银屑病的生物治疗研究进展

近年来,随着在银屑病发病机制研究上取得的实质性进展,尤其是对分子免疫学基础的认识不断深入,出现了一系列新的靶向干预制剂———新型生物制剂。它们主要分为两类:抗细胞因子治疗和抗T细胞治疗,且主要用于治疗中-重度银屑病及银屑病型关节炎患者。虽然,生物制剂的短期疗效尚令人满意,但它们的长期疗效和安全性还有待进一步研究,以便更好地指导临床医师合理用药。     

NLRP3 inflammasome: a new therapeutic target for high-risk reproductive disorders?

The NOD-like receptor protein 3 (NLRP3) inflammasome is a key regulator of the host''s immune response, and many immune and metabolic disorders are linked to its activation. This review aimed to investigate and clarify the relationship between this inflammasome and high-risk reproductive disorders. Papers cited here were retrieved from PubMed up to August 2020 using the keywords “NLRP3” or “NALP3”, “caspase-1”, “endometriosis”, “gestational diabetes”, “interleukin (IL)-18”, “IL-1β”, “pre-eclampsia (PE)”, “preterm birth”, “polycystic ovarian syndrome (PCOS)”, “recurrent spontaneous abortion (RSA)”, and combinations of these terms. The results show that NLRP3 inflammasome is associated with various high-risk reproductive disorders and many inflammatory factors are secreted during its activation, such as IL-1β induced during the development of endometriosis. PCOS is also associated with activation of the NLRP3 inflammasome, especially in overweight patients. It also participates in the pathogenesis of RSA and is activated in fetal membranes before preterm birth. The placentas of pregnant women with PE show higher expression of the NLRP3 inflammasome, and gestational diabetes mellitus occurs simultaneously with its activation. Current evidence suggest that the NLRP3 inflammasome plays an important role in female reproductive disorders. New treatment and management methods targeting it might help reduce the incidence of such disorders and improve neonatal outcomes.     

Antimicrobial peptides: bridging innate and adaptive immunity in the pathogenesis of psoriasis

Antimicrobial peptides (AMPs) are small molecules produced by a myriad of cells and play important roles not only in protecting against infections and sustaining skin barrier homeostasis but also in contributing to immune dysregulation under pathological conditions. Recently, increasing evidence has indicated that AMPs, including cathelicidin (LL-37), human β-defensins, S100 proteins, lipocalin 2, and RNase 7, are highly expressed in psoriatic skin lesions. These peptides broadly regulate immunity by interacting with various immune cells and linking innate and adaptive immune responses during the progression of psoriasis. In this review, we summarize the recent findings regarding AMPs in the pathogenesis of psoriasis with a main focus on their immunomodulatory abilities.     

Efficacy and safety of secukinumab in Chinese patients with moderate-to-severe plaque psoriasis: a real-life cohort study

Background:There have been few real-life dose-comparing studies on the efficacy and safety of secukinumab in Chinese patients with plaque psoriasis. We conducted a real-life cohort study to investigate the efficacy and safety of secukinumab 150 and 300 mg in Chinese patients with moderate-to-severe plaque psoriasis.Methods:A total of 106 patients with moderate-to-severe plaque psoriasis were included in this study. Patients received either secukinumab 150 mg or secukinumab 300 mg according to patients’ weights and severity of psoriasis. The treatment continued for at least 24 weeks. The efficacy was evaluated by improvement in the psoriasis area and severity index (PASI) scores. The safety was also analyzed.Results:Fifty-nine patients (55.7%) were treated with secukinumab 300 mg and 47 patients (44.3%) were treated with secukinumab 150 mg. After 12-week treatment, PASI75/90/100 responses were achieved in 100%, 97.8%, and 95.7% of patients, respectively, in secukinumab 150 mg group, and the efficacy was maintained to week 24. In secukinumab 300 mg group, PASI75/90/100 responses were achieved in 93.2%, 81.4%, and 76.3% of patients, respectively, at week 12. In this group, PASI75/90/100 responses reached 91.5%, 86.4%, and 79.9%, respectively, at week 24. Biologic-experienced patients had lower responses than biologic-naïve patients. Secukinumab 150 and 300 mg were well tolerated. Five patients discontinued treatment due to poor response, adverse event, or economic reasons.Conclusions:This real-life study demonstrated that high PASI 90 and PASI 100 responses were achieved in Chinese psoriasis patients receiving secukinumab 150 or 300 mg. Biologic-naïve was associated with better clinical efficacy.     

Alternative medicine and doping in sports

Athletes are high achievers who may seek creative or unconventional methods to improve performance. The literature indicates that athletes are among the heaviest users of complementary and alternative medicine (CAM) and thus may pioneer population trends in CAM use. Unlike non-athletes, athletes may use CAM not just for prevention, treatment or rehabilitation from illness or injuries, but also for performance enhancement. Assuming that athletes'' creative use of anything unconventional is aimed at “legally” improving performance, CAM may be used because it is perceived as more “natural” and erroneously assumed as not potentially doping. This failure to recognise CAMs as pharmacological agents puts athletes at risk of inadvertent doping.The general position of the World Anti-Doping Authority (WADA) is one of strict liability, an application of the legal proposition that ignorance is no excuse and the ultimate responsibility is on the athlete to ensure at all times whatever is swallowed, injected or applied to the athlete is both safe and legal for use. This means that a violation occurs whether or not the athlete intentionally or unintentionally, knowingly or unknowingly, used a prohibited substance/method or was negligent or otherwise at fault. Athletes are therefore expected to understand not only what is prohibited, but also what might potentially cause an inadvertent doping violation. Yet, as will be discussed, athlete knowledge on doping is deficient and WADA itself sometimes changes its position on prohibited methods or substances. The situation is further confounded by the conflicting stance of anti-doping experts in the media. These highly publicised disagreements may further portray inconsistencies in anti-doping guidelines and suggest to athletes that what is considered doping is dependent on the dominant political zeitgeist. Taken together, athletes may believe that unless a specific and explicit ruling is made, guidelines are open to interpretation. Therefore doping risk-taking behaviours may occur because of the potential financial, social and performance gains and the optimistically biased interpretation (that trying alternatives is part of the “spirit of sport”) and doping risk-taking behaviours may occur.This discussion paper seeks to situate the reader in a world where elite level sports and CAM intersects. It posits that an understanding of the underlying motivation for CAM use and doping is currently lacking and that anti-doping rules need to be repositioned in the context of the emerging phenomenon and prevalence of CAM use.     

A brand new era of cancer immunotherapy: breakthroughs and challenges

Immunotherapy has opened a new era in cancer treatment. Drugs represented by immune checkpoint inhibitors have led to important breakthroughs in the treatment of various solid tumors, greatly improving the survival rate of cancer patients. Many types of immunotherapeutic drugs have become widely available; however, their efficacy is variable, and relatively few patients with advanced cancer experience life-altering durable survival, reflecting the complex and highly regulated nature of the immune system. The research field of cancer immunotherapy (CIT) still faces many challenges in pursuing the broader social goal of “curing cancer.” Increasing attention has been paid to strengthening the understanding of the molecular or cellular drivers of resistance to immunotherapy, actively exploring more effective therapeutic targets, and developing combination therapy strategies. Here, we review the key challenges that have emerged in the era of CIT and the possible solutions or development directions to overcome these difficulties, providing relevant references for basic research and the development of modified clinical treatment regimens.     

Effects of Immunosuppressants on Immune Response to Vaccine in Inflammatory Bowel Disease

Objective:

To evaluate the response rate to vaccination in different treatment groups (nonimmunosuppressants and immunosuppressants).

Data Sources:

We completed an online systematic search using PubMed to identify all articles published in English between January 1990 and December 2013 assessing the effect of the response rate to vaccination in different treatment groups (with and without immunomodulators). The following terms were used: “inflammatory bowel disease (IBD)” OR “Crohn''s disease” OR “ulcerative colitis” AND (“vaccination” OR “vaccine”) AND (“corticosteroids” OR “mercaptopurine” OR “azathioprine” OR “methotrexate [MTX]”) AND “immunomodulators.”

Study Selection:

The inclusion criteria of articles were that the studies: (1) Randomized controlled trials which included patients with a diagnosis of IBD (established by standard clinical, radiographic, endoscopic, and histologic criteria); (2) exposed patients received immunomodulators for maintenance (weight-appropriate doses of 6-mercaptopurine/azathioprine or within 3 months of stopping, 15 mg or more MTX per week or within 3 months of stopping; (3) exposed patients received nonimmunomodulators (no therapy, antibiotics only, mesalazine only, biological agent only such as infliximab, adalimumab, certolizumab or natalizumab or within 3 months of stopping one of these agents). The exclusion criteria of articles were that the studies: (1) History of hepatitis B virus (HBV), influenza or streptococcus pneumoniae infection; (2) patients who had previously been vaccinated against HBV, influenza or streptococcus pneumoniae; (3) any medical condition known to cause immunosuppression (e.g. chronic renal failure and human immunodeficiency virus infection); (4) individuals with positive hepatitis markers or liver cirrhosis; (5) patients with a known allergy to eggs or other components of the vaccines and (6) pregnancy.

Results:

Patients treated with immunomodulators were associated with lower response rates to vaccination.

Conclusions:

Immunomodulators may impair the immune response to vaccination in patients with IBD. Vaccination should be made at the time of diagnosis or before starting immunosuppressed therapy.     

Diagnosis of pulmonary embolism

NO SINGLE NONINVASIVE TEST for pulmonary embolism is both sensitive and specific. Some tests are good for “ruling in” pulmonary embolism (e.g., helical CT) and some tests are good for “ruling out” pulmonary embolism (e.g., D-dimer); others are able to do both but are often nondiagnostic (e.g., ventilation–perfusion lung scanning). For optimal efficiency, choice of the initial diagnostic test should be guided by clinical assessment of the probability of pulmonary embolism and by patient characteristics that may influence test accuracy. This selective approach to testing enables pulmonary embolism to be diagnosed or excluded in a minimum number of steps. However, even with the appropriate use of combinations of noninvasive tests, it is often not possible to definitively diagnose or exclude pulmonary embolism at initial presentation. Most of these patients can be managed safely without treatment or pulmonary angiography by repeating ultrasound testing of the proximal veins after one and 2 weeks to detect evolving deep vein thrombosis. Helical CT and MRI are rapidly improving as diagnostic tests for pulmonary embolism and are expected to become central to its evaluation.     

T-lymphocyte chemotaxis to IL-8 in patients with psoriasis in vitro

OBJECTIVE: The critical role of infiltrating T cells in the pathogenesis of psoriasis is now well established. In order to determine whether circulating T cells from patients with psoriasis were also involved in the disease process, the authors investigated the biological behavior as studied by chemotactic activity of T cells in patients with psoriasis. METHODS: A 48 microchemotaxis chamber was employed to determine T-cell chemotaxis activity. In addition, the expression of T cell activation markers such as HLA-DR and interleukin 2 receptor were analysed with fluorescence activated cell sorting technique and serum IL-8 level was measured with ELISA methods. Forty-five patients with psoriasis (23 patients with severe psoriasis and 22 with mild psoriasis) and 21 patients with atopic dermatitis were investigated. For comparison, T-lymphocytes from 20 healthy controls were tested equally. RESULTS: T-cell chemotactic responses were significantly decreased in patients with severe psoriasis and atopic dermatitis as compared to healthy controls. Increased expression of activation markers such as HLA-DR and interleukin 2 receptor were demonstrated in circulating T cells from psoriatic patients and atopic dermatitis patients in comparison to healthy controls. Serum IL-8 level was significantly increased in patients with psoriasis and atopic dermatitis. CONCLUSIONS: Circulating T cells in patients with severe psoriasis show abnormal in vitro chemotactic response to IL-8. Furthermore, the in vivo activation state of T lymphocytes in these patients and increased level of serum IL-8 seemed to be associated to their decreased in vitro T-cell chemotactic responses.     

Activation and proliferation of T lymphocyte subpopulations in patients with brucellosis

BACKGROUND: T-cell proliferation is a standard method to evaluate cellular immune responses against intracellular infectious agents. The present study was undertaken to look for expression of an early activation marker (CD69) and proliferation using a nonradioactive method to evaluate cellular immune response against a salt-extractable antigen from Brucella melitensis 16M (RCM-BM) in patients suffering from brucellosis. METHODS: Expression of CD69 on membrane of CD4+ and CD8+ T-cells was determined by flow cytometry. Lymphoproliferation was determined by tritiated thymidine and 5-bromo-2'-deoxyuridine (BrdU) incorporation using liquid scintillation counter or flow cytometry, respectively, to evaluate DNA synthesis. RESULTS: Thirty healthy donors and 24 patients suffering from brucellosis were included in this study. In all cases, incubation with mitogen induced expression of CD69 and proliferation of both CD4+ and CD8+ T-cells. In contrast, only brucellosis patients responded with expression of CD69 and proliferation against RCM-BM antigen from Brucella melitensis (p < 0.001). CONCLUSIONS: Methods used in this study were useful to evaluate immune response against specific antigen or polyclonal stimulation. CD4+ and CD8+ T cells from patients became equally activated and proliferated in response to RCM-BM antigen. Our data suggest that both T-cell subpopulations play an important role in immune response against Brucella.     

银屑病的治疗进展

银屑病是一种多基因缺陷的疾病,难治易发,本文概括阐述了一些包括西药、中药、生物学制剂等在内的,较新的治疗银屑病的方法和药物,其中大部分在临床应用或实验中已取得一定疗效。虽然这些方法和药物目前仍无法根治银屑病,但它们为银屑病的治疗研究提供了一些新的方向和思路。     

Selective elimination of host cells harboring replication-competent human immunodeficiency virus reservoirs: a promising therapeutic strategy for HIV cure

Many seminal advances have been made in human immunodeficiency virus (HIV)/AIDS research over the past four decades. Treatment strategies, such as gene therapy and immunotherapy, are yielding promising results to effectively control HIV infection. Despite this, a cure for HIV/AIDS is not envisioned in the near future. A recently published academic study has raised awareness regarding a promising alternative therapeutic option for HIV/AIDS, referred to as “selective elimination of host cells capable of producing HIV” (SECH). Similar to the “shock and kill strategy,” the SECH approach requires the simultaneous administration of drugs targeting key mechanisms in specific cells to efficiently eliminate HIV replication-competent cellular reservoirs. Herein, we comprehensively review the specific mechanisms targeted by the SECH strategy. Briefly, the suggested cocktail of drugs should contain (i) latency reversal agents to promote the latency reversal process in replication-competent reservoir cells, (ii) pro-apoptotic and anti-autophagy drugs to induce death of infected cells through various pathways, and finally (iii) drugs that eliminate new cycles of infection by prevention of HIV attachment to host cells, and by HIV integrase inhibitor drugs. Finally, we discuss three major challenges that are likely to restrict the application of the SECH strategy in HIV/AIDS patients.     

红皮病型银屑病治疗进展

红皮病型银屑病是银屑病中少见的严重类型之一。该病的经典治疗方案疗效有限而不令人满意。一些生物制剂(如依那西普、英夫利西单抗)已成为红皮病型银屑病不可忽视的新兴治疗方案。由于该病的难治性和易复发性等特点,目前提倡建立社会-心理-生物医学模式,采用心理和药物治疗相结合的治疗方式。在此对红皮病型银屑病的治疗进展进行综述。     

组织疗法对寻常型银屑病疗效及免疫学指标的影响

①目的　探讨组织疗法对银屑病病人疗效及免疫学指标的影响。②方法　采用ELISA法和碱性磷酸酶抗碱性磷酸酶 (APAAP)法 ,观察 17例银屑病病人采用组织疗法治疗前及治疗 30d后外周血T淋巴细胞亚群补体及活化片段的变化 ,同时观察了组织疗法的效果。③结果　银屑病病人外周血CD4 ,CD4 /CD8,C3,C4明显降低 ,CD8,可溶性白细胞介素 2受体 (sIL 2R) ,C3d和sC5b 9明显增高 ,与对照组比较差异有显著性 (t =4.78 11.6 2 ,P <0 .0 0 1) ,治疗后各指标变化较治疗前更明显 (t=2 .994.79,P <0 .0 0 1) ;治疗后PASI评分较治疗前明显降低 (t =4.77,P <0 .0 0 1)。④结论　组织疗法可能通过减少补体活化和抑制免疫反应减轻银屑病的症状。     

A modified whole blood partial thromboplastin test for the assessment of heparinization

Current methods of assessment of heparinization are either inconvenient as bedside procedures or lack correlation with the Lee-White whole blood clotting time over the therapeutic range. A new thromboplastin time (CAT time) has been developed to overcome these disadvantages by offering uniform contact activation. The test makes use of a partial thromboplastin activated by celite-adsorbed “contact factor”, thus eliminating the activation phase of the activated partial thromboplastin time. Preliminary experiments suggest that this modification will be helpful in the study of “contact factor” deficiencies.     

Vertical transmission of hepatitis B virus: propositions and future directions

Chronic hepatitis B virus (HBV) infection due to vertical transmission remains a critical concern with regards to eliminating HBV infection. Implementation of hepatitis B vaccine, the foundation to prevent perinatal and horizontal transmission, has reduced the prevalence of HBV by >80%. In countries where the hepatitis B immune globulin (HBIG) is available, such as China and the United States, the administration of HBIG and hepatitis B vaccine to the infants of mothers who are positive for hepatitis B surface antigen has become a standard practice and is effective in preventing vertical transmission. Accumulating evidence on the efficacy and safety of antiviral prophylaxis during pregnancy indicates the probability of attaining the goal of the World Health Organization to eliminate hepatitis by 2030. In this review, we discuss the transmission routes, diagnostic criteria, and preventive strategies for vertical transmission. A preventive program that includes screening before pregnancy, antiviral prophylaxis during pregnancy, and postpartum immunoprophylaxis provides “perfect strategies” to eliminate vertical transmission. However, there is still a notable gap between “perfect strategies” and real-world application, including insufficient coverage of timely birth dose vaccine and the efficacy and necessity of HBIG, especially in mothers who are negative for hepatitis B envelope antigen. In particular, there is a clear need for a comprehensive long-term safety profile of antiviral prophylaxis. Therefore, feasible and cost-effective preventive strategies need to be determined across regions. Access also needs to be scaled up to meet the demands for prophylaxis and prevalence targets.     

Problems for clinical judgement: 2. Obtaining a reliable past medical history

ORDINARY HUMAN REASONING MAY LEAD PATIENTS to provide an unreliable history of past experiences because of errors in comprehension, recall, evaluation and expression. Comprehension of a question may change depending on the definition of periods of time and prior questions. Recall fails through the loss of relevant information, the fabrication of misinformation and distracting cues. Evaluations may be mistaken because of the “halo effect” and a reluctance to change personal beliefs. Expression is influenced by social culture and the environment. These errors can also occur when patients report a history of present illness, but they tend to be more prominent with experiences that are more remote. An awareness of these specific human fallibilities might help clinicians avoid some errors when eliciting a patient's past medical history.     

Effects of secukinumab and adalimumab on serum uric acid level in patients with plaque psoriasis

Background:Psoriasis is a chronic systemic inflammatory disease, and hyperuricemia is a common comorbidity in patients with psoriasis. However, there are limited reports on the relationship between serum uric acid levels and biological treatment efficacy. The purposes of this study were to compare the differences in serum uric acid levels between patients with psoriasis and healthy controls and analyze the risk of hyperuricemia.Methods:A total of 196 patients with psoriasis and 191 age- and sex-matched healthy controls were enrolled in this retrospective cohort study. One hundred and twenty-seven patients with severe psoriasis were treated with biologics. Sixty-eight patients received adalimumab, and 59 patients received secukinumab. Serum uric acid levels were measured at baseline, week 24, and week 48 of treatment.Results:Patients with psoriasis had higher serum uric acid levels than healthy controls (6.4 ± 1.7 mg/dL vs. 5.7 ± 1.5 mg/dL, P < 0.001). Hyperuricemia was found in 33.7% (66/196) of patients with psoriasis, which was significantly higher than that in healthy controls (13.1% [25/191], P < 0.001). Serum uric acid levels and hyperuricemia were not related to the severity of psoriasis (P > 0.05). No significant changes in serum uric acid levels and hyperuricemia were observed following adalimumab treatment (P > 0.05). The serum uric acid level in patients treated with secukinumab was 6.7 ± 1.6 mg/dL at week 24, which was not statistically different from that at baseline (6.6 ± 1.4 mg/dL, P = 0.885). Serum uric acid levels were significantly decreased at week 48 (6.3 ± 1.5 mg/dL vs. 6.6 ± 1.4 mg/dL, P = 0.007) in patients treated with secukinumab. Secukinumab had no significant effect on hyperuricemia either (P > 0.05).Conclusions:The serum uric acid levels and prevalence of hyperuricemia in patients with psoriasis were significantly higher than those in healthy controls. Secukinumab treatment for 48 weeks successfully decreased serum uric acid levels in patients with psoriasis, whereas adalimumab had no significant effect on serum uric acid levels.     

Current concepts in the diagnosis and management of Parkinson's disease

PARKINSON'S DISEASE IS A PROGRESSIVE NEUROLOGICAL disorder characterized by rest tremor, bradykinesia, rigidity and postural instability. The cause is unknown, but growing evidence suggests that it may be due to a combination of environmental and genetic factors. Treatment during the early stage of Parkinson's disease has evolved, and evidence suggests that dopamine agonist monotherapy may prevent the response fluctuations that are associated with disease progression. L-dopa therapy, however, remains the most efficacious treatment. Treatment during the advanced stage focuses on improving control of a number of specific clinical problems. Successful management of motor response fluctuations (e.g., “wearing off,” on–off fluctuations, nighttime deterioration, early morning deterioration and dyskinesias) and of psychiatric problems is often possible with specific treatment strategies. Surgical treatment is an option for a defined patient population.