Key considerations for modelling the long-term costs and benefits of treatments for ANCA-associated vasculitis.

OBJECTIVES: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of severe and chronic autoimmune diseases. Patients undergo two treatment phases: inducing remission and maintaining remission to prevent organ damage. Immunosuppressants, including glucocorticoids (GCs) are used as first-line treatment, but long-term GC use is associated with toxic effects. Novel treatments reduce or replace the need for long-term GC, and therefore can reduce GC-related toxicity. The evolving treatment landscape has presented new challenges for health technology assessment (HTA) of new treatments in AAV and long-term modelling of costs and outcomes in this disease. METHODS: Using the appraisal of avacopan in England (NICE) as a case study, this paper aims to identify the key challenges involved in the economic evaluation of new treatments for AAV, with a particular focus on the long-term modelling of the treatment costs and benefits for the purpose of HTA. The outcome of this study is a set of recommendations for modelling the cost-effectiveness of new treatments for AAV from the HTA perspective. RESULTS: The discussion focuses on the appropriate model structure, approach to modelling end-stage renal disease (ESRD) as a key determinant of costeffectiveness, capturing the impact of GC-related adverse events, and estimation of short and long-term costs of AAV. CONCLUSIONS: Economic evaluation of new treatments for AAV needs to capture all relevant downstream effects. ESRD is a key driver of cost-effectiveness but is associated with major uncertainty. Future observational studies need to offer sufficient detail to allow for differentiation in event rates across treatment options.

Healthcare and economic burden of ANCA-associated vasculitis in Italy: an integrated analysis from clinical and administrative databases.

ANCA-associated vasculitides (AAV) comprise a group of systemic vasculitides characterized by inflammation of small-sized blood vessels leading to multi-organ involvement. The worldwide annual incidence of AAV ranges from 1.2 to 3.3 cases per 100 000 individuals with a prevalence of 4.6-42.1 cases per 100 000 individuals. The prevalence of AAV is geographically heterogeneous; therefore, regional epidemiological studies can be more informative to improve health care systems. Even though clinicians are aware that the healthcare burden and the risk of hospitalization of AAV appear high, data on hospitalization and cost of illness due to AAV are still scarce or even lacking. This study aims to characterize the economic burden of AAV in Friuli Venezia Giulia (FVG), Italy. Thus, a retrospective study was conducted through the integration of many administrative health databases of the FVG as the source of information. From data integration, we estimated that more than two-thirds of AAV patients showed at least one hospitalization in their medical history, most frequently caused by the disease itself or superimposed infections. Around 10% of patients developed end-stage renal disease. In an 8-year follow-up, the overall healthcare cost was € 1,215,078, corresponding to € 6,168 patient-year. ANCA-positive patients showed much higher costs than ANCA-negative patients did. Overall, AAV are rare diseases, but imply very high healthcare costs. Early diagnosis and optimal treatment probably still remain unmet needs for AAV.

Cost-minimization analysis of individually tailored or fixed-scheduled rituximab maintenance therapy for antineutrophil-cytoplasm antibody associated vasculitides.

OBJECTIVE: Patients included in MAINRITSAN2 trial received either an individually tailored or a fixed-schedule therapy with rituximab as  maintenance treatment of antineutrophil cytoplasm antibody associated  vasculitides. The aim of this study was to compare the real-world costs  of both arms. METHOD: We performed a cost-minimization analysis over an 18-month time period, estimating direct costs -drug acquisition,  preparation, administration and monitoring costs- from the health  system perspective. We conducted a number of additional sensitivity  analyses with different assumptions for unit costs, with further scenarios including the interquartile range of the tailored-infusion group results,  different number of monitoring visits for fixed-schedule regimen and  different number of reported severe adverse events. A cost- effectiveness analysis was conducted as a sensitivity analysis using the  absolute difference in the relapse rate and its confidence interval. RESULTS: The individually tailored maintenance therapy with rituximab was shown to be a cost-saving treatment compared to the  fixed-schedule therapy (6,049 euros vs. 7,850 euros). Savings resulted  primarily from  lower drug acquisition costs (2,861 vs. 4,768 euros) and lower preparation and administration costs (892 vs. 1,486 euros), due to the lower number of infusions per patient in the tailored-infusion  regimen. The tailoredinfusion regimen presented higher monitoring  costs (2,296 vs. 1,596 euros). This result was replicated in all  assumptions considered in the sensitivity analysis of cost-minimization  approach. CONCLUSIONS: From the perspective of the health system, the  tailoredtherapy regimen seems to be the preferable option in terms of  direct costs. Further studies assessing all the effects and costs  associated to vasculitides maintenance treatment with rituximab are  needed to support clinical management and healthcare planning.

Objetivo: Los pacientes incluidos en el ensayo MAINRITSAN2 recibieron una pauta individualizada o un esquema fijo de rituximab  como tratamiento de mantenimiento para la vasculitis asociada con  anticuerpos contra el citoplasma de los neutrófilos. El objetivo de este  estudio es comparar los costes reales de ambos esquemas de  tratamiento.Método: Se llevó a cabo un análisis de minimización de costes sobre un periodo de 18 meses, estimando los costes directos ­adquisición del fármaco, preparación, administración y costes de monitorización­  desde la perspectiva del sistema de salud. Se realizaron varios análisis  de sensibilidad con diferentes supuestos para los costes unitarios,  añadiendo escenarios que incluían el rango intercuartílico de los  resultados en el grupo de la pauta individualizada, diferente número de  visitas de control para el grupo que seguía el esquema fijo y distinto  número de eventos adversos registrados. Se realizó un análisis de  coste-efectividad como parte del análisis de sensibilidad usando la  diferencia absoluta en la tasa de recaída y su intervalo de confianza.Resultados: El esquema de tratamiento con la pauta individualizada demostró una reducción del coste en comparación con el  esquema de dosis fijas (6.049 versus 7.850 euros). El ahorro se debió  principalmente a un menor coste en la adquisición del fármaco (2.861  versus 4.768 euros) dexchlorphey a menos costes de preparación y  administración (892 versus 1.486 euros), debido al menor número de  infusiones por paciente en el brazo del esquema individualizado. Este  esquema individualizado presentó mayores costes de monitorización  (2.296 versus 1.596 euros). Este resultado se repitió en todos los  supuestos considerados en el análisis de sensibilidad desde el enfoque  de minimización de costes.Conclusiones: Desde la perspectiva del sistema de salud, la pauta individualizada parece ser la opción preferible en términos de  costes directos. No obstante, son necesarios más estudios que evalúen  todos los efectos y costes asociados al tratamiento de mantenimiento  con rituximab de la vasculitis por anticuerpo anticitoplasma de neutrófilo para respaldar el manejo clínico y la asistencia sanitaria.

Minimización de costes del mantenimiento con rituximab a intervalos fijos o individualizados en vasculitis por anticuerpos contra el citoplasma de los neutrófilos / Cost-minimization analysis of individually tailored or fixed-scheduled rituximab maintenance therapy for antineutrophil-cytoplasm antibody associated vasculitides

OBJETIVO: Los pacientes incluidos en el ensayo MAINRITSAN2 recibieronuna pauta individualizada o un esquema fijo de rituximab como tratamiento de mantenimiento para la vasculitis asociada con anticuerpos contra el citoplasma de los neutrófilos. El objetivo de este estudio es comparar los costes reales de ambos esquemas de tratamiento. MÉTODO: Se llevó a cabo un análisis de minimización de costes sobre un periodo de 18 meses, estimando los costes directos -adquisición del fármaco, preparación, administración y costes de monitorización- desde la perspectiva del sistema de salud. Se realizaron varios análisis de sensibilidad con diferentes supuestos para los costes unitarios, añadiendo escenarios que incluían el rango intercuartílico de los resultados en el grupo de la pauta individualizada, diferente número de visitas de control para el grupo que seguía el esquema fijo y distinto número de eventos adversos registrados. Se realizó un análisis de coste-efectividad como parte del análisis de sensibilidad usan-do la diferencia absoluta en la tasa de recaída y su intervalo de confianza. RESULTADOS: El esquema de tratamiento con la pauta individualizada demostró una reducción del coste en comparación con el esquema de dosis fijas (6.049 versus 7.850 euros). El ahorro se debió principalmente a un menor coste en la adquisición del fármaco (2.861 versus 4.768 euros) y a menos costes de preparación y administración (892 versus 1.486 euros), debido al menor número de infusiones por paciente en el brazo del esquema individualizado. Este esquema individualizado presentó mayo-res costes de monitorización (2.296 versus 1.596 euros). Este resultado se repitió en todos los supuestos considerados en el análisis de sensibilidad desde el enfoque de minimización de costes. CONCLUSIONES: Desde la perspectiva del sistema de salud, la pauta individualizada parece ser la opción preferible en términos de costes directos. No obstante, son necesarios más estudios que evalúen todos los efectos y costes asociados al tratamiento de mantenimiento con rituximab de la vasculitis por anticuerpo anticitoplasma de neutrófilo para respaldar el manejo clínico y la asistencia sanitaria

OBJECTIVE: Patients included in MAINRITSAN2 trial received either an individually tailored or a fixed-schedule therapy with rituximab as maintenance treatment of antineutrophil cytoplasm antibody associated vasculi-tides. The aim of this study was to compare the real-world costs of both arms. METHOD: We performed a cost-minimization analysis over an 18-month time period, estimating direct costs-drug acquisition, preparation, administration and monitoring costs- from the health system perspective. We conducted a number of additional sensitivity analyses with different assumptions for unit costs, with further scenarios including the interquartile range of the tailored-infusion group results, different number of monitoring visits for fixed-schedule regimen and different number of reported severe adverse events. A cost-effectiveness analysis was conducted as a sensitivity analysis using the absolute difference in the relapse rate and its confidence interval. RESULTS: The individually tailored maintenance therapy with rituximab was shown to be a cost-saving treatment compared to the fixed-schedule therapy (6,049 euros vs. 7,850 euros). Savings resulted primarily from ower drug acquisition costs (2,861 vs. 4,768 euros) and lower prepara-tion and administration costs (892 vs. 1,486 euros), due to the lower number of infusions per patient in the tailored-infusion regimen. The tailored-infusion regimen presented higher monitoring costs (2,296 vs. 1,596 euros). This result was replicated in all assumptions considered in the sensitivity analysis of cost-minimization approach. CONCLUSIONS: From the perspective of the health system, the tailored-therapy regimen seems to be the preferable option in terms of direct costs. Further studies assessing all the effects and costs associated to vasculitides maintenance treatment with rituximab are needed to support clinical ma-nagement and healthcare planning

Cost-effectiveness of rituximab versus azathioprine for maintenance treatment in antineutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVES: Rituximab was proven superior to azathioprine for maintenance treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The high cost of rituximab might, however, limit its routine use. This study determined the cost-effectiveness of intravenous rituximab (5 x 500 mg until month 18), versus oral azathioprine (2 mg/kg per day, gradually decreased between month 12 and 22), for maintenance treatment of patients with granulomatosis with polyangiitis, microscopic polyangiitis, or renal-limited vasculitis, aged 18-75. METHODS: We performed a single-trial based economic evaluation. MAINRITSAN was a 28-month multicentre, prospective, randomised, controlled open-label trial. We estimated the cost of healthcare resources and quality of life using prospectively collected data. Healthcare costs were estimated from the perspective of the French Social Health Insurance's perspective, using 2016 tariffs for reimbursement. Utilities were derived from Short Form 36 scores. We estimated total average cost, incremental cost per incremental relapse averted and per quality-adjusted life-year (QALY) gained. Sensitivity analyses were performed to assess uncertainty over relapses, severe adverse events, discount rate, utility weights, time horizon and the cost of rituximab. Costs drivers were tested using a generalised linear model. RESULTS: Total average costs were €13,387 (€11,605-€15,646) and €10,217 (€7,567-12,949) in the rituximab and azathioprine groups respectively. The incremental cost-effectiveness ratio (ICER) was €12,824 per relapse averted and the incremental cost-utility ratio (ICUR) €37,782 per QALY gained. Besides the unit cost of rituximab, the major cost drivers were relapses and severe adverse events. CONCLUSIONS: Maintenance treatment by rituximab could be cost-effective for preventing relapses in patients with AAV.

[Relevance assessment of requests for antineutrophil cytoplasmic antibodies detection: Retrospective study led in Bordeaux Hospital, France]. / Évaluation de la pertinence des demandes d'anticorps anticytoplasme des polynucléaires neutrophiles : étude rétrospective menée au sein du centre hospitalier universitaire de Bordeaux.

INTRODUCTION: During year 2013, 5943 tests for antineutrophil cytoplasmic antibodies (ANCA) detection were performed in Bordeaux hospital, France. This seemed disproportionate, with regard to the low prevalence of ANCA-associated vasculitis (AAV). Our purpose was to evaluate the relevance of these requests. METHODS: Requests for detection of ANCA during 2013 were recorded, with their results. A sample of 501 requests was secondarily established. Relevance of requests was assessed independently by two reviewers. During year 2014, we developed strategies of information, in order to reduce the number of requests and increase their relevance. RESULTS: Only 17.8 % of the 5943 requests for detection of ANCA resulted in a positive test using indirect immunofluorescence (including 10.6 % of the requests with titles above 1/50). Using Luminex©, 9.7 % of the test of detection against antimyeloperoxidase or antiproteinase 3 antibodies were positive. Within the sample of 501 patients, only 28.7 % of the requests were relevant. A percentage of 40.2 of them weren't justified by a clinical affection typically associated with AAV. Exactly 15.9 of the requests were performed during systematic autoimmune screening. None of these requests could lead to the diagnosis of AAV. Combination of information procedures and use of a request form enabled a 19 % decrease of the number of requests. The percentage of requests without clinical justification also reduced from 40.2 % to 17.1 %. The reduction of the number of requests led to a 46,865 € saving. CONCLUSION: The majority of the requests for detection of ANCA was not relevant and could not lead to the diagnosis of AAV. Simple solutions enabled a partial but significant improvement of their relevance.

Clinical and Economic Burden of Antineutrophil Cytoplasmic Antibody-associated Vasculitis in the United States.

OBJECTIVE: To describe the prevalence of major relapse and healthcare costs among patients with granulomatosis with polyangiitis (GPA); to find patients with microscopic polyangiitis (MPA) in administrative databases, because no MPA diagnosis code exists; and to describe the clinical and economic burden associated with MPA. METHODS: Adults (≥ 18 yrs) with ≥ 2 diagnoses of GPA [International Classification of Diseases-9-Clinical Modification (ICD-9-CM 446.4)] during 2009-2013 were extracted from the Truven Health MarketScan Commercial and Medicare Supplemental databases. Evidence of major relapse (based on the Birmingham Vasculitis Activity Score) and healthcare costs were collected during 12-month and 24-month followup periods. Adults with ≥ 2 diagnoses of unspecified arteritis (ICD-9-CM 447.6) were found as potential patients with MPA and additional criteria based on clinical input were applied to refine the sample. Major relapse-associated conditions and healthcare costs in the 6 months pre- and post-diagnosis were measured. Costs were inflated to 2013 US$. RESULTS: A total of 2784 patients with GPA were found and 18.7% experienced a major relapse in the 12-month followup period. The patients with a major relapse incurred higher average all-cause (12-month: $88,065 vs $30,682; p < 0.0001) and GPA-related costs (12-month: $61,636 vs $15,748; p < 0.0001) than patients without a relapse. Trends were consistent over the 24-month followup period. There were 612 incident patients with MPA. Following MPA diagnosis, healthcare costs nearly doubled ($30,166 vs $56,642; p < 0.0001). CONCLUSION: In a real-world setting, patients with GPA who experience major relapse have higher economic burden, compared to patients without a relapse. MPA diagnosis was associated with nearly a 2-fold increase in healthcare costs.