Immunomodulation for Pompe Disease with high sustained antibodies against enzyme replacement therapy

Blasco-Alonso, Javier; Gil-Gómez, Raquel; Jurado, Alfonso Lendínez; Macías, Raquel Yahyaoui

doi:10.1016/j.medcli.2020.09.017

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Hospital Materno-Infantil, Hospital Regional Universitario de Málaga, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Grupo IBIMA Multidisciplinar de Investigación Pediátrica, Universidad de Málaga, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Unidad de Gestión Clínica de Cuidados Críticos y Urgencias de Pediatría, Hospital Materno-Infantil, Hospital Regional Universitario de Málaga, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Unidad de Gestión Clínica Laboratorio, Hospital Materno-Infantil, Hospital Regional Universitario de Málaga, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Inmunomodulación con altos títulos mantenidos de anticuerpos contra terapia de reemplazo enzimático en la enfermedad de Pompe" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 3028 "Ancho" => 2167 "Tamanyo" => 376924 ] ] "descripcion" => array:1 [ "en" => "Measurement of left ventricular index, Glc4 levels and Anti-rhGAA antibody titers in different moments before and after administration of immunomodulatory agents." ] ] ] "textoCompleto" => "Enzyme replacement therapies (ERT) have prolonged the survival and improved clinical outcomes of patients suffering from a multitude of disorders. Some of the Infantile Pompe Disease (IPD) patients treated with alglucosidase alfa develop anti-rhGAA IgG antibodies<a class="elsevierStyleCrossRef" href="#bib0030">1</a> and the longer term therapeutic efficacy of alglucosidase alfa appears to be more strongly associated with them. Several investigators have unsuccessfully made attempts<a class="elsevierStyleCrossRefs" href="#bib0035">2–5</a> in IPD treated with therapeutic proteins to either achieve immune tolerance or mitigate the immune response, including increasing the dose of therapeutic protein and implementing various drug regimens.Here, we report the first successful achievement in Spain of true immune tolerance to ongoing ERT in a IPD girl with high sustained antibody titles (HSAT).Patient is a Chinese descent girl who presented at age 15 days with normal motor development and a cardiac murmur; echocardiogram showed significant biventricular hypertrophy. She was diagnosed with IPD at age 1 month and ERT was started at 20mg/kg biweekly. Later on, she was cataloged as CRIM-negative IPD at age 4 months. Initial Glc4 levels were 21.8mmol/mol creatinin at age 1 month.She initially benefited clinically from ERT, as evidenced by reduction in left ventricular mass index (LVMI) from 107g/m2 to 94g/m2 at 6 months of age) and maintaining normal Gross Motor Function (level 1). She maintained adequate physical activity and progressed in developmental motor milestones; an initial phase of improvement in LVMI (100g/m2, 20 months, to 62.3g/m2, 24 months) was also noted. At 24 months of age, she first developed HSAT (1/700) and began generalized hypotonia, tongue protrusion, facial myopathy, and cardiomegaly (LVMI values deteriorated from 62.3g/m2 at 24 months of age, to 139g/m2 at 30 months and 200.9g/m2 at 36 months); however, she did not need any respiratory support and tolerated normal oral feeds and was growing normally (62 percentile of weight and height at 33 percentile). For several weeks, ERT was increased from 20 to 35mg/kg/dose with no difference in clinical or functional evaluation. Her antibody titers continued to rise, peaking at 1/1600 at 36 months of age, accompanied by increased urinary Glc4 levels (19.4mmol/mol creatinine at 6 months, to 21.5mmol/mol creatinine at 3 years). At age 41 months, she was hospitalized in the intensive care unit because of an upper respiratory tract infection, and she became ventilator dependent for 2 months and required nasogastric tube feeds. After improvement from acute phase and ventilation withdrawal she was discharged with a Gross Motor Function classification system at level 3 and an increase in antibody titers up to 1/32,000.An ITI protocol was initiated at 49 months of age (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>), with intravenous rituximab (4 doses) and subcutaneous methotrexate (9 doses) for 6 weeks and monthly immunoglobulin infusion for 5 months, resulting in a reduction in titers (1/800 after 6 weeks of treatment, 1/200 after 32 weeks, 1/100 after 112 weeks) and an improvement in gross motor function indexes (level 2), although maintaining facial amymia and easy tiredness in school activities. Urinary Glc4 levels were 20mmol/mol creatinine and LVMI was 104g/m2 at 24 weeks after the end of ITI. ERT continued to be successfully administered afterwards.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Although the ITI treatment described here prolongs survival and improves significant overall clinical outcomes, closer examination clearly demonstrates residual muscle weakness and gross motor function below age-appropriate levels along with feeding difficulties.We believe our immune-modulating strategy has potentially broader clinical implications. Use of the protocol described herein is designed to take place over a relatively brief period of time. This protocol has helped lower antibody titers in these ill IPD patient; however, there is still a need for development of a less extensive protocol with agents that are antigen specific to reduce the immune response. Additional research will be needed to establish the proper dosing regimen of immune-suppressive agents in Pompe and other conditions and the optimal way to taper the maintenance regimen following rituximab and/or other immunomodulatory agent treatments to ensure long-lasting tolerance. Our protocol was well tolerated, safe, and effective in reducing a life-threatening immune response and was successful in inducing long-term immune tolerance.<elsevierMultimedia ident="tb0005"></elsevierMultimedia>" "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 3028 "Ancho" => 2167 "Tamanyo" => 376924 ] ] "descripcion" => array:1 [ "en" => "Measurement of left ventricular index, Glc4 levels and Anti-rhGAA antibody titers in different moments before and after administration of immunomodulatory agents." ] ] 1 => array:5 [ "identificador" => "tb0005" "tipo" => "MULTIMEDIATEXTO" "mostrarFloat" => false "mostrarDisplay" => true "texto" => array:1 [ "textoCompleto" => "What's already known on this feature?Several immune tolerance regimes have been described but always in very few patients, none of them in Spain to the best of our knowledge.What's new on this feature?Although clinical experience and current literature on the use of ITI protocols are greatly limited, success is more likely when immune modulation is previously demonstrated." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:5 [ 0 => array:3 [ "identificador" => "bib0030" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical guidelines for infantile-onset Pompe disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S.I. 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Herzog" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jpeds.2013.06.055" "Revista" => array:4 [ "tituloSerie" => "J Pediatr" "fecha" => "2013" "volumen" => "163" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23958115" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0050" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Bortezomib in the rapid reduction of high sustained antibody titers in disorders treated with therapeutic protein: lessons learned from Pompe disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S.G. Banugaria" 1 => "S.N. Prater" 2 => "J.K. McGann" 3 => "J.D. Feldman" 4 => "J.A. Tannenbaum" 5 => "C. Bailey" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/gim.2012.110" "Revista" => array:6 [ "tituloSerie" => "Genet Med" "fecha" => "2013" "volumen" => "15" "paginaInicial" => "123" "paginaFinal" => "131" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23060045" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/00257753/0000015700000008/v1_202110170505/S0025775320307557/v1_202110170505/en/main.assets" "Apartado" => array:4 [ "identificador" => "66430" "tipo" => "SECCION" "es" => array:2 [ "titulo" => "Cartas al Editor" "idiomaDefecto" => true ] "idiomaDefecto" => "es" ] "PDF" => "https://static.elsevier.es/multimedia/00257753/0000015700000008/v1_202110170505/S0025775320307557/v1_202110170505/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775320307557?idApp=UINPBA00004N"]

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