Eficacia y seguridad de fingolimod en pacientes adultos con esclerosis múltiple recurrente remitente con falla al tratamiento con interferón beta / Efficacy and safety of fingolimod in adult patients with relapsing-remitting multiple sclerosis with interferon beta treatment failure

INTRODUCCIÓN: El presente dictamen expone la evaluación de la eficacia y seguridad de fingolimod en el tratamiento de pacientes adultos con esclerosis múltiple recurrente remitente con falla al tratamiento con interferón beta. La esclerosis múltiple (EM) es una enfermedad inflamatoria y neurodegenerativa del cerebro y la médula espinal, caracterizada por episodios de disfunción neurológica que usualmente presentan recuperación; aunque también puede presentar un curso progresivo gradual. La esperanza de vida de los pacientes con EM es de 7 a 14 años menos que la población general. Más de la mitad de las muertes de pacientes con EM están directamente relacionadas a complicaciones de la enfermedad. Fingolimod, producto farmacéutico de administración oral, es un modulador del receptor de la esfingosina 1-fosfato, que, al ser metabolizado, da lugar al metabolito activo fingolimod fosfato. El metabolito activo actúa como antagonista funcional del receptor S1P, bloqueando la capacidad de los linfocitos de salir de los ganglios linfáticos; lo que produce una redistribución de los linfocitos sin disminución en su número. Este efecto reduciría la infiltración de células linfocíticas patógenas al sistema nervioso central; disminuyendo así la inflamación y lesión del tejido nervioso. A pesar que en EsSalud se dispone de interferón beta-1b para el tratamiento de la EM recurrente-remitente (EMRR) y de interferón beta-1a para pacientes con EMRR que presentan eventos adversos al tratamiento previo con interferón beta-1b, existen pacientes que no logran un control adecuado de la enfermedad con la terapia basada en interferón beta. Por ello, existe el interés de brindar una terapia que disminuya la tasa de recaída anualizada por la EMRR y mejore además la calidad de vida. Así, especialistas de EsSalud consideran que el uso de fingolimod beneficiaría a los pacientes con EMRR y falla al tratamiento con interferón beta. METODOLOGÍA: Se realizó una búsqueda de la literatura científica con el objetivo de identificar evidencia sobre la eficacia y seguridad de fingolimod, comparado con la mejor terapia de soporte, en pacientes adultos con EMRR con falla al tratamiento con interferón beta. Para identificar los documentos de interés para la presente evaluación, se buscó evidencia disponible en las siguientes bases de datos bibliográficas: PubMed, The Cochrane Library y LILACS. Adicionalmente, se realizó una búsqueda en sitios web pertenecientes a grupos que realizan evaluaciones de tecnologías sanitarias y guías de práctica clínica, incluyendo The Canadian Agency for Drugs and Technologies in Health (CADTH), Scottish Medicines Consortium (SMC), The National Institute for Health and Care Excellence (NICE), Institute for Quality and Efficiency in Health Care (IQWiG), Haute Authorité de Santé (HAS), el portal BRISA (Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas), y sitios web de organizaciones internacionales en neurología. Adicionalmente, se llevó a cabo una búsqueda manual en el portal ClinicalTrials.gov del National Institutes of Health e International Clinical Trials Registry Platform de la Organización Mundial de la Salud (http://apps.who.int/trialsearch/) para la identificación de estudios que emplearan la tecnología de interés. Finalmente, se revisaron protocolos para revisiones sistemáticas (RS) que pudieran contemplar el uso de la tecnología de interés en el portal PROSPERO del Centre for Reviews and Dissemination de la University of York (https://www.crd.york.ac.uk/PROSPERO/) y en el Systematic Review Register del Joanna Briggs Institute Centre (https://joannabriggs.org/resources/systematic_review_register). RESULTADOS: Se describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad. CONCLUSIONES:  En el presente documento, se evaluó la mejor evidencia científica disponible hasta la actualidad sobre la eficacia y seguridad de fingolimod en pacientes adultos con esclerosis múltiple recurrente-remitente (EMRR) con falla al tratamiento con interferón beta.  Se incluyeron cinco documentos: dos GPC elaboradas por la AAN y la ECTRIMS/EAN, dos ETS realizadas por NICE y SMC, y el análisis post hoc del ECA FREEDOMS. Este ECA fue incluido como evidencia indirecta dado que evaluó a una población más amplia que la población de interés del presente dictamen. Las GPC de la AAN y ECTRIMS/EAN recomiendan el empleo de otra terapia modificadora de la enfermedad, incluyendo dentro las alternativas a fingolimod, en el caso de que no se presente una respuesta favorable a la terapia con una terapia modificadora de la enfermedad en pacientes con EMRR como el interferón beta. Ninguna de estas GPC establece una recomendación específica sobre el uso de fingolimod en pacientes con fallo a la terapia con interferón beta. Las ETS de NICE y SMC recomiendan fingolimod para el tratamiento de la EMRR altamente activa en adultos, solo si los pacientes tienen una tasa de recaída sin cambios o aumentada o recaídas graves en curso en comparación con el año anterior a pesar del tratamiento adecuado con interferón beta, y que la compañía fabricante proporcione fingolimod con una reducción de costo que haga costo-efectivo el empleo de fingolimod en el sistema sanitario británico y escocés. Cabe precisar que este tipo de regulaciones de costo de medicamentos no son extrapolables al sistema sanitario de EsSalud. En el análisis post hoc del ECA FREEDOMS, para el subgrupo de pacientes con EMRR previamente tratados con interferón beta, se observó menor tasa de recaída anualizada en el grupo que recibió fingolimod, comparado al que recibió placebo. No se observó diferencia en la progresión de la discapacidad para pacientes con EMRR previamente tratados con interferón beta entre los grupos de fingolimod y placebo. No se reportaron resultados sobre las pruebas para evaluar discapacidad (EDSS o MSFC), ni resultados de seguridad (eventos adversos). Entre las principales limitaciones del ECA FREEDOMS, este no fue diseñado para evaluar fingolimod en la población de interés del presente dictamen, sino para una población más amplia (pacientes con EMRR sin tratamiento o previamente tratados con interferón beta u otra terapia modificadora de la enfermedad). Dado que los resultados del ECA FREEDOMS para pacientes con EMRR previamente tratados con interferón beta provienen de un análisis post hoc, estos son de tipo exploratorio, no siendo de este modo concluyentes para determinar eficacia. Adicionalmente, el desenlace primario (tasa de recaída anualizada) presenta limitaciones, al ser un desenlace subjetivo, con la posibilidad de introducción de sesgos por parte del evaluador o el paciente. Asimismo, no se dispone de resultados específicos para pruebas de discapacidad como EDSS o MSFC, limitándose la evaluación del beneficio de esta tecnología en los pacientes de interés, siendo que se recomienda que la evaluación del beneficio de una tecnología no solo sea medida desde este desenlace, sino de la conjunción de lo observado en varios desenlaces de eficacia. En cuanto a la seguridad, la ausencia de información sobre eventos adversos en el subgrupo de pacientes con EMRR previamente tratados con interferón beta, no permite establecer conclusiones sobre la seguridad del empleo de la tecnología. Ante la limitada evidencia para la presente evaluación, se consideró la opinión del experto clínico de la institución. El clínico señala que, dado que fingolimod emplea un mecanismo de acción distinto al interferón beta, sería de utilidad para el control de la enfermedad en pacientes con EMRR y falla a interferón beta. Adicionalmente, fingolimod es fácil de administrar comparado al interferón beta, (vía oral comparada a la administración intramuscular o subcutánea del interferón beta 1a y 1b, respectivamente), lo que facilita su administración. Lo descrito por el especialista está en línea con lo descrito por las GPC, las que incluyen a fingolimod como alternativa terapéutica en pacientes con fracaso a terapia con interferón beta u otra terapia modificadora de efecto. De este modo, la evidencia científica disponible a la fecha sugiere que fingolimod tendría un beneficio en pacientes con EMRR con fallo al tratamiento con interferón beta, bajo los siguientes argumentos técnicos: 1) La evidencia indirecta procedente del ECA FREEDOMS sugiere un beneficio favorable para fingolimod en comparación con placebo en pacientes con EMRR; 2) aunque las GPC revisadas en este dictamen no generan recomendaciones para la población de interés de manera específica, se señala a fingolimod como una alternativa en pacientes con una respuesta no favorable al tratamiento previo con alguna terapia modificadora de la enfermedad (como el interferón beta) y 3) el vacío terapéutico (en el sistema sanitario de EsSalud, a la fecha, los pacientes con EMRR y fallo a la terapia con interferón beta no cuentan con una terapia específica disponible). Por lo expuesto, el IETSI aprueba el uso de fingolimod en pacientes adultos con esclerosis múltiple recurrente remitente con falla al tratamiento con interferón b. La vigencia del presente dictamen es de 1 año, según lo establecido en el Anexo N° 1. Así, la continuación de dicha aprobación estará sujeta a la evaluación de los resultados obtenidos y de nueva evidencia que pueda surgir en el tiempo.

Assessment of cancer risk with ß-interferon treatment for multiple sclerosis.

OBJECTIVE: The risk of cancer after exposure to the ß-interferons (IFNßs) for multiple sclerosis (MS) has not been established. We assessed whether IFNß treatment for MS is associated with cancer risk or the risk of specific cancers in a population-based observational study. METHODS: The British Columbia MS database was linked to the provincial Cancer Registry, Vital Statistics death files and Health Registration files. Using a nested case-control design, MS cancer cases were matched with up to 20 randomly selected MS controls at the date of cancer diagnosis by sex, age (± 5 years) and study entry year using incidence density sampling. Associations between treatment exposure and overall or specific (breast, colorectal, lung and prostate) cancers were estimated by conditional logistic regression, adjusted for MS disease duration and age. Tumour size at cancer diagnosis was compared between treated and untreated patients using the stratified Wilcoxon test to explore potential lead time bias. RESULTS: The cohort included 5146 relapsing-onset MS patients and 48,705 person-years of follow-up, during which 227 cancers were diagnosed. Exposure to IFNß was not significantly different for cases and controls (OR 1.28; 95% CI 0.87 to 1.88). There was a non-significant trend towards an increased risk of IFNß exposure in the breast cancer cases (OR 1.77; 95% CI 0.92 to 3.42), but no evidence of a dose-response effect. Tumour size was similar between IFNß treated and untreated cases. CONCLUSIONS: There was no evidence of an increased cancer risk with exposure to IFNß over a 12-year observation period. However, the trend towards an association between IFNß and breast cancer should be investigated further.

Fingolimode para o tratamento da esclerose múltipla (2014) / Fingolimode para o tratamento da esclerose múltipla (2014)

CONTEXTO: A Esclerose Múltipla (EM) é uma doença autoimune, desmielinizante, crônica do sistema nervoso central, comum em adultos jovens, predominante entre mulheres, com evolução progressiva e imprevisível. A incidência mundial é de 2,5 casos novos a cada 100.000 pessoas por ano e no Brasil sua taxa de prevalência média é de aproximadamente 15 casos/100.000 habitantes, variando entre as regiões e sendo mais prevalente nas regiões sul e sudeste. Atualmente, segundo PCDT vigente (Portaria SAS/MS nº 493, de 23 de setembro de 2010), acetato de glatirâmer e betainterferona (1A ou 1B) são os fármacos de primeira escolha para o tratamento de Esclerose Múltipla Remitente Recorrente (EMRR). O uso de natalizumabe ocorre em casos refratários, tanto às betainterferonas quanto a glatirâmer. Atualmente, existem 11.650 pacientes recebendo betainterferonas, acetato de glatirâmer e natalizumabe para o tratamento de EM (DATASUS). TRATAMENTO: O tratamento é preconizado apenas para as formas EM-RR e EM-SP, pois não há evidência de benefício para as demais. O Protocolo Clínico e Diretrizes Terapêuticas da Esclerose Múltipla do Ministério da Saúde publicado em novembro de 2013 preconiza as betainterferonas e glatirâmer como primeira escolha e recomenda que o natalizumabe seja iniciado somente em casos refratários tanto a betainterferonas quanto a glatirâmer. A CONITEC já avaliou outras demandas por incorporação do fingolimode ao tratamento de esclerose múltipla no SUS, tendo emitido o relatório número 04, de julho de 2012, no qual não recomendou a incorporação desta tecnologia para a primeira linha de tratamento da esclerose múltipla. O relatório, à época, trouxe como um dos motivos para a não incorporação do medicamento os dados de segurança, que demandava a realização de estudos clínicos de fase IV ou de pós-comercialização a fim de avaliar a segurança do medicamento, especialmente os efeitos adversos cardiovasculares, para que então se reavaliasse a relação risco e benefício da tecnologia. A TECNOLOGIA: Fingolimode é indicado como terapia modificadora de doença para tratamento de pacientes adultos com esclerose múltipla remitente recorrente para reduzir a freqüência de reincidências e retardar a progressão da incapacidade7 (CID G35.0, ou seja, esclerose múltipla). EVIDÊNCIAS CIENTÍFICAS: os demandantes apresentaram em seus pareceres técnico-científicos as buscas realizadas por evidências científicas. Nos três casos, a pergunta de pesquisa foi adequada, considerando os comparadores disponíveis no SUS. Nas três propostas encaminhadas, os demandantes selecionaram o estudo que comparou o fingolimode ao betainterferona-1a (TRANSFORMS) e mais dois artigos que derivaram deste estudo principal, um de extensão do estudo e outro de análise de subgrupo. Os três estudos são de nível de evidência 1B, segundo maior nível de evidência. Os resultados apontam para eficácia superior do fingolimode em relação ao betainterferona-1a, porém ainda há incertezas sobre os resultados de segurança, especialmente para o uso em primeira linha. DELIBERAÇÃO FINAL: Com discussão posterior à Consulta Pública, tendo como base a ausência de dados novos que superassem a incerteza quanto ao balanço de riscos e benefícios do uso do fingolimode em primeira e segunda linha, devido, sobretudo, aos potenciais eventos cardiovasculares relacionados à primeira dose do fingolimode, os membros do plenário, na reunião realizada nos dias 7 e 8/5/2014, deliberaram, por unanimidade, por não recomendar a incorporação do fingolimode para a primeira e segunda linha do tratamento da esclerose múltipla. DECISÕES: PORTARIA Nº 24, de 27 de junho de 2014 - Torna pública a decisão de incorporar o fingolimode no Sistema Único de Saúde nos casos de: pacientes com esclerose múltipla remitente-recorrente; com surtos incapacitantes após falha ao uso de betainterferona e de glatirâmer; com impossibilidade de uso de natalizumabe e sem contraindicação ao uso de fingolimode conforme Protocolo Clínico e Diretrizes Terapêuticas.

Multiple sclerosis beyond EDSS: depression and fatigue.

Depression and fatigue are common symptoms of multiple sclerosis and are the primary determinants of impaired quality of life in this demyelinating neurological disease. The twelve-month prevalence of major depression in patients with multiple sclerosis is around 15%. Untreated depression is associated with suicidal ideation, impaired cognitive function and poor adherence to immunomodulatory treatment. For these reasons, systematic screening and management of depressive symptoms is recommended for all patients with multiple sclerosis. There is some evidence that interferon-beta treatment may exacerbate depressive symptoms and a switch to glatiramer acetate can be envisaged in patients treated with an interferon-beta in whom depressive symptoms become an issue. Fatigue is present in over three-quarters of patients with multiple sclerosis. It is considered the most debilitating symptom of the disease and is a major reason for work absenteeism. There is growing evidence that immunomodulatory treatments, in particular glatiramer acetate, improve fatigue symptoms in patients with multiple sclerosis.

Quantitative risk-benefit analysis of natalizumab.

OBJECTIVE: To model the long-term risks and benefits of natalizumab in individuals with relapsing multiple sclerosis (MS). METHODS: We created a Markov model to evaluate treatment effects on reducing relapses and slowing disease progression using published natural history data and clinical trial results. Health changes, measured in quality-adjusted life-years (QALYs), were based on patient health preferences. Patient cohorts treated with no disease-modifying treatment, natalizumab, subcutaneous interferon beta-1a, and a theoretical "perfect" MS treatment were modeled. Sensitivity analysis was used to explore model uncertainty, including varying risks of developing progressive multifocal leukoencephalopathy (PML). RESULTS: Treatment with natalizumab resulted in 9.50 QALYs over a 20-year time horizon, a gain of 0.80 QALYs over the untreated cohort and 0.38 QALYs over interferon beta-1a. The health loss due to PML was small (-0.06 QALYs). To offset natalizumab's incremental health gain over interferon beta-1a, the risk had to increase from 1 to 7.6 PML per 1,000 patients treated over 17.9 months. The "perfect" MS treatment accumulated 10.59 QALYs over the 20-year time horizon, 1.89 QALYs above the untreated cohort. Interferon beta-1a resulted in greater QALY gains compared with natalizumab if natalizumab's relative relapse reduction was reduced from 68% to 35% or if interferon beta-1a's relative reduction was increased from 32% to 65%. CONCLUSIONS: A more than sevenfold increase in actual risk of progressive multifocal leukoencephalopathy was required to decrease natalizumab's health gain below that of interferon beta-1a, and there remains considerable room for additional gains in health (>50%) beyond those already achieved with current therapies.

Natalizumab: new drug. Multiple sclerosis: risky market approval.

(1) In relapsing-remitting multiple sclerosis, the standard therapy (other than symptomatic treatment) is interferon beta. It prevents about one exacerbation every 2.5 years but has no demonstrated effect on the progression of disability. However, interferon beta can cause serious adverse effects. (2) Natalizumab, an immunosuppressant, has been approved for first-line treatment of patients with "aggressive" multiple sclerosis (with frequent exacerbations) and for second-line treatment after failure of interferon beta. (3) In first-line treatment, natalizumab has not been compared with interferon beta. In a double-blind placebo-controlled trial involving 942 patients who were treated for 2 years, natalizumab prevented about 1 exacerbation every 2 years (0.24 versus 0.73 exacerbations per year). A retrospective subgroup analysis suggested that efficacy was better in patients with aggressive disease. As this was a post-hoc subgroup analysis, this exploratory hypothesis requires further testing. Natalizumab appeared to slow the progression of disability, but this result is undermined by the small percentage of patients who had an exacerbation (18% versus 27%). (4) In second-line treatment, a combination of natalizumab and interferon beta (rather than natalizumab monotherapy) was compared with interferon beta in 1171 patients in whom interferon beta had failed. The combination prevented about one exacerbation every 2.5 years. It is not known whether a combination of natalizumab and interferon is more effective than natalizumab alone. (5) Three cases of progressive multifocal leukoencephalopathy occurred during clinical trials, two of which were fatal. The risk of this viral infection, which is usually symptomatic only in severely immunosuppressed patients, was estimated at about 1 case per 1000 patients on natalizumab. (6) Little is known of the risks of long-term treatment with natalizumab, especially the risks of infections and cancer. (7) During two years of treatment, 6% of patients developed persistent anti-natalizumab antibodies, leading to reduced efficacy and a higher incidence of reactions during the infusion, as well as hypersensitivity reactions. (8) In practice, given the poorly assessed and potentially fatal risks of long-term treatment with natalizumab, the limited improvement in efficacy does not justify the use of natalizumab other than in comparative trials.

Interferon beta-1b (betaseron/betaferon) is well tolerated at a dose of 500 microg: interferon dose escalation assessment of safety (IDEAS).

The approved interferon beta-1b (Betaseron/Betaferon) dose is 250 microg (8 MIU) administered subcutaneously (sc) every other day (eod). Clinical trial data suggest a dose response effect for interferon beta in multiple sclerosis (MS) treatment and a maximum dose has yet to be established. The Interferon Dose Escalation Assessment of Safety (IDEAS) study evaluated the safety and tolerability of interferon beta-1b 500 microg (16 MIU) sc eod with structured dose escalation and adverse event (AE) management in 22 patients (20 interferon beta-1b-treated (SD) and two interferon beta-1b-naïve (ND)) with relapsing-remitting (RR) MS, secondary-progressive (SP) MS, or progressive relapsing MS. IDEAS comprised an eight-week dose escalation period and a 12-week maintenance period, with modification as clinically warranted. Autoinjectors were used for all injections > or =0.4 mL. Clinical laboratory values were monitored monthly. Baseline and exit assessments included the MS Functional Composite score, EDSS, and neutralizing antibody MxA assay. AEs were recorded at every injection. Dose escalation ranged from two to 12 weeks. Some 91% of patients (20/22) achieved the 500-microg dose, and of these 90% (18/20) completed the maintenance phase. There were no differences in response between ND and SD patients. Most common AEs were decreased general well-being, insomnia, and injection site reactions (mostly mild). The 500-microg dose of interferon beta-1b was well tolerated in the short-term with escalation and premedication in these patients, most of whom had previously been receiving 250 microg interferon beta-1b.

Prospective assessment of changing from placebo to IFN beta-1a in relapsing MS: the PRISMS study.

The efficacy of interferon (IFN) beta has been shown in several placebo-controlled, parallel-group studies in relapsing-remitting multiple sclerosis (RRMS). PRISMS, the largest such study to date, clearly demonstrated the efficacy of IFN beta-1a on all outcome measures over 2 years during the placebo-controlled, parallel-group phase. However, this study's placebo-crossover design also provided us with a unique opportunity to conduct a prospective within-group assessment, eliminating the impact of inter-patient variability. At the start of year 3, patients receiving placebo during years 1-2 were re-randomized in a dose-blinded fashion to receive IFN beta-1a, 22 or 44 mcg subcutaneously three times weekly, during years 3 and 4. Clinic visits occurred 3-6 monthly and T2 MRI scans were obtained after 1 and 2 years on therapy. Comparison of the mean relapse count per patient over 2 years (the primary outcome measure) during time on placebo (years 1 and 2) with that during active treatment (years 3 and 4) revealed a decrease from 2.6 to 1.2 in both dose groups (54% relative reduction; p<0.001). Disability progression, T2 MRI lesion activity and accumulation of T2 lesion burden were also significantly improved with therapy (p<0.01). No new safety issues were noted. These data provide further support for IFN beta-1a's efficacy in RRMS. The ability to detect significant treatment effects with reduced patient numbers in this type of before/after analysis, may be due to the reduction in inter-patient variability.

Subcutaneous recombinant interferon-beta-1a (Rebif): a review of its use in relapsing-remitting multiple sclerosis.

Subcutaneous recombinant interferon-beta-1a (Rebif) 22 or 44 microg three times weekly is a valuable option in the first-line treatment in patients with relapsing-remitting multiple sclerosis (RRMS). It has shown benefits on outcome measures related to relapses, progression of disability and magnetic resonance imaging (MRI) in clinical trials. A significant efficacy advantage for subcutaneous interferon-beta-1a three times weekly over intramuscular interferon-beta-1a 30 microg once weekly was shown at 24 and 48 weeks. The most common adverse events are generally mild and clinically manageable. Considering both direct and indirect comparative clinical trial data, an assessment suggests that subcutaneous interferon-beta-1a 44 microg three times weekly has the best benefit-to-risk values of the available disease-modifying drugs used to treat RRMS.

Importance of benefit-to-risk assessment for disease-modifying drugs used to treat MS.

Interferon (IFN) beta has been shown to be an effective therapy in pivotal studies of multiple sclerosis (MS), with differences in outcomes based on dose and/or frequency of administration. Glatiramer acetate (GA) has also shown to have an effect on relapses and magnetic resonance imaging measures, but not on disability. All products are associated with adverse events, and utilisation of a specific therapy needs to consider benefit in relation to risk. Evidence-based medicine provides a means of assessing benefit and risk in the context of the number of patients one needs to treat to obtain benefit (NNT) compared with the number needed to treat for an adverse outcome (NNH). Efficacy and safety data are presented from IFN beta-1a (Rebif) clinical trials, including relevant NNT and NNH values, to allow assessment of the overall benefit-to-risk ratio compared with placebo. Additional comparisons are made with published data for other IFN products and GA. The indirect comparative information reviewed demonstrates that IFN appears to have a better benefit- to-risk ratio than GA. Indirect comparisons suggest better efficacy of thrice weekly (tiw) IFN beta-1a compared with alternate-day IFN beta-1b, but no direct comparative data are available. Direct comparative data show that IFN beta-1a at a dose of 44 mcg tiw has a favourable benefit-to-risk ratio compared with both 22 mcg tiw and 30 mcg once weekly, suggesting that 44 mcg tiw currently has the best benefit- to-risk ratio for the treatment of relapsing MS.

Benefit-risk assessment of interferon-beta therapy for relapsing multiple sclerosis.

IFN-beta therapy has a central place in the management of relapsing multiple sclerosis, as demonstrated by the pivotal studies of three IFN-beta treatment regimens. However, questions remain concerning the optimal choice of preparation and dose regimen. The benefit-risk ratio for a given preparation is an important consideration in optimising treatment for an individual patient. Of the three IFN-beta preparations currently available, all have shown benefit on activity measures (relapses and active lesions apparent on magnetic resonance imaging), while benefit on progression measures (disability and total lesion burden) has been less consistent. Available data across studies suggest that dose and/or dose frequency are important determinants of efficacy, a finding supported by direct comparative data on different IFN-beta preparations. The added benefit of high-dose, high-frequency IFN-beta therapy is not achieved at the cost of compromised safety or tolerability, indicating that three-times-weekly treatment offers a superior benefit-risk ratio to once-weekly treatment. The potential advantages of IFN-beta therapy may be enhanced by regular monitoring of efficacy and safety in order to maintain patients on therapy beyond the first few months when side effects are most apparent.

Disease modifying agent related skin reactions in multiple sclerosis: prevention, assessment, and management.

BACKGROUND: The objective for this article is to highlight some of the adverse skin manifestations associated with injectable disease modifying therapy for multiple sclerosis (MS). Early identification and intervention can often lead to minimal consequences and prolonged patient tolerance and compliance with these agents. At the University of Texas Southwestern Medical Center at Dallas and Texas Neurology in Dallas we actively follow approximately 5000 MS patients. The majority of our patients with relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS) are treated with one of the currently available disease modifying agents (DMAs). Our experience with these patients, and the challenges they face in continuing long-term treatment, constitutes the basis of our proposed treatment strategies. CONCLUSION: Skin reactions in response to injectable DMA therapy in MS are generally mild. However, some reactions can evolve into potentially serious lesions culminating in infection, necrosis, and in some circumstances requiring surgical repair.

[Immunomodulatory staged therapy of multiple sclerosis. New aspects and practical applications, March 2002]. / Immunmodulatorische Stufentherapie der Multiplen Sklerose. Neue Aspekte und praktische Umsetzung, März 2002.

This update of the consensus on escalating immunotherapy in multiple sclerosis includes for the first time also important aspects of diagnosis, documentation, and cost of disease. The application of evidence-based therapeutic recommendations as described in the first two publications of the MSTKG has already improved the treatment situation for MS patients. It appears that the positive attitude towards a more active immunomodulatory therapy also helped to improve MS therapy in general. Due to the increasing use of standardized clinical documentation, individual recommendations for the application of innovative products are now clearer for patients as well as health care providers. The study on the cost of MS performed in several European countries demonstrated that medical treatment constitutes only a small part of the total cost of MS. It was demonstrated that MS-related costs correlate almost exponentially with increasing disability. Therefore, pharmacoeconomic reasons might also speak for early, individually adjusted, and escalating immunotherapy. This would also include a stringent therapy of individual relapses aimed at a complete resolution of clinical symptoms. Recent studies focus on a possible dose-effect relation for recombinant beta-interferons. The available data suggest a possible relation, but they have to be interpreted with caution, as important issues in the design of the studies (e.g., maintenance of blinding) were not adequately addressed. Up to now, there has been no general recommendation for a differential indication of the individual licensed substances, but the different available dose regimes and modes of application allow for an individual adjustment of therapy. In addition to immunomodulatory treatment, vaccinations and their effect on the disease course are important aspects in patient care. According to recent large epidemiological studies, the recommendations have changed as the relevant immunizations with split vaccines (e.g., influenza, tetanus) are now regarded as safe and without increased risk of relapse or disease progression.

A phenomenologic assessment of relapsing MS patients' experiences during treatment with interferon beta-1a.

The purpose of this study was to describe the experiences of patients with relapsing multiple sclerosis (MS) who are being treated with interferon beta-1a. MS patients often experience fear and uncertainty about their future and derive benefit from understanding their diagnosis as well as learning about their anticipated disease course. Interferon beta-1a treatment can delay the accumulation of physical disability that naturally occurs over time in patients with untreated relapsing MS and thus offer hope for their future. However, patients may be afraid to start interferon beta-1a because they do not know what to expect. To answer the question, "What is the patient's experience on interferon beta-1a," we used Heideggerian phenomenologic and Colaizzi's qualitative data analysis techniques to interpret serial interviews of 15 patients with relapsing MS. Interviews were audiotaped, transcribed verbatim, and analyzed by using the Martin qualitative data analysis computer program. The theme clusters that emerged were learning, feelings, adaptation, and interferon beta-1a issues. An exhaustive description of the phenomena that were derived illustrates the patients' process of learning about their illness and adapting to changes in their lives. Starting a new treatment requires coping and challenges use of resources. Social support is vital to patients, particularly those who have difficulty injecting themselves. Most of the patients expressed a sense of improvement in their condition since starting on interferon beta-1a treatment and considered it crucial to their hope for the future.

[Early multiple sclerosis therapy in the effects of public health economics]. / Frühe Multiple-Sklerose-Therapie und ihre gesundheitsökonomischen Auswirkungen.

BACKGROUND: Meanwhile, a number of drugs are available for the course-modifying therapy of multiple sclerosis. Their use depends on the individual indication as well as on the patient's compliance, but also increasingly on the economic considerations of the public health system. For years, the costs of multiple sclerosis and the critically evaluated cost-benefit analyses were based on estimated figures. PATIENTS AND METHODS: For better transparency of the actual costs of the disease, a cross-sectional study of multiple sclerosis patients was performed for the first time in Germany, where the patients answered questionnaires as to their financial resources and quality of life. Within this representative framework of questionnaires, data of 737 patients were evaluated. RESULTS: This study came up with a total cost of DM 65,400.-per patient and year. The complete costs of multiple sclerosis, based on an estimated number of 120,000 patients, thus run up to 7.85 bio. DM a year. Only a small percentage is caused by medication (7%), including the use of new extremely expensive drugs. There is a positive correlation between the severity of the disease and the underlying costs of treatment. CONCLUSION: Due to these results, concrete health-economic goals in the treatment of patients with multiple sclerosis should aim at stabilization on a low disability level at an early stage of the disease.

[A short history of beta-interferon therapy of multiple sclerosis]. / Eine kurze Geschichte der Beta-Interferontherapie der multiplen Sklerose.

Basic sciences including biotechnology and diagnostic imaging as well as dedicated and substantial clinical research have contributed to the progress in the therapy of multiple sclerosis (MS) which is no longer an orphan disease. Pivotal studies using interferon beta-1b for early and later phases of MS are described in their historical context. In addition, possible mechanisms of action of interferon beta-1b and new directions for future research are discussed. Interferon beta-1b already now has become a global standard for the expected further therapeutic progress.

Interferon beta-1b and secondary progressive multiple sclerosis: licence extension. Useful, but further assessment required.

(1) Interferon beta-1b is now licensed to treat patients with secondary progressive multiple sclerosis. (2) The clinical file that we compiled on this indication, includes a double-blind placebo-controlled trial in which 718 patients were treated for 2-3 years. The trial is methodologically sound. (3) In this trial, interferon beta-1b, at the only dose tested (8 MIU every two days by the subcutaneous route), significantly reduced the progression of the disability linked to the disease. After 2-3 years of treatment the percentage of patients confined to a wheelchair was, in absolute values, 16.7% in the interferon beta-1b group and 24.6% in the placebo group. (4) In this trial the adverse effects linked to interferon beta-1b were already known, i.e. mainly a 'flu-like syndrome at the outset of treatment, and reactions at the injection site. (5) More than a quarter of patients on interferon beta-1b had neutralising antibodies against interferon beta-1b. More follow-up is needed to determine the possible impact of these antibodies on treatment efficacy and on the possible risk of autoimmune diseases. (6) Treatment with interferon beta-1b is still costly.

Long-term interferon beta-1b therapy for MS: is routine thyroid assessment always useful?

BACKGROUND: The authors previously reported on the development of thyroid dysfunction and autoimmunity during 1-year treatment of patients with MS with interferon-beta 1b (IFN beta-1b). OBJECTIVE: To evaluate the evolution of incident thyroid disease and the possible development of more thyroid disease during longer term therapy. PATIENTS: The authors studied 31 patients (aged 34 +/- 7 years; 21 women) with relapsing-remitting MS during 3 years of IFN beta-1b treatment. Systematic thyroid assessment was performed every 3 or 6 months, depending on the development of thyroid disease. RESULTS: After the first year of IFN beta-1b treatment, no further cases of thyroid disease were observed. Among the six patients with early incident subclinical hypothyroidism, thyroid dysfunction persisted only in those with baseline autoimmune thyroiditis (n = 2). The three patients who developed transient hyperthyroidism remained euthyroid throughout the treatment course. A positive autoantibody titer was continually detected in only two out of five patients without baseline autoimmunity. CONCLUSIONS: The risk of thyroid disease seems related to IFN beta-1b treatment during the first year only, particularly in patients with preexisting thyroiditis. Furthermore, incident thyroid dysfunction is generally transient and mild in degree. Indeed, we recommend a routine systematic thyroid assessment only in patients with baseline thyroiditis. During the first year of therapy, serum thyroid-stimulating hormone measurement should suffice as first line test; a systematic thyroid assessment is only useful for those patients with incidental and persistent dysfunction. Further studies with many patients will be necessary to confirm our suggestions as broad clinical guidelines.