The Efficacy Of The Adalimumab And Total Glucosides Of Peony In Treating Psoriasis And The Effect On The T Helpcells In Psoriasis

Psoriasis is a common,easily repeated,complex etiology of chronic inflammatory skin disease.It induces damage not only in the skin,but also arthritis,cardiovascular disease,obesity,metabolic syndrome.The patients often are anxious tension and depressed.Psoriasis is a recurrent heart-body disorders systemic disease.C urrently the pathogenesis of psoriasis is not fully understood.There is no completely effective specific treatment.So the pathogenesis of psoriasis in-depth study is particularly important.There is no cure for psoriasis,cyclosporine,methotrexate,acitretin have effect,but their nephrotoxicity,hepatotoxicity and teratogenicity limit their long-term use.Safe and effective treatment for psoriasis is one of attentions of research goals.Tumor necrosis factor-a(TNF-a)antagonist adalimumab with rapid relief of psoriasis symptoms,opens a new era in the treatment of moderate to severe psoriasis.After receiving adalimumab 16 weeks,71%of Caucasian psoriasis patients achieved PASI75.It shows adalimumab significantly improve psoriasis.There is no clinical reports of the efficacy and safety of adalimumab treatment on C hinese psoriasis patients,so we will use a randomized,double-blind,placebo-controlled trial to assess the clinical efficacy and safety on adalimumab treating moderate to severe psoriasis.Total glucosides of peony(TGP)is a medicine plant glycosides substances extracted peony root.It play suppress autoimmune responses,immunomodulatory,antioxidant efficacy.TGP was used in a variety of autoimmune diseases such as rheumatoid arthritis,systemic lupus erythematosus,liver fibrosis,colitis,ankylosing spondylitis.The dermatologists apply TGP combined with acitretin treating moderate to severe psoriasis and achieve good effect.But there is no reports on of randomized,placebo-controlled trial,we used a randomized,double-blind,placebo-controlled trial for assessment of the efficacy and safety of TGP treating moderate to severe psoriasis.The clinical experience of diagnosis and treatment for psoriasis and psoriasis associated with cell culture in vitro,animal model experiment showed the changes of immune cells and cytokines may be one of the causes of psoriasis.Previous studies found that Thl lymphocytes(CD4+INF-+)and its secretion and attribution of cytokines INF-,IL-2 and IL-18 were significantly increased in psoriasis.At same time the expression of genes related to its regulation have also changed significantly.With the further progress of scientific research,it was found that Th17 lymphocytes(CD4+IL-17+)and Th22 lymphocyte(CD4+IL17-INF-?-IL-22+)may play an important role in the pathogenesis of psoriasis.IL-17 secreted by Thl 7 cells increased keratinocytes to express the chemokins which attract myeloid dendritic cells infiltration into dermis.IL-17 can increase the yield of antimicrobial peptides and other maintenance of skin inflammatory immune response required.Th22 cells are the important T lymphocyte subsets of human epidermal immune regulation and reconstruction.Th22 cells secret IL-22 and TNF-?,but not INF-?,IL-4 and IL-17.IL-22 is a key factor in psoriatic lesions formation.IL-22 can enhance the proliferation of keratinocyte,inhibition differentiation,of keratinocyte,attract inflammatory cell infiltration into the dermis.What subgroup is the dominant role in the psoriasis pathogenesis?We want to investigate the proportion of the different T helper lymphocyte subsets in psoriasis,the relationship between the different T helper lymphocyte subsets and psoriasis disease severity,the analysis of each subgroup.We try to find the important subset in the psoriasis pathogenesis.We aim to provide a new idea for treating psoriasis by reducing the targeted Th subset in the futureThe mechanism of TNF-? antagonists treating psoriasis is still controversial.Some scholars believe that TNF-? antagonists reduced the amount of Th17 cells and related gene expression of L-17 pathway;While other study have found that TNF-? antagonists enhancements Th17 cells in psoriasis-like mouse model;Another study found that TNF-a antagonists can show a dual role:enhance the peripheral blood of patients with psoriasis Thl and Th17 cell and inhibition of psoriatic skin lesions and functional responses of T lymphocytes.Therefore,we will compare the change of Thl/Th17 cells before and after TNF-a antagonist adalimumab treatment to further clarify the effects of TNF-a antagonists on Thl/TH17 cellular pathways.There is no reports on the change of Th22 cells by TNF-a antagonists.We investigate the change of Th22 cells before and after TNF-? antagonist adalimumab therapy.Found in animal experiments,TGP inhibits the autoimmune response,anti-inflammatory,analgesic,immunomodulatory,antioxidant efficacy.We also observed TGP could reduce inflammation in psoriasis,but the mechanism is not clear,There are no reports how TGP change T helper lymphocyte subsets in peripheral blood of psoriasis patients.We will compare the change of Thl/Thl7/Th22 cells before and after using TGP in psoriasis patients.We try to find the mechanism of TGP treating psoriasis.Aim:1.Analysis of the efficacy and safety of adalimumab treating moderate to severe psoriasis;2.Analysis of the efficacy and safety of TGP treating moderate to severe psoriasis;3.The different role of T-helper lymphocytes(Thl/Thl7/Th22)subsets in the pathogenesis of psoriasis;4.The treatment mechanism of TNF-? antagonist adalimumab influence(Th1/Th17/Th22)subsets;5.The treatment mechanism of TGP influence(Thl/Th17/Th22)subsets;Method:1.Apply randomized,double-blind,placebo-controlled trial to observe psoriasis severity score and related laboratory and record adverse events by using adalimumab treating moderate-severe psoriasis;2.Apply randomized,double-blind,placebo-controlled trial to observe psoriasis severity score and related laboratory and record adverse events by using TGP treating moderate-severe psoriasis;3.Use flow cytometry to investigate peripheral blood T-helper lymphocytes;Real-time PCR method for detection of transcription factors(Tbet/RORyt/AHR),enzyme-linked immunosorbent assay for detection of plasma cytokine levels(INF-y/IL-17/IL/22)in psoriasis and healthy controls;4.Compare the changes in T lymphocyte subtypes,transcription factors and cytokine levels in cell differentiation and proliferation before and after adalimumab treatment:the use of flow cytometry to peripheral blood T-helper lymphocytes and T-effector lymphocytes subtypes,Real-time PCR method for detection of transcription factors(Tbet/RORyt/AHR),enzyme-linked immunosorbent assay for detection of plasma cytokine levels(INF-y/IL-17/I L/22/TNF-?/IL-6);5.Compare the changes in T lymphocyte subtypes,transcription factors and cytokine levels in cell differentiation and proliferation before and after total glucosides of paeony treatment:the use of flow cytometry to peripheral blood T-helper lymphocytes and T-effector lymphocytes subtypes,Real-time PCR method for detection of transcription factors(Tbet/RORyt/AHR),enzyme-linked immunosorbent assay for detection of plasma cytokine levels(IN F-?/IL-17/IL/22/TNF-?/IL-6);Result:1.After 3 weeks of treatment,the PASI decline was significantly higher in adalimumab treatment group than in control;after 7 weeks,the mean PASI score was significantly lower in adalimumab treatment group than in the control group;after 12 weeks,76.2%of patients treated with adalimumab reached PASI75;the efficacy was significantly higher than the placebo group,;C-reactive protein levels were significantly lower than before treatment;Relative PASI decline were no significantly different among 3rd weeks,7th weeks,12th weeks treatment in adalimumab treatment group;2.Adalimumab treatment group:Two cases of respiratory infections,one case of suspected TB infection withdraw from the trial;The incidence of adverse events was 14.8%and serious events was 3.7%.Placebo control:one case of respiratory infections t,no one withdrew from the study;The incidence of adverse events was 16.7%.The incidence of adverse events had no significant difference between the two groups.Before and after treatment,blood,urine,ECG,X-ray chest(except exit person),liver function,renal function and other tests had no abnormal changes in the two group;3.After 8 weeks of treatment,the PASI decline was significantly higher in TGP treatment group than in control;after 8 weeks,the mean PASI score was significantly lower in TGP treatment group than in the control group;after 8 weeks,72.7%of patients treated with TGP reached PAS 175;the efficacy was significantly higher than the placebo group;Relative PASI decline were no significantly different among 2nd,4th weeks,8th weeks,12th weeks treatment in TGP treatment group;4.TGP treatment group:Two cases of impaired liver function;The control group:four cases of impaired liver function,The incidence of adverse events was 18.2%in TGP treatment group and lower tthan in control group(28.6%);Before and after treatment,blood,urine,renal function had no abnormal changes in the two group;5.The proportion of Thl/Thl7/Th22 type cells in psoriasis peripheral blood was significantly higher than normal;.the level of INF-?/IL-17/IL/22/TNF-a/IL-6 in psoriasis were significantly higher than normal;.transcription factors of Tbet/RORyt/AHR relative expression in psoriasis were significantly higher than normal people;6.Th17 cells in peripheral blood of patients with psoriasis positively correlated with plasma levels of IL-17,and both of them correlate with PASI;.Th22 cells in peripheral blood of patients with psoriasis positively correlated with plasma levels of IL-22,and both of them correlate with PASI;7.After adalimumab treatment,the proportion of Thl/Thl7/Th22 type cells in psoriasis peripheral blood significantly decreased;the level of serum INF-?/IL-1 7/IL/22/TNF-a/IL-6 significantly reduced;transcription factors of RORyt/AHR relative expression significantly reduced;8.After total glucosides of paeony treatment,the proportion of Thl/Th17 type cells in psoriasis peripheral blood significantly decreased;the level of serum INF-?/IL-17/TNF-a in psoriasis significantly reduced;transcription factors of Tbet and RORyt relative expression significantly reduced;Conclusion:1.Adalimumab is effective in treating moderate to severe psoriasis,After 3 weeks,PAS I decline was significantly;After 7 weeks,PASI was reduced significantly;biological effects of adalimumab did not accumulate;Common adverse events were upper respiratory tract infection in using adalimumab;2.TGP is effective in treating moderate to severe psoriasis,After 8 weeks,PASI decline was significantly;After 8 weeks,PASI was reduced significantly;biological effects of TGP did not accumulate;TGP would protect the liver organ.3.T helper cells-Th17 and Th22 and their effector cytokines IL-17/IL-22 may play an important role by themselves and their secretion in psoriasis.Thl cells and its secredted IFN-yplay a supporting role.IL-6 was an important regulating cytokine in psoriasis.4.TNF-? antagonist is effective for the treatment of psoriasis,by interfering the differentiation of Th1/Th17/Th22 cells.TNF-a antagonist also interfere the differentiation of Th17/Th22 cells by donw-regulating IL-6.5.TGP is effective for the treatment of psoriasis,by interfering the differentiation of Th1/Th17 cells.The reduced number of Th1/Thl 7 cells,inhibit the secretion of factors related effects,thus resulting in the improvement of Psoriasis.6.TNF-a antagonist and TGP could downregulate the level of TNF-a,resulting the hinderance of the inflammatory progress induced by TNF-?.