Opinion Article
Cytokine Pathways and the Role of Dysbiosis in Psoriasis, Psoriatic Arthritis, and Crohn Disease
Psoriasis, artritis psoriásica y enfermedad de Crohn: circuitos de citocinas y papel de la disbiosis
L. Puig
Servicio de Dermatología, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
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Puig" "autores" => array:1 [ 0 => array:3 [ "nombre" => "L." "apellidos" => "Puig" "email" => array:1 [ 0 => "lpuig@santpau.cat" ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Dermatología, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain" "identificador" => "aff0005" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Psoriasis, artritis psoriásica y enfermedad de Crohn: circuitos de citocinas y papel de la disbiosis" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Psoriasis, psoriatic arthritis, and other spondyloarthropathies such as those associated with inflammatory bowel disease (IBD) and IBD itself (Crohn disease being the paradigm), share many pathogenic features. The first characteristic to be identified, and one that was key for defining the concept of immune-mediated inflammatory disease (IMID), was the response of all these conditions to biologic agents that block tumor necrosis factor (TNF). However, there are subtle differences in the pattern of response that are worthy of comment. Examples include the lack of efficacy of etanercept in Crohn disease<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">1</span></a> (which has never been satisfactorily explained),<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">2</span></a> the fact that ustekinumab is only effective in Crohn disease after prior failure of at least one other anti-TNF agent,<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">3</span></a> and clinical worsening in patients treated with interleukin (IL) 17A inhibitors,<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">4</span></a> whose spectacular efficacy in psoriasis confirms the fundamental pathogenic role of IL-17A in this disease.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">5</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Another feature common to IMIDs is the appearance of paradoxical manifestations during treatment with anti-TNF agents. Explanations have been proposed for this contradictory behaviour, such as the activation of alternative cytokine pathways. For example, TNF blockade through treatment might induce an increased production of interferon alpha by plasmacytoid dendritic cells, which in turn may then activate production of IL-17A (sustained by IL-23) and IL-22 by the corresponding T-cell subpopulations, as well as expression of IL-22 receptors in keratinocytes.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">6</span></a> This would explain the onset of paradoxical psoriasis in some patients (for example patients with Crohn disease) who receive anti-TNF agents. These patients may have a certain genetic predisposition due to uncommon alleles of the IL23R gene and respond to treatment with ustekinumab,<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">7,8</span></a> whereas activation of another feedback circuit in which the cytokines IL-17<span class="elsevierStyleHsp" style=""></span>C and IL-36γ participate may go some way towards explaining the activation of keratinocytes in paradoxical psoriasis. These observations may provide a basis for a new therapeutic approach to this disease<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">9</span></a> and perhaps to other pustular dermatoses.</p><p id="par0015" class="elsevierStylePara elsevierViewall">With regards to the counterproductive effect of IL-17A blockade in Crohn disease, it has been observed that patients with active disease have lower circulating CD45RO<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>CD4+<span class="elsevierStyleHsp" style=""></span>T helper (Th) 17 cell levels than those present when the disease is controlled with adalimumab; the lymphocyte count inversely correlates with mucosal inflammation estimated from the levels of fecal calprotectin.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">10</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">This apparent paradox requires an explanation, given that IL-23 (which in principle can expand Th17 cell populations and is able to activate tissue-resident IL-17A–producing Tγδ cells) has a fundamental role in autoimmune intestinal inflammation in murine models of IBD.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">11</span></a> There are probably different types of Th17 cells, able to produce different combinations of cytokines that determine a relatively specific antimicrobial action, and the imbalanced intestinal microflora in Crohn disease, and certain Gram+ bacteria in particular—segmented filamentous bacteria—may play a key role in differentiation of Th17 cells and induction of colitis in murine models of IBD.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">11</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The levels of IL-22 produced by type 3 innate lymphoid cells in the intestine are critical for maintaining intestinal barrier function, and in absence of IL-22, overgrowth of segmented filamentous bacteria may occur, along with an increase in the number of Th17 cells both in the mucosa and the corresponding lymph nodes.<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">12,13</span></a> Inhibition of IL-17A, one of the cytokines produced by Th17 cells, exacerbates intestinal disease in some patients with Crohn disease, thus suggesting a protective role of IL-17A, consistent with the observations in some murine models of colitis.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">14</span></a> Although a pathogenic role has been proposed for IL-17F and IL-25 in IBD,<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">15</span></a> treatment with brodalumab has not proved effective.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">2</span></a> On the other hand, it has been postulated that exacerbations observed in patients treated with IL-17A inhibitors may be related to altered intestinal mycological flora.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">16</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Currently, it is accepted that a disturbed immune response to an altered intestinal microbiome at the mucosal interface has a fundamental role in the pathogenesis of Crohn disease and ulcerative colitis in individuals with a certain genetic predisposition.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">17</span></a> The microbiome is the set of commensal bacteria associated with each individual, located in the skin, vagina, oral cavity, and principally (70%), the gastrointestinal tract. The dominant phyla are <span class="elsevierStyleItalic">Bacteroidetes</span> and <span class="elsevierStyleItalic">Firmicutes</span>. The intestinal microbiome contributes to digestion of fiber and polyphenols, the production of certain vitamins, and maintenance of epithelial barrier integrity, regulating homeostasis of the host immune system.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">18</span></a> Taxonomic alterations or imbalances in the intestinal microbiome (dysbiosis) have been associated with a range of conditions, including obesity, colorectal cancer, liver diseases, irritable colon, IBD, and other IMIDs.<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">19</span></a> Both in IBD and spondyloarthritis, disturbances in the intestinal microbiome have been reported, with a decrease in the number of <span class="elsevierStyleItalic">Firmicutes</span>, which may indicate another common pathogenic mechanism,<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">20</span></a> and the existence of analogous disturbances (relative decrease of <span class="elsevierStyleItalic">Coprococcus</span> and other beneficial taxa) in psoriatic arthritis.<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">21</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Numerous studies have shown that the intestinal microbiome may have an impact on Th17/Treg balance in the lamina propria, and that intestinal Th17 cells may be responsible for the onset of arthritis in experimental models. The activation of Toll-like receptors plays a key role in the differentiation of Th17 cells in the lamina propria and in the induction of autoimmune arthritis; possible mechanisms include cross-recognition of bacterial and endogenous antigens, migration of Th17 cells of intestinal origin to the joints, and an alteration in the microenvironment of cytokines that may stimulate differentiation of autoreactive Th17 cells.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">22</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Although this mechanism may provide a plausible explanation for the role of a possible dysbiosis in the pathogenesis of psoriasis and psoriatic arthritis, in the case of psoriasis, more attention has been paid to possible alterations in the skin microbiome, by analogy with atopic dermatitis.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">23</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">The pathogenic role of intestinal dysbiosis, that is, disturbed immunologic tolerance of intestinal microflora, would seem an important and common feature of different IMIDs. Some physicians, however, may be reluctant to explore the possible therapeutic implications (fecal transplantation) of this mechanism. They may prefer an alternative explanation involving alteration in the skin microbiome, which may have a similar role (alternative or complementary) to intestinal dysbiosis in psoriasis<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">24</span></a> and psoriatic arthritis.<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">25</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">In conclusion, psoriasis, psoriatic arthritis, and Crohn disease share common pathogenic features, but they also show differences that may help elucidate the complete inflammatory cycles implicated and so develop new therapeutic approaches.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of Interest</span><p id="par0055" class="elsevierStylePara elsevierViewall">L. Puig has received consultancy and/or speaker fees, and has participated as an investigator in clinical trials sponsored by AbbVie, Amgen, Janssen, Lilly, Novartis, and Pfizer.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflicts of Interest" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Puig L. Psoriasis, artritis psoriásica y enfermedad de Crohn: circuitos de citocinas y papel de la disbiosis. Actas Dermosifiliogr. 2016;107:95–97.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:25 [ 0 => array:3 [ "identificador" => "bib0130" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Biological therapies for inflammatory bowel diseases" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "P. Rutgeerts" 1 => "S. 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| año/Mes | Html | Total | |
|---|---|---|---|
| 2024 Noviembre | 9 | 4 | 13 |
| 2024 Octubre | 75 | 55 | 130 |
| 2024 Septiembre | 94 | 27 | 121 |
| 2024 Agosto | 107 | 66 | 173 |
| 2024 Julio | 71 | 40 | 111 |
| 2024 Junio | 75 | 41 | 116 |
| 2024 Mayo | 66 | 31 | 97 |
| 2024 Abril | 60 | 24 | 84 |
| 2024 Marzo | 74 | 33 | 107 |
| 2024 Febrero | 65 | 36 | 101 |
| 2024 Enero | 47 | 38 | 85 |
| 2023 Diciembre | 44 | 21 | 65 |
| 2023 Noviembre | 48 | 25 | 73 |
| 2023 Octubre | 56 | 26 | 82 |
| 2023 Septiembre | 52 | 30 | 82 |
| 2023 Agosto | 32 | 26 | 58 |
| 2023 Julio | 36 | 35 | 71 |
| 2023 Junio | 52 | 25 | 77 |
| 2023 Mayo | 52 | 24 | 76 |
| 2023 Abril | 37 | 22 | 59 |
| 2023 Marzo | 41 | 23 | 64 |
| 2023 Febrero | 48 | 26 | 74 |
| 2023 Enero | 34 | 50 | 84 |
| 2022 Diciembre | 49 | 37 | 86 |
| 2022 Noviembre | 31 | 26 | 57 |
| 2022 Octubre | 21 | 23 | 44 |
| 2022 Septiembre | 21 | 42 | 63 |
| 2022 Agosto | 20 | 27 | 47 |
| 2022 Julio | 21 | 30 | 51 |
| 2022 Junio | 17 | 25 | 42 |
| 2022 Mayo | 29 | 41 | 70 |
| 2022 Abril | 38 | 29 | 67 |
| 2022 Marzo | 37 | 37 | 74 |
| 2022 Febrero | 42 | 29 | 71 |
| 2022 Enero | 30 | 29 | 59 |
| 2021 Diciembre | 21 | 32 | 53 |
| 2021 Noviembre | 40 | 34 | 74 |
| 2021 Octubre | 47 | 48 | 95 |
| 2021 Septiembre | 43 | 40 | 83 |
| 2021 Agosto | 28 | 26 | 54 |
| 2021 Julio | 34 | 30 | 64 |
| 2021 Junio | 46 | 28 | 74 |
| 2021 Mayo | 37 | 35 | 72 |
| 2021 Abril | 46 | 73 | 119 |
| 2021 Marzo | 83 | 31 | 114 |
| 2021 Febrero | 59 | 30 | 89 |
| 2021 Enero | 33 | 22 | 55 |
| 2020 Diciembre | 42 | 9 | 51 |
| 2020 Noviembre | 48 | 27 | 75 |
| 2020 Octubre | 22 | 11 | 33 |
| 2020 Septiembre | 37 | 10 | 47 |
| 2020 Agosto | 43 | 20 | 63 |
| 2020 Julio | 25 | 16 | 41 |
| 2020 Junio | 41 | 36 | 77 |
| 2020 Mayo | 24 | 17 | 41 |
| 2020 Abril | 31 | 13 | 44 |
| 2020 Marzo | 48 | 15 | 63 |
| 2020 Febrero | 9 | 1 | 10 |
| 2020 Enero | 4 | 0 | 4 |
| 2019 Diciembre | 8 | 0 | 8 |
| 2019 Noviembre | 4 | 0 | 4 |
| 2019 Septiembre | 6 | 0 | 6 |
| 2019 Agosto | 4 | 0 | 4 |
| 2019 Julio | 4 | 0 | 4 |
| 2019 Junio | 4 | 0 | 4 |
| 2019 Mayo | 6 | 1 | 7 |
| 2019 Abril | 2 | 2 | 4 |
| 2019 Marzo | 4 | 5 | 9 |
| 2019 Febrero | 1 | 2 | 3 |
| 2019 Enero | 4 | 0 | 4 |
| 2018 Diciembre | 6 | 0 | 6 |
| 2018 Noviembre | 9 | 0 | 9 |
| 2018 Octubre | 13 | 0 | 13 |
| 2018 Septiembre | 7 | 0 | 7 |
| 2018 Marzo | 1 | 0 | 1 |
| 2018 Febrero | 23 | 12 | 35 |
| 2018 Enero | 29 | 6 | 35 |
| 2017 Diciembre | 20 | 9 | 29 |
| 2017 Noviembre | 24 | 12 | 36 |
| 2017 Octubre | 34 | 10 | 44 |
| 2017 Septiembre | 14 | 10 | 24 |
| 2017 Agosto | 28 | 11 | 39 |
| 2017 Julio | 19 | 9 | 28 |
| 2017 Junio | 34 | 5 | 39 |
| 2017 Mayo | 32 | 5 | 37 |
| 2017 Abril | 25 | 6 | 31 |
| 2017 Marzo | 18 | 9 | 27 |
| 2017 Febrero | 30 | 12 | 42 |
| 2017 Enero | 25 | 6 | 31 |
| 2016 Diciembre | 21 | 18 | 39 |
| 2016 Noviembre | 18 | 18 | 36 |
| 2016 Octubre | 32 | 25 | 57 |
| 2016 Julio | 2 | 3 | 5 |
| 2016 Mayo | 0 | 1 | 1 |
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