TITLE: Rituximab for Granulomatosis with Polyangiitis or Microscopic Polyangiitis: A Review of the Clinical and Cost-effectiveness

Transcription

1 TITLE: Rituximab for Granulomatosis with Polyangiitis or Microscopic Polyangiitis: A Review of the Clinical and Cost-effectiveness DATE: 28 January 2015 CONTEXT AND POLICY ISSUES Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are both antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) variants. AAVs are a subtype of antibody-associated autoimmune diseases and can be associated with circulating ANCAs. ANCAs against proteinase 3 are often equivalent to cytoplasmic ANCA and found in GPA, while ANCAs against myeloperoxidase are often equivalent to perinuclear ANCA and found in MPA. 1 Besides ANCA differences, respiratory tract granulomas are a characteristic specific to GPA along with an increased risk of relapse as compared to MPA. The most common severe manifestation of both GPA and MPA is associated with pauci-immune necrotising glomerulonephritis, which left untreated progresses to end-stage renal disease. 2 Other symptoms of GPA and MPA are heterogeneous, involve multiple systems, and tools such as the Birmingham Vasculitis Activity Score (BVAS) can assist in defining disease remissions, relapses, and flares. 1,3-5 Traditional AAV remission induction treatment regimens of cyclophosphamide (CYC) and highdose glucocorticoids have reduced the one-year mortality from 80% to 10-20%. 2 Rituximab (RTX) is a chimeric monoclonal antibody against CD20 that results in rapid B cell depletion. Originally approved for use in B cell lymphoma, RTX has also demonstrated efficacy in rheumatoid arthritis, another antibody-associated autoimmune disease. 2 Two randomized controlled trials (RCTs), RAVE and RITUXVAS, have also demonstrated RTX was not inferior to the traditional CYC-based remission induction treatments for AAV. 1,3 Maintenance of remission also remains a challenging aspect of GPA and MPA. Standard therapies result in a relapse rate of 50% for newly diagnosed AAV patients, and for those experiencing a relapse the relapse rate is higher still. 2 An initial course of RTX is a clinically efficacious treatment for remission induction, 2,3 and subsequent RTX treatments beyond the initial course are being used for remission maintenance in some AAV patients. 2,4-7 RTX mediated B cell depletion is effective in reducing ANCA-producing cells but, like CYC, can significantly reduce immunoglobulin (Ig) levels and increase the risk of infection. 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 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.

2 Hypogammaglobulinaemia (HGG) is a condition associated with B cell depletion which is commonly associated with a large increase in the risk of severe infections in other contexts. 6 RTX is contraindicated in patients with malignancy, infection (including hepatitis B and human immunodeficiency virus), and pregnancy. 8 While long-term repeated dosing of RTX appears safe in the treatment of rheumatoid arthritis, safety concerns specific to AAV patients are warranted. 1 The purpose of this report is to retrieve and review existing evidence for the clinical effectiveness, safety, and cost-effectiveness of RTX treatments, beyond the initial course, for the maintenance of remission in GPA and MPA patients. RESEARCH QUESTIONS 1. What is the clinical effectiveness and safety of rituximab beyond the initial course for patients with GPA and MPA who respond to initial re-treatment and experience a flare? 2. What is the clinical effectiveness and safety of rituximab beyond the initial course for patients with GPA and MPA who partially respond to initial treatment and need continued treatment to maintain remission? 3. What is the clinical effectiveness and safety of rituximab beyond the initial course for patients with GPA and MPA who initially do not respond but subsequent doses achieve remission and maintenance is required to maintain remission? 4. What is the cost-effectiveness of rituximab beyond the initial course for patients with GPA and MPA to achieve or maintain remission? KEY FINDINGS No evidence was identified that compared the clinical effectiveness of rituximab and cyclophosphamide and/or glucocorticoids for granulomatosis with polyangiitis or microscopic polyangiitis remission maintenance after remission induction with rituximab. Adverse event evidence from four identified uncontrolled, observational trials suggested that the most common serious adverse event was infection. METHODS Literature Search Strategy A limited literature search was conducted on key resources including PubMed, The Cochrane Library (2014, Issue 12), 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 December 20, Selection Criteria and Methods One reviewer screened the titles and abstracts of the retrieved publications and evaluated the full-text publications for inclusion, according to selection criteria presented in Table 1. RC0631 Rituximab for GPA or MPA 2

3 Population Intervention Comparator Outcomes Study Designs Table 1: Selection Criteria Patients in the community setting with GPA or MPA Rituximab beyond an initial course of weekly intravenous (IV) treatment for 4 weeks Cyclophosphamide, glucocorticoids, or no extended treatment (for safety only) Clinical outcomes, safety, cost-effectiveness Health Technology Assessments (HTA)/ Systematic review (SR)/Meta-analysis (MA); RCTs; non-randomized studies; and Economic evaluations Exclusion Criteria Studies were excluded if they did not meet the selection criteria, were duplicate publications, or were published prior to Critical Appraisal of Individual Studies A formal quality assessment of the included uncontrolled, observational studies was not conducted since they provide limited information on adverse events. The quality of these studies is discussed in the limitations section. SUMMARY OF EVIDENCE Quantity of Research Available The literature search strategy identified 174 citations. One reviewer screened titles and abstracts and identified 18 potentially relevant articles for which the full text was retrieved for further review. One additional potentially relevant report was identified in the grey literature. Upon review, four uncontrolled, observational studies met the selection criteria (Table 1). The excluded 15 studies consisted of six that examined an irrelevant population, two examined irrelevant outcomes, one examined an irrelevant intervention, one evaluated an irrelevant comparator, one was a duplicate publication, three were reviews, and one was correspondence. No health technology assessments, systematic reviews, meta-analyses, or cost-effectiveness studies met the inclusion criteria. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart describes the selection procedure of the included studies of this review (Appendix 1). One RCT examined AAV patients in complete remission after a cyclophosphamideglucocorticoid regimen. The findings from this open-label RCT demonstrated RTX superiority to azathioprine for relapse prevention in newly diagnosed and relapsing granulomatosis with polyangiitis patients. 1 This study was excluded due to the irrelevant comparator, azathioprine. RC0631 Rituximab for GPA or MPA 3

4 Summary of Study Characteristics Clinical effectiveness The characteristics of the included studies are tabulated in Appendix 2. Study design The included studies were uncontrolled, observational studies. Population Two studies included GPA patients. 4,6 The remaining two studies included patients in remission for GPA or MPA. 5,7 In total, these observational studies included 176 patients with these AAV variants. Patients in these studies had received RTX for induction of remission either as part of the study or prior to enrollment. 4-7 Intervention and Comparators Interventions examined in the identified studies varied considerably. 4-7 In two studies, RTX was used to induce remission, 4,6 and all four also examined RTX for remission maintenance. 4-7 One examined intravenous (IV) RTX, 1g per week for two weeks annually or 1g every six months, with prednisolone and other IDs and/or CYC or nothing for remission maintenance. 6 Remission maintenance using IV RTX at 375mg/m 2 per week for four weeks or 1g per week for two weeks along with continuation of AZA, MTX, CYC, or mycophenolate mofetil (MMF) was examined in one study. 4 Another observational study examined the use of 375mg/m 2 IV RTX per week for four weeks or 1g per week for two weeks to maintain remission. 5 The observational study published in 2012 included examined remission maintenance using 375mg/m 2 IV RTX biannually, 1g biannually, 1g annually, and other regimens. This study also included corticosteroids and/or other IDs and the doses were tapered to varying degrees or not at all. 7 Outcomes This report presents outcomes related to safety. A complete list of outcomes reported in the included studies, however, is available in Appendix 2, Table A2.1. Two studies reported Ig levels and HGG, 6,7 and these outcomes were the primary focus of one of these studies. 6 One observational study reported infusion related adverse events, 4 three reported infections, 4,5,7 and two reported malignancies and death. 4,5 One study distinguished between chronic, opportunistic, and non-opportunistic infections. Chronic infections were defined as lasting more than three months and requiring multiple courses of antibiotic treatment. The authors did not describe how opportunistic and non-opportunistic infections were differentiated. 4 Summary of Critical Appraisal A formal quality assessment of the included studies was not conducted. The limitations section comments on the quality of these studies. RC0631 Rituximab for GPA or MPA 4

5 Summary of Findings The studies reported infection as the most common serious adverse event. 4-7 HGG, a known risk factor for severe infection in other contexts, was reported to occur more frequently in males, in patients receiving 1g RTX biannually as compared to 2g annually, and in those patients receiving a higher cumulative CYC dose. 6 HGG was examined in one other study where it occurred in 15 out of 21 patients in 38 months. Both studies did not attribute HGG exclusively to RTX remission maintenance as the patients had received other medications, including CYC and corticosteroids, which possibly contributed to decreased Ig levels. It was also not established, but suggested that HGG in the context of the AAV maintenance therapy contributed to an increased risk of infection. 6,7 Infusion-related adverse events were reported in three studies, one reported no infusion-related events in 21 patients, 7 while one study reported one severe reaction to RTX infusion out of 66 patients. 4 One study reported 16 infusion-related events in 53 patients during patient-years, and the authors note that these adverse events were mild, they did not preclude retreatment, and 14 of the 16 infusion-related events occurred during the first RTX infusion. 5 There was no evidence identified supporting an optimal RTX dose or maintenance regimen. Limitations Safety data presented in this report are from uncontrolled, observational studies with numerous limitations. While these studies contained information on adverse events occurring during RTX maintenance therapy for AAV, the studies lacked controls, consistent intervention, and blinding. Clinical effectiveness data from these studies was a challenge to interpret and was not included in this report. Further investigation into the long-term safety of RTX for AAV remission maintenance is required. CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING No evidence was identified comparing RTX remission maintenance to CYC and/or glucocorticoids in any AAV population after an initial RTX induced remission. Evidence from identified in four uncontrolled, observational studies provided adverse event evidence and demonstrated that, after an initial RTX induced remission, infection was the most common serious adverse event during RTX remission maintenance. With treatment, infection is now considered to be the leading cause of death among GPA patients. 4,9 The longest follow-up time averaged 4.4 years in one uncontrolled, observational study of 53 GPA patients, therefore evidence for long-term RTX safety requires further investigation, especially in the context of AAV remission maintenance requiring regular RTX infusions. 5 No cost-effectiveness studies were identified that met the inclusion criteria. PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: RC0631 Rituximab for GPA or MPA 5

6 LIST OF ABBREVIATIONS ANCA AVA BVAS CI CYC GPA HR ID IV MMF MPA MTX RCT RTX TMP-SMX VDI anti-neutrophil cytoplasmic antibody ANCA-associated vasculitis Birmingham Vasculitis Activity Score confidence interval cyclophosphamide granulomatosis with polyangiitis hazard ratio immunosuppressive drug intravenous mycophenolate mofetil microscopic polyangiitis methotrexate randomized controlled trial rituximab trimethoprimsulfamethoxazole Vasculitis Damage Index RC0631 Rituximab for GPA or MPA 6

7 REFERENCES 1. Guillevin L, Pagnoux C, Karras A, Khouatra C, Aumaitre O, Cohen P, et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med Nov 6;371(19): Jones RB. Rituximab in the Treatment of Anti-Neutrophil Cytoplasm Antibody-Associated Vasculitis. Nephron Clin Pract [Internet] Nov 14 [cited 2015 Jan 2]. Available from: 3. Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med [Internet] Jul 15 [cited 2015 Jan 2];363(3): Available from: 4. Calich AL, Puechal X, Pugnet G, London J, Terrier B, Charles P, et al. Rituximab for induction and maintenance therapy in granulomatosis with polyangiitis (Wegener's). Results of a single-center cohort study on 66 patients. J Autoimmun May;50: Cartin-Ceba R, Golbin JM, Keogh KA, Peikert T, Sanchez-Menendez M, Ytterberg SR, et al. Rituximab for remission induction and maintenance in refractory granulomatosis with polyangiitis (Wegener's): ten-year experience at a single center. Arthritis Rheum [Internet] Nov [cited 2015 Jan 2];64(11): Available from: 6. Besada E, Koldingsnes W, Nossent JC. Serum immunoglobulin levels and risk factors for hypogammaglobulinaemia during long-term maintenance therapy with rituximab in patients with granulomatosis with polyangiitis. Rheumatology (Oxford) Oct;53(10): Roubaud-Baudron C, Pagnoux C, Meaux-Ruault N, Grasland A, Zoulim A, LE GJ, et al. Rituximab maintenance therapy for granulomatosis with polyangiitis and microscopic polyangiitis. J Rheumatol Jan;39(1): Kattah AG, Fervenza FC. Rituximab: emerging treatment strategies of immune-mediated glomerular disease. Expert Rev Clin Immunol Jul;8(5): Latimer N, Carroll C, Wong R, Tappenden P. Rituximab in combination with corticosteroids for the treatment of anti-neutrophil cytoplasmic antibody-associated vasculitis [Internet]. Sheffield, UK: University of Sheffield; 2013 May 30. [cited 2015 Jan 5]. Available from: data/assets/pdf_file/0006/82635/ergreport pdf RC0631 Rituximab for GPA or MPA 7

8 APPENDIX 1: Selection of Included Studies 174 citations identified from electronic literature search and screened 156 citations excluded 18 potentially relevant articles retrieved for scrutiny (full text, if available) 1 potentially relevant report retrieved from other sources (grey literature, hand search) 19 potentially relevant reports 15 reports excluded: -irrelevant population (6) -irrelevant intervention (1) -irrelevant comparator (1) -irrelevant outcomes (2) -duplicate publication (1) -other (review articles, correspondence) (4) 4 reports included in review RC0631 Rituximab for GPA or MPA 8

9 APPENDIX 2: Summary of Study Characteristics Table A2.1: Summary of Study Characteristics of Included Uncontrolled, observational Studies (Safety only) Study Design Population (sample size of trials) Intervention Outcomes Uncontrolled, observational Studies Besada et al., Uncontrolled, retrospective observational study in Norway Median followup of 4 years GPA (n = 29) Induction: IV RTX (1g per week for 2 weeks) with 125mg methylprednisolone, 1000mg paracetamol and 10 mg cetirizine or 4mg polaramine. Maintenance: IV RTX (1g per week for 2 weeks annually or 1g every 6 months) with prednisolone and other IDs (n = 27) and/or CYC (n = 9, median dose 5g) or nothing (n=2) Ig levels Hypogammaglobulinaemia Calich et al., Uncontrolled, retrospective observational study in France Average followup of 34 months GPA (n = 66) Cartin-Ceba et al., Uncontrolled, Patients in retrospective remission of observational GPA or MPA study in (n = 53) France Average followup of 4.4 years Roubaud-Baudron et al., Uncontrolled, Patients in retrospective remission of Induction: IV RTX (375mg/m 2 per week for 4 weeks (92.4%) or 1g per week for 2 weeks (7.6%)) with prednisone and/or methylprednisolone and/or AZA and/or MTX and/or CYC and/or MMF and/or TMP-SMX Maintenance: IV RTX (375mg/m 2 or 500mg every 6 months for 18 months) along with some continuation of AZA (n = 4), MTX (n = 3), CYC (n = 6), or MMF (n = 3). Additionally 26 patients were prescribed TMP-SMX. Relapse: IV RTX (375mg/m 2 per week for 4 weeks or 1g per week for 2 weeks) with oral prednisone, IV methylprednisolone with stepwise dosage reductions Maintenance: IV RTX (375mg/m 2 per week for 4 weeks or 1g per week for 2 weeks) with no prednisone Relapse was indicated by defined conditions of ANCA levels or B lymphocyte reconstitution Maintenance: IV RTX therapy (Average 4 IV doses RTX BVAS score VDI Relapse Ig levels Adverse events (infusion related, chronic and opportunistic infections, malignancy, and death) BVAS score Relapse Ig levels Adverse events (infusion related, infections, malignancy, and death) Relapse ANCA levels RC0631 Rituximab for GPA or MPA 9

10 Study Design observational study Rochester MN Median followup of 38 months Population (sample size of trials) GPA (n = 24) or MPA (n = 4) Intervention (375mg/m 2 biannually (n = 13), 1g biannually (n = 4), 1g annually (n = 3) and other regimens (n = 8) over an average of 38 months). First maintenance included corticosteroids (n = 23), and/or other IDs (n = 14; AZA (n = 6), MMF (n = 5), lefunomide (n = 1), and/or MTX (n = 4)). Corticosteroids and other IDs were tapered or stopped to varying degrees. Outcomes CD19+ lymphocytes Adverse events (infusion related, hypogammaglobulinaemia, infections) ANCA=antineutrophil cytoplasmic antibody; AZA=azathioprine; BVAS/WG=Birmingham Vasculitis Activity Score; CYC=cyclophosphamide; GPA=granulomatosis with polyangiitis; ID=immunosuppressive drug; MMF=mycophenolate mofetil; MPA=microscopic polyangiitis; MTX=methotrexate; RTX=rituximab; TMP-SMX=trimethoprimsulfamethoxazole; VDI=Vasculitis Damage Index; RC0631 Rituximab for GPA or MPA 10

11 Appendix 3: Summary of Findings Table A3.1: Summary of Adverse Event Findings of Included Uncontrolled, observational Studies Main Relevant Study Findings Authors Conclusions Uncontrolled, observational Studies Besada et al., HGG Male gender and the 1 g biannually 8/29 (28%) discontinued RTX maintenance therapy due regimen were risk factors for RTX to HGG discontinuation due to hypogammaglobulinaemia. (pp.1822) Risk factors for HGG (p 0.05) Male gender - multivariate analysis HR (95% CI): 8.7 (1.00, 76) p = HR>1 increased hazard of HGG occurrence for males 1g biannual RTX regimen vs 2g annual RTX regimen - multivariate analysis HR (95% CI): 8.7 (1.14, 63) p = HR>1 increased hazard of HGG occurrence for 1g biannual regimen Total cumulative CYC dose - unadjusted analysis HR (95% CI): 1.14 (1.01, 1.3) p = HR>1 increased hazard of HGG occurrence for totally cumulative CYC dose Calich et al., reported over the followup period (188.1 patient-years) Infections (non-opportunistic) (no. of events)) 11 Infections (opportunistic) (no. of events) 2 Infections (chronic) (no. of events)) 2 Infusion reaction (no. of events) 1 Malignancy (no. of events) 2 Pulmonary embolism (no. of events) 1 As hypogammaglobulinaemia may limit the number of times anti-cd20- mediated B cell depletion can be carried out, close monitoring of Ig and lymphocyte subtypes during maintenance is warranted, as hypogammaglobulinaemia with a low CD4/CD8 ratio is a known risk factor for severe infections in AAV. (pp Maintenance treatment with low doses of RTX in a routine time-based protocol was safe. (pp. 135) We detected no association between low immunoglobulin levels and infection, possibly because of the low dose of RTX used in our study. (pp. 140) RC0631 Rituximab for GPA or MPA 11

12 Main Relevant Study Findings Authors Conclusions Late-onset neutropenia (grade IV) (no. of events) 1 Cartin-Ceba et al., reported over the followup period (53 patients with an average followup of 4.4 years) Death (no. of events) 2 Infection (no. of events) 30 Infusion-related events (no. of events) 16 Roubaud-Baudron et al., Adverse events recorded for 21 patients over median followup of 38 months Infusion-related events (no. of events) 0 HGG (no. of events) 15 Overall, 30 infections were reported. Most of these were related to the respiratory tract... No case of progressive multifocal leukoencephalopathy was identified. (pp. 3775) Infusion-related adverse events were few, mild, and did not preclude retreatment with RTX. The number of infections requiring antimicrobial therapy was very low, given the extended followup period and the large number of sequential courses of RTX received by these patients. (pp. 3775) Three patients developed infections: 1 cutaneous abscess, 1 otitis media that resolved rapidly under antibiotics, and 1 fatal H1N1 flu infection. The latter patient had normal immunoglobulin levels at the time of her last RTX infusion 6 months before she died (not measured when she developed H1N1 flu), and the 2 others were hypogammaglobulinemic. (pp. 128) Infection (no. of events) 3 (1 fatal H1N1 flu) CI=confidence interval; CYC=cyclophosphamide; HGG=hypogammaglobulinaemia; HR=hazard ratio; RTX=rituximab; RC0631 Rituximab for GPA or MPA 12