rituximab for musk antibody-positive myasthenia gravis: a ... ritixumab for myasthenia...

$: Rituximab for MuSK Antibody-Positive Myasthenia Gravis: A ... Ritixumab for Myasthenia Gravis...receptor kinase (MuSK) antibody-positive myasthenia gravis refractory to standard therapy?$
TITLE: Rituximab for MuSK Antibody-Positive Myasthenia Gravis: A Review of the

Clinical Effectiveness, Safety, and Cost-Effectiveness DATE: 29 September 2014 CONTEXT AND POLICY ISSUES Myasthenia gravis (MG) is an autoimmune disorder involving the binding of pathogenic auto-antibodies to acetylcholine receptors and other proteins in the neuromuscular junction1,2 which subsequently results in both damage and remodelling of the junction. MG is characterized by muscle weakness and can affect everything from walking, to breathing, to swallowing.2 In those with severe disease, mechanical ventilation may be necessary to support breathing as patients can ultimately experience respiratory distress.2 MG has a prevalence of approximately 1501 to 2002 per million. There is a distinct bimodal distribution of MG, with the first incidence peak occurring in the third decade of life and a second in the elderly.1 There are several genetic variants or subtypes of MG that are associated with different disease severity, treatment response, or prognosis.2 They are classified according to the age of onset, patterns of muscle weakness, the presence of thymoma, or the presence of auto-antibodies (specifically the acetylcholine receptor [AChR] antibodies or the muscle specific receptor kinase [MuSK] antibodies).2 The MuSK subtype is not associated with thymic abnormalities and its antibodies are of the IgG4 isotype. These IgG4 anti-MuSK antibodies have been observed to reduce acetylcholine expression in the neuromuscular junction and are effective at disrupting both the pre- and post-synaptic ultrastructure, leading to the increased disease severity of patients with MuSK MG.1 The first-line treatment for MG are steroids, which have been noted to be effective.1 Other immunosuppressant drugs used to treat MG include azathioprine, mycophenolate mofetil, cyclosporine, methotrexate, tacrolimus, and cyclophosphamide.1,3 However, side effects can be severe with immunosuppressants and can lead to discontinuation or intolerance. Other therapies include plasmapheresis (PE) and intravenous immunoglobulins (IVIg) which are often used in patients with severe disease that are refractory to other treatments, or those experiencing relapse or exacerbations.1 In certain cases of MG, thymectomy is also an available treatment but is considered controversial with regard to its effectiveness and comes with the possibility of severe complications from surgery.1 Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. Rapid responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material and may contain material in which a third party owns copyright. This report may be used for the purposes of research or private study only. It may not be copied, posted on a web site, redistributed by email or stored on an electronic system without the prior written permission of CADTH or applicable copyright owner. Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners’ own terms and conditions.

Rituximab is a chimeric monoclonal antibody that is used to deplete white cells of B-lineage that express CD20. It has been used in the past for the treatment of B-cell malignancies, refractory rheumatoid arthritis, microscopic polyangitis, and Wegener`s granulomatosis.2 While there is currently no regulatory approval in Canada or the United States for autoimmune disorders (including MG), rituximab has been used off-label under certain circumstances in these patients. This review will focus on reviewing on the clinical- and cost-effectiveness and safety of off-label use of rituximab for patients with MuSK MG refractory to standard therapy. RESEARCH QUESTIONS 1. What is the clinical effectiveness and safety of rituximab for patients with muscle specific

receptor kinase (MuSK) antibody-positive myasthenia gravis refractory to standard therapy?

2. What is the cost-effectiveness of rituximab for patients with MuSK antibody-positive

myasthenia gravis refractory to standard therapy? KEY FINDINGS Rituximab appears to be a viable option in patients with MuSK myasthenia gravis who are refractory to standard treatment as there appears to be both clinical benefit (reduced use of IVIg and PE treatments, and some reductions in concomitant medications) and few side effects. However, caution is required when interpreting this evidence as all the information was obtained from case series or reports with small sample sizes and varying treatment regimens. In addition, side effects in these studies may have been underreported. METHODS Literature Search Strategy A limited literature search was conducted on key resources including PubMed, The Cochrane Library (2014, Issue 8), University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology agencies, as well as a focused Internet search. No filters were applied to limit the retrieval by study type. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2009 and August 27, 2014. Rapid Response reports are organized so that the evidence for each research question is presented separately. Selection Criteria and Methods One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.

Rituximab for MuSK Antibody-Positive Myasthenia Gravis 2

Table 1: Selection Criteria Population

Patients with muscle specific receptor kinase (MuSK) antibody-positive myasthenia gravis refractory to standard therapy

Intervention

Intravenous rituximab

Comparator

• Standard therapy (i.e. immunotherapy, plasmapheresis exchange, steroids)

• No comparator Outcomes

• Clinical benefit (i.e. reduction in need for steroids, plasmapheresis, and immunotherapy, quality of life, laboratory parameters)

• Cost-effectiveness Study Designs

Health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, non-randomized studies, economic evaluations

Exclusion Criteria Studies were excluded if they did not satisfy the selection criteria, if they were duplicate publications, or were published prior to 2009. Critical Appraisal of Individual Studies Key methodological aspects relevant to each study design were appraised and summarized narratively. The AMSTAR tool4 was used to guide the critical appraisal of the methodological quality of the health technology assessment (HTA) included in this report. Emphasis was placed upon the methods used to conduct the literature search, study selection, quality assessment, data extraction, and conflict of interest declaration. The Drummond et al.5 checklist was used to guide the economic evaluation included in the HTA. SUMMARY OF EVIDENCE Quantity of Research Available A total of 59 citations were identified in the literature search. Following screening of titles and abstracts, 38 citations were excluded and 21 potentially relevant reports from the electronic search were retrieved for full-text review. Three potentially relevant publications were retrieved from the grey literature search. Of these potentially relevant articles, 23 publications were excluded for various reasons, while one publication met the inclusion criteria and was included in this report. Appendix 1 describes the PRISMA flowchart of the study selection. Summary of Study Characteristics Detailed study characteristics and findings are presented in Table 2, Appendix 2. What is the clinical effectiveness and safety of rituximab for patients with MuSK antibody-positive myasthenia gravis refractory to standard therapy? One HTA2 originating in Montreal, Canada was included in this review and focused on rituximab treatment for four different autoimmune neurologic diseases; myasthenia gravis, neuromyelitis


optica, dermatomyositis, and chronic inflammatory demyelinating polyneuropathy. All of these diseases were assessed separately and disease-specific recommendations were made. Due to the paucity of available evidence on MG, the HTA centered the analysis on numerous case series, case reports, and any information available in the German Register in Autoimmune Diseases (GRAID) registry. Ten case series containing at least five patients each were included, of which seven were full text articles and three were abstracts (full text not obtained as the article was in a language other than French or English). One hundred and twelve patients from the case series received rituximab for MG and had a median age of 48 years (range 14 to 83 years) and median disease duration was 6 years (range 0 to 45 years). Rituximab was indicated for patients with refractory disease with or without intolerance to standard treatments. Some studies presented individual symptoms before and after treatment while others reported changes using various scales or changes in medication use (indicating disease management or even remission). Descriptions of scales used to assess MG are presented in Table 3, Appendix 3. Most patients had severe disease with bulbar symptoms and were classified as MGFA Class IIIb (18.8%), IVb (44.7%), and V (10.6%). In addition, the majority of patients had AChR antibodies (60.0%), while 35.3% had MuSK antibodies, and one patient had both. Seven of the included studies were retrospective case series, two were prospective case series, and one study was an open-label phase I study. However, the prospective case series and phase I study were available in abstract form only. Adverse events were reported for a number of case series and some case reports and were provided in either full text or abstract form. Both the results for the change in disease status and the adverse events were not discriminated between the two subtypes of MG when patients were combined in the same trial. In addition, no standard rituximab treatment was used; however, most studies included initial dosing reflective of the standard dosing used to treat lymphoma. This included four doses of 375 mg/m2 (dosed according to body surface area, estimated to be 1.7 m2 in an adult) administered weekly followed by one to two maintenance doses of 375 mg/m2 administered monthly, every three months, or every six months. Three other studies used a dosing regimen similar to what is approved for rheumatoid arthritis which included 500 mg to 1.0 g administered twice, two weeks apart. Concomitant medications were also reported and included steroids, immunosuppressants, anticholinesterase-inhibitors, and premedications used to reduce the risk of infusion reactions. A mean of 3.7 (range 1 to 8) different treatments were received prior to rituximab treatment. Thymectomy was performed in 57.6% patients, and 37.6% and 30.6% of patients had received previous intravenous immunoglobulins (IVIg) and plasmapheresis (PE) therapy, respectively. Follow-up to rituximab therapy ranged anywhere from four months to greater than five years. What is the cost-effectiveness of rituximab for patients with MuSK antibody-positive myasthenia gravis refractory to standard therapy? Detailed costs associated with rituximab, IVIg therapy, and PE therapy are presented in Table 4, Appendix 4. The HTA sought to determine the direct costs associated with the use of rituximab. For the economic evaluation, the authors contacted a local physician to obtain treatment regimens associated with rituximab therapy for the patients with MG that he had cared for. They observed that rituximab was administered according to regimens used for patients with rheumatoid arthritis and this included two initial doses of 1 g each administered two weeks apart. This was followed by a maintenance regimen of 1 g every six months. The authors estimated the gross direct costs that would be associated with a therapeutic trial of rituximab and 2 years of


maintenance therapy. In addition, they also estimated the 2 year maintenance therapy costs associated with two of the more expensive treatments: IVIg and PE. Their aim was to show that if any of the medication and nursing costs of the latter treatments could be foregone by using rituximab instead, that there may be potential cost savings or net gains. Summary of Critical Appraisal Details of the critical appraisal of the included HTA are presented in Table 5, Appendix 5 What is the clinical effectiveness and safety of rituximab for patients with MuSK antibody-positive myasthenia gravis refractory to standard therapy? The HTA2 reported rigorous methodology that included descriptions of a comprehensive literature search, clearly defined objectives, a priori research questions, and explicit inclusion criteria. The authors clearly described the study selection and data extraction methods which were performed in duplicate by independent reviewers. In addition, in-depth patient and study characteristics along with findings were included from the articles in which they were available. When discussing the results and forming the recommendations, the level of evidence of the case series and reports were appropriately taken into consideration. However, there was not a defined grading system used to assess the strength of the recommendations. In addition, primarily case series (whereby there was no control group and clinical observations were made after their rituximab treatment) were available to produce these recommendations due to the rarity of MG. This hindered the authors from being able to generalize their recommendations regarding rituximab therapy to all patients with MuSK MG or even those with AChR MG. An additional limitation of the HTA was the lack of a declaration of conflicts of interest. The authors also noted the real potential for publication and reporting bias, though publication bias was not formally assessed. While the literature search was not limited by publication language, only those that had English or French abstracts were the ones obtained. Therefore, the lack of the full text articles of the included abstracts introduces limitations of the information that may be present in the full article. In addition, there remains the possibility of additional publication bias in the studies on rituximab in this population as there is the potential to forego publishing negative results, especially when dealing with such small sample sizes. What is the cost-effectiveness of rituximab for patients with MuSK antibody-positive myasthenia gravis refractory to standard therapy? Due to the nature of the included studies, and the fact that the authors did not identify any information on the cost-effectiveness of rituximab treatment for patients with MG, a full economic analysis was not possible. The authors compared costs of rituximab treatment with IVIg and PE. They did not, however, provide any comparison between rituximab and other, more common, standards of care. In addition, basing the analysis on a single physician’s experience with rituximab treatment for MG limits generalizability as may or may not be representative of general practice or even off-label use.


Summary of Findings What is the clinical effectiveness and safety of rituximab for patients with MuSK antibody-positive myasthenia gravis refractory to standard therapy? Individual study findings are presented in Table 2, Appendix 2. Clinical Effectiveness Efficacy results from the case studies indicated that, from the total population of those with MG (AChR and MuSK MG inclusive) 89.6% (69/77) and 85.3% (29/34) showed clinical improvement in the case series and case reports, respectively, with the remainder unchanged or worse at the end of follow-up. One patient in the case series died due to worsening of their disease. Two patients from the GRAID registry had complete response while two other had a partial response. All patients in the case series with the MuSK subtype (n=34) improved with rituximab therapy while 83.3% of patients with the AChR subtype (n=62) improved. Changes in the original treatment regimens upon receiving rituximab were of particular interest to the authors, as numerous patients were classified with severe disease (MGFA Class IV and V) and were not responding to one or more standard therapies. These patients were also receiving frequent re-treatment with IVIg or PE. Reductions in the use of IVIg and PE were reported (patients with either MuSK or AChr subtypes were not specified) in 12 of 15 total patients receiving IVIg and in 18 of 18 total patients receiving PE, with all of these patients eventually discontinuing PE treatment altogether. The authors also noted that many patients of both MG subtypes were able to decrease or stop their concomitant mediations (e.g. prednisone, immunosuppressants, and other non-specified medications) or the medications they had been on prior to rituximab therapy. The authors also did not observe any relationship between pre-rituximab medical status and their medical status at follow-up. In addition, there was no relationship between the dichotomous outcomes of improved versus unchanged or worsening and specific population characteristics such as age, sex, and disease duration. Safety Two patients of the 161 total patients in the case series and case reports had serious adverse events related to rituximab therapy, while 17 were observed to have non-serious adverse events. Of the overall adverse events that were noted, 16 patients experienced infusion reactions and four developed infections, two of which were hospitalized. The serious adverse events were both infectious in nature. One was the occurrence of granulocytosis, leukopenia, and pneumonia one month post-rituximab (due to disease relapse) in an individual who had also been started on mycophenolate mofetil. The other included the development of spondylodiscitis one year after rituximab therapy, which required the hospitalization of the individual. One discontinuation of rituximab therapy was noted in a man diagnosed with Waldenstrom`s macroglobulinemia and lymphoplasmocytic lymphoma prior to being diagnosed with MG who experience an infusion reaction. Based on the evidence, the authors of the HTA recommended the temporary and conditional approval of rituximab for the treatment of MG in hospitalize patients refractory or intolerant to


standard therapies, or who require frequent (more than 10 days) IVIg or PE therapy (Table 6, Appendix 6). What is the cost-effectiveness of rituximab for patients with MuSK antibody-positive myasthenia gravis refractory to standard therapy? Gross direct costs associated with a six-month therapeutic trial of rituximab for a patient with refractory MuSK MG was estimated to cost $9,462 Canadian dollars. This cost includes both the rituximab treatment as well as the nursing care. The gross direct cost associated with two years of rituximab maintenance therapy was estimated at $18,924, and $28, 986 when accounting for the additional therapeutic trial portion. The authors examined how much could be saved if MuSK MG patients who were frequent users of either IVIg or PE treatments switched to rituximab treatment instead. There were some patients with MuSK MG identified in case reports that were no longer in need of their IVIg or PE treatments due to their response to rituximab. Therefore, for this subset of patients where rituximab abolishes the need for these treatments, the reduction in direct net treatment costs per patient over two years is estimated to be $7,614 (for those patients on monthly PE treatments) to $167,134 (for patients administered weekly IVIg therapy). The authors concluded that “a 50% reduction in the total requirement for IVIg/PE would-be associated with an increased cost of $10,386 (monthly PE) to a reduction in cost of $69,374 (weekly IVIg) per patient over 2 years.” (p. 25) Detailed estimates of the costs associated with rituximab, IVIg, and PE for a therapeutic trial and two years of maintenance therapy are presented in Table 4, Appendix 4. Limitations What is the clinical effectiveness and safety of rituximab for patients with MuSK antibody-positive myasthenia gravis refractory to standard therapy? Due to the rarity of MG there were not high quality phase III placebo- or active-controlled trials to evaluate the effects of rituximab therapy. However, obtaining information solely from case series, case reports, and a registry imparts serious limitations on the interpretation of the evidence and the applicability to those with MG. The case series are uncontrolled studies that follow patients through their respective treatments. While they provide valuable information in situations where treatments for rare diseases are evaluated, there is simply not the population size or controlled aspect of bigger trial that would allow for generalizability and statistical analyses. The authors were cognizant of these limitations and their recommendation reflected that fact that they were utilizing sparse and uncontrolled data coming from studies with very small sample sizes. Therefore, one needs to use caution when interpreting the clinical effectiveness and safety of rituximab in patients with MuSK MG. There were many case series that contained mixed populations of patients with AChR, MuSK, both subtypes, or MG with no subtype specificity. While the results seemed promising in a lot of these studies, there remained ambiguity surrounding which subtype had what result. The only way clinical effectiveness and safety could be assessed in patients with MuSK MG was if the case series or case reports included only these patients (which a few did) or if the results for this group were reported separately (which was not done in the studies with mixed populations).


This creates problems when trying to assess the effects of rituximab in the MuSK subtype of MG, which was the focus of this review. As safety is a main outcome of interest in all studies that examine the use of biologics, the authors noted that there was a possibility that not all adverse events were reported or that adverse events may have been underreported. This comes from the observation of the low number of adverse events reported in each individual case series or report and the lack of commonly seen adverse events when biologics are used for other indications. It appeared that the adverse events of interest were those known to be the more serious adverse events associated with the use of rituximab. No economic analyses were identified for the treatment of rituximab for patients with MuSK MG; therefore, the authors provided cost estimates associated with a six month trial of rituximab and two years of maintenance therapy. While they did estimate the costs and potential costs savings associated with two more expensive treatments (IVIg and PE) there was not comparison of rituximab treatment versus other pharmacological therapies. In addition, the therapeutic strategy that was the basis for the analysis was from based on the experience of one physician which, therefore, may differ from the use of rituximab by other physicians. The generalizability of this treatment regimen is unknown. CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING While the evidence presented in this review support the use of rituximab for the treatment of patients with MuSK MG that have refractory disease or are intolerant of or contraindicated to the standards of care, the results should be interpreted with caution due to the paucity of high quality data. The evidence for effectiveness comes from case series and case reports with small sample sizes, differing treatment regimens, and mixed populations. Of the case reports and series reporting on patients with the MuSK subtype of MG (and in mixed populations), the data suggested that there is often clinical benefit in the reduction of symptoms (as observed with the MGFA-cc, MGFA-ps, and QMG scales), reduction or complete stop in concomitant medications (e.g. prednisone and immunosuppressants), reduction or complete stop in more costly therapies (e.g. IVIg and PE), and few adverse events. Again, results should be interpreted with caution given the lack of a control group (effects cannot be directly attributable to the intervention as one cannot account for placebo effects or changes over time) and the possibility of biased reporting (as such small studies are unlikely report negative results), especially in regard to the underreporting of adverse events. However, one should note that other case series and case reports reported clinical benefit of rituximab treatment in patients with MuSK MG,6,7 long-term benefits,6,8 and benefits in patients with co-morbid diseases.9,10 In addition, there appears to be some cost recovery or benefit when using rituximab in patients with MG, as there may be less of a need for the more expensive therapies such as the IVIg and PE treatments. Based on the available evidence, temporary and conditional approval of rituximab therapy in patients with MG that are hospitalized and either refractory to or intolerant of standard treatments or frequent users of IVIg or PE therapies was recommended in the included HTA. Randomized controlled trials are required to ascertain the true clinical effectiveness of rituximab in patients with MuSK MG; however, due to the rare nature of this disease, observational studies may be the best available evidence. The authors of the included HTA also recommend an ongoing, regularly maintained registry with study results and the most up-to-date information for neurological autoimmune diseases.


PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: 1-866-898-8439 www.cadth.ca


http://www.cadth.ca/

REFERENCES 1. Querol L, Illa I. Myasthenia gravis and the neuromuscular junction. Curr Opin Neurol.

2013 Oct;26(5):459-65.

2. Sinclair A, Nicolau I, Xie X, Dendukri N, McGregor M. The effectiveness and safety of rituximab (anti-CD20) in neurologic autoimmune diseases [Internet]. Montreal: Technology Assessment Unit (TAU) of the McGill University Health Centre (MUHC); 2013 Aug 30. Report no. 64. [cited 2014 Sep 28]. Available from: http://www.mcgill.ca/tau/files/tau/muhc_tau_2013_64_rituximab.pdf

3. El-Salem K, Yassin A, Al-Hayk K, Yahya S, Al-Shorafat D, Dahbour SS. Treatment of MuSK-Associated Myasthenia Gravis. Curr Treat Options Neurol. 2014 Apr;16(4):283.

4. Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol [Internet]. 2007 [cited 2014 Sep 28];7:10. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1810543/pdf/1471-2288-7-10.pdf

5. Department of General Practice, University of Glasgow. Critical appraisal checklist for economic evaluations [Internet]. Glasgow: The University; [cited 2014 Sep 23]. Available from: http://www.gla.ac.uk/media/media_64048_en.pdf Adapted from: Critical Appraisal Skills Programme (CASP), Public Health Resource Unit, Institute of Health Science, Oxford and Drummond et al. Methods for the economic evaluation of health care programmes. 2nd Edition. Oxford: Oxford Medical Publications, 1997.

6. Keung B, Robeson KR, DiCapua DB, Rosen JB, O'Connor KC, Goldstein JM, et al. Long-term benefit of rituximab in MuSK autoantibody myasthenia gravis patients. J Neurol Neurosurg Psychiatry. 2013 Dec;84(12):1407-9.

7. Maddison P, McConville J, Farrugia ME, Davies N, Rose M, Norwood F, et al. The use of rituximab in myasthenia gravis and Lambert-Eaton myasthenic syndrome. J Neurol Neurosurg Psychiatry. 2011 Jun;82(6):671-3.

8. Burusnukul P, Brennan TD, Cupler EJ. Prolonged improvement after rituximab: two cases of resistant muscle-specific receptor tyrosine kinase + myasthenia gravis. J Clin Neuromuscul Dis. 2010 Dec;12(2):85-7.

9. Kuntzer T, Carota A, Novy J, Cavassini M, Du Pasquier RA. Rituximab is successful in an HIV-positive patient with MuSK myasthenia gravis. Neurology. 2011 Feb 22;76(8):757-8.

10. Sadnicka A, Reilly MM, Mummery C, Brandner S, Hirsch N, Lunn MP. Rituximab in the treatment of three coexistent neurological autoimmune diseases: chronic inflammatory demyelinating polyradiculoneuropathy, Morvan syndrome and myasthenia gravis. J Neurol Neurosurg Psychiatry. 2011 Feb;82(2):230-2.


http://www.mcgill.ca/tau/files/tau/muhc_tau_2013_64_rituximab.pdf

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1810543/pdf/1471-2288-7-10.pdf

http://www.gla.ac.uk/media/media_64048_en.pdf

11. Jaretzki A, III, Barohn RJ, Ernstoff RM, Kaminski HJ, Keesey JC, Penn AS, et al. Myasthenia gravis: recommendations for clinical research standards. Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Neurology. 2000 Jul 12;55(1):16-23.


APPENDIX 1: Selection of Included Studies

59 citations identified from electronic literature search and screened

38 citations excluded

21 potentially relevant articles retrieved for scrutiny (full text, if

available)

3 potentially relevant reports retrieved from other sources (grey

literature)

24 potentially relevant reports

23 reports excluded: -irrelevant population (3) -irrelevant outcomes (1) -irrelevant study design (12) -already included in the selected HTA (7)

1 report included in review


APPENDIX 2: Summary of Selected Study and Patient Characteristics and Clinical Findings

Table 2: Patient and Study Characteristics and Clinical Findings for the Studies Included in the HTA

Author, Year

Pt Nos

Ab (n)

Study Design, Criteria for RI

Prior Tmts (n)

RI Dosing (n)

Starting Pt Status (n)

Ending Pt Status (n)

Medication Changes

Follow-up

AEsa (n)

Efficacy and Safety Full-Text Articles Collongues, 2013

20 • AChR (12) • MuSK (4) • Both (1) • None (3)

• Retro • Rf or

non-Rf

• Tx (18) • P (20) • AZA (11) • CYC (7) • MMF (12) • CPA (1)

• 375 mg/m2 weekly x 4 weeks (14) OR

• 1000 mg x 2 (6)

• MGFA-cc IIb (2)

• MGFA-cc IIIb (9)

• MGFA-ccIVb (8)

• MGFA-cc V (1)

• MGFA-cc I (1)

• MGFA-cc IIa (6)

• MGFA-cc IIb (6)

• MGFA-cc IIIa (3)


• MGFA-cc cIVb (1)

• NA (2)

• P stopped in non-Rf

• P decreased in 86% of Rf

• 27.9 mos

• Spondylo-discitis at 1 year post RI(1)

Diaz-manera, 2012

17 • AChR (11) • MuSK (6)

• Retro • Rf

• Tx (3/6) • P (14) • AZA (5) • CYC (1/3) • MMF (3) • CPA (4) • MTX (1) • TAC (1) • IVIg (6)

• 375 mg/m2 weekly x 4 weeks (14) the 375 mg/m2 monthly x 2

• MGFA-cc IIIa (2)


• MGFA-cc IVb (11)

• MGFA-cc V (2)

• MGFA-ps CSR (2)

• MGFA-ps I (10)

• MGFA-ps MM1 (2)

• MGFA-ps PR (2)

• MGFA-ps U (1)

• NR • 31 mos

• Mild infustion reaction (2)

Blum, 2011 14 • AChR (11) • MuSK (3)

• Retro, • Inadeq

uate

• Tx (8) • P (13) • AZA (9)

• 0.5 g x 2 within 2 weeks(n=1 x

• MGFA-cc IIa (1)

• MGFA-cc IIIb

• MGFA-ps CSR (1)

• MGFA-ps I

• Decrease of IS (n=12/14)

• 14.3 mos

• Mild infusion reaction (2)

• Altered



Author, Year

Pt Nos

Ab (n)


Prior Tmts (n)

RI Dosing (n)



Medication Changes

Follow-up

AEsa (n)

response

• Con-traindi- cation to IS

• CYC (1) • MMF (1) • CPA (5) • MTX (5) • TAC (3) • IVIg (11) • PE (2)

4 doses, n=1 x 1 dose)

(1) • MGFA-cc Iva

(1) • MGFA-cc IVb

(9) • MGFA-cc V

(2)

(5) • MGFA-ps

MM (3) • MGFA-ps

PR (3) • MGFA-ps

U (2)

• Decrease in P dose 52%

• IVIg -50% (n=6/9), +100% (n=1-9)

sense of taste and eosinophilia [presumed reactivation of giardiases] (1)

• Reactivation of oral herpes (1)

Guptill, 2011 6 • MuSK (6) • Retro • Rf

• Tx (2) • P (6) • MMF (5) • CPA (4) • IVIg (3) • PE (4)

• 375 mg/m2 weekly x 4 weeks then 375 mg/m2 monthly x 0-2

• NR • MGFA-ps I (2)

• MGFA-ps MM (3)

• MGFA-ps PR (1)

• NR • 21.8 mos

• No significant AEs

Maddison, 2011

9s • AChR (6) • MuSK (3)

• Retro • Not

de-fined

• Tx (6) • P (9) • CYC (1) • MMF (4) • CPA (2) • MTX (2) • IVIg (8) • PE (6)

• 375 mg/m2 weekly x 4 weeks, with repeat monthly dose in n=3


• MGFA-cc IVb (3)

• MGFA-cc V (4)

• MGFA-ps CSR (1)

• MGFA-ps I (3)

• MGFA-ps PR (1)

• MGFA-ps U (3)

• MGFA-ps W (1)

• NR • NR • No serious or significant AEs

• Fever and rigors (1)

Nowak, 2011 with follow-up in Nowak,

14 (9)

• AChR (6) • MuSK (8)

• Retro • Rf

• Tx (8) • P (14) • AZA (8)

• 375 mg/m2 weekly x 4 weeks, repeat every

• Only individual symptoms

• In update all pts achieved clinical

• 12/12 stopped PE after 3 cycles

• NR • Infusion reactions [flushing and



Author, Year

Pt Nos

Ab (n)


Prior Tmts (n)

RI Dosing (n)



Medication Changes

Follow-up

AEsa (n)

2012 (abstract)

• MMF (1) • CPA (1) • IVIg (1) • PE (12)

6 months remission chills/rigor] (6)

• Leucopenia (1)

Lindburg, 2010

5 • AChR (5)

• Retro • Not

de-fined

• Tx (3) • P (5) • AZA (3) • MMF (3) • CPA (3) • IVIg (3)

• 375 mg/m2 weekly x 4 weeks, then 375 mg/m2 every 3 months

• QMG mean 17.8

• QMG mean 6.2

• NR • 39.5 mos

• Deaths (1) due to HF 2 months post-RI [history of aortic valve disease, hyper-tension]

• Pneumonia and agranulocytosis (1) 1 month post-infusion

Abstracts Desnuelle, 2011

13 • AChR (10) • MuSK (1)

• Pros • Rf

• ≥ 3 lines conventional therapy including P, IvIg, PE

• 375 mg/m2 weekly x 4 weeks, then 375 mg/m2 x 2 at 6 months

• MGFA-cc IV-V (5)

• MGFA-cc II-III (8)

• MGFA-cc I-II (13)

• Decrease in P in 42%

• 6 mos (n=13)

• 12 mos (n=8)

• None

Di Virgillo, 2011

8 • MuSK (2) • Pros • Tmt

failure or se-rious

• NR • 1000 mg x 2 within 15 days

• NR • 6/8 clinical response

• Decrease in P 75%

• Decrease in other meds

• 4-24 mos

• None



Author, Year

Pt Nos

Ab (n)


Prior Tmts (n)

RI Dosing (n)



Medication Changes

Follow-up

AEsa (n)

side effects, need for frequent PE

75%

Tandan, 2008

6 • NR • OL, Phase I, pros, 35 week, active, symptomatic

• Rf

• NR • 375 mg/m2 weekly x 4 weeks

• QMG 16.2 • QMG 12.8 ± 9.6

• NR • 7 mos • Hypotension during infusion (2)

Safety Only Full-Text Articles Rezania, 2012

2 • Follicular lymphoma (1)

• Walden- Strom, LPL (1)

• NR • NR • NR • NR • NR • NR • ≥ 5 yrs n=1

• 4 yrs n=1

• Severe allergic reaction leading to discontinuation (1)

Butterly, 2010

2 • AChR (1) • MuSK (1)

• NR • NR • NR • NR • NR • NR • 18 mos

• None

Hain, 2006 1 • MuSK

• NR • NR • NR • NR • NR • NR • 12 mos

• None

Zaja, 2000 1 • Not specified

• AML

• NR • NR • NR • NR • NR • NR • 6 mos • None



Author, Year

Pt Nos

Ab (n)


Prior Tmts (n)

RI Dosing (n)



Medication Changes

Follow-up

AEsa (n)

Abstracts or Posters Menge, 2012

3 • NR • NR • NR • NR • NR • NR • NR • 11 mos (5-36 range)

• Unspecified AEs (1)

Kundi, 2010 3 • NR • NR • NR • NR • NR • NR • NR • NR • None Michaels, 2009

3 • NR • NR • NR • NR • NR • NR • NR • 22-35 mos

• Well tolerated

Gardner, 2008

2 • AChR (1) • MuSK (1)

• NR • NR • NR • NR • NR • NR • > 1 year

• None attributable to RI

Jordan, 2007

1 • MuSK • NR • NR • NR • NR • NR • NR • 34 mos

• No therapy-associated AEs, no SAEs

Ab = antibody; AChR = acetylcholine receptor; AE = adverse event; AML = acute myeloid elukemia; AZA = azathioprine; CPA = cyclosporine; CYC = cyclophaosphamide; HTA = health technology receptor; IS = immunosuppressants IVIg = intravenous immunoglobulin; LPL = lymphoplasmacytic lymphoma; MG = myasthenia gravis; MGFA-cc = Myasthenia Gravis Foundation of America Clinical Classification; MGFA-ps = Myasthenia Gravis Foundation of America PostIntervention Status (CSR = complete stable remission; I = improved; MM, MM1, MM2, MM3 = minimal manifestations; PR = pharmacological remission; U = unchanged; W = worsened; D = died); MMF = mycophenolate mofetil; mos = months; MTX = methotrexate; MuSK = muscle specific receptor kinase; NA = not available; Nos = numbers; NR = not reported; OL = open label; P = prednisone; PE = plasmapheresis; pros = prospective; retro = retrospective; Rf = refractory; RI = rituximab; SAE = serious adverse event; TAC = tacrolimus; tmt = treatment; Tx = thymectomy; yrs = years. a Only specific of-interest adverse events were reported


APPENDIX 3: Description of Scales Used to Assess Myasthenia Gravis

Table 3: Description of Scales Used to Assess MGa

Scale Level Description MGFA-cc Class I • “Any ocular muscle weakness”

• “May have weakness of eye closure” • “All other muscle strength is normal”

Class II • “Mild weakness affecting other than ocular muscles” • “May also have ocular muscle weakness of any severity”

IIa • “Predominantly affecting limb, axial muscles, or both” • “May also have lesser involvement of oropharyngeal muscles”

IIb • “Predominantly affecting oropharyngeal, respiratory muscles, or both” • “May also have lesser or equal involvement of limb, axial muscles, or

both” Class III • “Moderate weakness affecting other than ocular muscles”

• “May also have ocular muscle weakness of any severity” IIIa • “Predominantly affecting limb, axial muscles, or both”

• “May also have lesser involvement of oropharyngeal muscles” IIIb • “Predominantly affecting oropharyngeal , respiratory muscles, or both”

• May also have lesser or equal involvement of limb, axial muscles, or both”

Class IV • “Severe weakness affecting other than ocular muscles” • “May also have ocular muscle weakness of any severity”

IVa • “Predominantly affecting limb and /or axial muscles” • “May also have lesser involvement of oropharyngeal muscles”

IVb • “Predominantly affecting oropharyngeal , respiratory muscles, or both” • May also have lesser or equal involvement of limb, axial muscles, or

both” Class V • “Defined by intubation, with or without mechanical ventilation, except

when employed during routine postoperative management. The use of a feeding tube without intubation places the patient in class IVb.

MGFA-ps CSR • “The patient has had no symptoms or signs of MG for at least 1 year

and has received no therapy for MG during that time. There is no weakness of any muscle on careful examination by someone skilled in the evaluation of neuromuscular disease. Isolated weakness of eyelid closure is accepted.”

PR • “The same criteria as for CSR except that the patient continues to take some form of therapy for MG. Patients taking cholinesterase inhibitors are excluded from this category because their use suggests the presence of weakness.”

MM • “The patient has no symptoms of functional limitations from MG but has some weakness on examination of some muscles. This class recognizes that some patients who otherwise meet the definition of CSR or PR do have weakness that is only detectable by careful examination.”

MM-0 • “The patient has received no MG treatment for at least 1 year” MM-1 • “The patient continues to receive some form of immunosuppression

but no cholinesterase inhibitors or other symptomatic therapy” MM-2 • “The patient has received only low-dose cholinesterase inhibitors

(<120 mg pyridostigmine/day) for at least 1 year”



Scale Level Description MM-3 • “The patient has received cholinesterase inhibitors or other

symptomatic therapy and some form of immunosuppression during the past year”

Change in status in MGFA-ps I • “A substantial decrease in pretreatment clinical manifestations or a

sustained substantial reduction in MG medications as defined in the protocol. In prospective studies, this should be defined as a specific decrease in QMG score”

U • “No substantial change in pretreatment clinical manifestations or reduction in MG medications as defined in the protocol. In prospective studies, this should be defined in terms of a maximum change in QMG score”

W • “A substantial increase in pretreatment clinical manifestations or a substantial increase in MG medications as defined in the protocol. In prospective studies, this should be defined as a specific increase in QMG score”

E • “Patients who have fulfilled criteria of CSR, PR, or MM but subsequently developed clinical findings greater than permitted by these criteria”

D of MG • Patients who died of MG, of complications of MG therapy, or within 30 days after thymectomy”

QMG Test Item None Mild Moderate Severe Score Grade 0 1 2 3 - DB on lateral gaze right or left, s 61 11-60 1-10 SP - Ptosis (upwards gaze), s 61 11-60 1-10 SP -

Facial muscles N lid closure Complete, weak, some R

Complete, without R Incomplete -

Swallowing 4 oz. water N Min coughing,

throat clearing

Severe coughing/choking,

or nasal regurgitation

Cannot swallow (test

un-attempted)

-

Onset of dysarthria b None at 50 30-49 10-29 9 - Right arm outstretched (90 deg sitting), s

240 90-239 10-89 0-9 -

Left arm outstretched (90 deg sitting), s

240 90-239 10-89 0-9 -

Vital capacity, % predicted ≥ 80 65-79 50-64 < 50 - Right-hand grip, kgW

Men ≥ 45 15-44 5-14 0-4 - Women ≥ 30 10-29 5-9 0-4 -

Left-hand grip, kgW Men ≥ 35 15-34 5-14 0-4 - Women ≥ 25 10-24 5-9 0-4 -

Head lifted (45 deg 120 30-119 1-29 0 -



Scale Level Description supine), s Right leg outstretched (45 deg supine), s

100 31-99 1-30 0 -

Left leg outstretched (45 deg supine), s 100 31-99 1-30 0 - cc = clinical classification; CSR = complete stable remission; D = death; DV = double vision; E = exacerbation; I = improved; MG = myasthenia gravis; MGFA = Myasthenia Gravis Foundation of America; min = minimal; MM = minimal manifestations; N = normal; oz. = ounces; PR = pharmacologic remission; ps = postintervention status; QMG = Quantitative Myasthenia Gravis scoring system; R = resistance; s = seconds; SP = spontaneous; U = unchanged; W = worse. a Verbatim descriptions. b Test: Speech after counting aloud from 1 – 50. Source: Jaretzki et al.11


APPENDIX 4: Summary of Economic Estimates Table 4: Estimates of Average Therapeutic and 2 Year Treatment Costs with Rituximab, IVIg,

and PE Therapy Estimated Cost ($)

Therapeutic Trial Rituximab (1 g) 9,262 Nursing (hour) 200 Total 9,462 Maintenance Therapy in 2 years Rituximab Rituximab (1 g) 18,524 Nursing 400 Total 18,924 Total (trial plus maintenance) 28,986 IVIg IVIg (3 vials/week) 174,720 IVIg (3 vials/3 weeks) 58,800 Nursing (1 therapy/week) 20,800 Nursing (1 therapy/3 weeks) 7,000 Total (1 therapy/week) 195,520 Total (1 therapy/3 weeks) 65,800 PE Total: PE (1 session/week) 156,000 Total: PE (1 session/month) 36,000 IVIg = intravenous immunoglobulins; PE = plasmapheresis.


APPENDIX 5: Summary of Critical Appraisal

Table 5: Critical Appraisal Summary of the Health Technology Assessment Author, Year Strengths Limitations

Sinclair et al., 20132

• Objectives, research questions, and inclusion criteria clearly presented and established a priori.

• Comprehensive literature search.

• In depth patient and study

characteristics included where available from the articles.

• Scientific quality of the included

studies was used appropriately when forming recommendations.

• Provided an economic analysis

based on the direct cost of treatment when used for a brief trial or a two year maintenance program.

• Discussed with expert the costs

associated with the IVIg, PE, and rituximab therapy in Canada

• Quality of evidence was limited and low (included only available evidence - case series and reports).

• Even though no language restrictions

were in place for the search, information was not included if the abstracts were not presented in English or French.

• No formal grading of evidence or

recommendations.

• Conflicts of interest not declared. • No estimate of cost of rituximab

versus standard of care.

• Did not consider all outcomes when assessing the costs; only costs associated with a therapeutic trial, maintenance therapy, and the potential impacts of costs when more costly therapies were affected. Costs of treatments other than rituximab, IVIg and PE were not considered.

• Obtained rituximab treatment

information to base their estimates on from only one physician.

• Complications were not considered in

the cost analysis. MG = myasthenia gravis.


APPENDIX 6: Summary of Findings and Recommendations

Table 6: Summary of Findings and Recommendations of the Health Technology Assessment

Author, Year Main Study Findings Recommendations/Author`s Conclusions

Sinclair et al., 20132

Clinical Improvement: • Majority of MG pts (most of whom

were classified as having severe disease) had clinical improvement:

o 69/77 (89.6%) of pts in CS o 29/34 (85.3%) of pts in

CR. • ~1/3 of those in CS and ~ ½ of

those in CR were asymptomatic or had minimal disease manifestations at follow-up.

IVIg and PE Discontinuations after RI Treatment in: • 12/15 pts (2 CS) receiving IVIg. • 18/18 pts (3 CS) receiving PE.

Safety: • 2 pts hospitalized with infections. • 1 pt had infusion reaction and

discontinued treatment.

• No AEs of an unexpected type.

• Due to small pt samples and uncontrolled study-types, the main study findings cannot be considered generalizable.

Recommendations: MG, Neuromyelitis Optica, Dermatomyositis, and Chronic Inflammatory Demyelinating Polyneuropathy: • “The data are of insufficient quantity

and quality to support a recommendation for the routine use of rituximab in any of these four conditions.” page 29

Myasthenia gravis: • “There is sufficient evidence to

support temporary and conditional approval of rituximab in the treatment of patients with myasthenia gravis under the conditions outlined below: o Hospitalized patients whose

disease is refractory to other therapies

o Hospitalized patients whose treatment options are limited due to intolerance or contraindications to more accepted therapies.

o Patients who require very frequent use (more frequently than 10 days) of IVIg or PE

o The number of new patients treated per year be limited to 10.” page 30

• “Since the present evidence

concerning the use of rituximab is sparse, all relevant patient data should be collected and maintained in a regularly updated registry. In particular this should contain: Diagnostic data, reason for treatment, symptomatic status before and after treatment, dosage, adverse events.”


Table 6: Summary of Findings and Recommendations of the Health Technology Assessment

Author, Year Main Study Findings Recommendations/Author`s Conclusions

page 30 • “The registry should be examined

whenever appropriate, and at the latest in two years, at which time the question of permanent approval should be considered.” page 30

AE = adverse event; CR = case report; CS = case series; IVIg = intravenous immunoglobulin; MG = myasthenia gravis; PE = plasmapheresis; pts = patients.


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