Evolution of disease activity and biomarkers on and off rapamycin in 28 patients with autoimmune lymphoproliferative syndrome

Klemann, Christian; Esquivel, Myrian; Magérus-Chatinet, Aude; Lorenz, Myriam Ricarda; Fuchs, Ilka; Neveux, N.; Castelle, Martin; Rohr, Jan; Cunha, Claudia Bettoni da; Ebinger, Martin; Kobbe, Robin; Kremens, Bernhard; Kollert, Florian; Gambineri, Eleonora; Lehmberg, Kai; Seidel, Markus G.; Siepermann, Kathrin; Voelker, Thomas; Schuster, Volker; Goldacker, Sigune; Schwarz, Klaus; Speckmann, Carsten; Pïcard, Capucine; Fischer, Alain; Rieux-Laucat, Frédéric; Ehl, Stephan; Rensing‐Ehl, Anne; Neven, Bénédicte

doi:10.3324/haematol.2016.153411

Cited by 48 publications

(37 citation statements)

References 14 publications

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“…Additional published studies have since demonstrated similar results, suggesting moving sirolimus to upfront, first-line therapy 7 , 19 , 62 . In a recent retrospective study of 18 patients with definitive ALPS (9 type 1a, eight sFAS, and one homozygous) treated with sirolimus as first-line therapy, the majority (94%, 17 out of 18 patients) experienced a CR.…”

Section: Managementmentioning

confidence: 69%

“…In a recent retrospective study of 18 patients with definitive ALPS (9 type 1a, eight sFAS, and one homozygous) treated with sirolimus as first-line therapy, the majority (94%, 17 out of 18 patients) experienced a CR. In addition, those with a CR had an associated normalization of known biomarkers, including DNTs and serum levels of vitamin B 12 , IL-10, and sFASL 7 . MMF has similarly been shown to be effective in improving autoimmune cytopenias; however, unlike with sirolimus, many of these patients have partial responses prompting continued steroid use while others have relapsed 58 , 63 .…”

Section: Managementmentioning

confidence: 95%

“…DNTs express CD3 and the alpha/beta T-cell receptor (TCRα/β) but lack CD4 and CD8. Other signature laboratory abnormalities in ALPS include elevated levels of interleukin 10 (IL-10), IL-18, vitamin B 12 , soluble FAS ligand (sFASL), and IgG in plasma or sera as well as i n vitro evidence of defective FAS-mediated apoptosis 3 , 4 , 6 , 7 . Significant advances in our understanding of the pathophysiology of ALPS led to improved diagnostic criteria and eventually targeted therapeutic strategies, including the mammalian target of rapamycin (mTOR) inhibitor sirolimus (also known as rapamycin or Rapamune).…”

Section: Introductionmentioning

confidence: 99%

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Autoimmune lymphoproliferative syndrome: more than a FAScinating disease

Bride

Teachey

2017

F1000Res

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Autoimmune lymphoproliferative syndrome (ALPS) is an inherited syndrome characterized by abnormal lymphocyte survival caused by failure of apoptotic mechanisms to maintain lymphocyte homeostasis. This failure leads to the clinical manifestations of non-infectious and non-malignant lymphadenopathy, splenomegaly, and autoimmune pathology, most commonly, autoimmune cytopenias. Since ALPS was first characterized in the early 1990s, insights in disease biology have improved both diagnosis and management of this syndrome. Sirolimus is the best-studied and most effective corticosteroid-sparing therapy for ALPS and should be considered first-line for patients in need of chronic treatment. This review highlights practical clinical considerations for the diagnosis and management of ALPS. Further studies could reveal new proteins and regulatory pathways that are critical for lymphocyte activation and apoptosis.

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Section: Managementmentioning

confidence: 69%

Section: Managementmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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Autoimmune lymphoproliferative syndrome: more than a FAScinating disease

Bride

Teachey

2017

F1000Res

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“…Existe evidencia de que la vigilancia periódica mediante imágenes anatómicas combinadas, es decir, tomografía computarizada o por emisión de positrones, puede ser útil para monitorear la eficacia y el tiempo necesario de administración del sirolimus, aunque es indispensable la recopilación de datos a largo plazo para determinar el costo-beneficio de estos estudios de imagen antes de que se usen de forma rutinaria. 15,44,45,46,47,48 Diversos hallazgos de laboratorio, incluido el número de DNT y los niveles de IL-10, FASLG y otros biomarcadores, no solo tienen un propósito diagnóstico, sino que también se pueden usar para monitorear la actividad de la enfermedad y la respuesta al tratamiento.…”

Section: Diagnóstico (Figura 2)unclassified

“…El rituximab y los inhibidores de la rapamacina, como el sirolimus y la pentostatina, se han aplicado en pacientes con enfermedad resistente o considerable linfoproliferación; han sido efectivos en la remisión de citopenias y linfadenopatías. 15,43,44,45 La esplenectomía está indicada en citopenias resistentes, especialmente en anemia hemolítica y trombocitopenia autoinmune, sin embargo, se sugiere como última alternativa, principalmente por el riesgo posterior de infecciones graves y sepsis. 32,42 El trasplante alogénico de células progenitoras hematopoyéticas es el tratamiento curativo y se ha indicado en pacientes con enfermedad grave o resistente.…”

Section: Linfoproliferaciónunclassified

Síndrome linfoproliferativo autoinmune. Actualización y revisión

Suárez-Gutiérrez¹,

Yamazaki‐Nakashimada

Espinosa

et al. 2019

RAM

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El síndrome linfoproliferativo autoinmune (ALPS, autoimmune lymphoproliferative syndrome) es un error innato de la inmunidad, resultado de un grupo heterogéneo de alteraciones en los genes que regulan el fenómeno de apoptosis. Se manifiesta típicamente en los primeros años de vida. Las manifestaciones clínicas más comunes son la expansión linfoide con linfadenopatía, esplenomegalia y hepatomegalia, enfermedad autoinmune con citopenias, incluyendo trombocitopenia y anemia hemolítica, así como linfoma. Las anomalías de laboratorio que facilitan el diagnóstico de ALPS incluyen presencia de células alfa-beta T doble negativas, niveles elevados de interleucina 10, vitamina B12 en sangre y apoptosis defectuosa mediada por FAS en ensayo in vitro. El tratamiento de ALPS se centra en tres aspectos: el tratamiento de las manifestaciones de la enfermedad, la prevención y tratamiento de las complicaciones y el tratamiento curativo (trasplante de células progenitoras hematopoyéticas [TCPH]). Se sugiere el uso de tratamiento inmunosupresor solo para las complicaciones graves de la linfoproliferación o manifestaciones autoinmunes concomitantes. La esplenectomía no se recomienda para las manifestaciones autoinmunes en pacientes con ALPS. El TCPH se reserva para pacientes seleccionados. La tasa de supervivencia a 50 años se estima en 85 % para los pacientes con deficiencia de FAS.

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Inborn errors of immunity and immunodeficiencies: Antibody‐mediated pathology and autoimmunity as a consequence of impaired immune reactions

et al. 2022

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B-cell tolerance to self-antigen is an active process that requires the temporal and spatial integration of signals of defined intensity. In common variable immune deficiency disorders, CTLA-4 deficiency, autoimmune lymphoproliferative syndrome, or in collagen VII deficiency, genetic defects in molecules regulating development, activation, maturation, and ECM composition alter the generation of B cells, resulting in immunodeficiency. Paradoxically, at the same time, the defective immune processes favor autoantibody production and immunopathology through impaired establishment of tolerance. The development of systemic autoimmunity in the framework of defective BCR signaling is relatively unusual in genetic mouse models. In sharp contrast, such reduced signaling in humans is clearly linked to pathological autoimmunity. The molecular mechanisms by which tolerance is broken in these settings are only starting to be explored resulting in novel therapeutic interventions. For instance, in CTLA-4 deficiency, homeostasis can be restored by CTLA-4 Ig treatment. Following this example, the identification of the molecular targets causing the reduced signals and their restoration is a visionary way to reestablish tolerance and develop novel therapeutic avenues for immunopathologies. Keywords: B-cell receptor r autoantibodies r autoimmunity r extracellular matrix r inborn errors of immunity See accompanying Commentary by Ehl and Thimme.

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Evolution of disease activity and biomarkers on and off rapamycin in 28 patients with autoimmune lymphoproliferative syndrome

Cited by 48 publications

References 14 publications

Autoimmune lymphoproliferative syndrome: more than a FAScinating disease

Autoimmune lymphoproliferative syndrome: more than a FAScinating disease

Síndrome linfoproliferativo autoinmune. Actualización y revisión

Inborn errors of immunity and immunodeficiencies: Antibody‐mediated pathology and autoimmunity as a consequence of impaired immune reactions

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