Developing a Therapeutic Range of Adalimumab Serum Concentrations in Management of Psoriasis: A Step Toward Personalized Treatment.
Menting Stef P,Coussens Emma,Pouw Mieke F,van den Reek Juul M P A,Temmerman Linda,Boonen Hugo,de Jong Elke M G J,Spuls Phyllis I,Lambert Jo
IMPORTANCE:Adalimumab has proven to be effective in suppressing psoriasis disease activity and is administered in a standard dose. OBJECTIVE:To establish a therapeutic range for adalimumab trough levels in the treatment of plaque-type psoriasis, leading to a more personalized treatment. DESIGN, SETTING, AND PARTICIPANTS:A multicenter, prospective, observational, daily practice cohort study conducted at an academic hospital with affiliated secondary care hospitals in Belgium (cohort 1) and 2 academic hospitals in the Netherlands (cohort 2). Both cohorts included adult patients treated with adalimumab for plaque-type psoriasis. Cohort 1 comprised 73 patients who were being treated with adalimumab for more than 24 weeks until 401 weeks. In cohort 2 (n = 62), serum samples were obtained between weeks 24 and 52 of treatment. INTERVENTIONS:Before the start of adalimumab therapy and at time of serum sampling, Psoriasis Area and Severity Index (PASI) scores were determined. MAIN OUTCOMES AND MEASURES:Adalimumab trough level and PASI score at the time of serum sampling to determine the receiver-operator characteristics analyses and concentration effect curve. RESULTS:By means of receiver-operator characteristics analyses with an area under the curve of 0.756 (SD, 0.046; 95% CI, 0.666-0.847) and a sensitivity of 78% and a specificity of 70%, 3.51 mg/L was established as the lower margin for the therapeutic range. By means of a concentration effect curve, 7 mg/L was established as the upper margin. One-third of patients had an adalimumab trough concentration exceeding 7 mg/L. CONCLUSIONS AND RELEVANCE:A therapeutic range of adalimumab trough levels of 3.51 mg/L to 7.00 mg/L, which corresponds to an optimal clinical effect, was identified. In one-third of patients, it was observed that trough concentrations exceeded the therapeutic window. Based on the established range, a therapeutic algorithm for adalimumab treatment for patients with psoriasis can be developed and validated in a prospective patient cohort. By identifying this range, a step has been taken toward a more rational use of biological therapy in psoriasis. Developing a therapeutic algorithm may lead to less overtreatment of patients and cost savings.
New Method of Inhibition of Activity of Tumor Necrosis Factor Alpha In Patients with Psoriasis.
Gerasun Borys A
Recent patents on endocrine, metabolic & immune drug discovery
INTRODUCTION:A new method of reduction of tumor necrosis factor alpha activity via intradermal immunization with inactivated autoleukocytes (patent UA97493 (2015) ) has been presented in the article. New patents from various countries have been analyzed [2-7]. OBJECTIVE:Patients with psoriasis (24) with high level of tumor necrosis factor alpha in their blood (. 30pg/ml) were immunized with autoleukocytes. METHOD:Leukocytes were isolated by centrifuging plasma, obtained after precipitation of a patient's heparinized peripheral venous blood. Precipitate was suspended in 1.0 - 1.5ml of a patient's blood serum and 0.1ml of blood was injected into the skin of the back. For determination of autoleukocyte immunization efficacy, concentration of tumor necrosis factor alpha in a patient's blood was compared prior to immunization and at different periods after immunization. RESULTS:In 30 days after single immunization, a considerable decrease in cytokine concentration was observed in all patients (100%); it reduced to zero in 16 out of 24 of immunized individuals (66.7%). The degree of reduction and duration of the achieved effect were individual, thus, if necessary the immunization was repeated several times. The procedure was well tolerated, and general condition of patients was improved. CONCLUSION:The method of reduction of tumor necrosis factor alpha activity is recommended for implementation into clinical practice.
In-depth serum proteomics reveals biomarkers of psoriasis severity and response to traditional Chinese medicine.
Xu Meng,Deng Jingwen,Xu Kaikun,Zhu Tiansheng,Han Ling,Yan Yuhong,Yao Danni,Deng Hao,Wang Dan,Sun Yaoting,Chang Cheng,Zhang Xiaomei,Dai Jiayu,Yue Liang,Zhang Qiushi,Cai Xue,Zhu Yi,Duan Hu,Liu Yuan,Li Dong,Zhu Yunping,Radstake Timothy R D J,Balak Deepak M W,Xu Danke,Guo Tiannan,Lu Chuanjian,Yu Xiaobo
Serum and plasma contain abundant biological information that reflect the body's physiological and pathological conditions and are therefore a valuable sample type for disease biomarkers. However, comprehensive profiling of the serological proteome is challenging due to the wide range of protein concentrations in serum. : To address this challenge, we developed a novel in-depth serum proteomics platform capable of analyzing the serum proteome across ~10 orders or magnitude by combining data obtained from Data Independent Acquisition Mass Spectrometry (DIA-MS) and customizable antibody microarrays. : Using psoriasis as a proof-of-concept disease model, we screened 50 serum proteomes from healthy controls and psoriasis patients before and after treatment with traditional Chinese medicine (YinXieLing) on our in-depth serum proteomics platform. We identified 106 differentially-expressed proteins in psoriasis patients involved in psoriasis-relevant biological processes, such as blood coagulation, inflammation, apoptosis and angiogenesis signaling pathways. In addition, unbiased clustering and principle component analysis revealed 58 proteins discriminating healthy volunteers from psoriasis patients and 12 proteins distinguishing responders from non-responders to YinXieLing. To further demonstrate the clinical utility of our platform, we performed correlation analyses between serum proteomes and psoriasis activity and found a positive association between the psoriasis area and severity index (PASI) score with three serum proteins (PI3, CCL22, IL-12B). : Taken together, these results demonstrate the clinical utility of our in-depth serum proteomics platform to identify specific diagnostic and predictive biomarkers of psoriasis and other immune-mediated diseases.
Serum C-reactive protein levels in Japanese patients with psoriasis and psoriatic arthritis: Long-term differential effects of biologics.
Asahina Akihiko,Umezawa Yoshinori,Yanaba Koichi,Nakagawa Hidemi
The Journal of dermatology
Psoriasis has been shown to accompany systemic inflammation. We aimed to examine serum C-reactive protein (CRP) levels in Japanese psoriatic patients, and to elucidate their long-term as well as short-term changes by treatment with different biologics. A retrospective study was conducted in those who initiated and successfully continued the treatment for up to 24 months with either infliximab, adalimumab or ustekinumab, at the psoriasis special clinic of Jikei University School of Medicine. A total of 212 patients were included, 171 with plaque-type psoriasis (PsV) and 41 with psoriatic arthritis (PsA). A statistically significant elevation of CRP values was found in the group with a Psoriasis Area and Severity Index (PASI) of 12 or more compared with the PASI of less than 12 for both PsV and PsA. The CRP-positive patients had a higher proportion of PsA compared with the CRP-negative patients, and they had significantly higher PASI scores. Serum CRP values declined as early as at 3 months after systemic treatment with biologics. Tumor necrosis factor (TNF)-α antagonists did lead to a notable and sustained CRP decline up to 24 months. Infliximab showed rapid decline, while CRP decline by adalimumab treatment was time-dependent. The interleukin-12/23 p40 antagonist, ustekinumab, appeared to be less potent than TNF-α antagonists in stabilizing CRP values at low levels despite good control of cutaneous lesions. In conclusion, serum CRP levels can be used to assess disease severity in Japanese psoriatic patients as a marker of systemic inflammation. TNF-α antagonists may be more beneficial than ustekinumab in this regard.
IL-17A, IL-22, and IL-23 as Markers of Psoriasis Activity: A Cross-sectional, Hospital-based Study.
Fotiadou Christina,Lazaridou Elizabeth,Sotiriou Eleni,Gerou Spiridon,Kyrgidis Athanasios,Vakirlis Efstratios,Ioannides Demetris
Journal of cutaneous medicine and surgery
INTRODUCTION:T-helper 1 (Th1), Th17 cells, and their related cytokines are implicated in psoriasis pathogenesis although the contribution of each group of cytokines in psoriasis activity has not been fully clarified. OBJECTIVES:To investigate whether Th17-related cytokines are associated with psoriasis activity. METHODS:The serum levels of interleukin (IL)-1β, 6, 8, 17Α, 22, 23, and tumor necrosis factor-α (TNFα) were measured with flow cytometry in 35 patients with plaque psoriasis (21 with stable and 14 with active disease) and in 20 healthy controls. RESULTS:Interleukin-6, 8, 17A, 22, 23, and TNFα were significantly elevated in psoriasis patients compared with controls. In the sensitivity analyses, patients with active disease showed significantly increased levels of IL-17A, IL-23, and IL-22 as compared to the group of patients with stable psoriasis. CONCLUSIONS:Our study highlights a possible crucial role of IL-17A, IL-22, and IL-23 in the activity of psoriasis and the early stages of the disease.
Serum levels of LL-37 and inflammatory cytokines in plaque and guttate psoriasis.
Hwang Young Ji,Jung Ho Jung,Kim Min Jung,Roh Nam Kyung,Jung Jae Wook,Lee Yang Won,Choe Yong Beom,Ahn Kyu Joong
Mediators of inflammation
Psoriasis is a chronic inflammatory skin disease. It is assumed that the plaque phenotype of psoriasis is associated with T helper (Th) 1 immune response activation, while the guttate phenotype is associated with the Th17 immune response. Previous investigations of differences in the serum levels of cytokines relative to the clinical psoriatic phenotype have yielded conflicting results. This study compared the levels of circulating inflammatory cytokines and LL-37 relative to the morphological phenotype in patients with psoriasis. Seventy-four age-matched patients with psoriasis (32 with guttate psoriasis and 42 with plaque psoriasis) and 12 healthy controls were included. A multiplex cytokine assay and enzyme-linked immunosorbent assay were used to measure levels of Th1- and Th17-derived cytokines and LL-37, respectively. Circulating levels of interferon- (IFN)-γ, interleukin- (IL)-1RA, IL-2, and IL-23, and LL-37 were significantly higher in patients with psoriasis than in healthy controls. However, the serum levels of inflammatory cytokines (IL-7, IL-22, and IL-23) and LL-37 did not differ significantly between the guttate and plaque phenotypes of psoriasis. There was a positive correlation between serum inflammatory cytokine levels and the Psoriasis Area and Severity Index score. The findings of this study suggest that the serum levels of inflammatory cytokines reflect the disease activity rather than determine the morphological phenotype.
Serum IL-6 and IL-23 Levels and Their Correlation with Angiogenic Cytokines and Disease Activity in Ankylosing Spondylitis, Psoriatic Arthritis, and SAPHO Syndrome.
Przepiera-Będzak Hanna,Fischer Katarzyna,Brzosko Marek
Mediators of inflammation
OBJECTIVES:To assess serum interleukin-6 (IL-6) and interleukin-23 (IL-23) and their correlation with angiogenic cytokines and disease activity in ankylosing spondylitis (AS), psoriatic arthritis (PsA), and SAPHO syndrome. PATIENTS AND METHODS:We studied 152 spondyloarthritis (SpA) patients: 69 PsA, 61 AS, 22 SAPHO, and 29 controls. We recorded age, sex, disease duration, and treatment. We assessed BASDAI, VAS, and PASI scores. Serum IL-6, IL-23, VEGF, EGF, FGFb, and FGFa levels were determined using ELISA. We estimated ESR and CRP. RESULTS:Serum IL-6 and IL-23 levels were higher in SpA than in control (P < 0.00001 and P = 0.0004, resp.). There was a positive correlation between serum IL-6 and CRP in AS (P = 0.000001), PsA (P = 0.000001), and SAPHO (P = 0.0003) patients. There was a positive correlation between serum IL-6 and ESR in AS (P = 0.000001), PsA (P = 0.002), and SAPHO (P = 0.02) patients. There was no correlation of serum IL-6 and IL-23 with VAS, BASDAI, and angiogenic cytokines in SpA. CONCLUSIONS:Serum IL-6 but not serum IL-23 correlated with ESR and CRP in SpA. No correlation was found of serum IL-6 and IL-23 with VAS, BASDAI, and angiogenic cytokines.
Guselkumab (an IL-23-specific mAb) demonstrates clinical and molecular response in patients with moderate-to-severe psoriasis.
Sofen Howard,Smith Stacy,Matheson Robert T,Leonardi Craig L,Calderon Cesar,Brodmerkel Carrie,Li Katherine,Campbell Kim,Marciniak Stanley J,Wasfi Yasmine,Wang Yuhua,Szapary Philippe,Krueger James G
The Journal of allergy and clinical immunology
BACKGROUND:IL-23 expression is increased in psoriatic lesions and might regulate TH17 T-cell counts in patients with psoriasis. OBJECTIVES:We sought to test a novel IL-23-specific therapeutic agent for the treatment of psoriasis. METHODS:In this randomized, double-blind, placebo-controlled study the safety, tolerability, and clinical response of guselkumab, an anti-IL-23-specific mAb, were evaluated in patients with moderate-to-severe plaque psoriasis. A total of 24 patients were randomized to receive a single dose of placebo or 10, 30, 100, or 300 mg of guselkumab. Clinical response was assessed by using the Psoriasis Area and Severity Index (PASI). Additionally, histologic analysis and gene expression in skin biopsy specimens from guselkumab-treated patients were compared with those from placebo-treated patients. RESULTS:At week 12, 50% (10 mg), 60% (30 and 100 mg), and 100% (300 mg) of guselkumab-treated patients, respectively, achieved a 75% improvement in PASI scores from baseline compared with 0% of placebo-treated patients. Improvements in PASI scores were generally maintained through week 24 in all guselkumab-treated patients. The proportion of patients experiencing an adverse event was comparable between the combined guselkumab (13/20 [65.0%]) and placebo (2/4 [50.0%]) groups through week 24. Analysis of lesional and nonlesional skin biopsy specimens demonstrated decreases in epidermal thickness and T-cell and dendritic cell expression in guselkumab-treated patients compared with values seen in placebo-treated patients. At week 12, significant reductions in psoriasis gene expression and serum IL-17A levels were observed in guselkumab-treated patients. CONCLUSION:IL-23 inhibition with a single dose of guselkumab results in clinical responses in patients with moderate-to-severe psoriasis, suggesting that neutralization of IL-23 alone is a promising therapy for psoriasis.
Correlation of IL-12, IL-22, and IL-23 in patients with psoriasis and metabolic syndrome. Preliminary report.
Brito-Luna M J,Villanueva-Quintero D G,Sandoval-Talamantes A K,Fafutis-Morris M,Graciano-Machuca O,Sanchez-Hernandez P E,Alvarado-Navarro A
BACKGROUND:Psoriasis is an autoimmune skin disease characterised by proliferation of keratinocytes, primarily due to cytokines Th1 and Th17. This profile is involved in pathogenesis of metabolic syndrome, a frequently found comorbidity in patients with psoriasis. OBJECTIVE:In this study we determine the correlation of levels of pro-inflammatory cytokines TNF-α, IL-23, IL-12, and IL-22 in patients with psoriasis with and without metabolic syndrome and clinically healthy controls. METHODS:We included 55 patients with plaque psoriasis: 30 with metabolic syndrome (PPMS), 25 without metabolic syndrome (PP), 15 healthy subjects (HS) and 15 with metabolic syndrome (MS). Quantification of serum levels of IL-12, TNF-α, IL-22, and IL-23 was done by ELISA. RESULTS:We observed that serum levels of IL-12 were more elevated in PP group, while the lowest levels of TNF-α were seen in HS group. IL-22 was found to be higher in PP than in PPMS (p<0.05). PP patients with PASI scores rating as severe showed higher levels of IL-12. TNF-α level analysis showed significant differences in HS group compared with the others; levels of this cytokine were lower in patients with PP and moderate PASI scores than in MS group (p<0.05). We found no correlation between cytokine levels and psoriasis or between cytokines and PASI scores. In PP group, a positive correlation was observed between IL-23 and fasting glucose (r=0.432, p<0.05), as well as a negative correlation between IL-23, IL-22, and IL-12 versus waist circumference (r=-0.504, r=-0.556 and r=-0.511, respectively; p<0.05). CONCLUSIONS:Psoriasis is not just a skin disorder, but rather a condition with systemic implications, with intervention of pro-inflammatory cytokines that contribute to metabolic syndrome and other comorbidities, which in turn increases the risk of developing cardiovascular disease.
The level of proinflammatory cytokines: interleukins 12, 23, 17 and tumor necrosis factor α in patients with metabolic syndrome accompanying severe psoriasis and psoriatic arthritis.
Pirowska Magdalena,Obtułowicz Aleksander,Lipko-Godlewska Sylwia,Goździalska Anna,Podolec Katarzyna,Wojas-Pelc Anna
Postepy dermatologii i alergologii
Introduction:The incidence of metabolic syndrome is estimated at 15-24% in the general population and at 30-50% in patients with psoriasis. A probable cause of the described correlation is a constant release in chronic dermatosis of proinflammatory cytokines and their influence on individual systems and organs. Aim:Assessment of the concentration of the proinflammatory cytokines (IL-12, IL-23, IL-17 and TNF-α) in blood serum and their correlation with the intensity of skin lesions, the presence of psoriatic arthritis and the risk of development of obesity and metabolic syndrome. Material and methods:The concentrations of subunit p70 IL-12, IL-17 and IL-23, and TNF-α in subjects with psoriasis and metabolic syndrome were determined. Results:The level of the studied cytokines, IL-17, IL-23 and TNF-α was higher in patients diagnosed with psoriasis. Higher levels of IL-17, IL-23 and TNF-α were observed in patients with metabolic syndrome accompanying psoriasis. A higher level of IL-17 and IL-23 was found in sera of patients with psoriatic arthritis in comparison to normal psoriasis. Conclusions:In the study, a higher level of IL-17 and IL-23 was also shown in patients with psoriatic arthritis in comparison to patients with normal psoriasis. The effectiveness of anti-IL12/23 drugs in psoriatic arthritis is a confirmation of the obtained results of the studies. Additionally, the increased level of IL-17, both in patients with metabolic syndrome and with psoriasis, could indirectly indicate an increased cardiovascular risk in patients with affected joints in comparison to psoriasis affecting only the skin.
Interleukin 22 and 6 serum concentrations decrease under long-term biologic therapy in psoriasis.
Olejniczak-Staruch Irmina,Narbutt Joanna,Bednarski Igor,Woźniacka Anna,Sieniawska Joanna,Kraska-Gacka Marzena,Śmigielski Janusz,Lesiak Aleksandra
Postepy dermatologii i alergologii
Introduction:Psoriasis, affecting approximately 2% of the worldwide population, is a chronic, inflammatory skin disease in which overexpression of proinflammatory cytokines is observed. Most of the available data on the influence of antipsoriatic therapy on the cytokine serum concentration are inconsistent and based on short-term observations. Aim:To evaluate the influence of long-term biologic therapy with tumor necrosis factor α (TNF-α) blockers (adalimumab, etanercept, infliximab) and IL-12/23 inhibitor (ustekinumab) on the level of IL-6, IL-22 in the sera of patients with psoriasis. Material and methods:Blood samples were collected from 42 psoriatic patients in order to determine IL-6 and IL-22 serum concentrations prior to and at the 3, 12, 24 and 36 month of biologic therapy. Psoriasis Activity and Severity Index (PASI) was assessed at the same time points. The control group consisted of 30 sex- and age-matched healthy volunteers. Results:Mean PASI index at baseline was 14.49 ±3.69 and decreased significantly until the end of the observation. Mean IL-6 serum concentration decreased significantly in all study groups ( < 0.05). A statistically significant decrease in IL-22 concentrations was demonstrated during the treatment with adalimumab and infliximab but not etanercept or ustekinumab. Conclusions:According to obtained results, IL-6 and IL-22 serum concentration may be an accurate marker of response to antipsoriatic therapy, even though not correlated with PASI index. Biologic therapy in psoriasis allows for long-term clinical improvement expressed not only by the remission of skin lesions, but also by lowering serum concentrations of pro-inflammatory interleukins.
Serum cytokine measurements and biological therapy of psoriasis - Prospects for personalized treatment?
Solberg Silje M,Sandvik Lene F,Eidsheim Marianne,Jonsson Roland,Bryceson Yenan T,Appel Silke
Scandinavian journal of immunology
Psoriasis is an immune-mediated disease where the IL-23/Th17 axis as well as TNF comprise main targets of biological therapy. Immune profiling has so far not been embraced as a clinical tool. We aimed to investigate relationships between individual serum cytokine levels in 40 psoriasis patients before and after receiving biological therapy and Psoriasis Area and Severity Index (PASI) and Dermatological Life Quality Index (DLQI). Serum concentration of 25 cytokines was determined by Luminex technology. Mean PASI and DLQI decreased by 71% and 65%, respectively. Increase of IL-2 positively correlated with improvement of PASI and DLQI. Moreover, increase of IL-5, IL-10, IL-12, IL-22 and GM-CSF correlated with treatment effect. Notably, logistic regression revealed four times higher risk of having severe psoriasis when IL-17A increased by 1 pg/mL (OR: 4.06, P < 0.05). Selected serum cytokines might constitute useful biomarkers for monitoring disease activity and optimizing therapeutic strategies in psoriasis patients.
Serum concentration of osteopontin and interleukin 17 in psoriatic patients.
Przepiórka-Kosińska Joanna Małgorzata,Bartosińska Joanna,Raczkiewicz Dorota,Bojar Iwona,Kosiński Jakub,Krasowska Dorota,Chodorowska Grażyna
Advances in clinical and experimental medicine : official organ Wroclaw Medical University
BACKGROUND:Psoriasis is a chronic, autoinflammatory disease characterized by activation and differentiation of naive T lymphocytes towards T helper CD4+ (including Th1 and Th17) and T cytotoxic CD8+. Osteopontin (OPN), which plays an important role in both physiological processes and inflammatory, neoplastic and autoimmune diseases, is also considered in the context of psoriasis pathogenesis. Current data indicates that OPN is a multifunctional protein involved in the modulation of Th1 and Th17 cellular responses, in stimulating keratinocyte proliferation, and in the regulation of cellular apoptosis. OBJECTIVES:The assessment of OPN and interleukin 17 (IL-17) concentrations in the peripheral blood of psoriatic patients in comparison to healthy volunteers as well as the correlations of OPN and IL-17 with the severity of psoriasis. MATERIAL AND METHODS:The study included 107 male psoriatic patients and 41 age-matched healthy men. The serum concentrations of IL-17 and OPN were examined using the enzyme-linked immunosorbent assay (ELISA) method. The skin change severity of psoriasis was assessed using the Psoriasis Area and Severity Index (PASI), Body Surface Area (BSA), Physician Global Assessment (PGA), and Dermatology Life Quality Index (DLQI). RESULTS:Psoriatic patients had significantly higher concentrations of OPN (31.65 ng/mL on average) than the healthy volunteers (11.42 ng/mL on average) (p < 0.001). Interleukin 17 was also higher in psoriatic patients (0.53 pg/mL on average) compared to healthy volunteers (0.09 pg/mL on average) (p < 0.001). There was no significant correlation between OPN and IL-17 concentrations in psoriatic patients and in healthy volunteers. Psoriasis severity correlated positively to IL-17 serum concentration, but not to OPN. CONCLUSIONS:Although the study did not show a relationship between OPN and IL-17 concentrations in psoriatic patients, it should be emphasized that serum concentrations were significantly higher in the patients with psoriasis compared to healthy volunteers.
Assessment of serum biomarkers in patients with plaque psoriasis on secukinumab.
Morita Akimichi,Tani Yumiko,Matsumoto Kazuko,Yamaguchi Masako,Teshima Rie,Ohtsuki Mamitaro
The Journal of dermatology
The molecular basis of interleukin (IL)-17A in driving psoriasis pathogenesis is not fully elucidated yet. To investigate the underlying mechanisms and biomarkers associated with IL-17A and the role in psoriasis pathogenesis, over 30 serum proteins were evaluated in a study assessing the effectiveness and safety of secukinumab, where treatment was directly switched from cyclosporin A to secukinumab. Serum β-defensin 2 (BD-2) levels rapidly and robustly reduced following secukinumab treatment. BD-2 levels were well-correlated with Psoriasis Area and Severity Index (PASI) score; changes in BD-2 levels preceded change in PASI score. Serum BD-2, an easily measurable protein, can possibly be used as a suitable surrogate biomarker to monitor responses to IL-17A-targeted therapies for psoriasis in clinical practice.