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Bài giảng Điều trị bệnh vảy nến: Quá khứ - hiện tại và tương lai do TS.BS. Nguyễn Thị Hồng Chuyên biên soạn gồm các nội dung: Tiến bộ trong hiểu biết về sinh bệnh học của bệnh vảy nến; Bệnh hệ thống bệnh đồng mắc điều trị phòng ngừa; Những bước tiến trong điều trị.

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Nội dung Text: Bài giảng Điều trị bệnh vảy nến: Quá khứ - hiện tại và tương lai - TS.BS. Nguyễn Thị Hồng Chuyên

Hội nghị Y học liên ngành TP.HCM, 12/11/2022 Điều trị bệnh vảy nến: Quá khứ - Hiện tại và Tương lai TS.BS. NGUYỄN THỊ HỒNG CHUYÊN BỘ MÔN DA LIỄU – ĐHYD TP. HCM
VẢY NẾN: BỆNH MẠN TÍNH HIỆN CHƯA CÓ THUỐC CHỮA KHỎI HOÀN TOÀN
TIẾN BỘ TRONG HIỂU BIẾT VỀ SINH BỆNH HỌC CỦA BỆNH VẢY NẾN
mechanisms of disease 1112 Gooderham et al. KHÁM PHÁPHÁTRÒ CỦA TẾ BÀO LYMPHO CỦA TẾ BÀO LYMPHO T KHÁM VAI VAI TRÒ TRUNG TÂM T A B C Chứng PERSPECTIVE Vảy nến PERSPECTIVE D E CD3 CD3 P P R R P E C T IT I E E E E S SPEC V V Ustekinumab Ustekinumab milestones FIH Psoriasis FIH Psoriasis milestones Psoriasis Ustekinumab Ustekinumab FIH FIH Psoriasis Psoriasis Psoriasis Psoriasis FDA milestones milestones Canadian FDA Psoriasis registration Canadian registration approval approval Phase 2 Psoriasis2 Phase Psoriasis Phase 2b sarcoidosis 1 week post-dose 16 weeks post-dose Phase 2b sarcoidosis Psoriasis Crohn’s FDA and Psoriasis FDA 1 week post-dose 16 weeks post-dose Ustekinumab Ustekinumab Ustekinumab Ustekinumab PASI = 14.3 PASI0.50.5 = Canadian registration and Canadian registration Crohn’s F G PASI = 14.3 PASI = diseasePhase 3 Psoriasisapproval Phase 3 generation generation INDto FDA IND to FDA disease Psoriasisapproval study Phase 2 regulatory study Phase 2 study study PsA PsA regulatory Phase 2b sarcoidosis sarcoidosis starts Preclinical IND enabling studies Preclinical IND enabling studies 16 weeks post-dose submissions2b start 1 week post-dose 16 weeks post-dose submissions 1 week post-dose Phase start starts Ustekinumab Ustekinumab UstekinumabPASI = 14.314.3 Ustekinumab Crohn’s and and Crohn’s PASI = PASI = 0.5 0.5 PASI = generation generation INDIND to FDA to FDA disease Phase 3 3 Psoriasis disease Psoriasis Phase 1982 1989-1991 1989–1991 1989–1991 2000 2000 2000 2001 2001 2001 2003 2003 2003 2007 regulatory 2007 2008 2010 regulatory study20082008PsA2009 2009 2007 study PsA study study 2014 Preclinical IND IND enabling studies Preclinical enabling studies submissions startstart submissions starts starts TH TH lineage lineage Discovery Discovery Characterization Characterization IL-23 IL-23 Characterization of of Characterization milestones milestones of IL-12 1989–1991 the TH1 lineage IL-12 of of1989–1991 of the TH1 lineage 20002000 reported reported 2001 2001 2003 the 2003 17 lineage T 17 theHTH lineage 2007 2007 2008 2008 20092009 T lineage H H T lineage Discovery Discovery Characterization Characterization IL-23 IL-23 Characterization of of Characterization milestones p40 IL-12 of p35 Figure 1 Historical timeline of discoveries and evolving p35 p40 p19 milestones p40 pathophysiologic concepts. Time (x-axis) notp19 of IL-12 of the TH1TH1 lineage reported scale. IL, interleukin; PsO,TH17 lineage of the lineage p40 to the TH17 lineage reported the psoriasis; Th, T-helper cell. T 1 T H1 THT 17 17 H H p40p40 p35 p35 p40 p40 p19 p19 Figure 1. Clinical and Histologic Features of Psoriasis. TH1TH1 TH17 H17 T 13Erythematous, scaly, sharply demarcated plaques in different sizes and shapes are hallmarks of psoriasis. Although subunit of IL-12 there are predilection sites such as the elbows, knees, and the sacral cells lesions the cover the entirety of the of were identiﬁed in psoriatic lesions. These data Th17 region, and may pathophysiology supported the clinical(Panels A and C). Concurrent psoriatic arthritisbio- affects multipleRETAKE inﬂammation joints of skin development of TNF-aICM blockers as often autoimmune of the interphalangeal AUTHOR Nestle aspects 1st 2nd logic treatments for psoriasis.14 B). The nails are frequently affected, 1a-g nail dystrophy and psoriatic lesions of the nail bed. ıve T cells into a distinct the hand (Panel REG F FIGURE with IL-23 maintains the differentiation of na€ IFN- 3rd The IL-17A histopathological picture (Panel D, CASE TITLE and eosin) is characterized Revised Subsequently, IL-23 elongated rete ridges, and a mixed cellularunique CD3+ T cells (Panel E, Th17, characterized by the secretion of IL-17A hematoxylin IFN- by thickening of the epidermis, paraker- atosis, was discovered comprised of a infiltrate. Line EMail T-cell 4-Clineage, 3,3 -diaminobenzidine and hema- IL-17F pro- sharing the T cells (Panel F, Enon IL-12.15 mst of ARTIST: This H/T SIZE 25 p19 subunit andtoxylin) and CD8+ p40 subunit 3,3 -diaminobenzidine and inﬂammatory detected around capillaries of the previously been associ- hematoxylin) are IL-17 (Fig. 2). IL-17 had der- H/T IL-17F IL-22 mis and in that IL-23, and perhaps cells IL-12, Combo IFN- animal models of inﬂammation, FILL IFN-33p9 IL-17A IL-22 IL-17A Nature Biotechnology 29, 615–624 (2011); JEADV 2018, 32, 1111–1119 shared subunit suggested the epidermis. CD11c+ dendritic not (Panel G, 3,3 -diaminobenzidine and hematoxylin) are detected 26,27 and this led to ated with AUTHOR, PLEASE NOTE: mainly within the upper part of the dermis. (Clinical photographs courtesy of St. John’s Institute of Dermatology.) IL-17F IL-17F 3 could play Figurein the pathogenesis important has beenp40 ustekinumab milestones. FDA,the treatment and Drug Administration; FIH, first-in-human; IND, investigational new a role 1 Timeline of of psoriasis. T and and type has been reset. of IL-17 inhibition in US Food of various Figure The redrawn the investigation IL-22 H Please IL-22 Figure 1 IL-23, but of important T ofarea and severity index; PsA, psoriatic arthritis; T , T-helper. (From refs. 2,3,19,21 and adapted from ref. 45.) and p19 subunits ofTimeline not the p35 subunit H and checkautoimmune diseases including psoriasis, US Food arthritis, drug application; PASI, psoriasis IL-12,ustekinumab milestones. FDA, rheumatoid and Drug Administration; FIH, first-in-human; IND, investigational new carefully. 13,16,17 H are elevated in multiple forms PASI, psoriasis areaJEADV 2018, 32, 1111–1119 spondylitis arthritis; T , T-helper. (From refs. 2,3,19,21 and adapted from ref. 45.) Nature Biotechnology of psoriasis, JOB: (2011);and ustekinumab milestones.psoriaticUS inﬂammatoryAdministration; FIH, first-in-human; IND, investigational new Figure 1 Timeline 615–624 36105 H and severity index; PsA, Figure 1 29, of of role of IL-23 in bowel disease (IBD). Both Th17 cells and drug application;Timeline important Tnot in psoriatic arthritis, ankylosing FDA, US Food and Drug but ISSUE: 7-30-09 and other dermatitides,18 highlighting the centralimportant TH and ustekinumab milestones. FDA, IL-17Food and Drug Administration; FIH, first-in-human; IND, investigational new H are elevated in drug application; ustekinumabmed 361;5 areathese july 30, 2009 28 Three biologics were arthritis; T H,T H IL- drug application; PASI, psoriasis area and severity index; PsA, psoriatic developed targeting , T-helper. (From refs. 2,3,19,21 and adapted from ref. 45.) psoriasis. Two IL-12/23p40 blockers, PASI,engl j 19,20 and andconditions. index; PsA, psoriatic arthritis; T-helper. (From refs. 2,3,19,21 and adapted from ref. 45.) psoriasis nejm.org severity n 497 briakinumab,21–23 were demonstrated more effective than pla- 17 signalling: secukinumab and ixekizumab target the IL-17A The New England Journal of Medicine cebo or etanercept, at improving spleens of psoriasisdemonstrating titerswhile human IL-12.the IL-17 receptor generated from symptoms of mice 17, 2018. For personal speciﬁcally, for brodalumab blocks Downloaded from nejm.org on June (Pso- isoform use only. No other uses without permission. Discovery of IL-23, T 17 cells and ustekinumab IL-23 activity H
1112 Gooderham et al. PHÁT HIỆN PHÁ IL-12p40 Ở SANG THƯƠNG VẢY NẾN KHÁM IL-12p40 P E R S P E C T I VChứng E Vảy nến Figure 2. Immunohistochemical Figure 2. Immunohistochemical PERSPECTIVE localization of p40 in psoriatic localization of p40 in psoriatic skin. The four panels are from skin. The four panels are from frozen sections of human skin frozen sections of human skin from psoriasis patients. A and B from psoriasis patients. A and B P P R R P E C T IT I E E E E S SPEC V V Ustekinumab Ustekinumab milestones FIH Psoriasis are IgG isotype controls in unin- FIH Psoriasis are IgG isotype controls in unin- volved and lesional skin, respec- volved and lesional skin, respec- milestones tively. C and D are stained with tively. C and D are stained with mouse anti–human IL-12p40 as mouse anti–human IL-12p40 as indicated. The arrow indicates indicated. The arrow indicates Psoriasis Ustekinumab Ustekinumab FIH FIH Psoriasis morphology consistent with DCs. Psoriasis morphology consistent with DCs. PsoriasisPsoriasisFDA milestones milestones The color represents 3-amino-9- The color represents 3-amino-9- ethylcarbazole deposition at the ethylcarbazole deposition at the Canadian FDA Psoriasis registration Canadian registration approval site of antibody binding. Melanin site of antibody binding. Melanin approval Phase 2 IL-12p40 IL-12p40 appears in A as dark stain in the appears in A as dark stain in the Psoriasis2 Phase Psoriasis Phase 2b sarcoidosis 1 week post-dose basal16 weeks post-dose cell layer. basalweeks post-dose Phase 2b sarcoidosis Psoriasis Crohn’s FDA and Psoriasis FDA Ustekinumab Ustekinumab 1 week post-dose 16 cell layer. and Canadian registration Crohn’s Ustekinumab Ustekinumab PASI = = 14.3 PASI 14.3 PASI = 0.50.5 PASI = Canadian registration diseasePhase 3 Psoriasisapproval Phase 3 generation generation IND to FDA IND to FDA disease Psoriasisapproval study Phase 2 regulatory study Phase 2 study study PsA PsA regulatory Phase 2b sarcoidosis Preclinical IND enabling studies immunohistochemical and FACS ®weeks post-dose submissions2b sarcoidosis starts Preclinical IND enabling studies immunohistochemical and FACS staining of dermal cells Phase start start By ® By 16 staining of dermal cells 1 week post-dose 16 weeks post-dose submissions 1 week post-dose starts UstekinumabPASI = 14.314.3increases in=presumptive monocytes from other biopsies,=large increases PASI = 0.5 Crohn’s and and Crohn’s Ustekinumab Ustekinumab from other biopsies, large Ustekinumab PASI PASI presumptive monocytes in 0.5 generation to(CD11cϩ CD14ϩ CD83Ϫ and mature DCs (CD11c ϩ disease INDIND to FDA CD14ϩ CD83Ϫ)) and mature DCs Psoriasisϩ Psoriasis disease Phase 3 3 Phase 1982 1989-1991 1989–1991 1989–1991 generation 2000 (CD11cϩ 2001 FDA 2000 2000 2001 2001 2003 2003 2003 (CD11c 2007 regulatory 2007 2008 2010 regulatory study20082008PsA2009 2009 2007 study PsA study study 2014 Preclinical enabling studiesCD14 Ϫ CD83ϩ) were detected in active psoriasis lesions Preclinical IND IND enabling studies Ϫ CD83ϩ) were detected in active psoriasissubmissions startstart CD14 lesions submissions starts starts TH TH lineage lineage Discovery Discovery Characterization Characterization compared with unaffected skin of the same patients. compared with unaffected skin of the of of patients. IL-23 IL-23 Characterization same Characterization milestones milestones of IL-12 1989–1991 the TH1 lineage of of1989–1991 of the TH1 lineage IL-12 reported and Sustained Expression lineage and p40 in2007 2000Strong and 2001 the 2003 17 of p19 and p40 in Mature Strong 2001 2000 reported Sustained theHTH lineage Expression of p19 T 172003 Mature 2007 2008 2008 20092009 DCs. To further examine the control of IL-12 and IL-23 DCs. To further examine the control of IL-12 and IL-23 p40expression in monocytes and 17 lineage used standard pro- expression IL, interleukin;Characterization ofused aa standard pro- in monocytes and DCs,ofwe TH lineage TH lineage Discovery Discovery Characterization Characterization IL-23 IL-23 Characterization we DCs, milestones p40 IL-12 of p35 Figure 1 Historical timeline of discoveries and evolving p35 milestones p40 pathophysiologic concepts. Time (x-axis) notp19 of IL-12 of the TH1TH1 lineage reported scale. of the lineage p40 p19to PsO, psoriasis; Th, T-helper cell. TH1 TH 1 cedure to generate the THfromTperipheral blood monocytes cedure to generate DCs 17Tlineage reported the TH DCs from peripheral blood monocytes H 1717 H using 4 d of culture in GM-CSF and IL-4 to produce im- using 4 d of culture in GM-CSF and IL-4 to produce im- p40p40 p35 p35 p40mature DCs and a cytokine cocktail to mature the DCs p40 p19 DCs and a cytokine cocktail to mature the DCs mature p19 TH1TH1 TH17 H (14). Fig. 4 displays quantitative17 T (14). Fig. 4 displays quantitative expression of p19, p40, and expression of p19, p40, and subunit of IL-1213 were identiﬁed in psoriatic lesions. These data Th17 cells and the pathophysiology of supported the clinical development of TNF-a blockers as bio- autoimmune inﬂammation p35 mRNAs in monocytes and in monocyte-derived DCs p35 mRNAs in monocytes and in monocyte-derived DCs logic treatments for psoriasis.14 IL-23 maintains the differentiation of na€ T cells into aaddition of our maturation stimu- IFN- at various times after the addition of our maturation stimu- at various times after the distinct ıve IL-17A Subsequently, IL-23 was discovered comprised of a unique T-cell lineage, Th17, characterized by the secretion ofresults seen with CD40L-stimu- IFN- lus, and essentially parallelsIL-17F seen with CD40L-stimu- lus, and essentially parallels results IL-17A pro- lated DCs (1). Monocytes associ- h), as well as monocytes p19 subunit and sharing the p40 subunit of IL-12. This inﬂammatory IL-17 (Fig. 2). IL-17 had previously been IL-17F 15 25 (Ϫ144 lated DCs (1). Monocytes IL-22 h), as well as monocytes (Ϫ144 IL-17A IL-22 shared subunit suggested that IL-23, and perhaps not IL-12, ated IFN- 2018, models of inﬂammation,26,27 and this led to Nature Biotechnology 29, 615–624 (2011); JEADV animal 32, 1111–1119 IFN- with IL-17A 4 IL-17F IL-17F could play Figurein the pathogenesis important T and ustekinumab milestones. FDA,the treatment and Drug Administration; FIH, first-in-human; IND, investigational new a role 1 Timeline of of psoriasis. The p40 the investigation of IL-17 inhibition in US Food of various IL-22 H IL-22 Figure 1 IL-23, but of important T ofarea and severity index; including 22ddat 37ЊC and the cellsTexitingthe cultured dermis (B, C, and D) and p19 subunits ofTimeline not the p35 subunit H and ustekinumab milestones.psoriasis, US Food arthritis,the cultured dermis (B, C, and D) drug application; PASI, psoriasis IL-12, autoimmune diseases PsA, psoriatic arthritis; andT-helper. (From refs. 2,3,19,21 and adapted from ref. 45.) tional FDA, rheumatoid exitingDrug Administration; FIH, first-in-human; IND, investigational new tional at 37ЊC and the cells , are elevated inBiotechnology 29, 615–624 (2011); in psoriatic arthritis, 1111–1119collected for arthritis; H , T-helper. (Fromp19 using 2,3,19,21 and adapted from ref. 45.) multiple of psoriasis,13,16,17 but Nature application;Timelinepsoriasis area and severity index; PsA, psoriaticUS Food andHDruggene expression for FIH, first-in-human; IND, investigational newnew JEADV 2018, 32, milestones. FDA,forsubsequent quantitative gene expression for refs. drug Figure 1 forms PASI, important Tnotand ustekinumab milestones. FDA, US Food inﬂammatoryAdministration; p19 FIH, first-in-human; IND, investigational were collected were ankylosing spondylitis and T subsequent quantitative using Figure Timeline of of important T and ustekinumab 18 1 H and Drug Administration; in bowel disease (IBD). Both Th17 cells and IL-17 are elevated inantibodies to CD3, CD11c, or other dermatitides, highlighting the central role of IL-23 H immunomagnetic beads coated with antibodies to CD3, CD11c, or immunomagnetic beads coated with psoriasis. Twodrug application; PASI, psoriasis area and severity index; PsA, CD83.In eachdevelopedcell populations were (From refs. 2,3,19,21 andand adapted from ref. 45.) IL-12/23p40 blockers, ustekinumab19,20 and these conditions.28 Three biologics In eachcase, two cell H,T H, T-helper. (From refs. 2,3,19,21 adapted from ref. 45.) drug application; PASI, psoriasis area and severity index; PsA, psoriatic arthritis; T-helper. obtained: one adherent to CD83. were arthritis; T populations were obtained: one adherent to psoriatic case, two targeting IL- briakinumab,21–23 were demonstrated more effective than pla- 17 signalling: secukinumabthe beads expressing target the IL-17ACD68 (B), and one nonadherent the beads expressingCD83, CD11c, or CD68 (B), and one nonadherent and ixekizumab CD83, CD11c, or cebo or etanercept, at improving spleens of psoriasisdemonstrating titerswhile human that was used toDiscovery of by FACS .. For the latter, (C and D) that was used tomonitor the depletion by FACS® For the latter, (C and D) monitor the depletion ® generated from symptoms of mice (Pso- isoform speciﬁcally, for brodalumab blocks the IL-17 receptor the presence of HLA-DR andcells and ustekinumab IL-23 IL-12. IL-23, TH17 flow-through cells were analyzed for the presence of HLA-DR and flow-through cells were analyzed for activity
mab antigen binding fragment (Fab) and human IL-12 was Our understanding of human TH cell lineages continues to evolve to determine the precise epitope and molecular specificity as additional TH profiles, such as TH22 and TH9, are described25,26. It umab. Ustekinumab was shown to bind IL-12p40 with the 1112 is currently believed that certain human CD4+ T-cell lineages exhibit Gooderham et al. 2:1 cytokine/antibody stoichiometry18. Mutational analyses plasticity, depending upon the local cytokine milieu27. This adapt- d the precise residues within domain 1 of IL-12p40 that pro- ability includes another CD4 + T-cell lineage, termed T-regulatory PHÁT HIỆN PHÁ SỰ HIỆN DIỆN CỦA IL-23 KHÁM IL-23 ortant molecular binding interactions with ustekinumab 18. cells or Tregs, that are proposed to regulate immune responses. Tregs gly, none of the neutralizing human anti-IL-12 mAbs gen- express the forkhead box P3 (Foxp3) transcription factor and may Centocor were specific for the IL-12p35 subunit and may play an immunomodulatory role through cell-cell interactions or immune-dominant role of the p40 upon IL-12 immunization of the a b mmunoglobulin transgenicC T I V E P E R S P E mice. Ustekinumab Ustekinumab PERSPECTIVE IL-12 IL-23 p40 p35 p19 p40 stekinumab and its target. (a) IL-12 p40 p35 p19 p40 and their respective receptors. P E C T I V E P P R R P E C T I V E IL-12R ESS E subunit of Ustekinumab 1 FIH PsoriasisIL-1 1 2 2 IL- R FIH Psoriasis 2R IL- umab binds to the p40 Ustekinumab milestones 2 12 23 12 R R R 3R IL- IL- 2 2 1 1 R -1 -1 milestones L-23 preventing their interaction with IL IL killer (NK) or T-cell surface IL-12 NK or T-cell NK or T-cell Psoriasis membrane membrane 1 (IL-12R 1) and inhibiting IL-12Ustekinumab Ustekinumab milestones FIH FIH Psoriasis Psoriasis Psoriasis PsoriasisFDA milestones signaling, activation and cytokine Canadian FDA Psoriasis registration Canadian registration approval . (Image not drawn to scale; adapted approval Phase 2 Psoriasis2 Phase Psoriasis sarcoidosis ssion from ref. 84 (Fig. 1).) Intracellular signaling 1 week post-dose No signal Psoriasis Phase 2bFDA 16 weeks post-dose Phase 2b sarcoidosis Psoriasis FDA 1 week post-dose 16 weeks post-dose Crohn’s and and Ustekinumab Ustekinumab Canadian registration Crohn’s Ustekinumab Ustekinumab PASI = = 14.3 PASI 14.3 PASI = 0.50.5 PASI = Canadian registration diseasePhase 3 Psoriasisapproval Phase 3 generation generation INDto FDA IND to FDA disease Psoriasisapproval study Phase 2 regulatory study Phase 2 study study PsA regulatory Phase 2b sarcoidosis PsA sarcoidosis starts Preclinical IND enabling studies Preclinical IND enabling studies 16 weeks post-dose submissions2b start 1 week post-dose 16 weeks post-dose submissions 1 week post-dose Phase start starts Ustekinumab Ustekinumab UstekinumabPASI29 = 14.3 VOLUMEPASI NUMBER PASI JULY Ustekinumab = 14.3 7 = PASI = 0.5 0.5 2011 NATURE BIOTECHNOLOGY Crohn’s and and Crohn’s generation generation INDIND to FDA to FDA disease Phase 3 3 Psoriasis disease Psoriasis Phase 1982 1989-1991 1989–1991 1989–1991 2000 2000 2000 2001 2001 2001 2003 2003 2003 2007 regulatory 2007 2008 regulatory study20082008PsA2009 2009 2007 study PsA study study 2010 2014 Preclinical IND IND enabling studies Preclinical enabling studies submissions startstart submissions starts starts TH TH lineage lineage Discovery Discovery Characterization Characterization IL-23 IL-23 Characterization of of Characterization milestones milestones of IL-12 1989–1991 the TH1 lineage IL-12 of of1989–1991 of the TH1 lineage 20002000 reported reported 2001 2001 2003 the 2003 17 lineage T 17 theHTH lineage 2007 2007 2008 2008 20092009 T lineage T lineage H H Discovery Discovery Characterization Characterization IL-23 IL-23 Characterization of of Characterization milestones p40 IL-12 of p35 Figure 1 Historical timeline of discoveries and evolving p35 p40 p19 milestones p40 pathophysiologic concepts. Time (x-axis) notp19 of IL-12 of the TH1TH1 lineage reported scale. IL, interleukin; PsO,TH17 lineage of the lineage p40 to the TH17 lineage reported the psoriasis; Th, T-helper cell. T 1 T H1 THT 17 17 H H p40p40 p35 p35 p40 p40 p19 p19 TH1TH1 TH17 H17 T subunit of IL-1213 were identiﬁed in psoriatic lesions. These data Th17 cells and the pathophysiology of supported the clinical development of TNF-a blockers as bio- autoimmune inﬂammation logic treatments for psoriasis.14 IL-23 maintains the differentiation of na€ T cells into a distinct IFN- ıve IL-17A Subsequently, IL-23 was discovered comprised of a unique T-cell lineage, Th17, characterized by the secretion of IL-17A IFN- IL-17F pro- p19 subunit and sharing the p40 subunit of IL-12.15 This inﬂammatory IL-17 (Fig. 2).25 IL-17 had previously been associ- IL-17F IL-22 IFN- IFN- IL-17A IL-22 IL-17A shared subunit suggested that IL-23, and perhaps not IL-12, ated with 2018, models of inﬂammation, Nature Biotechnology 29, 615–624 (2011); JEADV animal 32, 1111–1119 26,27 and this led to 5 IL-17F could play Figurein the pathogenesis important T and ustekinumab milestones. FDA,the treatment and IL-17F Administration; FIH, first-in-human; IND, investigational new a role 1 Timeline of of psoriasis. The p40 the investigation of IL-17 inhibition in US Food of various IL-22Drug H IL-22 Figure 1 IL-23, but of important T ofarea and severity index; including FDA, arthritis; T , T-helper. (From refs. 2,3,19,21 and adapted from ref. 45.) and p19 subunits ofTimeline not the p35 subunit H and ustekinumab milestones.psoriasis, US Food arthritis, drug application; PASI, psoriasis IL-12, autoimmune diseases PsA, psoriatic rheumatoid and Drug Administration; FIH, first-in-human; IND, investigational new H are elevated in multiple forms PASI, psoriasis area in psoriatic arthritis, 1111–1119 Nature Biotechnologyof psoriasis, 29, 615–624 (2011); JEADV 2018, index; PsA, FDA, US Food and Drug Administration; FIH, first-in-human; IND, investigational new 13,16,17 and severity 32, ankylosing spondylitis arthritis; T H, drug application;Timeline important Tnotand ustekinumab milestones.psoriaticUS inﬂammatoryT-helper. (From refs. 2,3,19,21 and adapted from ref. 45.) but and Figure 1 Timeline of of Figure 1 other dermatitides,18 highlighting the centralimportant TH and ustekinumab milestones. FDA, IL-17Food and Drug Administration; FIH, first-in-human; IND, investigational new H role of IL-23 in bowel disease (IBD). Both Th17 cells and are elevated in IL-12/23p40 blockers, ustekinumab19,20 and these conditions.28 Three biologics were arthritis; T H,T H IL- drug application; PASI, psoriasis area and severity index; PsA, psoriatic arthritis; T-helper. (From refs. 2,3,19,21 and adapted from ref. 45.) psoriasis. Twodrug application; PASI, psoriasis area and severity index; PsA, psoriatic developed targeting , T-helper. (From refs. 2,3,19,21 and adapted from ref. 45.) briakinumab,21–23 were demonstrated more effective than pla- 17 signalling: secukinumab and ixekizumab target the IL-17A cebo or etanercept, at improving spleens of psoriasisdemonstrating titerswhile human IL-12.the IL-17 receptor generated from symptoms of mice (Pso- isoform speciﬁcally, for brodalumab blocks Discovery of IL-23, T 17 cells and ustekinumab IL-23 activity H
1112 Gooderham et al. SỰ HIỆN DIỆN CỦA IL-17A TẠI SANG THƯƠNG VẢY NẾN PHÁT HIỆN IL-17 Harper et al. Page 10 PERSPECTIVE Sang thương vảy nến Da bình thường PERSPECTIVE P P R R P E C T IT I E E E E S SPEC V V NIH-PA Author Manuscript Ustekinumab FIH Psoriasis Ustekinumab milestones FIH Psoriasis milestones Psoriasis Ustekinumab Ustekinumab FIH FIH Psoriasis Psoriasis Psoriasis Psoriasis FDA milestones milestones Canadian FDA Psoriasis registration Canadian registration approval approval Phase 2 Psoriasis2 Phase Psoriasis Phase 2b sarcoidosis 1 week post-dose 16 weeks post-dose Phase 2b sarcoidosis Psoriasis Crohn’s FDA and Psoriasis FDA 1 week post-dose 16 weeks post-dose Ustekinumab Ustekinumab and Canadian registration Crohn’s Ustekinumab Ustekinumab PASI = = 14.3 PASI 14.3 PASI = 0.50.5 PASI = Canadian registration diseasePhase 3 Psoriasisapproval Phase 3 generation generation IND to FDA IND to FDA disease Psoriasisapproval study Phase 2 regulatory study Phase 2 study study PsA regulatory Phase 2b sarcoidosis PsA sarcoidosis starts Preclinical IND enabling studies Preclinical IND enabling studies 16 weeks post-dose submissions2b start 1 week post-dose 16 weeks post-dose submissions 1 week post-dose Phase start starts Ustekinumab Ustekinumab UstekinumabPASI = 14.314.3 Ustekinumab Crohn’s and and Crohn’s PASI = PASI = 0.5 0.5 PASI = generation generation INDIND to FDA to FDA disease Phase 3 3 Psoriasis disease Psoriasis Phase 1982 1989-1991 1989–1991 1989–1991 2000 2000 2000 2001 2001 2001 2003 2003 2003 2007 regulatory 2007 2008 2010 regulatory study20082008PsA2009 2009 2007 study PsA study study 2014 Preclinical IND IND enabling studies Preclinical enabling studies submissions startstart submissions starts starts TH TH lineage lineage Discovery Discovery Characterization Characterization IL-23 IL-23 Characterization of of Characterization milestones milestones of IL-12 1989–1991 the TH1 lineage IL-12 of of1989–1991 of the TH1 lineage 20002000 reported reported 2001 2001 2003 the 2003 17 lineage T 17 theHTH lineage 2007 2007 2008 2008 20092009 H HT lineage T lineage Discovery Discovery Characterization Characterization IL-23 IL-23 Characterization of of Characterization milestones p40 IL-12 of p35 Figure 1 Historical timeline of discoveries and evolving p35 p40 p19 milestones p40 pathophysiologic concepts. Time (x-axis) notp19 of IL-12 of the TH1TH1 lineage reported scale. IL, interleukin; PsO,TH17 lineage of the lineage p40 to the TH17 lineage reported the psoriasis; Th, T-helper cell. T 1 T H1 THT 17 17 H H p40p40 p35 p35 p40 p40 p19 p19 TH1TH1 TH17 H17 T subunit of IL-1213 were identiﬁed in psoriatic lesions. These data Th17 cells and the pathophysiology of supported the clinical development of TNF-a blockers as bio- autoimmune inﬂammation logic treatments for psoriasis.14 IL-23 maintains the differentiation of na€ T cells into a distinct IFN- ıve IL-17A Subsequently, IL-23 was discovered comprised of a unique T-cell lineage, Th17, characterized by the secretion of IL-17A IFN- IL-17F pro- p19 subunit and sharing the p40 subunit of IL-12.15 This inﬂammatory IL-17 (Fig. 2).25 IL-17 had previously been associ- IL-17F IL-22 NIH-PA Auth IL-17A IL-22 shared subunit suggested that IL-23, and perhaps not IL-12, ated IFN- 2018, models of inﬂammation,26,27 and this led to Nature Biotechnology 29, 615–624 (2011); JEADV IFN- with animal 32, 1111–1119 IL-17A 6 IL-17F could play Figurein the pathogenesis important T and ustekinumab milestones. FDA,the treatment and IL-17F Administration; FIH, first-in-human; IND, investigational new a role 1 Timeline of of psoriasis. The p40 the investigation of IL-17 inhibition in US Food of various IL-22Drug H IL-22 Figure 1 IL-23, but of important T ofarea and severity index; including FDA, arthritis; T , T-helper. (From refs. 2,3,19,21 and adapted from ref. 45.) and p19 subunits ofTimeline not the p35 subunit H and ustekinumab milestones.psoriasis, US Food arthritis, drug application; PASI, psoriasis IL-12, autoimmune diseases PsA, psoriatic rheumatoid and Drug Administration; FIH, first-in-human; IND, investigational new are Nature in multiple forms PASI, psoriasis areaJEADV 2018, 32, 1111–1119 spondylitis arthritis; H , T-helper. (From refs. 2,3,19,21 and adapted from ref. 45.) elevated Biotechnology of psoriasis,13,16,17 but not in psoriatic arthritis, ankylosingpsoriatic and inﬂammatory Figure 1 Timeline 615–624 (2011);and ustekinumab milestones. Figure 1 29, of of role of IL-23 in bowel disease (IBD). Both Th17 cells and Food and Drug Administration; FIH, first-in-human; IND, investigational new drug application;Timeline important TH T and severity index; PsA, FDA, US US Food andHDrug Administration; FIH, first-in-human; IND, investigational new T other dermatitides,18 highlighting the centralimportant H and ustekinumab milestones. FDA, IL-17 are elevated in IL-12/23p40 blockers, ustekinumab19,20 and these conditions.28 Three biologics were arthritis; T H,T H IL- drug application; PASI, psoriasis area and severity index; PsA, psoriatic arthritis; T-helper. (From refs. 2,3,19,21 and adapted from ref. 45.) psoriasis. Twodrug application; PASI, psoriasis area and severity index; PsA, psoriatic developed targeting , T-helper. (From refs. 2,3,19,21 and adapted from ref. 45.) briakinumab,21–23 were demonstrated more effective than pla- 17 signalling: secukinumab and ixekizumab target the IL-17A cebo or etanercept, at improving spleens of psoriasisdemonstrating titerswhile human IL-12.the IL-17 receptor generated from symptoms of mice (Pso- isoform speciﬁcally, for brodalumab blocks Discovery of IL-23, T 17 cells and ustekinumab IL-23 activity H
MÔ HÌNH SINH BỆNH HỌC VẢY NẾN MÔ HÌNH SINH BỆNH HỌC CỦA VẢY NẾN IL-23 as a master regulator of inﬂammation 5 Figure 3 Current model of the pathophysiology of psoriasis. IL-23 bridges the innate and adaptive immune responses and plays a key J Eur Acad Dermatol Venereol. 2018 inducing Th17plaque formation. IL, interleukin; Th, T-helper cell; TGF, transformingthe pathological response ofnecrosis factor. role in Feb 13. cell differentiation. The resulting elevated IL-17 secretion maintains growth factor; TNF, tumour keratinocytes, resulting in psoriatic a PASI 90 response and 28.6% achieved PASI 100.80 In NAVI- tildrakizumab-treated patients compared to placebo by week
tion subunit interactions ACT 1 mutations Drewniak et al,83 2013 Impairs IL-17 cytokine receptor subunit interacti Candida infection subunit interactions AIRE, autoimmune regulator; CARD, caspase recruitment domain-containing; CMC, chronic mucocutaneous AIRE, autoimmune regula ACT, Actin related; candidiasis; J AM ACAD1. transducer J AACT,candidiasis;SINH HỌC Fig DERMATOL CỦA AActin related; in autoimmune regulator; CARD, caspase recruitment STAT, signal tr M CAD D -containing; CMC, TÁC ĐỘNGof activator concepts AIRE,Th, T helper cell. IFN, interferon; IL, interleukin; Lynde et a TRỤC chronic mucocutaneousTHUỐC ERMATOL nterleukin; STAT, signal Timeline andevolvingof transcription;psoriasis pathophysiology. IL, Interleukin; Th,domain-contain T-helper rough helper cell. complex ĐỘNG CỦA CÁC THUỐC ĐIỀU TRỊtransducer HỌC through transcription;comple Th, T a TRỤC TÁC that includes IFN, interferon; IL, interleukin; not determined. receptor cell. SINH and activator of a receptor Th, T h IL-17RA; impact on IL-17E was STAT, signal *IL-17E also acts 7E was not determined. *IL-17E also acts through a receptor complex that includes IL-17RA; impact on IL-17E was IL-23p19 inhibitor Guselkumab Tildrakizumab TNF-⍺ IL-23 IL-17A Activated Th17 cells Keratinocytes Dendritic cell 17A acts most proximally to the Fig 5. Key cytokine targets in psoriasis: interleukin (IL)-17A ac g 5. Key LyndeAcad Dermatol Venereol. 2018 Feb 13. interleukin (IL)-17A acts most proximally to tumor necrosis factor. cytokine targets in 2014 J Eur et al, J Am Acad Dermatol psoriasis: keratinocyte.48 Th, T helper; TNF, the Fig 5. Key cytokine tar ratinocyte.48 Th, T helper; TNF, tumor necrosis factor. keratinocyte.48 Th, T help
MÔ HÌNH SINH BỆNH HỌC CỦA VẢY NẾN Allerg Immunol IL-22 IL-17A/F LL-37 hBD2 Pro-IL-36 hBD3 Th17 Th17 CXCL1 CXCL2 IL-36 CXCL8 pDC pDC N Th17 N IFN- Th17 IL-1b IL-23 TNF- flammatory pathways inAllergypathogenesis of psoriasis. Psoriasis Clinical Reviews in the & Immunology 2018 figure). Another inflammatory pathway, mediated by plasmacy ed by the https://doi.org/10.1007/s12016-018-8668-1 dendritic cells (DCs) aberrant activation of dermal dendritic cells (pDCs) producing large amounts of type I IFNs, g TNF and IL-23. These DCs stimulate autoimmune Th17 and emerged by studying early events in the pathogenesis of psoriasis. s to migrate into the epidermis, where they recognize epidermal pDC-IFN pathway is dominant in acute forms of psoriasis suc
MÔ HÌNH SINHBỆNH HỌC CỦA VIÊM KHỚP VẢY NẾN MÔ HÌNH SINH BỆNH HỌC PsA S. MANTRAVADI ET AL. INF-⍺ inhibitors • Etanercept • Adalimumab • Infliximab TNF IL-12/23 inhibitor Ustekinumab IL-17A inhibitor IL-23p19 inhibitor • Secukinumab • Guselkumab • Ixekizumab • Tildrakizumab gure 3. Pathogenesis of psoriatic arthritis. • Brodalumab he Th1 and Th17 pathways are important pathways involved in the pathogenesis of PsA. TNF, a pro-inflammatory cytokine, is a key player in osteoclastogenesis via RANK-L an hibition of osteoblastogenesis via Dkk-1. Both processes eventuallyJlead to bone erosions [42]. In addition, IL-22 is involved in the pathologic formation of new bone (osteoproliferat Expert Review Of Clinical Pharmacology, 2017; N Engl Med 2017;376:957-70 3]. APC, antigen presenting cell; Dkk-1, dickkopf-related protein 1; IFNγ, interferon gamma; IL-12, interleukin-12; IL-17, interleukin-17; IL-22, interleukin-22; IL-23, interleukin-23; RAN ceptor activator of nuclear factor-κB ligand; T cell, T lymphocyte; Th1, type 1 T helper cell; Th17, T helper 17 cell; TNF, tumor necrosis factor 38 Expert Review Of Clinical Pharmacology, 2017; N Engl J Med 2017;376:957-70
MÔ HÌNH SINH BỆNH HỌC CỦA VIÊM KHỚP VẢY NẾN THUỐC SINH HỌC MÔ HÌNH SINH BỆNH HỌC PsA và TÁC ĐỘNG CỦA S. MANTRAVADI ET AL. INF-⍺ inhibitors • Etanercept • Adalimumab • Infliximab TNF IL-12/23 inhibitor Ustekinumab IL-17A inhibitor IL-23p19 inhibitor • Secukinumab • Guselkumab • Ixekizumab • Tildrakizumab ure 3. Pathogenesis of psoriatic arthritis. • Brodalumab Th1 and Th17 pathways are important pathways involved in the pathogenesis of PsA. TNF, a pro-inflammatory cytokine, is a key player in osteoclastogenesis via RANK-L an bition of osteoblastogenesis via Clinical Pharmacology, 2017; N Engl lead to2017;376:957-70[42]. In addition, IL-22 is involved in the pathologic formation of new bone (osteoprolifera Expert Review Of Dkk-1. Both processes eventually J Med bone erosions . APC, antigen presenting cell; Dkk-1, dickkopf-related protein 1; IFNγ, interferon gamma; IL-12, interleukin-12; IL-17, interleukin-17; IL-22, interleukin-22; IL-23, interleukin-23; RAN eptor activator of nuclear factor-κB ligand; T cell, T lymphocyte; Th1, type 1 T helper cell; Th17, T helper 17 cell; TNF, tumor necrosis factor 38 Expert Review Of Clinical Pharmacology, 2017; N Engl J Med 2017;376:957-70
BỆNH HỆ THỐNG BỆNH ĐỒNG MẮC ĐIỀU TRỊ PHÒNG NGỪA
VIÊM HỆ THỐNG GẮN LIỀN VỚI BỆNH ĐỒNG MẮC VIÊM THỐNG GẮN LIỀN VỚI BỆNH ĐỒNG MẮC
assessment of insulin resistance (HOMA-IR) index, calculated note that inflammation-induced insulin resistance may well help on the basis of a blood test, or an oral glucose tolerance test to explain the altered epidermal homeostasis observed in the (115, 116). Using these approaches, two cross-sectional studies epidermis of psoriatic plaques (123, 124), a phenomenon that demonstrated that psoriasis patients exhibit insulin resistance might have implications beyond psoriasis (125). THE CONCEPT OF OF THE “PSORIATIC MARCH” THE CONCEPT THE “PSORIATIC MARCH” Psoriatic inflammation as a driver for atherosclerosis FIGURE 2 | The concept of the “psoriatic march.” Thisinsulin resistance that psoriasis is a systemicBoehncke W-Hcondition, as numerous 9:579. HOMA-IR, homeostasis assessment of hypothesis suggests inﬂammatory (2018) Front. Immunol. biomarkers of inﬂammation are elevated in the patients’ blood compartment. Functional consequences are insulin resistance, evidenced by an increased HOMA-IR (homeostasis HOMA-IR, homeostasis assessment of insulin resistance Boehncke W-H (2018) Front. Immunol. 9:579. assessment of insulin resistance), and endothelial dysfunction, resulting in increased vascular stiffness. This provides the basis for atherosclerosis, observable
Caiazzo et al. Psoriasis, CV Events, and Biologics VAI TRÒ QUAN TRỌNG CỦA CÁC CYTOKINES TRONG XƠ VỮA ĐỘNG MẠCH DC, dendritic cell; IL, interleukin; MHC, major histocompatibility complex; PMN, polymorphonuclear; TCR, T cell receptor; Th, T helper; TNF, tumor necrosis factor; VEGF, Giuseppina Caiazzo et al (2018). vascular endothelial growth factor. FIGURE 1 | Interactions between main cell types and cytokines present in psoriasis plaque showing their functional significance in atherosclerosis process. Front. Immunol. 9:1668. Abbreviations: DC, dendritic cell; IL, interleukin; MHC, major histocompatibility complex; PMN, polymorphonuclear; TCR, T cell receptor; Th, T helper; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.
THE VIP-U TRIAL: A Phase IV, Randomized, Double-Blind, Placebo-Controlled Crossover Study of the Effects of Ustekinumab on Vascular Inflammation in Psoriasis • KẾT QUẢ Ở TUẦN 52: KHÔNG có sự khác biệt trong viêm động mạch chủ so với trước điều trị, tuy nhiên giảm có ý nghĩa các chỉ điểm viêm hệ thống bao gồm TNF-alpha, IL-1b, IL-17A, và IL-6 (là các chỉ điểm liên quan viêm và xơ vữa động mạch) • KẾT LUẬN: Ức chế IL12/23 có thể giảm viêm động mạch chủ ngắn hạn, nhưng có thể giúp giảm viêm hệ thống lâu dài bằng cách ức chế các cytokines liên quan bệnh lý tim mạch. J Invest Dermatol. 2019 Jul 19. pii: S0022-202X(19)32537-0. doi: 10.1016/j.jid.2019.07.679
290 BN à theo dõi trong 1 năm với 215 BN • Khảo sát đặc tính của mảng xơ vữa (canxi hoá và không canxi hoá) bằng CCTA • Kết quả: BN điều trị sinh học giảm 6% nguy cơ hình thành mảng xơ vữa không canxi hoá (P=0.005) với giảm nguy cơ hoại tử lõi (p=0.03) và chậm tiến triển hình thành mảng xơ vữa (p=0.02) • Kết luận: Điều trị sinh học cho nhóm BN vảy nến nặng giúp ích trong điều hoà đặc tính mảng xơ Change in non-calcified coronary plaque burden vữa à nền tảng cho nghiên cứu RCT over one-year between treatment groups CCTA: coronary computed tomography angiography Cardiovascular Research (2019) 115, 721–728
TRẦM CẢM VÀ HIỆN TƯỢNG VIÊM HỆ THỐNG Finnell JE, Wood SK. Neurobiol Stress. 2016;4:1-14 19
TRẦM CẢM VÀ HIỆN TƯỢNG VIÊM HỆ THỐNG ĐIỀU TRỊ THUỐC SINH HỌC: NHỮNG HIỆU QUẢ TRÊN BIỂU HIỆN TRẦM CẢM ORIGINAL ARTICLE Depressive symptoms, depression, and 8 Strober et al the effect of biologic therapy among J AM ACAD DERMATOL patients in Psoriasis Longitudinal n 2017 Assessment and Registry (PSOLAR) Bruce Strober, MD, PhD,a,b Melinda Gooderham, MD, MSc,c,d Elke M. G. J. de Jong, MD, PhD,e Table V. Multivariate Cox model for symptoms suggestive of depression Alexa B. Kimball, MD, MPH,f Richard G. Langley, MD, FRCPC,g Nikita Lakdawala, MD,h Kavitha Goyal, MD,i Fabio Lawson, MD,i Wayne Langholff, PhD,j Lori Hopkins, PharmD,i Steve Fakharzadeh, MD, PhD,i Bhaskar Srivastava, MD, PhD,i and Alan Menter, MDk Covariate* Hazard Ratio (95% CI) Farmington, Connecticut; Waterloo, Kingston, and Peterborough, Ontario, and Halifax, Nova Scotia, P value Canada; Nijmegen, The Netherlands; Boston, Massachusetts; Milwaukee, Wisconsin; Horsham and Spring Exposure Horse, Pennsylvania; and Dallas, Texas Biologic agents vs conventional systemicwith psoriasis are at an increased risk for depression. However, the impact of Background: Patients agents 0.76 (0.59-0.98) .0367 Ustekinumab vs conventional systemicunclear. treatment on this risk is agents 0.80 (0.60-1.06) .1208 Infliximab vs conventional systemic agents Objective: Evaluate the incidence and impact of treatment on depression among patients with0.70 (0.47-1.03) .0699 moderate-to-severe psoriasis. Etanercept vs conventional systemic agents 0.91 (0.67-1.23) .5220 Adalimumab vs conventional systemic agents 0.63 (0.46-0.86) .0034 Phototherapy vs conventional systemic agents Farmington ; From the University of Connecticut Health Center, a 1.05 (0.71-1.54) Regeneron Pharmaceuticals for services as a consultant and/or .8159 Age/10 y c b Probity Medical Research, Waterloo ; Queen’s University, Kingston ; and SKiN Centre for Dermatology, Peterborough, principal investigator. Dr 1.12has received honoraria from Langley (1.05-1.21) AbbVie, Amgen, Centocor, Pfizer, Janssen Pharmaceuticals, Leo .0015 Thuốc University, Nijmegen ; Beth Israel Deaconess Hospital and; tần suất Ingelheim Internationalfor and/or Lilly and Sex: male vs female điều trị Boston ; Dalhousie University, Halifax sinh học giảm Pharma, Boehringer các triệuservingspeaker. 1.09 (0.91-1.30)as an chứng trầm cảm .3644 d Ontario ; Radboud University Medical Center and Radboud GmbH, Eli e Company, and Valeant Pharmaceuticals Race: nonwhite vs white Medical Medical School, Harvard f h College of Wisconsin, Milwaukee ; Janssen Scientific advisory board member, 1.72 investigator, g principal (1.39-2.13) Drs Goyal, Lawson, Langholff, Hopkins, Fakharzadeh, and