Discontinuation of biologic therapy in patients with rheumatoid arthritis and ankylosing spondylitis: analysis from multicenter cohort study.

Despite of the availability of several effective bDMARDs, a significant proportion of rheumatoid arthritis (RA) and ankylosing spondylitis (AS) patients discontinued bDMARDs. The aims of this study were to analyze causes of bDMARDs discontinuation in RA and AS included in the Moroccan registry RBSMR. A historical prospective multicenter cohort study based on the RBSMR database at 12 months of follow-up, which included 225 RA and 170 AS. Using T student, Mann-Whitney U, chi-squared or Fischer exact tests, baseline demographic and clinical features were compared between patients discontinuing bDMARDs and patients remaining on initiated bDMARDs or switching bDMARDs. Logistic regression models were used to identify factors associated with drugs discontinuation. 61 RA discontinued bDMARDs and 47 AS interrupted anti-TNF. The most common reasons for drugs discontinuation were adverse events (7.5%) in RA patients and social security reimbursement problems (16.8%) in AS. RA patients discontinuing bDMARDs were more frequently first-line biological drugs users, more frequently female and had more comorbidities and lower DAS28 CRP than RA patients remaining on initiated bDMARDs or switching bDMARDs (p < 0.001, p = 0.01, p < 0.001 and p < 0.001 respectively). Female sex and comorbidities were the significant predictors of bDMARDs discontinuation in RA patients. Higher baseline BASDAI had a protective role on anti-TNF interruption in AS patients. Adverse events and social security reimbursement problems were the main reasons for drugs discontinuation in RA and AS patients respectively. Female sex and comorbidities in RA patients, baseline BASDAI in AS patients impacted bDMARDs discontinuation in real-life settings.

A safety review of biologic therapies for the management of hidradenitis suppurativa and unmet needs.

INTRODUCTION: Hidradenitis suppurativa (HS) is a chronic, debilitating inflammatory skin disorder characterized by nodules, abscesses, fistulae, and significant scarring in intertriginous areas rich in apocrine glands. Immunomodulator drugs, including biologics, are a mainstay of treatment for this disease. AREAS COVERED: This review details the safety profiles of various biologic therapies currently available commercially that have been tried for HS as assessed in clinical trials and observational studies. As the only Food and Drug Administration (FDA)-approved medication for the treatment of moderate-to-severe HS, adalimumab is discussed in the most detail. Additional biologic medications, including tumor necrosis factor α (TNFα) inhibitors, interleukin 1 (IL-1) inhibitors, IL-12 and IL-23 inhibitors, IL-17 inhibitors, and IL-23 inhibitors, are discussed as well. Safety concerns in special populations, including pregnant women and children, are outlined. EXPERT OPINION: Existing data support excellent short-term and long-term safety profiles for adalimumab, although caution must be taken with use in high-risk patient populations, including those with chronic infections or increased risk of malignancy. Based on their safety data for other indications, additional biologic agents appear safe in HS as well. However, further research is needed to fully understand the safety profiles of these medications in the HS population.

Assessment of Body Weight Changes in Patients with Inflammatory Bowel Diseases Initiating Biologic Therapy: A Prospective Cohort Study.

BACKGROUND: Prior studies have inconsistently suggested that biologic therapy may be associated with weight gain in inflammatory bowel disease patients (IBD). Our aim was to compare weight gain across different biologic therapy classes with distinct mechanisms of action. METHODS: This prospective cohort study recruited patients with moderate to severe IBD initiating outpatient biologic therapy with anti-TNF (infliximab, adalimumab), vedolizumab, or ustekinumab. Weight measurements were performed at weeks 0, 14, 30, and 54. Changes in weight between baseline and each of the follow-up visits were modeled as a continuous variable, and multivariate regression assessed the independent effect of therapeutic class on this outcome. RESULTS: Our study enrolled 269 patients (163 CD, 106 UC) initiating biologic therapy [99 anti-TNF (37%), 122 vedolizumab (45%), 48 ustekinumab (18%)]. From baseline, the weight significantly increased at week 14 with a mean of 0.36 kg (± 3.8 kg, p = 0.004) and continued to increase compared to baseline with 0.96 kg (± 3.9 kg, p < 0.001) and 1.29 kg (± 4.2 kg, p < 0.001) at week 30 and 54, respectively. On univariate and multivariable analysis, no significant differences between any of the biologic therapies for weight gain were seen at any time point (weight gain anti-TNF: 0.31 kg, 1.06 kg, 1.33 kg; VDZ: 0.30 kg, 0.83 kg, 1.10 kg; UST: 0.63 kg, 1.21 kg, 2.31 kg at wk 14, wk 30, and wk 54, respectively). None of the disease activity parameters showed any statistical association with weight gain. CONCLUSION: There was no difference in weight gain among the different biologic therapeutic classes.

T-Cell Dependent Immunogenicity of Protein Therapeutics Pre-clinical Assessment and Mitigation-Updated Consensus and Review 2020.

Immune responses to protein and peptide drugs can alter or reduce their efficacy and may be associated with adverse effects. While anti-drug antibodies (ADA) are a standard clinical measure of protein therapeutic immunogenicity, T cell epitopes in the primary sequences of these drugs are the key drivers or modulators of ADA response, depending on the type of T cell response that is stimulated (e.g., T helper or Regulatory T cells, respectively). In a previous publication on T cell-dependent immunogenicity of biotherapeutics, we addressed mitigation efforts such as identifying and reducing the presence of T cell epitopes or T cell response to protein therapeutics prior to further development of the protein therapeutic for clinical use. Over the past 5 years, greater insight into the role of regulatory T cell epitopes and the conservation of T cell epitopes with self (beyond germline) has improved the preclinical assessment of immunogenic potential. In addition, impurities contained in therapeutic drug formulations such as host cell proteins have also attracted attention and become the focus of novel risk assessment methods. Target effects have come into focus, given the emergence of protein and peptide drugs that target immune receptors in immuno-oncology applications. Lastly, new modalities are entering the clinic, leading to the need to revise certain aspects of the preclinical immunogenicity assessment pathway. In addition to drugs that have multiple antibody-derived domains or non-antibody scaffolds, therapeutic drugs may now be introduced via viral vectors, cell-based constructs, or nucleic acid based therapeutics that may, in addition to delivering drug, also prime the immune system, driving immune response to the delivery vehicle as well as the encoded therapeutic, adding to the complexity of assessing immunogenicity risk. While it is challenging to keep pace with emerging methods for the preclinical assessment of protein therapeutics and new biologic therapeutic modalities, this collective compendium provides a guide to current best practices and new concepts in the field.

Effectiveness, Complications, and Costs of Rheumatoid Arthritis Treatment with Biologics in Alberta: Experience of Indigenous and Non-indigenous Patients.

OBJECTIVE: To examine clinical effectiveness, treatment complications, and healthcare costs for indigenous and non-indigenous Albertans with rheumatoid arthritis (RA) participating in the Alberta Biologics Pharmacosurveillance program. METHODS: Patients initiating biologic therapy in Alberta (2004-2012) were characterized for disease severity and treatment response. Provincial hospitalization separations, physician claims, outpatient department data, and emergency department data were used to estimate treatment complication event rates and healthcare costs. RESULTS: Indigenous patients (n = 90) presented with higher disease activity [mean 28-joint count Disease Activity Score (DAS28) 6.11] than non-indigenous patients (n = 1400, mean DAS28 5.19, p < 0.0001). Improvements in DAS28, function, swollen joint count, CRP, and patient and physician global evaluation scores were comparable to non-indigenous patients, but indigenous patients did not have a significant improvement in erythrocyte sedimentation rate (-0.31 per month, 95% CI -0.79 to 0.16, p = 0.199). At the end of study followup, 13% (12/90) of indigenous and 33% (455/1400) of non-indigenous patients were in DAS28 remission (p < 0.001). Indigenous patients had a 40% increased risk of all-cause hospitalization [adjusted incidence rate ratio (IRR) 1.4, 95% CI 1.1-1.8, p = 0.01] and a 4-fold increase in serious infection rate (adjusted IRR 4.0, 95% CI 2.3-7.0, p < 0.001). Non-indigenous patients incurred higher costs for RA-related hospitalizations (difference $896, 95% CI 520-1273, p < 0.001), and outpatient department visits (difference $128, 95% CI 2-255, p = 0.047). CONCLUSION: We identified disparities in treatment outcomes, safety profiles, and patient-experienced effects of RA for the indigenous population in Alberta. These disparities are critical to address to facilitate and achieve desired RA outcomes from individual and population perspectives.

Pediatric psoriasis: Evolving perspectives.

BACKGROUND/OBJECTIVES: Childhood-onset psoriasis is a common skin disorder that has recently received increasing attention, particularly because of its significant medical, social, financial, and psychological burdens and its associated comorbidities. With limited data available and lack of standardized management guidelines for pediatric psoriasis, an expert panel desired to provide an updated critical overview and practical guidance for management of the affected population. METHODS: A panel of pediatric dermatologists with extensive experience in pediatric psoriasis defined and prioritized a core set of topics, performed an English-language literature review, prepared critical evaluations and presentations of topic areas, and carried out a consensus meeting and follow-up consensus manuscript. RESULTS: The summation of evolving perspectives in pediatric psoriasis includes epidemiology and natural history of the disease, precipitating factors and comorbidities, quality of life and burden of disease, clinical features and disease presentation, differential diagnosis, pathogenesis and treatment, including topical, photo, and systemic therapies. CONCLUSION: Pediatric psoriasis is an important immune-mediated inflammatory skin disease with potential for significant impact on affected individuals and their caregivers. Current state-of-the-art care is based primarily on experience and expert consensus, but pediatric data are accumulating and therapeutic options are rapidly evolving.

Systematic review with network meta-analysis: comparative assessment of tofacitinib and biological therapies for moderate-to-severe ulcerative colitis.

BACKGROUND: Biological therapies have improved the care of patients with ulcerative colitis (UC). Tofacitinib, an oral small-molecule Janus kinase inhibitor, is potentially a new treatment option. AIM: To comparatively assess efficacy and harm of tofacitinib and biologics (infliximab, adalimumab, golimumab and vedolizumab) in adult patients not previously exposed to TNF antagonists. METHODS: We performed a comprehensive search of PubMed, Embase, Scopus, clinical trial registries, regulatory authorities' websites and major conference proceedings, through August 2017, to identify randomised, placebo-controlled or head-to-head trials assessing tofacitinib or biologics as induction and/or maintenance therapy in moderate-to-severe UC. Two reviewers independently extracted study data and outcomes, and investigated each trial's risk-of-bias. We used conventional meta-analysis to synthesise direct evidence, and network meta-analysis for adjusted indirect treatment comparisons. RESULTS: Fifteen randomised, double-blind, placebo-controlled trials (n = 3130) contributed data for induction: All treatments are superior to placebo. Indirect treatment comparisons showed that infliximab is better than adalimumab (OR: 2.01, 95% CI: 1.36-2.98) and golimumab (1.67, 1.08-2.59) in clinical response, better than adalimumab (2.10, 1.21-3.64) in clinical remission, and better than adalimumab (1.87, 1.26-2.79) and golimumab (1.75, 1.13-2.73) in mucosal healing. No indirect comparisons between tofacitinib and biologics reached statistical significance. Nine studies (n = 1776) contributed maintenance data showing that all treatments have higher clinical efficacy than placebo. Safety analyses indicated no increased rates of adverse events for the treatments under evaluation (except for infliximab), while vedolizumab may have an advantage regarding the occurrence of serious adverse events. CONCLUSIONS: Tofacitinib and biologics are efficacious and safe for UC. Further high-quality research is warranted to establish the best therapeutic option.

Valoración previa a la inmunosupresión farmacológica en Reumatología / (Pre-assessment of pharmacological immunosuppression in Rheumatology)

ResumenEn los últimos 15 años se han desarrollado terapias y esquemas terapéuticos para inducir la remisión a la gran mayoría de enfermedades reumatológicas. La mejoría clínica lograda se consigue a expensas de una inmunosupresión más agresiva y específica, lo que conlleva un aumento en el riesgo de infecciones. La principal causa de muerte de las enfermedades autoinmunes, en los primeros 5 años de evolución, es la infección secundaria a la inmunosupresión. El objetivo del presente trabajo fue elaborar un documento de consenso con el afán de reducir este riesgo, basado en la mejor evidencia médica disponible, utilizando los recursos disponibles en el hospital para disminuir la morbimortalidad de los pacientes que reciben estas terapias. Contar con un documento de consenso permitirá minimizar los efectos secundarios y mejorar la acción terapéutica, con mayores oportunidades de remisión y una más adecuada utilización del recurso institucional.

AbstractIn the last 15 years therapies and therapeutic schemes have been developed to induce remission to the vast majority of rheumatologic diseases. The clinical improvement achieved is at the cost of a more aggressive and specific immunosuppression, which leads to an increase in the risk of infections. The main cause of death of autoimmune diseases in the first 5 years of evolution is infection secondary to immunosuppression. The objective of the present study was to develop a consensus document with the aim of reducing this risk of infection, based on the best available medical evidence, using the resources available in our hospital to reduce the morbidity and mortality of patients receiving these therapies. Having a consensus document will allow us to minimize side effects and improve therapeutic action with greater opportunities for referral and better utilization of institutional resources.

Comparative assessment of immune complex-mediated hypersensitivity reactions with biotherapeutics in the non-human primate: Critical parameters, safety and lessons for future studies.

With the emergence of novel biotherapeutic formats and immunostimulatory biotherapeutics in cancer immunotherapy, an understanding of immune-complex (IC) mediated hypersensitivity reactions in toxicology studies - and their differentiation from pharmacology - remains key to the preclinical evaluation of these drugs. In this review we provide an in-depth evaluation and comparison of case examples where IC-mediated hypersensitivity reactions were observed in cynomolgus monkeys. We provide details of the parameters evaluated in each study to substantiate and guide the interpretation of these findings. Five study cases (1 therapeutic protein, 4 monoclonal antibodies) are discussed for which effects ranged from minor to fatal. Common characteristics are the high incidence of clinical signs, detectable antidrug antibodies, and accelerated drug clearance up to virtual loss of exposure. In our experience, measurement of cytokine levels in vivo and detection of complement (split products) were supportive markers in situations where coagulopathy was suspected to play a role in the observed effects. Recommendations are outlined to prepare for root-cause analysis of suspected hypersensitivity reactions. Overall, a thorough analysis of the findings has helped to start clinical trials despite major findings. The hypersensitivity reactions with our human(ized) immunoglobulins have not proven to be predictive for humans.

Biosimilars: A new scenario in biologic therapies. / Fármacos biosimilares: un nuevo escenario en las terapias biológicas.

There is no doubt that biologic therapies provide added value for health systems. However, due to their special nature, they also raise some questions that make highly rigorous and demanding quality control and monitoring of their use indispensable. This circumstance is reinforced with the appearance on the scene of biosimilars, which, given their lower cost, are having an increasing impact on the international market. The purpose of this article is to review the major issues posed by their manufacture, distribution and control systems, as well as the most important aspects related to their safety in clinical practice. In this report, we assess the pharmacovigilance of these products, with special attention to traceability, as a key tool to enable earlier detection of adverse events.

Low cost biological lung volume reduction therapy for advanced emphysema.

BACKGROUND: Bronchoscopic lung volume reduction (BLVR), using biological agents, is one of the new alternatives to lung volume reduction surgery. OBJECTIVES: To evaluate efficacy and safety of biological BLVR using low cost agents including autologous blood and fibrin glue. METHODS: Enrolled patients were divided into two groups: group A (seven patients) in which autologous blood was used and group B (eight patients) in which fibrin glue was used. The agents were injected through a triple lumen balloon catheter via fiberoptic bronchoscope. Changes in high resolution computerized tomography (HRCT) volumetry, pulmonary function tests, symptoms, and exercise capacity were evaluated at 12 weeks postprocedure as well as for complications. RESULTS: In group A, at 12 weeks postprocedure, there was significant improvement in the mean value of HRCT volumetry and residual volume/total lung capacity (% predicted) (P-value: <0.001 and 0.038, respectively). In group B, there was significant improvement in the mean value of HRCT volumetry and (residual volume/total lung capacity % predicted) (P-value: 0.005 and 0.004, respectively). All patients tolerated the procedure with no mortality. CONCLUSION: BLVR using autologous blood and locally prepared fibrin glue is a promising method for therapy of advanced emphysema in term of efficacy, safety as well as cost effectiveness.

To test or not to test? An updated evidence-based assessment of the value of screening and monitoring tests when using systemic biologic agents to treat psoriasis and psoriatic arthritis.

BACKGROUND: Safety profiles of systemic biologic agents for the treatment of psoriasis and psoriatic arthritis (PsA) encompass a wide spectrum of adverse events. To date, no uniform evidence-based guidelines exist regarding screening and monitoring patients who are undergoing biologic therapy. OBJECTIVE: We sought to identify studies evaluating screening and monitoring tests in the treatment of psoriasis and PsA with systemic biologic agents, and to propose evidence-based practical guidelines. METHODS: The MEDLINE database was searched to identify data on risks associated with adalimumab, etanercept, infliximab, and ustekinumab. Articles were reviewed and graded according to methods developed by the US Preventative Services Task Force. RESULTS: Evidence was strongest (grade B) for tuberculosis screening. Interferon-gamma release assay was preferable to tuberculin skin testing. Among known hepatitis B virus carriers, the evidence grade was C for monitoring liver function tests and viral load. LIMITATIONS: This study was limited by the lack of high-quality controlled trials evaluating screening and monitoring tests in patients treated with biologic agents. CONCLUSIONS: Baseline tuberculosis testing remains the only screening test with strong evidence to support its practice. Other screening and monitoring tests commonly performed in patients who are taking biologic agents are supported only in certain clinical settings or lack evidence to support or recommend against their practice.

A fit-for-purpose strategy for the risk-based immunogenicity testing of biotherapeutics: a European industry perspective.

There is much debate in the pharmaceutical industry on how to translate the current guidelines on immunogenicity testing for biotherapeutics into a testing strategy that suits the specific requirements of individual drug candidates. In this paper, member companies from the European immunogenicity platform (EIP) present a consensus view on the essential requirements for immunogenicity testing of a biotherapeutic throughout the various phases of drug development, to ensure patient safety and to enable successful market entry. Our aim is to open the debate and provoke discussion on this important topic which is unique to biotherapeutic drug development. The scope of this paper is limited to aspects relevant to biotherapeutic drug development and does not include fundamental academic studies of immunogenicity. Here, we propose two pre-defined testing strategies for the detection and characterization of anti-drug antibody (ADA) responses where the different strategies are based on the phase of development for a biotherapeutic, a. without (category 1) and b. with (category 2) the expected potential to elicit ADA mediated severe clinical consequences. The harm of a potential ADA response determines which of the two testing strategies is adopted. Rather than replacing the overall risk assessment which is known to be challenging and multi-factorial, the testing strategy selection is a starting point for immunogenicity testing which adapts throughout drug development as more information becomes available. The scientific rationale on which the "case-by-case" approach advocated in white papers and guidance documents may be translated for each individual drug development program is provided and, underpins the recommendations made here.

Non-viral opportunistic infections in new users of tumour necrosis factor inhibitor therapy: results of the SAfety Assessment of Biologic ThERapy (SABER) study.

OBJECTIVES: To determine among patients with autoimmune diseases in the USA whether the risk of non-viral opportunistic infections (OI) was increased among new users of tumour necrosis factor α inhibitors (TNFI), when compared to users of non-biological agents used for active disease. METHODS: We identified new users of TNFI among cohorts of rheumatoid arthritis (RA), inflammatory bowel disease and psoriasis-psoriatic arthritis-ankylosing spondylitis patients during 1998-2007 using combined data from Kaiser Permanente Northern California, two pharmaceutical assistance programmes for the elderly, Tennessee Medicaid and US Medicaid/Medicare programmes. We compared incidence of non-viral OI among new TNFI users and patients initiating non-biological disease-modifying antirheumatic drugs (DMARD) overall and within each disease cohort. Cox regression models were used to compare propensity-score and steroid- adjusted OI incidence between new TNFI and non-biological DMARD users. RESULTS: Within a cohort of 33 324 new TNFI users we identified 80 non-viral OI, the most common of which was pneumocystosis (n=16). In the combined cohort, crude rates of non-viral OI among new users of TNFI compared to those initiating non-biological DMARD was 2.7 versus 1.7 per 1000-person-years (aHR 1.6, 95% CI 1.0 to 2.6). Baseline corticosteroid use was associated with non-viral OI (aHR 2.5, 95% CI 1.5 to 4.0). In the RA cohort, rates of non-viral OI among new users of infliximab were higher when compared to patients newly starting non-biological DMARD (aHR 2.6, 95% CI 1.2 to 5.6) or new etanercept users (aHR 2.9, 95% CI 1.5 to 5.4). CONCLUSIONS: In the USA, the rate of non-viral OI was higher among new users of TNFI with autoimmune diseases compared to non-biological DMARD users.

FDA oversight of cell therapy clinical trials.

The U.S. Food and Drug Administration applies regulatory flexibility to balance benefits and risks to subjects in cell-therapy clinical trials.

[Requirements for long-term follow-up on efficacy and safety of advanced therapy medicinal products. Risk management and traceability]. / Regelungen zur Uberwachung von Wirksamkeit und Sicherheit nach der Zulassung. Risikomanagement und Rückverfolgbarkeit von Arzneimitteln für Neuartige Therapien.

Advanced therapy medicinal products (ATMPs) are an innovative treatment option. To promote timely access of the innovative medicinal product and to safeguard public health, new elements have been introduced into legislation. A key element of the ATMP regulation is the requirement for long-term follow-up on safety and efficacy of patients enrolled in clinical trials with ATMPs, which is beyond the routine requirements on pharmacovigilance. For gene therapy medicinal products, a guideline on long-term follow-up, which lays down the technical requirements, is available. A further key element of the ATMP regulation is the traceability of the starting materials used to manufacture the ATMP. A common European coding system is imperative to ensure the traceability of starting materials, especially across the borders of European Member States.

Environmental risk assessment for medicinal products containing genetically modified organisms.

Many gene therapy medicinal products and also some vaccines consist of, or contain, genetically modified organisms (GMOs), which require specific consideration in the environmental risk assessment (ERA) before marketing authorisation or clinical trial applications. The ERA is performed in order to identify the potential risks for public health and the environment, which may arise due to the clinical use of these medicinal products. If such environmental risks are identified and considered as not acceptable, the ERA should go on to propose appropriate risk management strategies capable to reduce these risks. This article will provide an overview of the legal basis and requirements for the ERA of GMO-containing medicinal products in the context of marketing authorisation in the EU and clinical trials in Germany. Furthermore, the scientific principles and methodology that generally need to be followed when preparing an ERA for GMOs are discussed.