The Challenge of Treating Early-Stage Rheumatoid Arthritis: The Contribution of Mixed Treatment Comparison to Choosing Appropriate Biologic Agents

Background

Use of biologic drugs is approved for treatment in rheumatoid arthritis (RA), both in established disease and at the early stage of RA (ERA). Identification of ERA and an early therapeutic strategy would lead to greater clinical improvement. Only a few indirect comparisons of the efficacy of different biologic agents in established RA have been performed and, to date, no studies reporting direct comparisons have been performed in ERA.

Objective

The aim of this study was to compare, by use of a mixed treatment comparison (MTC), the efficacy profiles of biologic agents in ERA.

Methods

An extensive literature search was performed to identify results of randomized, controlled trials (RCTs) evaluating biologic agents at licensed doses to treat patients affected by ERA. The primary end points for the analysis were the American College of Rheumatology 20 % improvement (ACR20), ACR50, and ACR70 responses from baseline to various times of follow-up. WinBUGS 1.4 software (MRC Biostatistics Unit, Cambridge, UK) was used to perform the analyses. The MTC results are reported as the relative risk of a response for every single treatment coadministered with methotrexate, versus methotrexate plus placebo, which was used as a comparator in all RCTs.

Results

Ten scientific papers met the study inclusion criteria and were included in the analysis. Data on the use of infliximab, adalimumab, etanercept, abatacept, golimumab, and rituximab were included. No studies reported on the use of certolizumab pegol or tocilizumab in ERA. All biologic agents coadministered with methotrexate proved to be more efficacious than methotrexate plus placebo in inducing ACR20, ACR50, and ACR70 responses. The biologic agent characterized by the highest probability of inducing an ACR70 response was adalimumab (33.28 %). Etanercept was the biologic agent with the highest probability of inducing ACR20 and ACR50 responses, in comparison with all other biologic agents, with probability rates of 62.95 and 37.1 %, respectively.

Conclusion

In our analysis, adalimumab proved to be the biologic agent with the highest probability of inducing an ACR70 response in patients affected by ERA, while etanercept was the biologic agent with the highest probability of inducing ACR50 and ACR20 responses.

     

The Cost Effectiveness of Biologic Therapy for the Treatment of Chronic Plaque Psoriasis in Real Practice Settings in Italy

Background and Objectives

Biologic therapies are considered to be cost effective by leading Health Technology Assessment (HTA) agencies and, therefore, eligible for reimbursement by public health services. However, biologic therapies entail sizable incremental costs and, besides, have a considerable financial impact that in Italy amounts to 13.7 % of the national health service’s pharmaceutical expenditure. In the reimbursability decision process, an important role is played by both the drug efficacy data observed in pre-licensing RCTs and the economic modelling assumptions, as they give evidence on cost effectiveness. The administration of therapies in real practice settings is likely to produce a significant deviation from the results predicted by the models, theoretically outweighing the assumption on which the decision process is founded. This is a matter of concern for public health services and, consequently, an interesting topic to investigate.

Methods

To overcome the lack of knowledge concerning the actual cost effectiveness of biologic therapies for the treatment of plaque psoriasis in the clinical practice setting in Italy, an observational study was conducted in 12 specialist centres on patients switching to biologic therapy within a 6-month enrolment window.

Results

The study confirms in clinical practice the efficacy of the switch to biologic therapies, analysed using a number of clinical [Psoriasis Area and Severity Index (PASI), pain visual analogue scale (VAS) and itching VAS] and quality-of-life parameters. A general health-related quality of life (HR-QOL) improvement, with a 0.23 quality-adjusted life-year (QALY) mean gain per patient, has been reported in the 6-month observation period. The direct medical costs to treat plaque psoriasis with biologic therapies amount to €15,073.7 per year (prior to their enrolment, the same patients cost €2,166.2 on an annual basis). After the switch to biologic agents, the cost per QALY during the first year of treatment amounts to €28,656.3.

Conclusion

At least in the short-term, the clinical practice of the specialised Italian centres taking part in the study confirms that switching patients to a biologic drug produces an incremental cost-effectiveness ratio comparable with the values predicted by the HTA bodies.     

Interpretation of the CA125 kinetics during first line chemotherapy of the ovarian cancer: methodological aspects and characteristic profiles

Mathematical analysis of CA125 kinetics during first line chemotherapy allows calculation of various biologic parameters which are powerful indicators of the therapeutic efficiency. The purpose of this study is to present an original method of interpretation of CA125 kinetics based on both CA125 profile and its half-life value. The first part of this study reviews the practical modalities of CA125 kinetics analysis, the methods of calculation of the biologic parameters as well as the guidelines of interpretation. The second part of this work is dedicated to the presentation of CA125 profile characteristics in responders to chemotherapy, partially or totally nonresponders to chemotherapy, tumoral growth under treatment and tumor lysis syndrome.     

Development of the human umbilical vein scaffold for cardiovascular tissue engineering applications

Biologic function and the mechanical performance of vascular grafting materials are important predictors of graft patency. As such, "functional" materials that improve biologic integration and function have become increasingly sought after. An important alternative to synthetic materials is the use of biomaterials derived from ex vivo tissues that retain significant biologic and mechanical function. Unfortunately, inconsistent mechanical properties that result from tedious, time consuming, manual dissection methods have reduced the potential usefulness of many of these materials. We describe the preparation of the human umbilical vein (HUV) for use as an acellular, three-dimensional, vascular scaffold using a novel, automated dissection methodology. The goal of this investigation was to determine the effectiveness of the autodissection methodology to yield an ex vivo biomaterial with improved uniformity and reduced variance. Mechanical properties, including burst pressure, compliance, uniaxial tension testing, and suture holding capacity, were assessed to determine the suitability of the HUV scaffold for vascular tissue engineering applications. The automated methodology results in a tubular scaffold with significantly reduced sample to sample variation, requiring significantly less time to excise the vein from the umbilical cord than manual dissection methods. Short-term analysis of the interactions between primary human vascular smooth muscle cells and fibroblasts HUV scaffold have shown an excellent potential for cellular integration by native cellular remodeling processes. Our work has shown that the HUV scaffold is mechanically sound, uniform, and maintains its biphasic stress-strain relationship throughout tissue processing. By maintaining the mechanical properties of the native blood vessels, in concert with promising cellular interactions, the HUV scaffold may lead to improved grafts for vascular reconstructive surgeries.     

蛋白质统计偶联分析平台的构建

蛋白质中氨基酸位点之间的偶联对其功能和结构非常重要，如果采用生物信息学的方法进行氨基酸位点的偶联分析，可以克服传统生物学实验方法难以从宏观角度进行系统的功能分析的局限性。本文详细介绍了统计偶联分析平台的构建。基于该平台．可以分析蛋白质中各氨綦酸位点之间的偶联性。     

Evolution of evaluation criteria in the College of American Pathologists Surveys

This review of the evolution of evaluation criteria in the College of American Pathologists Survey and of theoretical grounds proposed for evaluation criteria explores the complex nature of the evaluation process. Survey professionals balance multiple variables to seek relevant and meaningful evaluations. These include the state of the art, the reliability of target values, the nature of available control materials, the perceived medical "nonusefulness" of the extremes of performance (good or poor), this extent of laboratory services provided, and the availability of scientific data and theory by which clinically relevant criteria of medical usefulness may be established. The evaluation process has consistently sought peer concensus, to stimulate improvement in state of the art, to increase medical usefulness, and to monitor the state of the art. Recent factors that are likely to promote change from peer group evaluation to fixed criteria evaluation are the high degree of proficiency in the state of the art for many analytes, accurate target values, increased knowledge of biologic variation, and the availability of statistical modeling techniques simulating biologic and diagnostic processes as well as analytic processes.     

Research Methodology: Endocrinologic Measurements in Exercise Science and Sports Medicine

Objective:

To provide background information on methodologic factors that influence and add variance to endocrine outcome measurements. Our intent is to aid and improve the quality of exercise science and sports medicine research endeavors of investigators inexperienced in endocrinology.

Background:

Numerous methodologic factors influence human endocrine (hormonal) measurements and, consequently, can dramatically compromise the accuracy and validity of exercise and sports medicine research. These factors can be categorized into those that are biologic and those that are procedural-analytic in nature.

Recommendations:

Researchers should design their studies to monitor, control, and adjust for the biologic and procedural-analytic factors discussed within this paper. By doing so, they will find less variance in their hormonal outcomes and thereby will increase the validity of their physiologic data. These actions can assist the researcher in the interpretation and understanding of endocrine data and, in turn, make their research more scientifically sound.     

Cigarette smoking and the pathogenesis of systemic lupus erythematosus

Introduction: Systemic lupus erythematosus (SLE) is a multi-system inflammatory autoimmune disease of incompletely understood etiology. It is thought that environmental exposures ‘trigger’ or accelerate the disease in genetically-predisposed individuals.

Areas covered: Substantial epidemiological evidence exists to support the association between cigarette smoking and the risk of incident SLE. Recent evidence points to current smoking as the specific risk factor, with decreasing risk 5 years after smoking cessation, and the greatest risk for disease characterized by the presence of SLE-specific autoantibodies. Research has begun to search for possible explanations for the temporal nature of the relationship between current smoking and autoantibody positive-SLE. Here we review potential biologic mechanisms linking smoking and SLE risk, including effects upon T and B cells, inflammatory cytokines, oxidative stress, and the formation of short-lived DNA adducts.

Expert commentary: The directions for future research in this field include studies of gene-environment interactions, epigenetics, metabolomics and putative biologic mechanisms.     

Joint anatomy, design, and arthroses: insights of the Utah paradigm.

This model of joint design argues 1) that excessive fatigue damage (MDx) in articular cartilage collagen can be the "final cause" of an arthrosis; 2) that known responses of a growing joint's anatomy and geometry, and modeling and maintenance activities, to mechanical loads minimize that cause and thus arthroses; 3) and many biomechanical, biochemical, cell-biologic, genetic and traumatic "first causes" of arthroses could lead to that final cause. The model depends partly on the following facts (marked by a single asterisk) and ideas (marked by a double asterisk). A) During growth a joint's total loads can increase over 20 times without causing an arthrosis, yet in adults an equal loading increase would cause one. B) Fatigue damage (MDx) occurs in joint tissues, larger strains increase it, and minimizing strains reduces it. C) Bone can repair amounts of MDx below an "MDx threshold," but larger amounts can escape repair and accumulate. The model assumes articular cartilage has similar features. D) Bone modeling makes bones strong enough to keep their strains below bone's MDx threshold and minimize MDx. Chondral modeling shapes and sizes joints during growth; that would keep articular cartilage strains below the chondral MDx threshold to minimize chondral MDx and arthroses. Normal chondral modeling nearly stops in adults, which might explain point A above. E) Throughout life maintenance activities preserve optimal physical, chemical and biologic properties of a joint's tissues. To past emphases on the biochemical, genetic, cellular and molecular biologic features of adult joint physiology, this model adds organ-level, tissue-level and vital-biomechanical features of growing joints that invite study and understanding at lower levels of biologic organization.     

New biologics for allergic diseases

Introduction: Allergic conditions such as asthma and atopic dermatitis have a high prevalence but represent a heterogeneous group of diseases despite similar clinical presentation and underlying pathophysiology. A better understanding of the phenotypes and endotypes of these diseases has driven rapid development of biologic medications targeting many steps of the inflammatory pathways.

Areas covered: There are 2 major inflammatory pathways that drive allergic diseases: Type-2 (Th-2) inflammation and non-type 2 inflammation. All of the biologic medications currently approved for use, and most of the biologic medications under development for allergic diseases have focused on the Th-2 inflammatory pathway. Biologic targets along this pathway include Anti-Immunoglobulin E (IgE), Anti-Interleukin 5 (IL-5), Anti-IL 4, and Anti-IL 13. Although the most study has been done in the realm of severe asthma, biologic targets for other allergic diseases including atopic dermatitis, chronic rhinosinusitis with nasal polyposis, chronic idiopathic urticaria, eosinophilic esophagitis, and eosinophilic granulomatosis with polyangiitis are also discussed.

Expert commentary: Novel biologic therapies have emerged over the last several years that have revolutionized the management of patients with refractory allergic disease.     

Mathematical models from laws of growth to tools for biologic analysis: fifty years of "Growth"

Mathematical models of size and shape have played a prominent role in the first half century of Growth. In honor of the fiftieth anniversary of the journal, this paper reviews the development of these models. An historical perspective is taken with a focus on the changing context in which mathematical models have been studied. Early models were thought to represent principles or laws of growth. Today, models are viewed as tools for biologic analysis. We trace this contextual shift through specific models developed and used in Growth.     

Evaluation of Process Efficiency and Bioequivalence of Biosimilar Recombinant Human Chorionic Gonadotropin (rhCG)

Background

Human chorionic gonadotropin (hCG) is a therapeutic protein used for ovulation induction in women with infertility. Dong-A Pharm. Co. has developed recombinant hCG (rhCG) [product code DA-3803] produced in Chinese hamster ovary cells and evaluated its biologic properties, such as biologic potency, efficacy, and pharmacokinetic profile, compared with a reference product, Ovidrel®.

Objective

The purpose of this study was to evaluate the efficiency of the purification process of Dong-A rhCG (DA-3803) and its bioequivalence from a biosimilar perspective.

Methods

The efficiency of the purification process was estimated through scale-down clearance studies for viruses, endotoxins, host cell DNAs (HCDs) and host cell proteins (HCPs). To confirm bioequivalence, the in vivo/in vitro biologic potency, ovulation induction rate, and pharmacokinetic profile of DA-3803 were compared with those of Ovidrel®.

Results

In the clearance studies, the lowest log reduction value (LRV) for model viruses was 8.43. LRVs for endotoxins, HCDs, and HCPs were greater than 5.27, 16.36, and 3.37, respectively. DA-3803 showed equivalent potency with Ovidrel®, and similarity between DA-3803 and Ovidrel® was observed in an efficacy evaluation that measured ovulation induction. The bioequivalence was also confirmed in a rat pharmacokinetic study, which compared pharmacokinetic parameters such as maximum serum concentration, area under the concentration-time curve, time to reach maximum serum concentration, and half-life. In a comparison of different isoform groups of DA-3803, it was shown that the potency and pharmacokinetic profile depend on the sialic acid content.

Conclusion

The purification process of DA-3803 was effective in removing the major process impurities, and DA-3803 showed similar biologic properties to the reference drug, Ovidrel®.     

Glassy cell carcinoma of the endometrium: a case report and review of the literature

Glassy cell carcinomas are composed of malignant cells showing a "ground glass" cytoplasm, distinct cell membranes, and large nuclei with prominent nucleoli. To our knowledge, only 12 cases of glassy cell endometrial carcinomas (EGCC) have been reported until now. A 63-year-old patient complaining of irregular vaginal bleeding underwent hysteroscopy-guided biopsy revealing a well-differentiated endometrial endometrioid adenocarcinoma. The patient underwent left salpingo-oophorectomy, total abdominal hysterectomy, and pelvic lymphadenectomy. The final diagnosis was FIGO stage IB poorly differentiated endometrial adenosquamous carcinoma with > 90% of glassy tumor cells. The patient is alive, with no evidence of disease for 69 months after diagnosis. We describe an additional case of EGCC and review the data of the literature, emphasizing the need to strictly define the criteria for the diagnosis and the potential usefulness of assessing biologic parameters for the prognostic characterization of this rare entity.     

Biocompatibility: meeting a key functional requirement of next-generation medical devices

The array of polymeric, biologic, metallic, and ceramic biomaterials will be reviewed with respect to their biocompatibility, which has traditionally been viewed as a requirement to develop a safe medical device. With the emergence of combination products, a paradigm shift is occurring that now requires biocompatibility to be designed into the device. In fact, next-generation medical devices will require enhanced biocompatibility by using, for example, pharmacological agents, bioactive coatings, nano-textures, or hybrid systems containing cells that control biologic interactions to have desirable biologic outcomes. The concept of biocompatibility is moving from a "do no harm" mission (i.e., nontoxic, nonantigenic, nonmutagenic, etc.) to one of doing "good," that is, encouraging positive healing responses. These new devices will promote the formation of normal healthy tissue as well as the integration of the device into adjacent tissue. In some contexts, biocompatibility can become a disruptive technology that can change therapeutic paradigms (e.g., drug-coated stents). New database tools to access biocompatibility data of the materials of construction in existing medical devices will facilitate the use of existing and new biomaterials for new medical device designs.     

Vedolizumab Is Safe and Efficacious for the Treatment of Pediatric-Onset Inflammatory Bowel Disease Patients Who Fail a Primary Biologic Agent

BackgroundVedolizumab (VDZ) is currently licensed for use in adults for the treatment of inflammatory bowel disease (IBD). We aimed to investigate the clinical course of pediatric-onset IBD following treatment with VDZ as more than a secondary biologic agent. We also evaluated factors associated with secondary loss of response (LOR) and durability of VDZ treatment.MethodsPediatric-onset IBD patients diagnosed at an age younger than 18 years who had received VDZ as more than a secondary biologic agent were included in this retrospective observational study conducted at the Department of Pediatrics of two centers in Korea. Comparative analysis was conducted between groups divided according to the development of secondary LOR during VDZ treatment.ResultsA total of 24 patients comprising 10 patients with Crohn’s disease and 14 with ulcerative colitis were included. Of these, 19 were male and 5 were female. The mean age at diagnosis was 14.6 ± 2.5 years. The mean age at initiation of VDZ was 20.5 ± 2.8 years. Nine patients (37.5%) had received two or more biologic agents before starting VDZ. During a median of 0.9 years follow-up from VDZ initiation, 9 patients (37.5%) experienced LOR requiring interval shortening and 4 patients (16.7%) were changed to a different biologic agent. According to multivariate Cox proportional hazard regression analysis, administration of two or more biologic agents before VDZ treatment was the only factor positively associated with LOR (hazard ratio [HR], 5.6; 95% confidence interval [CI], 1.026–30.56; P = 0.047), while LOR was the only factor negatively associated with VDZ durability (HR, 0.003; 95% CI, 0.00–0.08; P = 0.010). No adverse events were observed during treatment with VDZ.ConclusionVDZ is safe and efficacious for the treatment of pediatric-onset IBD patients failing a primary biologic agent. The durability of VDZ may be enhanced by introducing VDZ earlier in the disease course. Further prospective studies in children are required in the future to validate these findings.     

Sodium lactate infusions and panic attacks: a review and critique

Response to sodium lactate infusions has been proposed as an experimental model and a biologic marker for panic attacks. Several authors have claimed that patients suffering from panic attacks, but not normal controls, "panic" in response to lactate. A careful review of methods and results of 13 studies, however, reveals serious methodologic problems, lack of specificity and sensitivity, and a failure to consider cognitive variables. When baseline differences are ruled out, the responses of patients and controls may not differ. So far, response to lactate cannot be interpreted as a model and marker for panic attacks and does not provide evidence for their underlying biologic distinctness from other types of anxiety. Known biologic mechanisms do not sufficiently explain the effects of lactate. Instead, an interaction of peripheral physiologic changes, past experience, environmental cues, and their appraisal as threatening or dangerous seems to be a more appropriate model.     

Efficacy and Safety of Biologic Therapies for Systemic Lupus Erythematosus Treatment: Systematic Review and Meta-Analysis

Objectives

The objectives of this study were to evaluate the efficacy, safety, and tolerability of biologic drugs compared with placebo for systemic lupus erythematosus (SLE) treatment.

Methods

A systematic review evaluating the efficacy and safety of biologic therapies compared with placebo in adult SLE patients treatment was performed. Data from studies performed before September 2013 were collected from several databases (MEDLINE, Cochrane Library, SCIELO, Scopus, and International Pharmaceutical Abstracts). Study eligibility criteria included randomized, double-blind, placebo-controlled trials; regarding treatment with biologic agents in SLE adult patients; and published in English, German, Portuguese, and Spanish. Extracted data were statistically analyzed in a meta-analysis using the Review Manager (RevMan) 5.1 software. Efficacy outcomes included the SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index) score, the SRI (Systemic Lupus Erythematosus Responder Index), normalization of low C3 (<90 mg/dL), anti-double-stranded DNA positive to negative, and no new BILAG (British Isles Lupus Assessment Group index) 1A or 2B flares. Data on safety profile included adverse events, serious and severe adverse events, death, malignancy, infections, and infusion reactions. We also evaluated withdrawals from treatment due to lack of efficacy or adverse events.

Results

Thirteen randomized placebo-controlled trials met the criteria for data extraction for systematic review. A meta-analysis regarding the efficacy and safety of belimumab compared with placebo involving four of these trials was undertaken and the remainder contributed to a meta-analysis of the safety of biologic agents. In addition, two trials allowed the performance of a meta-analysis regarding the efficacy and safety of rituximab compared with placebo. Belimumab was more effective than placebo in most evaluated outcomes. No significant differences in the safety and tolerability data were observed between the belimumab and placebo groups. No differences were observed between the rituximab and placebo groups for the efficacy outcomes or safety parameters. Extracted data from the 13 studies were pooled, allowing assessment of the safety of biologic drugs. The meta-analysis revealed a satisfactory safety profile of these agents when used for SLE treatment, as there were no significant differences between the two evaluated groups (biologic agents and placebo) for all outcomes analyzed.

Conclusion

Belimumab exhibited a satisfactory profile regarding efficacy, safety, and tolerability. Rituximab showed no superiority over placebo in terms of efficacy, despite its suitable safety profile. Biologic agents exhibited a good safety profile for SLE treatment, indicating that these agents are promising therapies and should be further investigated.     

Papillary serous carcinoma of the retroperitoneum

We describe a retroperitoneal neoplasm in an 11-year-old girl which had a light microscopic appearance identical to that of papillary serous carcinoma of the ovary. There was no evidence of ovarian involvement. Immunohistochemical staining for amylase was positive within the cytoplasm of tumor cells. Since amylase is a marker for serous ovarian tumors, this finding supports the belief that "ovarian-type" neoplasms that occur at ectopic locations are essentially identical to their ovarian counterparts. We believe they originate from metaplasia of mesothelium. Our findings support the concept that these tumors should exhibit a biologic behavior and therapeutic response which are similar to those of an ovarian tumor of the same grade and comparable stage. The demonstration of intracytoplasmic amylase also may prove useful in differentiating peritoneal serous tumors from non-metaplastic mesothelial proliferations. We are unaware of a prior report of an extra-ovarian serous carcinoma in a child.