Editorial
A rational pharmacologic approach toward a biologically meaningful subtype of autism spectrum disorder
a Massachusetts General Hospital, Harvard Medical School, Department of Neurology, Lexington, United States
b Massachusetts General Hospital, Harvard Medical School, Department of Psychiatry, Boston, United States
c Massachusetts General Hospital, Harvard Medical School, Department of Psychiatry, Lexington, United States
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"apellidos" => "Deutsch" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0021755720301868?idApp=UINPBA000049" "url" => "/00217557/0000009700000001/v2_202102230657/S0021755720301868/v2_202102230657/en/main.assets" ] "asociados" => array:1 [ 0 => array:19 [ "pii" => "S0021755719304656" "issn" => "00217557" "doi" => "10.1016/j.jped.2019.10.012" "estado" => "S300" "fechaPublicacion" => "2021-01-01" "aid" => "878" "copyright" => "Sociedade Brasileira de Pediatria" "documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "J Pediatr (Rio J). 2021;97:22-9" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original Article</span>" "titulo" => "Effect of prednisolone on language function in children with autistic spectrum disorder: a randomized clinical trial" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "22" "paginaFinal" => "29" ] ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 879 "Ancho" => 2091 "Tamanyo" => 105437 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Comparison, only in the group treated with prednisolone, of the estimated marginal means of ADL's global language score (GLOL) between: <span class="elsevierStyleBold">(A)</span> the age groups ‘1’ (<5 years) and ‘2’ (≥5 years) and <span class="elsevierStyleBold">(B)</span> participants without (‘0’) and with (‘1’) developmental regression.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Adriana Rocha Brito, Giselle de Paula Teixeira Vairo, Ana Paula Botelho Henriques Dias, Beni Olej, Osvaldo José Moreira Nascimento, Marcio Moacyr Vasconcelos" "autores" => array:6 [ 0 => array:2 [ "nombre" => "Adriana Rocha" "apellidos" => "Brito" ] 1 => array:2 [ "nombre" => "Giselle de Paula Teixeira" "apellidos" => "Vairo" ] 2 => array:2 [ "nombre" => "Ana Paula Botelho Henriques" "apellidos" => "Dias" ] 3 => array:2 [ "nombre" => "Beni" "apellidos" => "Olej" ] 4 => array:2 [ "nombre" => "Osvaldo José Moreira" "apellidos" => "Nascimento" ] 5 => array:2 [ "nombre" => "Marcio Moacyr" "apellidos" => "Vasconcelos" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0021755719304656?idApp=UINPBA000049" "url" => "/00217557/0000009700000001/v2_202102230657/S0021755719304656/v2_202102230657/en/main.assets" ] ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Editorial</span>" "titulo" => "A rational pharmacologic approach toward a biologically meaningful subtype of autism spectrum disorder" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "1" "paginaFinal" => "3" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Ann M. Neumeyer, Robyn P. Thom, Christopher J. McDougle" "autores" => array:3 [ 0 => array:4 [ "nombre" => "Ann M." "apellidos" => "Neumeyer" "email" => array:1 [ 0 => "aneumeyer@mgh.harvard.edu" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Robyn P." "apellidos" => "Thom" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Christopher J." "apellidos" => "McDougle" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Massachusetts General Hospital, Harvard Medical School, Department of Neurology, Lexington, United States" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Massachusetts General Hospital, Harvard Medical School, Department of Psychiatry, Boston, United States" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Massachusetts General Hospital, Harvard Medical School, Department of Psychiatry, Lexington, United States" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Social communication and social interaction deficits are core symptoms of autism spectrum disorder (ASD), a clinically and etiologically heterogeneous neurodevelopmental condition. The heterogeneity of ASD has led to significant challenges in developing effective interventions for its core symptoms, suggesting a need to define and utilize clinical subtypes of ASD to guide the discovery of novel treatments. An immune-mediated subtype of ASD, characterized by systemic, multi-organ inflammation or immune dysregulation, is one such subtype which has been postulated by multiple groups and may serve as a guide to discovering novel interventions.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1–4</span></a> The randomized clinical trial assessing the efficacy of prednisolone, a synthetic immunosuppressive, on language function in children with ASD reported by Brito et al. in this issue of the <span class="elsevierStyleItalic">Jornal de Pediatria</span> represents a very important step in this direction.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">As the evidence base for immune dysregulation in a subset of patients with ASD grows, there has been increased interest in the role of immunomodulation for the treatment of core symptoms. In fact, the only two treatments for ASD currently indicated by the Food and Drug Administration (FDA), risperidone and aripiprazole – both second-generation antipsychotics approved for the treatment of severe irritability in children and adolescents with ASD – have demonstrated anti-inflammatory effects in cell culture and animal model studies.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6–8</span></a> Additionally, more than ten medications known to have immunomodulatory potential have been repurposed from other fields of medicine to undergo pilot investigations in either animal or initial human studies to determine whether they may modify the core symptoms of ASD (reviewed here).<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> For example, pioglitazone, an anti-diabetic medication which is known to exert anti-inflammatory activity on astroglial cells of the brain,<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> has been demonstrated to improve social interactions and normalize ultrasonic vocalizations in a rat model of maternal immune activation-mediated ASD through decreasing interleukin-6, an inflammatory cytokine.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> A follow-up open-label study demonstrated that children who received daily treatment with pioglitazone for three to four months had improvements in four out of five subscales of the Aberrant Behavior Checklist: irritability, lethargy, stereotypy, and hyperactivity.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Some other medications that have shown initial promise and merit further investigation for treating the core symptoms of ASD through immunomodulation include minocycline, valproic acid, and celecoxib.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Although immunomodulatory treatments for ASD represent an exciting, potentially new avenue for drug discovery, they are not currently the standard of care for ASD and much more research needs to be done to establish safety, tolerability, and efficacy. There are several factors to consider when conducting these studies. First, it will be important to identify the neurodevelopmental time points that are most sensitive to treatment with an immunomodulatory agent. Since acquisition of social and communication skills typically occurs during specific developmental periods, there may be timeframes before or during which immunomodulatory treatments are most impactful. The observation that there was an interaction between age and prednisolone administration, such that the younger group of children (<5 years) had a more robust response to prednisolone in the study by Brito et al.,<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> lends credence to this hypothesis. Second, there is still no evidence to assist in the identification of the subset of patients with ASD who may be more likely to respond to immunomodulatory treatments. Further studies on how to utilize a clinical phenotype and/or inflammatory biomarkers to identify this subset of patients and monitor the physiological response to treatment will be of great value. The fact that all of the participants in the study by Brito et al.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> underwent brain magnetic resonance imaging (MRI) and lumbar punctures is a remarkable feat, as participation in neuroimaging studies can be very difficult for adults, let alone children with ASD.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> It would be of interest to know if any of the MRI or cerebrospinal fluid findings correlated with response to prednisolone and could be used as biomarkers to predict response to immunomodulatory treatments. Perhaps the authors plan to report these findings in subsequent manuscripts. Since the inclusion criteria for the randomized clinical trial in the study by Brito et al.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> were not explicitly limited to children with a pro-inflammatory profile (such as co-occurring inflammatory medical conditions or a family history of autoimmunity), this may have attenuated the observed effect of prednisolone on language improvement. The observation that there was an interaction between developmental regression and prednisolone suggests this phenomenon may be a marker of an inflammatory-subtype of ASD and this should be further investigated. Finally, future studies will need to determine whether there are sex-specific responses to immunomodulatory treatments. Preclinical studies have demonstrated that in mouse maternal immune activation models of ASD, offspring exhibit sex-specific changes in gene expression affecting hundreds of genes.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> Furthermore, a two-hit (prenatal and early postnatal) mouse model of early-life immune activation demonstrated that male offspring exhibit a more severe ASD phenotype than female offspring.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> In this model, both sexes exhibited increased pro-inflammatory gene expression in the brain, but only males exhibited decreased expression of anti-inflammatory genes.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> The study by Brito et al. understandably only included boys to reduce sample heterogeneity. However, these recent preclinical findings suggest that it may be important to include girls in future studies to determine whether there is a sex-specific response to immunomodulatory treatments.</p><p id="par0020" class="elsevierStylePara elsevierViewall">There are many challenges to designing and conducting clinical trials in ASD. As in any drug study, patient recruitment is the first major challenge. However, recruiting an adequate number of patients to demonstrate a treatment effect of a medication for ASD is magnified by the fact that ASD is a heterogeneous and behaviorally-defined disorder. There are no well-established biomarkers that can be used to diagnose or characterize patients with ASD. Because of this, there is a need to recruit a larger sample size to attain adequate power. Highlighting the practical challenges of recruiting and enrolling children with ASD in a medication study, the study by Brito et al. was registered ten years ago in 2010 and screened more than 100 children to enroll 40 research subjects.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The second challenge in clinical trial design for subjects with ASD is the decision regarding which primary and secondary outcome scales to include, balancing the need to use well-recognized measures in the field with scales that are culturally appropriate and validated for the subjects included in the trial. Brito et al. navigated this challenge by utilizing an internationally recognized scale, as well as two Brazilian instruments. The authors used a clinical rating scale of autism, the Childhood Autism Rating Scale (CARS-BR),<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> to assess secondary outcomes. Although the results of the CARS-BR do not appear to be included in this report, it would be of interest to know if treatment with prednisolone resulted in any changes in the CARS-BR. The authors chose to assess language using two Brazilian instruments: the Child Language Test in Phonology, Vocabulary, Fluency, and Pragmatics (ABFW), a test of pragmatic language, and the Language Development Assessment (ADL) based on the Preschool Language Scale.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Third, there are significant challenges to interpreting the results of a clinical trial of small sample size. The study by Brito et al. included 18 children who were randomized to prednisolone treatment and 20 children who were randomized to placebo.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> The results demonstrated no significant effect of prednisolone on either the ADL global language scores or the ABFW total communicative acts. However, there were some statistically significant interactions between prednisolone and age; prednisolone and history of regression; as well as prednisolone, age, and regression history in some of the ABFW subscales. These interactions suggest that prednisolone may have a greater effect on language development in younger children and in those with a history of developmental regression, and possibly an even larger effect in patients with both these clinical characteristics. While the sample size was limited (only 13 of the 18 subjects randomized to prednisolone were under 5 years of age) and the study was not adequately powered to draw these conclusions with confidence, the authors of the study were aware of these limitations. They note that randomization which accounts for the presence or absence of developmental regression would allow for a more equitable distribution of subgroups for comparison. This randomization approach may be helpful to include in future studies. The statistically significant interactions observed between prednisolone administration and age – as well as a history of developmental regression – are very interesting and deserve further study with a larger sample size. In summary, there are no statistically significant findings overall, likely due to small sample size and a heterogeneous population, but there are intriguing hints that there may be a clinically identifiable subgroup of children with ASD who respond to immunomodulation. Notably, this study contributes important published data on the relative tolerability and safety of prednisolone in children with ASD for others to build upon. While the primary outcomes of the study were negative, the authors should be commended for publishing the results of this important and pioneering work, as these results provide initial evidence supporting the need for future work on immunomodulatory treatments in ASD.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Based on what we have learned from this trial, future studies on immunomodulatory treatments in ASD will need to be designed and adequately powered to confirm whether certain clinical features including a history of developmental regression and younger age predict response to immunomodulatory treatments. Although many immunomodulatory treatments are associated with significant side effects that carry the risk of unblinding, the authors in this study made considerable efforts to protect the blind by ensuring that the language scale raters were not part of the participants’ clinical care team and were unaware of randomization allocation. Pre- and post-treatment language assessments using internationally recognized and well-validated scales should be included in future work. Finally, future studies might benefit from including additional baseline demographic descriptors including validated cognitive and adaptive functioning measures, family history of inflammatory conditions, the presence of medical and psychiatric co-morbidities, and include inflammatory biomarkers to advance our ability to identify patients who may be most responsive to immunomodulatory treatments.</p><span id="sec1005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect1005">Funding</span><p id="par1040" class="elsevierStylePara elsevierViewall">This work was supported in part by the <span class="elsevierStyleGrantSponsor" id="gs1">Robert and Donna Landreth Family Fund</span> and the <span class="elsevierStyleGrantSponsor" id="gs2">Nancy Lurie Marks Family Foundation</span>.</p></span><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of interest</span><p id="par0040" class="elsevierStylePara elsevierViewall">The authors declare no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec1005" "titulo" => "Funding" ] 1 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflicts of interest" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Neumeyer AM, Thom RP, McDougle CJ. A rational pharmacologic approach toward a biologically meaningful subtype of autism spectrum disorder. J Pediatr (Rio J). 2021;97:1–3.</p>" ] 1 => array:2 [ "etiqueta" => "☆☆" "nota" => "<p class="elsevierStyleNotepara" id="npar1005">See paper by Brito et al. in pages 22–29.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:17 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Beyond the brain: a multi-system inflammatory subtype of autism spectrum disorder" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R.P. Thom" 1 => "C.J. Keary" 2 => "M.L. Palumbo" 3 => "C.T. Ravichandran" 4 => "J.E. Mullett" 5 => "E.P. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 8 | 2 | 10 |
| 2024 October | 25 | 25 | 50 |
| 2024 September | 45 | 29 | 74 |
| 2024 August | 54 | 25 | 79 |
| 2024 July | 40 | 46 | 86 |
| 2024 June | 31 | 45 | 76 |
| 2024 May | 27 | 15 | 42 |
| 2024 April | 35 | 29 | 64 |
| 2024 March | 40 | 25 | 65 |
| 2024 February | 50 | 33 | 83 |
| 2024 January | 33 | 31 | 64 |
| 2023 December | 23 | 25 | 48 |
| 2023 November | 34 | 31 | 65 |
| 2023 October | 26 | 31 | 57 |
| 2023 September | 33 | 40 | 73 |
| 2023 August | 30 | 20 | 50 |
| 2023 July | 27 | 18 | 45 |
| 2023 June | 27 | 15 | 42 |
| 2023 May | 28 | 10 | 38 |
| 2023 April | 23 | 9 | 32 |
| 2023 March | 39 | 18 | 57 |
| 2023 February | 28 | 16 | 44 |
| 2023 January | 29 | 24 | 53 |
| 2022 December | 39 | 28 | 67 |
| 2022 November | 25 | 22 | 47 |
| 2022 October | 54 | 33 | 87 |
| 2022 September | 29 | 36 | 65 |
| 2022 August | 37 | 33 | 70 |
| 2022 July | 29 | 32 | 61 |
| 2022 June | 60 | 30 | 90 |
| 2022 May | 42 | 20 | 62 |
| 2022 April | 26 | 28 | 54 |
| 2022 March | 33 | 48 | 81 |
| 2022 February | 21 | 20 | 41 |
| 2022 January | 25 | 22 | 47 |
| 2021 December | 25 | 13 | 38 |
| 2021 November | 16 | 20 | 36 |
| 2021 October | 18 | 11 | 29 |
| 2021 September | 23 | 19 | 42 |
| 2021 August | 13 | 9 | 22 |
| 2021 July | 18 | 12 | 30 |
| 2021 June | 8 | 7 | 15 |
| 2021 May | 16 | 15 | 31 |
| 2021 April | 35 | 29 | 64 |
| 2021 March | 32 | 20 | 52 |
| 2021 February | 71 | 28 | 99 |
| 2021 January | 134 | 24 | 158 |
| 2020 December | 10 | 11 | 21 |
| 2020 November | 12 | 11 | 23 |
| 2020 October | 10 | 6 | 16 |
| 2020 September | 16 | 11 | 27 |
| 2020 August | 20 | 5 | 25 |
| 2020 July | 11 | 9 | 20 |
| 2020 June | 2 | 3 | 5 |
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