as a result, these proposed criteria may change. For existing patients with Sjogren’s syndrome associated peripheral neuropathy, it is not anticipated that there will be any significant impact arising from the changes, provided patients are demonstrating clear benefit from Ig therapy (that has been measured) or have stabilised neurological disease. Patients may be required to undergo new formal assessment processes (including investigations) to ensure the correct diagnosis has been made and to assess the effect of Ig therapy. Six monthly reviews will be required to assess the effectiveness of Ig therapy to improve or stabilise both the neuropathy and the degree of disability. Given that patients will already require regular review by their specialist, this requirement will not place an added burden on patients. If an existing patient on ongoing treatment is not being managed by a neurologist, immunologist or rheumatologist, referral to one of these specialists will be required. If Ig therapy has not been effective in stabilising symptoms, it will be ceased as a different treatment should be used. A trial of reducing dose and then stopping Ig therapy will be considered by doctors when patients are well and symptoms are stable. If responding patients relapse after Ig therapy has been stopped, a further request for ongoing Ig therapy can be made. If there are any existing patients with Sjogren’s syndrome who are receiving Ig therapy for a manifestation of the disease other than neuropathy, alternative treatment approaches should be considered as Ig therapy is not considered to be the optimal treatment. In addition, it is inappropriate to treat patients with medication that has no demonstrable benefit and there are small but not insignificant risks of harm from Ig therapy, as well as a high cost. It is anticipated that prescribers (and thus patients) would be informed of any decision once governments have endorsed the recommendation so that ample lead time is provided for prescribers to manage and transition patients to an alternative treatment approach, if required.New patients authorised to receive Ig therapy will require an initial check after the first four months of treatment to confirm that Ig therapy has been effective in improving both the severity of neuropathy and the degree of disability. If improvement has been demonstrated after four months treatment, Ig maintenance therapy will be continued with ongoing annual reviews. If a response has not been demonstrated, Ig therapy will be stopped and a different treatment approach will be required. The ongoing arrangements for maintenance therapy are as outlined above for existing patients.Impact on demand:Given the lack of data regarding current approaches to the assessment and review of clinical response to Ig therapy, it is hard to estimate the impact of the recommended changes on prescribing practice and Ig use. It is possible that use in Sjogren’s syndrome is not currently limited to those patients with Sjogren’s associated peripheral neuropathy. It is possible that some patients will trial off Ig therapy and be in remission, reducing demand. Given the low level of use, there is not expected to be any significant change in overall demand. 2011-122012-132013-142014-152015-16The Specialist Working Group estimated magnitude of effect:Marginal reduction < $500,000 against projected demandPatient number1211152022Total Grams issued50774418664697619698% Total Grams issued0.16%0.12%0.17%0.22%0.19%Specialist Working Group knowledge development opportunities and recommendationsNone identified at this stage.END OF PUBLIC CONSULTATION DOCUMENTNext review: June 2017, following the public consultation period. ................
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