Biological Treatment Options Research Articles

Natalizumab in the treatment of Crohn’s disease patients

ABSTRACTIntroduction: Amongst the available therapies for moderate to severe Crohn’s disease (CD) patients who are refractory to conventional therapy, anti-TNF blockers are the most effective biological treatment option. However, many patients experience a primary or secondary non-response to anti-TNF therapy, creating the need for alternative biological drugs that target different mechanisms of action and inflammatory pathways. Natalizumab, the first non-anti-TNF biological drug to be approved for treatment of CD patients, is a recombinant humanized antibody that targets the α4-subunit of both α4β1 and α4β7 integrins, thus preventing activated leukocyte homing to the intestinal mucosa.Areas covered: This article summarizes the pathophysiological background and the efficacy and safety data of natalizumab, as well as the regulatory issues surrounding it.Expert opinion: Natalizumab represents an effective therapy for refractory CD patients. However, the rare but serious event of progressive multifocal leukoencephalopathy occurrence has compromised its widespread use. The subsequent advent of more specific anti-integrin drugs (i.e. vedolizumab) that carry a more favorable safety profile further reduces the clinical indications for natalizumab. The regulatory process for natalizumab distribution and monitoring in the US may provide a forum for discussion on how to optimally manage use of drugs that offer clinical benefits to patients, while minimizing associated risks.

Treatment Changes in Patients With Moderate to Severe Psoriasis: A Retrospective Chart Review.

Psoriasis treatment involves topical medications, oral medications, phototherapy, and/or biologics. The treatments used depend on a myriad of factors that change over time. To characterise the frequency of and reasons for treatment changes in patients with moderate to severe psoriasis. A chart review examined treatment changes at 902 visits by 116 patients seen between January 1, 2010, and June 30, 2015, for moderate to severe psoriasis and the physicians' justifications for those changes. 'Treatment change' was defined as switching between, adding, or removing medication classes or switching within the oral or biologic class. There were 221 visits with treatment changes identified, and a change occurred every 4.1 visits. On average, there were 1.2 treatment changes per year. Patients treated for at least 1 year averaged 1 treatment change every 16 months. The most common type of change was from one biologic to another biologic (24.9%), followed by adding a nonbiologic to a biologic (18.6%). The most common reason for switching was poor control or flare of psoriasis. Affordability was a more common problem for biologics than for nonbiologic treatments. Biologic treatment options provide a major improvement over older systemic treatments, but patients still undergo frequent treatment changes to help control their disease.

Biologic Treatment Options for Retinal Neovascularization in Behçet’s Disease

ABSTRACTPurpose: Relapsing ocular inflammation occurs in about 70% of patients with Behçet’s disease (BD) and can lead to permanent loss of vision. Neovascularization of the optic disc (NVD) or elsewhere in the retina (NVE) is a relatively uncommon but severe complication that lacks standardized treatment.Methods: We report on the therapeutic use of anti-TNF monoclonal antibodies for BD-associated NVD and NVE in one pediatric patient (subcutaneous adalimumab) and one young man (intravenous infliximab). Also, we review the previously published experience on biologic therapeutic options, namely anti-TNF agents and interferon-alpha in a total of three and eight patients, respectively.Results: A fast-onset therapeutic effect was observed in both patients leading to complete regression of neovascularizations.Conclusions: Both options may lead to regression of neovascularization, thus preventing loss of vision, but comparative studies need to determine the optimal treatment for this sight-threatening complication of BD.

Current status of biological treatment options in Autism Spectrum Disorder.

Autism Spectrum Disorders (ASDs) are characterised by deficits in social communication and restricted and repetitive behaviours. With an onset in early childhood, ASDs are thought to be heterogeneous, both genetically and clinically. This has led to the notion that "autism" is "autisms", however, there has been limited progress in understanding the different subgroups and the unique pathogenesis that would then allow targeted intervention. Although existing treatments are mainly symptom focussed, research is beginning to unravel the underlying genetic and molecular pathways, structural and functional neuronal circuitry involvement and the associated neurochemicals. This paper will review selected biological models with regard to pharmacological targets while also covering some of the non-pharmacological treatments such as neuro-stimulation.

Non-vascularised fibula grafts for reconstruction of segmental and hemicortical bone defects following meta- /diaphyseal tumour resection at the extremities

BackgroundThe reconstruction of meta−/diaphyseal bone defects following bone tumour resection is challenging, and biological treatment options should be applied whenever possible, especially in benign lesions and early stage sarcomas. We aimed to evaluate the results of segmental (SR) and hemicortical reconstructions (HR) at the extremities using non-vascularised fibula grafts.MethodsWe retrospectively enrolled 36 patients who were treated with non-vascularised fibula reconstructions (15 SR, 21 HR) after bone tumour resection (15 malignant, 21 benign). All cases were evaluated regarding consolidation, hypertrophy at the graft-host junctions, and complications; moreover, the functional and oncological results were assessed. The mean follow-up was 8.3 years (2.1–26.6 years).ResultsPrimary union was achieved in 94% (SR 87%, HR 100%) of patients, and 85% (SR 81%, HR 88%) showed hypertrophy at the graft-host junction. The overall complication rate was 36% with 4 patients (11%) developing local recurrence. There was a significant correlation between the development of mechanical complications (fracture, delayed-/non-union) and a defect size of ≥12 cm (p = 0.013), segmental defects (p = 0.013) and additional required treatment (p = 0.008). The functional outcome was highly satisfactory (mean MSTS score 86%).ConclusionsDue to encouraging results and advantages (such as their remodelling capacity at the donor site), non-vascularised fibula reconstructions should be considered a valuable alternative treatment option for patients with hemicortical defects or segmental reconstructions of less than 12 cm in which no additional neo-/adjuvant treatment is necessary.

Recent Advances in Small Molecule and Biological Therapeutic Approaches in the Treatment of Psoriasis.

New treatments continue to be developed for psoriasis. In this review, we aim to summarize the results of the major published studies on biologic and small molecule drugs for the treatment of psoriasis. We emphasize the safety, efficacy, and tolerability of these treatment options. A review of the MEDLINE database was conducted for each class of medication. Randomized controlled trials were identified for each medication; data on efficacy, safety, and tolerability were reviewed. Biologic and small molecule treatment options are more effective than placebo, although there were few head-to-head trials to assess relative efficacy between biologics and small molecule treatments. These drugs offer favorable safety profiles with only rare serious adverse events reported. Biologic and small molecule drugs offer diverse therapeutic regimens, particularly in patients with recalcitrant disease.

Effect of organic carbon enrichment on the treatment efficiency of primary settled wastewater by Chlorella vulgaris

This work evaluated the performance of a microalgae treatment process for settled municipal wastewater in a laboratory setting under static culturing conditions, as an alternative to traditional, energy intensive secondary and tertiary wastewater treatment systems. Primary tank settled wastewater (PSW) was first enriched with small quantities of glucose (<300mgL−1) as an organic carbon source to facilitate the bioremediation by the mixotrophic microalga Chlorella vulgaris. Characterisation of the wastewater revealed significant reductions in NH3-N (from 28.9 to 0.1mgL−1) and PO4-P (from 3.2 to 0.1mgL−1) in just 2days. Additionally, the exogenous glucose appeared completely removed from the wastewater after the first day. These achieved levels of treatment in respect of both the NH3-N and PO4-P were much higher than those recorded without C. vulgaris treatment with or without glucose enrichment. This would mean that the microalgae were chiefly responsible for removing the inorganic nitrogen and phosphorus, while the naturally occurring heterotrophic organisms had consumed the carbonaceous matter. The reliability of this process was evaluated across a further three independent batches of PSW with varying compositions of these inorganics and chemical oxygen demand using alternative organic (glycerol) and inorganic (CO2) carbon sources. The efficiency of the microalgae treatment process at reducing NH3-N and PO4-P was consistent in PSW enriched with organic carbon, resulting in >90% reduction of the inorganic compounds in each batch. The results demonstrate that microalgal culturing processes to treat PSW in bioreactors without aeration are a key area to develop as an alternative biological treatment option.

Spotlight on dupilumab in the treatment of atopic dermatitis: design, development, and potential place in therapy.

Atopic dermatitis (AD) is among the most common inflammatory skin diseases in children and adults in industrialized countries. Up to one-third of adults (probably a smaller proportion in childhood) suffer from moderate-to-severe AD, whose recommended treatment is usually based on systemic therapies. The currently available therapeutics are limited, and AD management becomes challenging in most cases. Over the last few years, new advances in the understanding of AD pathogenic mechanisms and inflammatory pathways have led to the identification of specific therapeutic targets and new molecules have been tested. Dupilumab is a fully human monoclonal antibody directed against the IL-4 receptor α subunit that is able to block the signaling of both IL-4 and IL-13 and achieve rapid and significant improvements in adults with moderate-to-severe AD. Dupilumab is ready to inaugurate a long and promising biological target treatment option for Th2 cell-mediated atopic immune response that characterizes AD.

The therapeutic potential of the phytocannabinoid cannabidiol for Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder, characterized by progressive loss of cognition. Over 35 million individuals currently have AD worldwide. Unfortunately, current therapies are limited to very modest symptomatic relief. The brains of AD patients are characterized by the deposition of amyloid-β and hyperphosphorylated forms of tau protein. AD brains also show neurodegeneration and high levels of oxidative stress and inflammation. The phytocannabinoid cannabidiol (CBD) possesses neuroprotective, antioxidant and anti-inflammatory properties and reduces amyloid-β production and tau hyperphosphorylation in vitro. CBD has also been shown to be effective in vivo making the phytocannabinoid an interesting candidate for novel therapeutic interventions in AD, especially as it lacks psychoactive or cognition-impairing properties. CBD treatment would be in line with preventative, multimodal drug strategies targeting a combination of pathological symptoms, which might be ideal for AD therapy. Thus, this review will present a brief introduction to AD biology and current treatment options before outlining comprehensively CBD biology and pharmacology, followed by in-vitro and in-vivo evidence for the therapeutic potential of CBD. We will also discuss the role of the endocannabinioid system in AD before commenting on the potential future of CBD for AD therapy (including safety aspects).

Insertional Achilles Tendon Injuries in the Athlete

Insertional Achilles tendon injuries are common among running and jumping athletes of all age ranges. Injuries to this site are often due to an overuse mechanism and are especially common in individuals who continue to participate in sports into middle age and beyond. They present with a broad spectrum of severity and chronicity from mild acute tendonitis to partial or complete tendon rupture. The causes of injuries and conditions of the distal Achilles tendon are often multifactorial and may include biomechanical factors, training errors, and medications that predispose the tendon to degeneration or tear. It is this variability of cause, severity, and chronicity coupled with many athletesʼ unwillingness to alter or curtail the inciting activity that makes determination of an ideal treatment option a challenge. Nonsurgical management, which may consist of oral nonsteroidal anti-inflammatory medications, physical therapy, shoewear modification, and training alterations, has been the mainstay of treatment for patients with tendon inflammation and early degeneration. However, when injuries become more chronic and debilitating or when complete rupture occurs at the calcaneal insertion, debridement to remove degenerative tissue and repair using a calcaneal anchor-based suture bridge are required. Augmentation of the repair with transfer of the flexor hallucis longus tendon may be required if more than 50% of the tendon has been damaged or if extensive debridement leads to inadequate tendon length. Recently, biological treatment options as well as less invasive procedures have become available for stimulating tendon healing.

Biologic Approaches for the Treatment of Partial Tears of the Anterior Cruciate Ligament: A Current Concepts Review.

Background:Anterior cruciate ligament reconstruction (ACLR) has been established as the gold standard for treatment of complete ruptures of the anterior cruciate ligament (ACL) in active, symptomatic individuals. In contrast, treatment of partial tears of the ACL remains controversial. Biologically augmented ACL-repair techniques are expanding in an attempt to regenerate and improve healing and outcomes of both the native ACL and the reconstructed graft tissue.Purpose:To review the biologic treatment options for partial tears of the ACL.Study Design:Review.Methods:A literature review was performed that included searches of PubMed, Medline, and Cochrane databases using the following keywords: partial tear of the ACL, ACL repair, bone marrow concentrate, growth factors/healing enhancement, platelet-rich plasma (PRP), stem cell therapy.Results:The use of novel biologic ACL repair techniques, including growth factors, PRP, stem cells, and bioscaffolds, have been reported to result in promising preclinical and short-term clinical outcomes.Conclusion:The potential benefits of these biological augmentation approaches for partial ACL tears are improved healing, better proprioception, and a faster return to sport and activities of daily living when compared with standard reconstruction procedures. However, long-term studies with larger cohorts of patients and with technique validation are necessary to assess the real effect of these approaches.

Healing response of rat pulp treated with an injectable keratin hydrogel.

BackgroundKeratin has shown promising outcomes as a biomaterial due to its inherent bioactivity, biocompatibility and regenerative effects. The effect of keratin on repair and regeneration of dental tissues has never been studied before. Current therapies to treat pulp tissues involve its replacement with inert, synthetic materials that do not have a proper biological function, leading to failure and tooth loss. This study aimed to develop a biocompatible keratin hydrogel (KH) suitable for pulp therapies.MethodsKeratins extracted from sheep wool were isolated, quantified and reconstituted to form KH. Different concentrations of keratin gel suitable for dental application were characterized by rheological analysis. The optimized gel based on flow characteristics was studied further for microstructure including porosity, percentage swelling ratio and contact angle measurements, using analytical tools such as scanning electron microscopy (SEM), micro-computed tomography and goniometer. To assess both biocompatibility and pulpal response, KH was implanted into rat upper molar teeth following partial pulpotomy. After 28 days, the tissue sections were analyzed by histological and immunohistochemical methods to identify dentin matrix protein 1 (DMP-1) formation and compared with control (Ca(OH)2-treated) teeth.ResultsThe results of the study demonstrated a viscous and injectable, porous, dimensionally stable, hydrophilic and biocompatible gel that allowed pulp healing to occur by a reparative response, with widespread DMP-1 expression.ConclusionsThe findings of this study indicate that keratins can be developed as a biomaterial source for alternate biological treatment options for pulp therapies.

Platelet-Rich Plasma: Formulations, Preparations, Constituents, and Their Effects

Platelet-rich plasma (PRP) is a biological treatment option that is increasingly used in sports medicine applications. Outcomes from treating tendon, ligament, muscle, and cartilage injuries with PRP have been variable across many studies, and these differences may be because of the variations in formulations and preparation of PRP. The purpose of this article is to describe the factors that determine the effects of PRP.

Associations between Two Seemingly “Contradictory” Diseases: Hereditary Hemorrhagic Telangiectasia and Pulmonary Hypertension

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant inherited disorder characterized by mucocutaneous telangiectases and arteriovenous malformations (AVMs) predominantly in the liver, lung and brain. Pulmonary hypertension (PH) is a devastating disease of the pulmonary vasculature, which could lead to an increase in pulmonary vascular resistance and eventually cause right heart failure or death. Early epidemiological studies suggested that PH is a rare complication of HHT, however, accumulated evidences have showed that the prevalence of PH in HHT is evaluated up to 74 %. Post-capillary PH is the most common type of PH in HHT, which most often results from hepatic arteriovenous malformations due to a high cardiac output state. Another kind of HHT is less frequent and associated with genetic mutations in ENG or ACVRL1, those patients are more likely to develope into precapillary pulmonary arterial hypertension. PH is associated with a higher mortality rate and worse prognosis, which largely affects the overall life-expectation among those HHT patients. However, ENG and ACVRL1 mutations can only explain the onset of HHT and arteriovenous malformations, revealing the precise mechanisms of the co-occurrence of both diseases deserve further scientific attentions. Our review aims to illustrate the epidemiology, clinical features, molecular biological basis, pathological characteristics and potential treatment options for these two close associated but seemingly “contradictory” diseases.

Review of Sjögren Syndrome: A Comparison of Two Topical Biologic Treatment Options

Review of Sjögren Syndrome: A Comparison of Two Topical Biologic Treatment Options

Denitrifying bioreactor clogging potential during wastewater treatment

Chemoheterotrophic denitrification technologies using woodchips as a solid carbon source (i.e., woodchip bioreactors) have been widely trialed for treatment of diffuse-source agricultural nitrogen pollution. There is growing interest in the use of this simple, relatively low-cost biological wastewater treatment option in waters with relatively higher total suspended solids (TSS) and chemical oxygen demand (COD) such as aquaculture wastewater. This work: (1) evaluated hydraulic retention time (HRT) impacts on COD/TSS removal, and (2) assessed the potential for woodchip clogging under this wastewater chemistry. Four pilot-scale woodchip denitrification bioreactors operated for 267 d showed excellent TSS removal (>90%) which occurred primarily near the inlet, and that COD removal was maximized at lower HRTs (e.g., 56% removal efficiency and 25 g of COD removed per m3 of bioreactor per d at a 24 h HRT). However, influent wastewater took progressively longer to move into the woodchips likely due to a combination of (1) woodchip settling, (2) clogging due to removed wastewater solids and/or accumulated bacterial growth, and (3) the pulsed flow system pushing the chips away from the inlet. The bioreactor that received the highest loading rate experienced the most altered hydraulics. Statistically significant increases in woodchip P content over time in woodchip bags placed near the bioreactor outlets (0.03 vs 0.10%P2O5) and along the bioreactor floor (0.04 vs. 0.12%P2O5) confirmed wastewater solids were being removed and may pose a concern for subsequent nutrient mineralization and release. Nevertheless, the excellent nitrate-nitrogen and TSS removal along with notable COD removal indicated woodchip bioreactors are a viable water treatment technology for these types of wastewaters given they are used downstream of a filtration device.

Does finding early recurrence improve outcomes, and at what cost?

The putative goal of surveillance is the early detection of recurrence while both the cancer and patient are still treatable. To be cost and clinically effective, surveillance requires a tailored approach based on stage, tumor biology, conditional survival, and available treatment options. Although surveillance is the major component of care for cancer patients after potentially curative treatment, current guidelines for surveillance lack the high-level data seen on the treatment side of the patient care continuum. J. Surg. Oncol. 2016;114:329-335. © 2016 Wiley Periodicals, Inc.

PSY15 - BUDGET IMPACT ANALYSIS OF THE INCORPORATION OF GOLIMUMAB AS AN ADDITIONAL TREATMENT OPTION FOR NAÏVE PATIENTS WITH PSORIATIC ARTHRITIS IN THE BRAZILIAN PUBLIC HEALTH SYSTEM

Clinical guidelines are available at a national level for the treatment of patients with psoriatic arthritis (PsA) in the Brazilian public health system (SUS). The present research aims to estimate the budget impact of the incorporation of golimumab (GOL) as an additional biological treatment option in these guidelines. A budget impact analysis (BIA) was developed using a two health states Markov model (new/first line and discontinued) with annual cycle length. The budget impact of GOL incorporation was compared to the current scenario, from SUS perspective. Target population was defined as patients naïve to biological treatment and estimated based on DATASUS database. A 5-year time horizon was employed, considering population growth according to IBGE statistics. GOL adoption rate was assumed as 40% at the end of 5 years, with annual discontinuation rate of 25%. Once discontinued, it was assumed patients remain in this state until the end of the analysis. Only drug acquisition costs were considered and prices were gathered from the official government website. Annual treatment costs were calculated following doses/intervals defined in the guidelines. Deterministic sensitivity analysis (DSA) was carried to determine the impact of the assumptions on results. 3,010 naïve patients were eligible to start treatment with biological drugs in the first year. Due to its lower annual treatment cost, the BIA estimated that GOL incorporation would bring a saving of R$633,000 in the first year of incorporation, reaching a total of R$17.7 million savings in 5 years. DSA confirmed the robustness of model and, regardless of the parameter altered, GOL would bring savings to the government budget, ranging from R$13.2 million to R$28.2 million in 5 years. Introduction of GOL in SUS as an option for patients with PsA shows potential to bring significant savings to government budget. The higher incorporation rate, the greater the economy.

Treatment Patterns, Direct Cost of Biologics, and Direct Medical Costs for Rheumatoid Arthritis Patients: A Real-world Analysis of Nationwide Japanese Claims Data

PurposeThe aims of this article were to characterize the patterns of treating rheumatoid arthritis with biologics and to evaluate costs using claims data from the Japan Medical Data Center Co, Ltd. MethodsPatients aged 16 to <75 years who were diagnosed with rheumatoid arthritis and prescribed adalimumab (ADA), etanercept (ETN), infliximab (IFX), tocilizumab (TCZ), abatacept, certolizumab, or golimumab between January 2005 and August 2014 were included. For the cross-sectional analysis, the annual costs of ETN, IFX, ADA, and TCZ from 2009 to 2013 were assessed. For the longitudinal analysis, patients prescribed these biologics as the first line of biologics, from January 2005 to August 2014, were included. The cost of biologic treatment over 1, 2, and 3 years (including prescription of subsequent biologics) and direct medical costs (including treatment of comorbidities) were compared between groups. Discontinuation and switching rates in each group were estimated, and multivariate analyses were conducted to estimate an adjusted hazard ratio of discontinuation and switching rates among each group. The dose of each first-line biologic treatment until discontinuation was analyzed to calculate relative dose intensity. FindingsThe cross-sectional annual biologic costs of ETN, IFX, ADA, and TCZ were ~$8000 (2009 and 2013), $13,000 (2009) and $15,000 (2013), $10,000 (2009) and $11,000 (2013), and $9000 (2009) and $8000 (2013), respectively. In longitudinal analyses (n = 764), 276 (36%) initiated ETN; 242 (32%), IFX; 147 (19%), ADA; and 99 (13%), TCZ. The 1-year cumulative annual biologic costs per patient from the initial prescription of ETN, IFX, ADA, and TCZ as the first-line biologic treatment were ~$11,000, $19,000, $16,000, and $12,000. The corresponding direct medical costs over 1 year from the initial prescription were ~$17,000, $26,000, $22,000, and $22,000. Costs remained greatest in the IFX-initiation group at year 3. The discontinuation rates at 36 months with ETN, IFX, ADA, and TCZ were 37.7%, 52.3%, 55.8%, and 39.5%; the switching rates were 12.5%, 27.1%, 31.0%, and 16.7%. The mean (95% CI) relative dose intensities until discontinuation of ETN 25 mg, ETN 50 mg, IFX, ADA, and TCZ were 1.02 (0.95–1.10), 0.82 (0.79–0.85), 1.16 (1.12–1.20), 0.95 (0.90–0.99), and 0.96 (0.93–1.00). ImplicationsConsidered costs and discontinuation and switching event rates were lowest with ETN versus IFX, ADA, or TCZ used as the first-line biologic. Despite limitations, these findings imply clinical cost-reductive benefits of ETN as the first-line biologic treatment option for rheumatoid arthritis in Japan.

Phycoremediation of landfill leachate with chlorophytes: Phosphate a limiting factor on ammonia nitrogen removal.

The potential of microalgae to bioremediate wastewater has been reported in numerous studies but has not been investigated as extensively for landfill leachate, which may be attributed to its complex nature and toxicity.In this study we explored if microalgal phycoremediation could constitute an alternative biological treatment option for landfill leachate management in regions with temperate climatic conditions. The aim of this study was to assess the performance of microalgae species at relatively low temperature (15 °C) and light intensity (14:10 h, light: dark, 22 μmol m−2 s−1) for reduction in energy inputs. Four chlorophyte strains originating from the North-West of Ireland were selected and used in batch experiments in order to evaluate their ability to reduce total ammonia nitrogen, oxidised nitrogen and orthophosphate in landfill leachate. The Chlamydomonas sp. strain SW15aRL isolated from raw leachate achieved the highest level of pollutant reduction whereby a decrease of 51.7% of ammonia nitrogen was observed in 10% raw leachate (∼100 mg l−1 NH4+-N) by day 24 in experiments without culture agitation. However, in the experiment conducted with 10% raw leachate supplemented with phosphate, a decrease of 90.7% of ammonia nitrogen was obtained by day 24 while also achieving higher biomass production. This series of experiments pointed to phosphorus being a limiting factor in the microalgae based phycoremediation of the landfill leachate.The effective reduction of ammonia nitrogen in landfill leachate can be achieved at lower temperature and light conditions. This was attained by employing native species adapted to such conditions and by improving nutrient balance.