Immunoinflammatory Diseases Research Articles

Analgesics in rheumatic diseases – a necessary component of therapy aimed at improving the quality of life

Control of chronic pain is one of the main elements of the complex therapy of rheumatic diseases (RD). The use of analgesics is of fundamental importance for the management of patients with osteoarthritis (OA), since a unified system of pathogenetic therapy has not yet been developed for this disease. In immunoinflammatory rheumatic diseases (IRDs), such as rheumatoid arthritis, effective pathogenetic therapy can successfully control inflammatory activity. However, in many cases, in patients with IRDs, unpleasant symptoms (pain, fatigue, poor general well-being, etc.) persist even during remission and low inflammatory activity. This is associated with persistent structural changes, “secondary” OA, central sensitization, and concomitant fibromyalgia. Therefore, approximately 50% of patients with IRDs receiving modern pathogenetic therapy require additional use of analgesics. Therapy for musculoskeletal pain in RD should be complex, include drugs with different mechanisms of action and non-drug methods. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the first line therapy, they have good analgesic and anti-inflammatory potential. The choice of a specific NSAID should be based on an individual assessment of the clinical situation and the presence of risk factors for possible complications. Among NSAIDs, aceclofenac should be singled out – an effective drug with a favorable safety profile, which is confirmed by a large number of clinical studies and real clinical practice.

Hyaluronic acid in rheumatic disorders of the periarticular soft tissues: a brief descriptive review

Periarticular soft tissue disorders (PSTD) are typical manifestation of immunoinflammatory rheumatic diseases, primarily spondyloarthritis. However, in real clinical practice, physicians involved in the management of patients with musculoskeletal diseases often have to deal with "non-systemic" PSTD resulting from trauma, physical exertion, or degenerative processes associated with endocrine, metabolic, and cardiovascular diseases. PSTD causes acute and chronic pain, significant impairment of function and deterioration in the quality of life. The treatment of this pathology is complex and includes non-drug methods, painkillers and local injection therapy. Hyaluronic acid (HA) drugs occupy an important place in this treatment. Their use is pathogenetically justified, because when the tendon and enthesis are involved, the internal environment (intercellular matrix) change, and its basis is natural hyaluronate, which provides the viscoelastic properties of biological structures, as well as regulates metabolism, proliferative and immune processes. A relatively low molecular weight HA drug (530–730 kDa) has favorable rheological parameters, anti-inflammatory and anabolic potential, which makes it the drug of choice for local injection therapy of PSTD. This review briefly presents data on the pathogenesis of PSTD and the advisability of HA drugs use for its therapy, as well as the evidence base for the use of HA (530–730 kDa) in various types of ligamentous apparatus lesions.

Pathological changes in organs in rheumatoid arthritis with secondary amyloidosis of the heart and kidneys on the background of COVID-19

The COVID-19 pandemic is a global health emergency. The relevance of this problem in immunoinflammatory rheumatic diseases is due to the increased risk of infection with SARS-CoV-2 and its severe course. The paper describes the clinical features and morphological changes in organs in a patient with rheumatoid arthritis and secondary amyloidosis of the heart and kidneys, who died from an infection caused by SARS-CoV-2.

Clinical Variations of Uveitis in Immuno-Inflammatory Diseases. Review of the Literature. Part 1

Non-infectious uveitis is one of the main and insufficiently studied causes of disability and blindness in patients with immuno-inflammatory diseases. Uveitis associated with spondyloarthritis, Behcet’s disease, juvenile idiopathic arthritis, systemic sarcoidosis and Vogt-Koyanagi-Harada syndrome are described more often and better than others, but the pathogenesis of different variants of their course is not well understood. Also, there remains a need to study the clinical and pathogenetic features of uveitis in rare autoimmune inflammatory diseases. Despite the currently existing diagnostic and therapeutic schemes, further study of the pathogenesis of uveitis associated with immune-inflammatory diseases is required, the research of a personalized approach and an algorithm for joint multidisciplinary diagnosis by specialists in various fields. A deeper understanding of the specific pathogenetic mechanisms will reveal new possibilities in the treatment of patients with autoimmune uveitis. This article is devoted to the current clinical and differential diagnostic aspects, common features and distinctive features associated with various variants of the course of non-infectious uveitis in patients with immuno-inflammatory diseases.

Tumor necrosis factor‐alpha genetic variants and its interaction with smoking and tobacco chewing in oral precancerous lesions and oral cancer

AbstractIntroductionOral cancer is one of the most common cancers in Northern India. Carcinogenic substances found in cigarette or tobacco can cause inflammation of the lining of oral cavity and pathogenesis of oral cavity cancer. Tumor necrosis factor is a pro‐inflammatory cytokine involved in the immunoinflammatory diseases. The aim of this research was to determine the impact of smoking and tobacco chewing and polymorphism in TNFα −238 G/A and TNFα −308 G/A, on the risk to precancerous oral lesions and oral cavity cancer.MethodsGenotyping was done by polymerase chain reaction and restriction fragment length polymorphism method in 75 patients with oral cavity cancer, 75 patients confirmed with precancerous lesions, and 100 controls.ResultsTNFα −238 G/A SNP was not associated with the risk of oral precancerous lesions or oral cavity cancer. TNFα −308 G/A was strongly associated with precancerous lesions and oral cancer. No correlation was found between smoking or tobacco chewing habits and TNFα −238 and TNFα −308 G/A polymorphism with oral precancerous lesions and oral cavity cancer.ConclusionThe study shows no significant interaction between smoking or tobacco chewing habits and polymorphism in TNFα −238 and TNFα −308 G to A with precancerous lesions and oral cancer although TNFα −308 G/A was strongly associated with precancerous lesions and oral cancer.

Predisposing role of childhood mental trauma in immunoinflammatory rheumatic diseases and mental disorders

Psychic trauma received in childhood is a common phenomenon that causes damage to the child’s body that hasn’t been fully formed. Severe traumatic events in childhood disrupt the development of regulatory systems, which can lead to the occurrence of many diseases and disorders: increased risk of developing mental disorders, rheumatic, cardiovascular and oncological diseases, and reduced life expectancy. This article discusses the pathogenetic aspects of the influence of psychotraumas experienced in childhood on the occurrence of systemic inflammation and, as a result, the development of mental disorders and rheumatic diseases in adults.

Vaccine Prophylaxis of Herpes Zoster In Rheumatic Diseases: Paradigm Revision and New Opportunities

Background. The issues of vaccination against the herpesvirus infection are still important in rheumatological practice.This infection often develops in patients receiving immunosuppressive treatment, especially Janus kinase inhibitors (a class-specific adverse reaction) and genetically engineered biologics.The aim of this review is to highlight the current state of the issue of vaccination against Herpes zoster (HZ).Materials and Methods. 37 publications (4 domestic, 33 foreign) were analyzed, in which the mechanisms of pathogenesisand clinical features of herpesvirus infection in patients with immunodeficiency, both with and without immunoinflammatory rheumatic diseases (IIRD), the frequency and variety of post-vaccination reactions, complications and exacerbations of the course of IIRD were considered.Results. There is currently a trend towards reassessment of the rheumatological community's opinion about HZ vaccination, including live vaccine. Literature data allow us to express optimism regarding the effective prevention of herpes zoster in patients who plan to take drugs, primarily from the group of Janus kinase inhibitors. The advantages of the adjuvant recombinant subunit vaccine (Shingrix®) include the possibility of its use against the background of treatment with antirheumatic drugs without significant restrictions, as well as no need to postpone the initiation of the necessary therapy.Conclusions. Publications on the issues of HZ vaccination are few. It is necessary to conduct carefully controlled studies on the efficacy and safety of antiherpetic vaccines with an emphasis on the post-vaccination course of IIRD in patients with rheumatological profile, including in the Russian Federation.

Chronic unilateral anterior nodular scleritis with local inflammation of the ciliary body associated with the varicella-zoster virus

AIM: To analyze the etiopathogenesis, clinical features, and treatment algorithm for chronic unilateral anterior nodular scleritis with local inflammation of the ciliary body to increase medical alertness to the herpetic etiology of the disease in the absence of extraocular manifestations of herpes infection, reduce the disease duration, and increase the effectiveness of treatment.
 RESULTS: Features of etiopathogenesis were analyzed. The characteristic clinical symptoms of chronic nodular scleritis, local anterior cyclitis, and pars planitis caused by the varicella-zoster virus (VZV) were described. The etiological role of VZV has been established based on high levels of VZV-IgG antibodies, presence of VZV-gE-IgG antibodies (markers of active virus replication), and effectiveness of antiherpetic therapy.
 DISCUSSION: The surgical removal of a melanocytic skin nevus with skin autotransplantation in the paraorbital region of the left eye, in the zone of innervation of the first branch of the trigeminal nerve, contributed to the reactivation of the ophthalmic herpes and the development of anterior nodular scleritis of the left eye. An intensive long-term ineffective therapy with corticosteroids and antibacterial drugs in the absence of etiotropic treatment caused a chronic course of anterior nodular scleritis, spread of the inflammatory process to the ciliary body, and development of local anterior cyclitis and pars planitis of herpetic etiology in a 17-year-old child.
 CONCLUSION: Maximum medical alertness and early and accurate clinical differential diagnosis between scleritis associated with immunoinflammatory rheumatic diseases and herpesvirus infections are necessary since the expansion of the range and number of anti-inflammatory drugs used in the absence of positive dynamics from their use leads to a chronic disease course, damage not only to deep layers of the sclera but also the spread of inflammation to the deeper layers of the eyeball, a decrease in visual acuity, undesirable effects of local glucocorticoid therapy, and an increase in intraocular pressure and development of cataracts. With any scleritis resistant to conventional treatment, the likelihood of a herpetic etiology of the inflammatory process and laboratory diagnosis of ophthalmic herpes should be considered. In the absence of a specialized laboratory, for etiological diagnosis, the possibility of ex juvantibus antiviral therapy should be considered. The described clinical symptoms of chronic nodular scleritis with local lesions of the ciliary body contribute to the early diagnosis of ophthalmoherpes, which allows the timely initiation of antiviral therapy with an antiherpetic effect, prevents the development of a chronic disease course, occurrence of complications, and preservation and/or restoration of visual acuity.

Immunomodulatory Effects of (R)-Sulforaphane on LPS-Activated Murine Immune Cells: Molecular Signaling Pathways and Epigenetic Changes in Histone Markers.

The aim of this study was to explore the immunomodulatory effects of the natural enantiomer (R)-Sulforaphane (SFN) and the possible signaling pathways involved in an ex vivo model of LPS-stimulated murine peritoneal macrophages. Furthermore, we studied the epigenetic changes induced by (R)-SFN as well as the post-translational modifications of histone H3 (H3K9me3 and H3K18ac) in relation to the production of cytokines in murine splenocytes after LPS stimulation. (R)-SFN was able to modulate the inflammatory response and oxidative stress induced by LPS stimulation in murine peritoneal macrophages through the inhibition of reactive oxygen species (ROS), nitric oxide (NO) and cytokine (IL-1β, IL-6, IL-17, IL-18 and TNF-α) production by down-regulating the expression of pro-inflammatory enzymes (iNOS, COX-2 and mPGES-1). We also found that activation of the Nrf-2/HO-1 axis and inhibition of the JAK2/STAT-3, MAPK, canonical and non-canonical inflammasome signaling pathways could have been responsible for the immunomodulatory effects of (R)-SFN. Furthermore, (R)-SFN modulated epigenetic modifications through histone methylation (H3K9me3) and deacetylation (H3K18ac) in LPS-activated spleen cells. Collectively, our results suggest that (R)-SFN could be a promising epinutraceutical compound for the management of immunoinflammatory diseases.

Coronavirus Infection 2019 (COVID-19) and Autoimmunity.

The pandemic of coronavirus disease 2019, etiologically associated with the SARS-CoV-2 virus, has drawn the attention of the medical community to new clinical and fundamental problems in the immunopathology of human diseases. During a detailed analysis of the clinical manifestations and immunopathological disorders in COVID-19, it became apparent that SARS-CoV-2 infection is accompanied by the development of a wide range of extrapulmonary clinical and laboratory disorders, some of which are characteristic of immunoinflammatory rheumatic diseases and other human autoimmune and autoinflammatory diseases. All this taken together served as a theoretical justification for the repositioning of anti-inflammatory drugs in COVID-19, previously specifically designed for the treatment of immunoinflammatory rheumatic diseases. The prospects for studying the autoimmune mechanisms of COVID-19 and the possibility of anti-inflammatory therapy are discussed.

A mathematical modeling approach for elucidating the signaling pathways involved in macrophage cholesterol homeostasis and validation of AEBP1 role in atherosclerosis

Background and Aims : Atherosclerosis is an immunoinflammatory disease, characterized by the development of cholesterol-rich arterial plaques, leading to several CVDs and is the major cause of death worldwide. Our goal is to construct a predictive, dynamic mathematical network model of atherosclerosis that integrates in vitro and in vivo results to uncover the role of macrophages in atherosclerosis.

Industrializing AI-powered drug discovery: lessons learned from the Patrimony computing platform

ABSTRACT Introduction As a mid-size international pharmaceutical company, we initiated 4 years ago the launch of a dedicated high-throughput computing platform supporting drug discovery. The platform named ‘Patrimony’ was built up on the initial predicate to capitalize on our proprietary data while leveraging public data sources in order to foster a Computational Precision Medicine approach with the power of artificial intelligence. Areas covered Specifically, Patrimony is designed to identify novel therapeutic target candidates. With several successful use cases in immuno-inflammatory diseases, and current ongoing extension to applications to oncology and neurology, we document how this industrial computational platform has had a transformational impact on our R&D, making it more competitive, as well time and cost effective through a model-based educated selection of therapeutic targets and drug candidates. Expert opinion We report our achievements, but also our challenges in implementing data access and governance processes, building up hardware and user interfaces, and acculturing scientists to use predictive models to inform decisions.

Pneumococcal vaccination in rheumatic diseases: 10 years of application experience at the V.A. Nasonova Research Institute of Rheumatology

In the coming XXI century, infectious diseases still retain their importance both in medical and social terms, this problem is very relevant for rheumatology, where comorbid infections (CI) have a significant impact on both the course of the main immuno-inflammatory rheumatic disease (IIRD) and mortality. One of the leading places in the structure of serious CI in patients with IIRD is occupied by pneumonia, which is a weighty argument in favor of the vaccination of these patients from pneumococcal infection. The article presents generalized data on the use of 23-valent pneumococcal polysaccharide vaccine (PPV-23) in patients with IIRD who received inpatient and outpatient treatment at the V.A. Nasonova Research Institute of Rheumatology for the last 10 years. It has been shown that the vaccination of PPV-23 in patients with IIRD is characterized by high preventive efficacy (>90%), is safe and does not increase the risk of exacerbation of the disease. The sufficient immunogenicity of vaccination is evidenced by a significant increase in the levels of pneumococcal antibodies in the blood serum and the coefficient of post-vaccination response. The use of glucocorticoids (methylprednisolone, prednisolone) has no significant effect on the effectiveness, immunogenicity and safety of PPV-23 vaccination. The possibility of vaccination of PPV-23 with any activity of the process in patients with rheumatoid arthritis, systemic lupus erythematosus and spondyloarthritis (ankylosing spondylitis, psoriatic arthritis) with the condition of adequate therapy has been demonstrated. In order to develop clearer indications for vaccination, to determine time intervals for revaccination, to evaluate the effectiveness and safety of new pneumococcal vaccines, as well as to study the effect on the results of immunization of various anti-rheumatic drugs in patients with IIRD, further multicenter large-scale studies are needed.

Interleukin-6 inhibitors: from the therapy of immuno-inflammatory rheumatic diseases to use in COVID-19

The key role in the development of chronic autoimmune inflammation is played by pro-inflammatory cytokines, in particular, interleukin 6 (IL-6). The introduction into clinical practice of monoclonal antibodies inhibiting IL-6 is a significant event in rheumatology and is currently considered as a promising direction in the treatment of immuno-inflammatory rheumatic diseases. The first inhibitor of IL-6 (IL-6), which entered the practice of rheumatologists, was tocilizumab (TCZ), the second – sarilumab (SAR). Numerous studies have shown the high effectiveness of iIL-6: the use of drugs leads to a rapid decrease in the clinical manifestations of rheumatoid arthritis (RA) and a decrease in laboratory signs of inflammation, contributing to the achievement of low activity or remission, improves the quality of life of patients, and also slows down the X-ray progression of the disease. At the same time, iIL-6 has a satisfactory safety profile. The universal problem of our time – the pandemic of a new coronavirus infection – has led to attempts to use IL-6 in patients with severe and critical disease, since IL-6 plays an important role in the pathogenesis of COVID-19, which is confirmed by the results of numerous studies. However, data on the efficacy and safety of these drugs in COVID-19 are contradictory, which requires conducting larger-scale controlled studies. This review examines the issues of the effectiveness and safety of TCZ and SAR in rheumatological patients and in patients with COVID-19. The review is illustrated with examples from real clinical practice.

Efficacy and safety of abrocitinib versus dupilumab in adults with moderate-to-severe atopic dermatitis: a randomised, double-blind, multicentre phase 3 trial

Phase 3 trials have assessed efficacy of abrocitinib versus placebo in moderate-to-severe atopic dermatitis, a common immunoinflammatory skin disease. This study assessed the efficacy and safety of abrocitinib versus dupilumab. This randomised, double-blind, double-dummy, active-controlled, parallel-treatment, phase 3 trial enrolled adults with moderate-to-severe atopic dermatitis who requir=ed systemic therapy or had inadequate response to topical medications. Participants were enrolled from 151 sites, located in Australia, Bulgaria, Canada, Chile, Finland, Germany, Hungary, Italy, Latvia, Poland, Slovakia, South Korea, Spain, Taiwan, and the USA. These participants were then randomly assigned (1:1) with block randomisation to receive oral abrocitinib (200 mg per day) or subcutaneous dupilumab (300 mg every 2 weeks) for 26 weeks. Participants were required to apply topical corticosteroids (medium or low potency), topical calcineurin inhibitors, or a topical phosphodiesterase 4 inhibitor to active lesion areas. Primary endpoints were response based on achieving a 4 point or higher improvement in Peak Pruritus Numerical Rating Scale (PP-NRS4) at week 2 and a 90% or better improvement in Eczema Area and Severity Index (EASI-90) at week 4. Family-wise type 1 error was controlled via a sequential multiple-testing procedure (two sided, α=0·05). Randomly assigned participants who received at least one dose of study intervention were included in the efficacy and safety analysis sets. This trial was completed on July 13, 2021 (NCT04345367). Between June 11, 2020, and Dec 16, 2020, 940 patients were screened and 727 were enrolled (362 in the abrocitinib group and 365 in the dupilumab group). Compared with dupilumab, a larger proportion of patients treated with abrocitinib reached the primary outcomes, PP-NRS4 at week 2 (172 [48%] of 357, 95% CI 43·0-53·4 vs 93 [26%] of 364, 21·1-30·0; difference 22·6%, 15·8-29·5; p<0·0001), and EASI-90 at week 4 (101 [29%] of 354, 23·8-33·2 vs 53 [15%] of 364, 10·9-18·2; difference 14·1%, 8·2-20·0; p<0·0001). Treatment-emergent adverse events were reported by 268 (74%) of 362 patients treated with abrocitinib and by 239 (65%) of 365 patients treated with dupilumab. Two non-treatment-related deaths occurred in the abrocitinib group. Abrocitinib 200 mg per day was more efficacious than dupilumab in adults with moderate-to-severe atopic dermatitis on background topical therapy in inducing early reductions of itch and atopic dermatitis disease signs. Both treatments were well tolerated over 26 weeks. Pfizer.

Emerging Pathophysiological Mechanisms Linking Diabetes Mellitus and Alzheimer's Disease: An Old Wine in a New Bottle.

Type-2 diabetes mellitus (T2DM) is a chronic immuno-inflammatory and metabolic disease characterized by hyperglycemia and insulin resistance with corresponding hyperinsulinemia. On the other hand, Alzheimer’s disease (AD) is a neurodegenerative disease involving cognitive impairment, neuronal dysfunction, and memory loss. Several recently published literatures suggest a causal relationship between T2DM and AD. In this review, we have discussed several potential mechanisms underlying diabetes-induced cognitive impairment which include, abnormal insulin signaling, amyloid-β accumulation, oxidative stress, immuno-inflammation, mitochondrial dysfunction, advanced glycation end products, acetylcholinesterase and butyrylcholinesterase, advanced lipid peroxidation products, and apolipoprotein E. All these interconnected mechanisms may act either individually or synergistically which eventually leads to neurodegeneration and AD.

Методические рекомендации по рентгенологическим методам исследования при ревматоидном артрите и анкилозирующем спондилите

Radiological examination remains the "gold standard" for instrumental diagnosis of the most common immunoinflammatory rheumatic diseases – rheumatoid arthritis (RA) and ankylosing spondylitis (AS). This publication discusses the indications and methodological aspects of performing standard radiography of the musculoskeletal system in RA and AS. It also describes the main radiological symptoms, methods for assessing the staging of the disease (according to O. Steinbrocker and J. Kellgren), methods for assessing radiological progression: in RA – according to J.T. Sharp/D.M. van der Heijde and A. Larsen, in AS – mSASSS, RASSS, BASRI.

Janus kinase inhibitors in immunoinflammatory rheumatic diseases

Despite great advances in the diagnosis and treatment of immunoinflammatory rheumatic diseases, which have led to a significant improvement in the prognosis in many patients, the fundamental medical problems of this pathology the restoration of the quality of life and the reduction of mortality to the population level are far from being resolved. This served as a stimulus for the study of new approaches to the pharmacotherapy of IVRD, one of which is associated with the use of low molecular weight chemically synthesized drugs that inhibit intracellular "signaling" molecules Janus kinase. Modern advances regarding the use of Janus kinase inhibitors in the treatment of immunoinflammatory rheumatic diseases and COVID -19 are considered.

Immuno-inflammatory rheumatic diseases and COVID-19: analysis of clinical outcomes according to the data of the register of patients of the Novosibirsk region receiving therapy with genetically engineered biological drugs

Currently, observations are accumulating indicating the negative effect of therapy with a number of biologic disease-modifying anti-rheumatic drugs (bDMARDs) drugs on the course of COVID-19. These facts determine the relevance of studying the factors of severe course and unfavorable outcome in immuno-inflammatory rheumatic diseases (IIRD) patients treated with bDMARDs in order to develop tactics for managing this category of patients in a pandemic. To evaluate the influence of clinical and demographic factors on the risk of development, severity of the course and clinical outcomes of a new coronavirus infection in patients suffering from IIRD and receiving therapy with genetically engineered biological drugs. A retrospective analysis of the database of the register of patients with IIRD receiving bDMARDs in the Novosibirsk region was performed, which included 318 patients, 94 of whom had indications of having suffered viral infection/pneumonia for the period from 01.04.2020 to 31.12.2020. According to the data obtained, at the time of the analysis, 94 people out of 318 patients with IIRD had a new coronavirus infection. Most (53%) of the patients had a mild infection. At the same time, the nosological form, the use of anti-rheumatic drugs and glucocorticoids did not increase the risks of severe coronavirus infection. When using bDMARDs, only anti-B-cell therapy (rituximab) associated with statistically significant increase in the risk of severe/extremely severe COVID-19. The mortality rate according to the analysis of the register was 6,38%. Patients with IIRD have a high risk of severe coronavirus infection, while the severity of the disease is associated with the type of therapy performed.

Isolated neuro-Behçet’s disease in a child, from headache to diagnosis: A case report

Behçet's disease (BD) is an immuno-inflammatory multi-systemic disease characterized by ophthalmological and skin involvement, also oral and genital ulcers. Its etiology and pathogenesis are not clearly known. Neuro-Behçet's disease can occur as an isolated form or a rare complication of BD. Besides, diagnosis of neuro-Behçet's disease is difficult. Since Neuro-Behçet can result in morbidity and mortality, early diagnosis and treatment are important. The most important genetic factor in the pathogenesis of BD is Human Leucocyte Antigen (HLA-B 51) allele positivity. A 9-year-old girl was brought to our outpatient clinic for 6 months with a migraine-like headache. The headache of the patient has a partial response to analgesics and rarely awakes from sleep at night accompanied by vomiting. The patient was diagnosed with an isolated neuro-Behçet's disease by HLA-B 51 allele positivity and brain magnetic resonance imaging (MRI) findings. In the current study, the roles of HLA-B 51 allele positivity and brain MRI findings were discussed in the diagnosis of neuro-Behçet's disease.