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11mediterranean journal 26
of RHEUMATOLOGY 1
E Л Л H N I К H РЕУМАТОЛОПД 2015
H ¿кфраоп tou jopíou Dickkopf-1 (Dkk-1) ото 6épja jerá rnv 9epaneía je pirouOjájnri auv6uáZerai pe iaioAoYiKn PeAríwian oe aa9eveíQ pe auainjariKn aKAnpo6epjía
A. AaoúanQ, MD, PhD, A. Taajaviáq1, MD, I. AviwvónouAoq, MD, PhD, А. ФьМппопоиЛои, MD, A. AviwvónouAoq MD, FACP PhD, Kai IiajáiriQ-NiKóAaoq люогк, MD, PhD.
PeujaioAoYiKó Tjnja, 1 naBoAoYoavaiojiKó Tjnja, laipiKr] IxoAn naveniairpou naipwv, naveniairpaKó NoaoKojeío naipwv
ПЕР1ЛИФИ
Еюауыуп: EpeuvnTiKá 6e6ojéva eianYoúvTai Tnv aujjeroxn rwv В Aej0oKuiTápwv arnv na9oYéveia rnQ auarnjaTiKnQ aKAnpo6epjíaQ (II). To aKAnpo6epjaiiKó 6épja xapaKTnpíZerai anó ioxupr evepYonoínan tou Wnt jovonaiioú-auió ni9avá o0eíAerai arnv anouaía éK0paanQ tou jopíou Dickkopf-1 (Dkk-1), evóQ avaaroAéa rou Wnt jovonarioú.
Zkohóq: Na eKiijn9eí n ni9avr ení6paan rnQ В KuirapiKnQ eE;áAe^nQ je pirouE;ijájnn (RTX) arnv éK0paan rou Dkk-1 aro aKAnpo6epjaiiKó 6épja.
Meöoöoi: EAr09naav ßloфíeQ 6épjaroQ anó 11 aa9eveíQ je II npo Kai 6 jnveQ jerá anó 9epaneía je RTX. Oi ßюфíeQ anó 8 aa9eveíQ xPnaijonoin9nKav Yia avoaoiaroxnjiKn aváAuan Kai anó 3 aa9eveíQ Yia Yovi6iaKn aváAuan (é0paan rou Yovi6íou DKK1 ae lvoßAáaтeQ 6épjaroQ). TpeíQ eninAéov aa9eveíQ je II nou 6ev eAaßav 9epaneía je RTX xpnaijonin9nKav wq jáprupeQ АиотеЛеаната: Anó óAeQ tiq ßlOфíeQ aro xpóvo jn6év anouaíaZe n éK0paan rou Dkk-1 anó lvoßAáaтeQ rou 6épjaroQ. Merá rnv 9epaneía je RTX, 4 anó touq 8 aa9eveíQ nou jeAern9nKav ej0áviaav éK0paan rou Dkk-1 ae lvoßAáaтeQ ae avrí9ean je touq aa9eveíQ rnQ ojá6aQ eAéYxou ónou KavévaQ 6ev napouaíaae éK0paan rou Dkk-1. H éK0paan rou TGFß jeiw9nKe anjavriKá jerá rnv 9epaneía-n jeíwan aurn nrav nio ej0avñQ arnv ojá6a aa9evwv nou ej0áviae éK0paan Dkk-1 jerá rnv 9epaneía ae axéan je auroúQ nou 6ev ej0áviaav (50.88% jeíwan ae avTi6iaaroAn je jóAiq 15.98%, p=0.022). Oi aa9eveíQ nou e^é0paaav Dkk-1 jerá rnv 9epaneía nrav auroí nou eíxav rnv KaAúrepn KAiviKn Kai iaroAoYiKn avianóKpian-n evanó9ean KoAAaYóvou jeiw9nKe Kará 49.47% ae axéan je jóAiq 18.18% otouq aa9eveíQ nou 6ev e^é0paaav, p=0.04. Ta KAiviKá 6e6ojéva nrav aváAoYa rwv iotoAoyikwv- to MRSS arov éva xpóvo jeiw9nKa Kará 63.23% arnv ojá6a nou e^é0paae Dkk-1 ae axéan je 28.08% arnv ojá6a nou 6ev e^é0paae Dkk-1 jerá rnv
9epaneía. H éK0paan rou Yovi6íou DKK1 otouq lvoßAáaтeQ 6épjaroQ au^n9nKe 4.8 0opéQ jerá rnv 9epaneía (p=0.03) Ynsoeuvoq A^^n^oYpафíаq: Еиниерааната^ éK0paan rou Dkk-1 aro aKAnpo6epjaiiKó
A. AaoúaqQ, Па9оЛоу1кг| КЛмкп,
реиМатолоу1к0 тМпма, 6épja jerá rnv 9epaneía je RTX auv6uáZerai je iaroAoYiKn
laipiKii ^хоЛп naveniaTHMÍou naTpúv,
26504 pío, пбтра, Еллбба. Kai кАмкп avranóKpian. H В KuirapiKn eEáAei^n ni9avá
ТпЛ: +30-2613-603 693, FAX: +30-2610-993 982.
email: [email protected] nepiopíZei rnv ívwan jéaw evíaxuanQ rnQ éK0paanQ rou Dkk-
Corresponding author:
Dr. D. Daoussis, Department of Internal Medicine, 1. O jnxaviajóQ eívai áYvWaTOQ, aAAá Ta 6e6ojéva jaQ
Division of Rheumatology,
Patras university Hospital, eianYoúvTai rnv aujjeroxn rou TGFß.
26504 Rion, Patras, Greece.
Tel: +30-2613-603 693, FAX: +30-2610-993 982.
E-mail [email protected] Mediterr J Remata1 201!S; 26(1): 74-7<S
Лé^elQ-KЛelбlá: Auroavoaía, В Aej0oKÚTiapa, jopiaKn anjaTo6óTnan, auainjariKn aKAnpuvan
H EKOPAXH TOY MOPIOY DiCKKOPF-1 (DKK-1) ITO AERMA META THN QEPAnEIA ME RITOYElMAMnH IYNAYAZETAI ME IXTOAORKH BEATDXH IE AX0ENEI ME XYXTHMATIKH IKAHPOAEPMIA UPREGULATiON OF DiCKKOPF-1 SKiN EXPRESSiON FOLLOWiNG B CELL DEPLETiON THERAPY ASSOCiATES WiTH ENHANCED RESOLUTiON OF SKiN FiBROSiS iN PATENTS WiTH SYSTEMiC SCLEROSiS
Upregulation of Dickkopf-1 skin expression following B cell depletion therapy associates with enhanced resolution of skin fibrosis in patients with systemic sclerosis
Dimitrios Daoussis MD, PhD, Athanassios Tsamandas1 MD, loannis Antonopoulos MD, PhD, Alexandra Filippopoulou MD, Andrew P. Andonopoulos M.D. FACP, PhD, and Stamatis-Nick Liossis MD, PhD.
Division of Rheumatology, and department of Patholology, Patras University Hospital, University of Patras Medical School , Patras, Greece.
ABSTRACT
Introduction: Experimental and clinical data indicate that B cells may actively participate in the fibrotic process in the context of systemic sclerosis (SSc). Recently, the Wnt pathway has emerged as a crucial regulator of fibrosis. In scleroderma skin, the Wnt pathway is highly activated; this is linked to the fact that Dickkopf-1 (Dkk-1), an inhibitor of the Wnt pathway, is virtually absent from scleroderma skin.
Objective: To assess the effect of B cell depletion therapy on Dkk-1 skin expression. Methods: Skin biopsies were obtained from 11 patients with SSc, prior to and 6 months following RTX administration (biopsies from 8 patients were used for immunohistochemical assessment and biopsies from 3 patients for gene expression analysis). Skin biopsies were also obtained from 3 additional patients with SSc at baseline and at 6 months for control purposes (2 patients receiving cyclophosphamide and 1 no treatment). Most of these patients were enrolled in a clinical study assessing the efficacy of RTX in SSc. All biopsies were taken from lesional skin of the forearm. Skin involvement was assessed both clinically by applying the MRSS tool and histologically. Collagen accumulation was assessed by Masson's thrichrome and computerized image analysis was used to quantify the results. Dkk-1 skin expression was assessed by immunohistochemistry and by RT-PCR. Circulating Dkk-1 levels were measured using a solid phase immunoassay. Results: In all baseline biopsies Dkk-1 had no expression in spindle like cells in the dermis. However, following RTX administration, 4 patients exhibited a significant upregulation of Dkk-1 expression in spindle like cells. In the control biopsies Dkk-1 was undetectable in spindle like cells at 6 months. TGF|3 skin expression in the upper dermis was significantly attenuated following treatment (p=0.018). However, the dowregulation of TGF| skin expression was significantly more pronounced in the subgroup of patients (n=4) which showed Dkk-1 upregulation. In this subgroup TGF| was downregulated by a mean percentage of 50.88% in sharp contrast to only 15.98% in patients that did not show Dkk-1 upregulation (p=0.022). In the subgroup of patients which exhibited upregulation of Dkk-1 skin expression, an enhanced response, in terms of resolution of skin fibrosis, was found. In these patients, histologic analysis revealed that Dkk-1 upregulation associated with a significant decrease in collagen accumulation in the upper dermis by a mean±SEM 49.47±10.63% compared to 18.18±6.67% in patients which did not exhibit Dkk-1 upregulation (p=0.04). Histologic data matched the clinical data; MRSS at 1 year
Keywords: Autoimmunity, B lymphocytes, molecular signaling, systemic sclerosis
mediterranean journal 26
of RHEUMATOLOGY 1
EAAHNIKH PEYMATQAOriA 2015
decreased by a median of 63.23% in the subgroup that exhibited Dkk-1 upregulation compared to only 28.08% in the subgroup with undetectable Dkk-1. PFT's improved following RTX treatment, irrespective of Dkk-1 skin expression. Circulating levels of Dkk-1 did not change following RTX treatment (mean±SEM of OD: 0.17±0.04 vs 0.19±0.03 for patients with SSc and healthy subjects, respectively, p=ns). Gene expression analysis in fibroblasts revealed that DKK1 was significantly upregulated following RTX treatment (p=0.03)
Conclusions: Upregulation of Dkk-1 skin expression associates with an enhanced resolution of skin fibrosis following B cell depletion therapy. RTX may mediate its beneficial effects on fibrosis by increasing Dkk-1 skin expression potentially by a TGF|-dependent mechanism. This could potentially downregulate the Wnt pathway, a well known driver of fibrosis.
Mediterr J Rheumatol 2015; 26(1): 74-76
