Division of Gastroenterology and Hepatology, University Hospital Zurich, Switzerland.
Division of Gastroenterology and Hepatology, Triemli Hospital Zurich, Switzerland.
J Crohns Colitis. 2018 Feb 28;12(3):347-354. doi: 10.1093/ecco-jcc/jjx158.
Pathogenesis of cutaneous extraintestinal manifestations [EIM] in inflammatory bowel disease [IBD] remains elusive. Efficacy of anti-TNF agents suggests TNF-dependent mechanisms. The role of other biologics, such as anti-integrins or JAK-inhibitors, is not yet clear.
We performed immunohistochemistry for TNFα, NFκB, STAT1/STAT3, MAdCAM1, CD20/68, caspase 3/9, IFNγ, and Hsp-27/70 on 240 intestinal [55 controls, 185 IBD] and 64 skin biopsies [11 controls, 18 erythema nodosum [EN], 13 pyoderma gangenosum [PG], 22 psoriasis]. A semiquantitative score [0-100%] was used for evaluation.
TNFα was upregulated in intestinal biopsies from active Crohn`s disease [CD] vs controls [36.2 vs 12.1, p < 0.001], but not ulcerative colitis [UC: 17.9]. NFκB, however, was upregulated in intestinal biopsies from both active CD and UC [43.2 and 34.5 vs 21.8, p < 0.001 and p = 0.017, respectively]. TNFα and NFκB were overexpressed in skin biopsies from EN, PG, and psoriasis. No MAdCAM1 overexpression was seen in skin tissues, whereas it was upregulated in active UC vs controls [57.5 vs 35.4, p = 0.003]. STAT3 was overexpressed in the intestinal mucosa of active and non-active IBD, and a similar upregulation was seen in skin biopsies from EN [84.7 vs 22.3, p < 0.001] and PG [60.5 vs 22.3, p = 0.011], but not in psoriasis. Caspase 3 and CD68 overexpression in skin biopsies distinguished EN/PG from psoriasis and controls.
Upregulation of TNFα/NFκB in EN and PG is compatible with the efficacy of anti-TNF in EIM management. Data on overexpressed STAT3, but not MAdCAM1, support a rationale for JAK-inhibitors in EN and PG, while questioning the role of vedolizumab.
炎症性肠病（IBD）的皮肤肠外表现（EIM）的发病机制仍不清楚。抗 TNF 药物的疗效表明存在 TNF 依赖性机制。其他生物制剂，如抗整合素或 JAK 抑制剂的作用尚不清楚。
我们对 240 例肠道活检标本（55 例对照，185 例 IBD）和 64 例皮肤活检标本（11 例对照，18 例结节性红斑[EN]，13 例化脓性汗腺炎[PG]，22 例银屑病）进行了 TNFα、NFκB、STAT1/STAT3、MAdCAM1、CD20/68、半胱天冬酶 3/9、IFNγ和 HSP-27/70 的免疫组织化学染色。采用 0-100%的半定量评分进行评估。
与对照组相比，活动期克罗恩病（CD）的肠道活检标本中 TNFα表达上调[36.2%比 12.1%，p<0.001]，但溃疡性结肠炎（UC）则没有[17.9%]。然而，NFκB 在活动期 CD 和 UC 的肠道活检标本中均上调[43.2%和 34.5%，分别 p<0.001 和 p=0.017]。EN、PG 和银屑病的皮肤活检标本中 TNFα和 NFκB 过度表达。皮肤组织中未见 MAdCAM1 过度表达，但在活动期 UC 与对照组中可见[57.5%比 35.4%，p=0.003]。STAT3 在活动期和非活动期 IBD 的肠道黏膜中过度表达，在 EN 的皮肤活检标本中也有类似的上调[84.7%比 22.3%，p<0.001]和 PG [60.5%比 22.3%，p=0.011]，但在银屑病中则没有。皮肤活检标本中 caspase 3 和 CD68 的过度表达可将 EN/PG 与银屑病和对照组区分开来。
EN 和 PG 中 TNFα/NFκB 的上调与 EIM 管理中抗 TNF 的疗效一致。STAT3 过度表达的数据，但不是 MAdCAM1，支持 JAK 抑制剂在 EN 和 PG 中的作用机制，而对 vedolizumab 的作用提出质疑。
