Regulatory Perspectives on Biopharmaceuticals for Chronic Inflammatory Diseases in North Africa: A Narrative Review

Introduction of innovative biopharmaceuticals has dramatically changed the treatment of chronic inflammatory diseases, but access to these very effective agents may be limited by economic constraints in some regions. The development of biosimilar products at a lower cost may allow wider access to treatment, but rigorous scientific evaluation is required to ensure similar quality, efficacy, and safety. The World Health Organization, European Medicines Agency, and United States Food and Drug Administration have created stringent guidelines for biosimilar regulatory approval, stipulating that high similarity be demonstrated in comprehensive comparability studies. Although these regulatory standards have been adapted in many countries, the legal/regulatory frameworks required for biosimilar authorization remain in development elsewhere, including North Africa. In some countries, “intended copies” are available despite inadequate evidence of comparability to the reference product and failure to satisfy biosimilar regulatory requirements. In North Africa, as the regulatory pathway for biosimilars is established, regulators will address several important challenges, including criteria for comparability, switching/substitution, post-marketing monitoring/risk management, and product naming conventions. Caution is advised to ensure that lower cost and broader access are not achieved at the expense of patient safety, and educational initiatives should be undertaken for clinicians/patients. In this review, we define the various types of biopharmaceuticals currently available for the treatment of chronic inflammatory disease, provide an overview of regulatory requirements for biosimilar approval and an update on the availability of these agents globally and in North Africa, and discuss crucial concerns related to their use from the viewpoint of North African rheumatologists.

Download Full-text

Targeting interleukin-17 in chronic inflammatory disease: A clinical perspective

Journal of Experimental Medicine ◽

10.1084/jem.20191123 ◽

2019 ◽

Vol 217 (1) ◽

Cited By ~ 11

Author(s):

Pascale Zwicky ◽

Susanne Unger ◽

Burkhard Becher

Keyword(s):

Rheumatoid Arthritis ◽

Inflammatory Diseases ◽

Chronic Inflammatory Disease ◽

Interleukin 17 ◽

Clinical Perspective ◽

Preclinical Models ◽

Chronic Inflammatory Diseases ◽

Recent Developments ◽

Disease Entities ◽

Barrier Tissues

Chronic inflammatory diseases like psoriasis, Crohn’s disease (CD), multiple sclerosis (MS), rheumatoid arthritis (RA), and others are increasingly recognized as disease entities, where dysregulated cytokines contribute substantially to tissue-specific inflammation. A dysregulation in the IL-23/IL-17 axis can lead to inflammation of barrier tissues, whereas its role in internal organ inflammation remains less clear. Here we discuss the most recent developments in targeting IL-17 for the treatment of chronic inflammation in preclinical models and in patients afflicted with chronic inflammatory diseases.

Download Full-text

Evaluation of the mechanisms of sarcopenia in chronic inflammatory disease: protocol for a prospective cohort study

Skeletal Muscle ◽

10.1186/s13395-021-00282-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Amritpal Dhaliwal ◽

Felicity R. Williams ◽

Jonathan I. Quinlan ◽

Sophie L. Allen ◽

Carolyn Greig ◽

...

Keyword(s):

Cohort Study ◽

Prospective Cohort Study ◽

Inflammatory Disease ◽

Prospective Cohort ◽

Inflammatory Diseases ◽

Chronic Inflammatory Disease ◽

Assessment Model ◽

Chronic Inflammatory Diseases ◽

Link Type ◽

Disease Specific

Abstract Background Several chronic inflammatory diseases co-exist with and accelerate sarcopenia (reduction in muscle strength, function and mass) and negatively impact on both morbidity and mortality. There is currently limited research on the extent of sarcopenia in such conditions, how to accurately assess it and whether there are generic or disease-specific mechanisms driving sarcopenia. Therefore, this study aims to identify potential mechanisms driving sarcopenia within chronic inflammatory disease via a multi-modal approach; in an attempt to help define potential interventions for future use. Methods This prospective cohort study will consist of a multi-modal assessment of sarcopenia and its underlying mechanisms. Recruitment will target three chronic inflammatory diseases: chronic liver disease (CLD) (n=50), with a subset of NAFLD (n=20), inflammatory bowel disease (IBD) (n=50) and rheumatoid arthritis (RA) (n=50) both before and after therapeutic intervention. In addition, 20 age and sex matched healthy individuals will be recruited for comparison. Participants will undergo 4 assessment visits at weeks 0, 2, 12 and 24. Visits will consist of the following assessments: blood tests, anthropometrics, functional assessment, quadriceps muscle imaging, actigraphy, quality of life questionnaires, food diary collection and muscle biopsy of the vastus lateralis (at weeks 2 and 24 only). In addition, stool and urine samples will be collected for future microbiome and metabolomics analysis. Discussion This is the first study to use a multi-modal assessment model to phenotype sarcopenia in these chronic inflammatory diseases. We hope to identify generic as well as disease-specific mechanisms driving sarcopenia. We appreciate that these cohorts do require separate standards of care treatments which limit comparison between groups. Ethics and dissemination The study is approved by the Health Research Authority - West Midlands Solihull Research Ethics Service Committee Authority (REC reference: 18/WM/0167). Recruitment commenced in January 2019 and will continue until July 2021. The study was halted in March 2020 and again in January 2021 with the COVID-19 pandemic. The findings will be disseminated through peer-reviewed publications and conference presentations. All data will be stored on a secure server. Trial registration ClinicalTrials.gov Identifier: NCT04734496

Download Full-text

Blood Immunoproteasome Activity Is Regulated by Sex, Age and in Chronic Inflammatory Diseases: A First Population-Based Study

Cells ◽

10.3390/cells10123336 ◽

2021 ◽

Vol 10 (12) ◽

pp. 3336

Author(s):

Ilona Elisabeth Kammerl ◽

Claudia Flexeder ◽

Stefan Karrasch ◽

Barbara Thorand ◽

Margit Heier ◽

...

Keyword(s):

Active Sites ◽

Mononuclear Cells ◽

Inflammatory Diseases ◽

Population Based ◽

Chronic Inflammatory Disease ◽

Chronic Obstructive ◽

Peripheral Blood Mononuclear ◽

Chronic Inflammatory Diseases ◽

Study Participants ◽

The Impact

Dysfunction of the immunoproteasome has been implicated in cardiovascular and pulmonary diseases. Its potential as a biomarker for predicting disease stages, however, has not been investigated so far and population-based analyses on the impact of sex and age are missing. We here analyzed the activity of all six catalytic sites of the proteasome in isolated peripheral blood mononuclear cells obtained from 873 study participants of the KORA FF4 study using activity-based probes. The activity of the immuno- and standard proteasome correlated clearly with elevated leukocyte counts of study participants. Unexpectedly, we observed a strong sex dimorphism for proteasome activity with significantly lower immunoproteasome activity in women. In aging, almost all catalytic activities of the proteasome were activated in aged women while maintained upon aging in men. We also noted distinct sex-related activation patterns of standard and immunoproteasome active sites in chronic inflammatory diseases such as diabetes, cardiovascular diseases, asthma, or chronic obstructive pulmonary disease as determined by multiple linear regression modeling. Our data thus provides a conceptual framework for future analysis of immunoproteasome function as a bio-marker for chronic inflammatory disease development and progression.

Download Full-text

Cross-tissue, single-cell stromal atlas identifies shared pathological fibroblast phenotypes in four chronic inflammatory diseases

10.1101/2021.01.11.426253 ◽

2021 ◽

Author(s):

Ilya Korsunsky ◽

Kevin Wei ◽

Mathilde Pohin ◽

Edy Y. Kim ◽

Francesca Barone ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Inflammatory Bowel Disease ◽

Single Cell ◽

Intestinal Inflammation ◽

Inflammatory Diseases ◽

Chronic Inflammatory Disease ◽

Chronic Inflammatory Diseases ◽

Single Cell Rna Sequencing ◽

Inflammatory Bowel ◽

Novel Therapeutic

SummaryPro-inflammatory fibroblasts are critical to pathogenesis in rheumatoid arthritis, inflammatory bowel disease, interstitial lung disease, and Sjögren’s syndrome, and represent a novel therapeutic target for chronic inflammatory disease. However, the heterogeneity of fibroblast phenotypes, exacerbated by the lack of a common cross-tissue taxonomy, has limited the understanding of which pathways are shared by multiple diseases. To investigate, we profiled patient-derived fibroblasts from inflamed and non-inflamed synovium, intestine, lung, and salivary glands with single-cell RNA-sequencing. We integrated all fibroblasts into a multi-tissue atlas to characterize shared and tissue-specific phenotypes. Two shared clusters, CXCL10+CCL19+ immune-interacting and SPARC+COL3A1+ vascular-interacting fibroblasts were expanded in all inflamed tissues and additionally mapped to dermal analogues in a public atopic dermatitis atlas. We further confirmed these human pro-inflammatory fibroblasts in animal models of lung, joint, and intestinal inflammation. This work represents the first cross-tissue, single-cell fibroblast atlas revealing shared pathogenic activation states across four chronic inflammatory diseases.

Download Full-text

The Biological Efficacy of Natural Products against Acute and Chronic Inflammatory Diseases in the Oral Region

Medicines ◽

10.3390/medicines5040122 ◽

2018 ◽

Vol 5 (4) ◽

pp. 122 ◽

Cited By ~ 8

Author(s):

Toshiaki Ara ◽

Sachie Nakatani ◽

Kenji Kobata ◽

Norio Sogawa ◽

Chiharu Sogawa

Keyword(s):

Natural Products ◽

Inflammatory Disease ◽

Alveolar Bone ◽

Inflammatory Diseases ◽

Herbal Medicines ◽

Chronic Inflammatory Disease ◽

Chronic Inflammatory Diseases ◽

Oral Region ◽

Biological Efficacy ◽

Clinical Conditions

The oral inflammatory diseases are divided into two types: acute and chronic inflammatory diseases. In this review, we summarize the biological efficacy of herbal medicine, natural products, and their active ingredients against acute and chronic inflammatory diseases in the oral region, especially stomatitis and periodontitis. We review the effects of herbal medicines and a biscoclaurin alkaloid preparation, cepharamthin, as a therapy against stomatitis, an acute inflammatory disease. We also summarize the effects of herbal medicines and natural products against periodontitis, a chronic inflammatory disease, and one of its clinical conditions, alveolar bone resorption. Recent studies show that several herbal medicines such as kakkonto and ninjinto reduce LPS-induced PGE 2 production by human gingival fibroblasts. Among herbs constituting these herbal medicines, shokyo (Zingiberis Rhizoma) and kankyo (Zingiberis Processum Rhizoma) strongly reduce PGE 2 production. Moreover, anti-osteoclast activity has been observed in some natural products with anti-inflammatory effects used against rheumatoid arthritis such as carotenoids, flavonoids, limonoids, and polyphenols. These herbal medicines and natural products could be useful for treating oral inflammatory diseases.

Download Full-text

Antibody-Based Therapeutics for Atherosclerosis and Cardiovascular Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms22115770 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5770

Author(s):

Eunhye Ji ◽

Sahmin Lee

Keyword(s):

Cardiovascular Diseases ◽

Apolipoprotein B ◽

Animal Studies ◽

Inflammatory Diseases ◽

Chronic Inflammatory Disease ◽

Clinical Effects ◽

Rheumatic Arthritis ◽

Chronic Inflammatory Diseases ◽

Cholesterol Levels ◽

Tnf Α

Cardiovascular disease is the leading cause of death worldwide, and its prevalence is increasing due to the aging of societies. Atherosclerosis, a type of chronic inflammatory disease that occurs in arteries, is considered to be the main cause of cardiovascular diseases such as ischemic heart disease or stroke. In addition, the inflammatory response caused by atherosclerosis confers a significant effect on chronic inflammatory diseases such as psoriasis and rheumatic arthritis. Here, we review the mechanism of action of the main causes of atherosclerosis such as plasma LDL level and inflammation; furthermore, we review the recent findings on the preclinical and clinical effects of antibodies that reduce the LDL level and those that neutralize the cytokines involved in inflammation. The apolipoprotein B autoantibody and anti-PCSK9 antibody reduced the level of LDL and plaques in animal studies, but failed to significantly reduce carotid inflammation plaques in clinical trials. The monoclonal antibodies against PCSK9 (alirocumab, evolocumab), which are used as a treatment for hyperlipidemia, lowered cholesterol levels and the incidence of cardiovascular diseases. Antibodies that neutralize inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-17, and IL-12/23) have shown promising but contradictory results and thus warrant further research.

Download Full-text

STUDY ON REGISTRATION AND REGULATORY REQUIREMENTS FOR VACCINES IN USA, EUROPE AND CANADA

Journal of Biomedical and Pharmaceutical Research ◽

10.32553/jbpr.v9i4.781 ◽

2020 ◽

Vol 9 (4) ◽

Author(s):

Shoukat Ali ◽

Shanthakumar GS ◽

Shrikanth P ◽

Ayushi Agrawal ◽

Navya BR

Keyword(s):

European Medicines Agency ◽

Pharmacovigilance System ◽

Regulatory Requirements ◽

Biological Preparation ◽

Biologics License Application ◽

License Application ◽

Regulatory Guidelines ◽

Post Marketing ◽

Protection Efficacy ◽

Health Canada

In recent years vaccines are the foremost necessary health intervention globally. An immunizing agent could also be a biological preparation that will increase the immunity to a specific wellness. The development of an immunizing agent could be a posh and tedious method. A strict regulatory guidelines used to figure out the protection, efficacy, and quality should be achieved throughout the development of a vaccine for its authorization. In USA biologics were regulated by the Centre for Biologics Evaluation and Research (CBER) beneath USFDA. In Europe, European Medicines Agency (EMA) regulates the biologics and authorization is granted by the European Commission (EC). In Canada, vaccines are regulated by Biologics and Genetics Therapy Directorate (BGTD) under Health Canada (HC). For Registration of vaccine, Biologics license application (BLA) in USA, marketing authorization application (MAA) in EU and New Drug Submission (NDS) Application in Canada ought to be submitted. While registration of a vaccine, post-marketing surveillancestudies such as VAERS should be done in USA, Pharmacovigilance system in Europe and Canadian Adverse Events Following immunization surveillance system (CAEFISS) in Canada monitors the safety of a vaccine.

Download Full-text

Heterogeneity of IgG Glycosylation in Adult Periodontal Disease

Journal of Dental Research ◽

10.1177/154405910508401005 ◽

2005 ◽

Vol 84 (10) ◽

pp. 897-901 ◽

Cited By ~ 19

Author(s):

J. Novak ◽

M. Tomana ◽

G.R. Shah ◽

R. Brown ◽

J. Mestecky

Keyword(s):

Periodontal Disease ◽

Plasma Cells ◽

Gingival Crevicular Fluid ◽

Inflammatory Diseases ◽

Chronic Inflammatory Disease ◽

Lectin Pathway ◽

Healthy Controls ◽

Chronic Inflammatory Diseases ◽

Altered Glycosylation ◽

Crevicular Fluid

Periodontal disease is a chronic inflammatory disease of bacterial etiology. In many other chronic inflammatory diseases, IgG glycans are galactose-deficient and thus capable of complement activation through the lectin pathway. In this study, we examined whether IgG in serum and gingival crevicular fluid, and IgG locally produced by plasma cells in gingiva of periodontal disease patients, display altered glycosylation. We developed a lectin-ELISA to measure levels of galactose-deficient IgG in the fluids and immunofluorescence staining to detect galactose-deficient IgG-producing cells in gingiva. Our results indicated higher levels of galactose-deficient IgG in sera and gingival crevicular fluid from periodontal disease patients, compared with levels in healthy controls. Furthermore, gingivae from periodontal disease patients exhibited infiltration of IgG-producing plasma cells; many of them contained galactose-deficient IgG in the cytoplasm. Analysis of our data suggests that IgG secreted by B-cells was aberrantly glycosylated, which resulted in the production of pro-inflammatory galactose-deficient IgG.

Download Full-text

Tissue–Resident Memory T Cells in Chronic Inflammation—Local Cells with Systemic Effects?

Cells ◽

10.3390/cells10020409 ◽

2021 ◽

Vol 10 (2) ◽

pp. 409

Author(s):

Anoushka Ashok Kumar Samat ◽

Jolijn van der Geest ◽

Sebastiaan J. Vastert ◽

Jorg van Loosdregt ◽

Femke van Wijk

Keyword(s):

Gene Expression ◽

T Cells ◽

Chronic Inflammation ◽

Memory T Cells ◽

Inflammatory Diseases ◽

Chronic Inflammatory Disease ◽

Chronic Inflammatory Diseases ◽

Recent Developments ◽

Resident Memory T Cells ◽

Barrier Tissues

Chronic inflammatory diseases such as rheumatoid arthritis (RA), Juvenile Idiopathic Arthritis (JIA), psoriasis, and inflammatory bowel disease (IBD) are characterized by systemic as well as local tissue inflammation, often with a relapsing-remitting course. Tissue–resident memory T cells (TRM) enter non-lymphoid tissue (NLT) as part of the anamnestic immune response, especially in barrier tissues, and have been proposed to fuel chronic inflammation. TRM display a distinct gene expression profile, including upregulation of CD69 and downregulation of CD62L, CCR7, and S1PR1. However, not all TRM are consistent with this profile, and it is now more evident that the TRM compartment comprises a heterogeneous population, with differences in their function and activation state. Interestingly, the paradigm of TRM remaining resident in NLT has also been challenged. T cells with TRM characteristics were identified in both lymph and circulation in murine and human studies, displaying similarities with circulating memory T cells. This suggests that re-activated TRM are capable of retrograde migration from NLT via differential gene expression, mediating tissue egress and circulation. Circulating ‘ex-TRM’ retain a propensity for return to NLT, especially to their tissue of origin. Additionally, memory T cells with TRM characteristics have been identified in blood from patients with chronic inflammatory disease, leading to the hypothesis that TRM egress from inflamed tissue as well. The presence of TRM in both tissue and circulation has important implications for the development of novel therapies targeting chronic inflammation, and circulating ‘ex-TRM’ may provide a vital diagnostic tool in the form of biomarkers. This review elaborates on the recent developments in the field of TRM in the context of chronic inflammatory diseases.

Download Full-text

Pulmonary Hypertension Is a Probable NO/ONOO− Cycle Disease: A Review

ISRN Hypertension ◽

10.5402/2013/742418 ◽

2013 ◽

Vol 2013 ◽

pp. 1-27 ◽

Cited By ~ 1

Author(s):

Martin L. Pall

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Inflammatory Diseases ◽

Pulmonary Arteries ◽

Chronic Inflammatory Disease ◽

Vicious Cycle ◽

Chronic Inflammatory Diseases ◽

Local Mechanism ◽

Pulmonary Arterial ◽

Symptoms And Signs

The NO/ONOO− cycle is a primarily local biochemical/physiological vicious cycle that appears to cause a series of chronic inflammatory diseases. This paper focuses on whether the cycle causes pulmonary arterial hypertension (PAH) when located in the pulmonary arteries. The cycle involves 12 elements, including superoxide, peroxynitrite (ONOO−), nitric oxide (NO), oxidative stress, NF-κB, inflammatory cytokines, iNOS, mitochondrial dysfunction, intracellular calcium, tetrahydrobiopterin depletion, NMDA activity, and TRP receptor activity. 10 of the 12 are elevated in PAH (NMDA?, NO?) and 11 have documented causal roles in PAH. Each stressor that initiates cases of PAH acts to raise cycle elements, and may, therefore, initiate the cycle in this way. PAH involves a primarily local mechanism as required by the cycle and the symptoms and signs of PAH are generated by elements of the cycle. Endothelin-1, which acts as a causal factor in PAH, acts as part of the cycle; its synthesis is stimulated by cycle elements, and it, in turn, increases each element of the cycle. This extraordinary fit to the principles of the NO/ONOO− cycle allows one to conclude that PAH is a NO/ONOO− cycle disease, and this fit supports the cycle as a major paradigm of chronic inflammatory disease.

Download Full-text