Immune-mediated Rheumatic Diseases Research Articles

Comorbid infections in spondyloarthritis: a modern view of the problem

The review considers the problem of comorbid infections (CIs) in ankylosing spondylitis and psoriatic arthritis (PsA) as the main nosological entities of spondyloarthritis (SpA). It analyzes the frequency of CIs during therapy with biological agents and targeted synthetic disease-modifying anti-rheumatic drugs. It is concluded that the problem of CI in SpA deserves the closest attention. The review also shows the importance of preventive measures for CI in the treatment of SpA. It is in particular noted that in accordance with the updated guidelines of the European League Against Rheumatism and other rheumatology research associations, all patients with immunemediated inflammatory rheumatic diseases (including SpA) on immunosuppressive therapy are recommended to get influenza and pneumococcal vaccines due to the high risk of death from respiratory tract infections. Moreover, vaccination is indicated even for patients with an expected suboptimal response. The review gives the main points of the recommendations of the Medical Board of the National Psoriasis (Ps) Foundation on the use of recombinant Herpes zoster vaccine in patients with Ps/PsA. There is a need for further investigations of the frequency and pattern of CIs and the impact of new therapy options on the prevalence of CIs in patients with SpA. Determination of the effectiveness and safety of vaccination in this patient population should become an important area for future investigations.

Type II diabetes mellitus risk assessment using FINDRISC questionnaire in systemic lupus erythematosus patients

Objective. To evaluate the prevalence of traditional risk factors in systemic lupus erythematosus (SLE) patients, assess the 10-years risk of developing type 2 diabetes mellitus (DM) in SLE patients and identify those necessitating preventive interventions following altered glucose metabolism using the Finnish Type 2 Diabetes Risk Score (FINDRISK) questionnaire.Materials and methods. The study included 119 SLE patients (107 women, 12 men, with median age 39 [33; 47] years and mean disease duration 6 [1,12] years.The control group included 100 age and sex matched individuals without immune-mediated inflammatory rheumatic diseases and without previous DM history. The 10-years risk of developing type 2 DM in SLE patients and the controls assessed using the Russian adaptation of Finnish Type 2 Diabetes Risk Score questionnaire. Fasting glucose levels in venous blood were measured in all SLE patients. Glucose levels ≥6.1 mmol/L were interpreted as fasting hyperglycemia.Results. The prevalence of traditional type 2 DM risk factors in SLE patients was as follows: abdominal obesity was found in 63.9%, lack of physical activity – in 62.2%, intake of antihypertensive drugs— in 52.9%, BMI ≥25 kg/m2 in 42.0%, unhealthy diets – in 40.3%, family history of DM – in 35.3%, age over 45 years – in 32.8%, history of hyperglycemia episodes – in 15.1%. Abdominal obesity and intake of antihypertensive drugs were more often documented in SLE patients, while all other risk factors were equally represented in SLE and control groups. On average 3 [2; 5] risk factors were found in each SLE patient. Low type 2 DM risk was a more rare phenomenon in SLE patients vs healthy controls (36.1 and 51%, р<0.05). Primary type 2 DM prophylaxis recommended in case of moderate, high and very high risk was more often indicated in SLE vs the healthy controls (29.4 and 17.0%, р=0.03), including those younger than 45 years (18.3 and 6.1% respectively, р=0.05). Fasting hyperglycemia was found in 1.2% patients with low-slightly increased type 2 DM risk and in 16.1% individuals with moderate, high and very high risk (p=0.04).Conclusions. High prevalence of such traditional type 2 DM risk factors as abdominal obesity, lack of physical activity and intake of antihypertensive drugs was demonstrated in SLE patients. Finnish Type 2 Diabetes Risk Score questionnaire identified moderate, high and very high 10-year risk of developing type 2DM in 29.4% SLE patients, necessitating prophylactic interventions in view of altered glucose metabolism.

JAK inhibitors in immune-mediated rheumatic diseases: From a molecular perspective to clinical studies

The Janus Kinase signalling pathway is implicated in the pathogenesis of immune-related diseases. The potency of small-molecule Janus Kinase inhibitors in the treatment of inflammatory diseases demonstrates that this pathway can be successfully targeted for therapeutic purposes. The outstanding relevant questions concerning drugs’ efficacy and toxicity challenge the research to enhance the selectivity of these drugs. The promising results of computational techniques, such as Molecular Dynamics and Molecular Docking, coupled with experimental studies, can improve the understanding of the molecular mechanism of Janus Kinase pathway and thus enable the rational design of new more selective inhibitor molecules.

Coronavirus disease-2019 (COVID-19): value of IL-6 inhibitors

The coronavirus disease 2019 (COVID-19) pandemic has drawn attention to new clinical and fundamental issues in the immunopathology of human diseases. Since in COVID-19 it is the ‘‘hyperimmune’’ response, called cytokine storm syndrome, which forms the basis of the pathogenesis of acute respiratory distress syndrome (ARDS) and multiorgan dysfunction in COVID-19, special attention is drawn to the possibility of “repurposing” (drug repurposing) of some widely used for treatment immune-mediated inflammatory rheumatic diseases (IMIRDs) anti-inflammatory drugs, including glucocorticoids (GC), disease-modified anti-rheumatic drugs (DMARDs), biologic agents and ‘‘targeted’’ DMARDs. In the spectrum of cytokines involved in the pathogenesis of cytokine storm syndrome in IMIRDs and COVID-19, great importance is attached to the pro-inflammatory cytokine, interleukin IL-6. The development and introduction into clinical practice of monoclonal antibodies (mAbs) that inhibit the activity of IL-6 are among the major advances in the treatment of IMIRDs, and in recent years, critical conditions within the framework of the cytokine storm syndrome, including in COVID-19. The review discusses the materials of numerous studies devoted to the problems of the efficacy and safety of mAbs to the IL-6 receptor (tocilizumab) and other mAbs that inhibit the activity of this cytokine in COVID-19. Despite the effectiveness of inhibiting IL-6 in patients with severe COVID-19, many theoretical and clinical problems of immunopathology and pharmacotherapy of this disease require further study.

Impact of Chronic Use of Antimalarials on SARS-CoV-2 Infection in Patients With Immune-Mediated Rheumatic Diseases: Protocol for a Multicentric Observational Cohort Study.

BackgroundCOVID-19, caused by the virus SARS-CoV-2, has brought extensive challenges to the scientific community in recent months. Several studies have been undertaken in an attempt to minimize the impact of the disease worldwide. Although new knowledge has been quickly disseminated, including viral mechanisms, pathophysiology, and clinical findings, there is a lack of information on the effective pharmacological management of this disease. In vitro studies have shown some benefits related to the use of antimalarials (chloroquine and hydroxychloroquine) for inhibiting SARS-CoV-2. However, the data from open clinical trials on COVID-19 patients are controversial.ObjectiveWe present the protocol for a research project that compares the potential protective effect of antimalarials in preventing moderate-to-severe forms of COVID-19 in two groups: (1) patients treated chronically with antimalarials for rheumatic diseases and (2) other members of the patients’ household who have not been diagnosed with rheumatic diseases and are not taking antimalarials.MethodsThis is a 24-week, prospective, observational cohort study comprising patients from public and private health services across Brazil, who chronically use antimalarials for the treatment of immune-mediated rheumatic diseases, osteoarthritis, or chikungunya-related arthropathy. A total of six sequential phone interviews were scheduled during the COVID-19 outbreak in five different regions of Brazil. Information regarding social, epidemiological, and demographic data, as well as details about rheumatic diseases, antimalarials, comorbidities, and concomitant medication, is being recorded using a specific online form in the REDCap database. Symptoms suggestive of COVID-19, including fever, cough, dyspnea, anosmia, and dysgeusia, are being self-reported and collected via phone interviews. Our main outcomes are hospitalization, need of intensive care unit, and death.ResultsRecruitment began at the end of March 2020, and the inclusion was done during an 8-week period (from March 29 to May 17) with a total of 10,443 individuals enrolled at baseline, 5166 of whom have rheumatic diseases, from 23 tertiary rheumatology centers across 97 Brazilian cities. Data analysis is scheduled to begin after all inclusion data have been collected.ConclusionsThis study, which includes a large sample of chronic antimalarial users, will allow us to explore whether SARS-CoV-2 infection may be associated with immune-mediated rheumatic diseases and long-term antimalarial usage.Trial RegistrationBrazilian Registry of Clinical Trials RBR–9KTWX6; http://www.ensaiosclinicos.gov.br/rg/RBR-9ktwx6/International Registered Report Identifier (IRRID)DERR1-10.2196/23532

Coronavirus disease 2019 (COVID-19) and immune-mediated inflammatory rheumatic diseases: at the crossroads of thromboinflammation and autoimmunity

Inflammation and coagulation are key basic mechanism of protection against all potentially pathogenic mechanical and biological factors targeting human organism from inner and outer environment. On the other hand, uncontrolled inflammation results in hypercoagulation, inhibition of anticoagulation and alteration of mechanisms responsible for resolution of inflammation, while production of “procoagulant” mediators (thrombin, tissue factor and others), activation of platelets and of vascular endothelial cells maintains inflammation. All factors taken together serve as the basis for a pathological process called thromboinflammation or immunothrombosis. Currently thromboinflammation is considered in the broad sense as a universal pathogenetic mechanism of numerous widespread acute and chronic conditions, including immune-mediated (autoimmune) inflammatory rheumatic diseases, oftentimes complicated by severe irreversible damage to vital organs. Thromboinflammation gained specific attention during СОVID-19 (coronavirus disease 2019) pandemic, caused by SARS-Cov-2 (severe acute respiratory syndrome Coronavirus-2). COVID-19 is considered currently as systemic thromboinflammation syndrome, manifesting via generalized thrombosis of arterial and venous macro- and microvasculature, termed as COVID-19-coagulopathy. The paper discusses common pathogenetic coagulopathy mechanisms in COVID-19 and immune-mediated (autoimmune) inflammatory rheumatic diseases (IMRDs), associated with overproduction of antiphospholipid antibodies, activation of the complement system, and dis-regulated synthesis of proinflammatory cytokines, etc. Delineating the autoimmune subtype of thromboinflammation, identification of genetic (i.e., genes encoding the complement system and others) and molecular-biologic biomarkers associated with higher occurrence of COVID-19-coagulopathy are the most relevant undertakings for the current practice. Gaining insights into mechanisms of thromboinflammation and converting them into potential pharmacotherapies of IMDs would facilitate and accelerate the drafting of effective therapeutic strategies for COVID-19.

The multifaceted functional role of DNA methylation in immune-mediated rheumatic diseases.

Genomic predisposition cannot explain the onset of complex diseases, as well illustrated by the largely incomplete concordance among monozygotic twins. Epigenetic mechanisms, including DNA methylation, chromatin remodelling and non-coding RNA, are considered to be the link between environmental stimuli and disease onset on a permissive genetic background in autoimmune and chronic inflammatory diseases. The paradigmatic cases of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sjogren's syndrome (SjS) and type-1 diabetes (T1D) share the loss of immunological tolerance to self-antigen influenced by several factors, with a largely incomplete role of individual genomic susceptibility. The most widely investigated epigenetic mechanism is DNA methylation which is associated with gene silencing and is due to the binding of methyl-CpG binding domain (MBD)-containing proteins, such as MECP2, to 5-methylcytosine (5mC). Indeed, a causal relationship occurs between DNA methylation and transcription factors occupancy and recruitment at specific genomic locus. In most cases, the results obtained in different studies are controversial in terms of DNA methylation comparison while fascinating evidence comes from the comparison of the epigenome in clinically discordant monozygotic twins. In this manuscript, we will review the mechanisms of epigenetics and DNA methylation changes in specific immune-mediated rheumatic diseases to highlight remaining unmet needs and to identify possible shared mechanisms beyond different tissue involvements with common therapeutic opportunities. Key Points • DNA methylation has a crucial role in regulating and tuning the immune system. • Evidences suggest that dysregulation of DNA methylation is pivotal in the context of immune-mediated rheumatic diseases. • DNA methylation dysregulation in FOXP3 and interferons-related genes is shared within several autoimmune diseases. • DNA methylation is an attractive marker for diagnosis and therapy.

BARICITINIB: NEW PHARMACOTHERAPY OPTIONS FOR RHEUMATOID ARTHRITIS AND OTHER IMMUNE-MEDIATED INFLAMMATORY RHEUMATIC DISEASES

Deciphering the mechanisms of the pathogenesis of immune-mediated inflammatory rheumatic diseases (IMIRDs) in conjunction with designing a wide range of biological agents is one of the major medical advances in the 21st century. A new promising area of pharmacotherapy for IMIRDs is associated with the design of the so-called targeted oral medications that primarily include Janus kinase (JAK) inhibitors. The review presents new data on the efficacy and safety of the new JAK inhibitor baricitinib in treating rheumatoid arthritis and other IMIRDs.

IMMUNOPATHOLOGY AND IMMUNOPHARMACOTHERAPY OF CORONAVIRUS DISEASE 2019 (COVID-19): FOCUS ON INTERLEUKIN 6

The Coronavirus Disease 2019 (COVID-19) pandemic has drawn closer attention than ever before to the problems of the immunopathology of human diseases, many of which have been reflected when studying immune-mediated inflammatory rheumatic diseases (IIRDs). The hyperimmune response called a cytokine storm, the pathogenetic subtypes of which include hemophagocytic lymphohistiocytosis, macrophage activation syndrome, and cytokine release syndrome, is among the most serious complications of IIRDs or treatment for malignant neoplasms and may be a stage of COVID-19 progression. A premium is placed to interleukin-6 (IL-6) in the spectrum of cytokines involved in the pathogenesis of the cytokine storm syndrome. The clinical introduction of monoclonal antibodies (mAbs) that inhibit the activity of this cytokine (tocilizumab, sarilumab, etc.) is one of the major advances in the treatment of IIRDs and critical conditions within the cytokine storm syndrome in COVID-19. The review discusses data on the clinical and prognostic value of IL-6 and the effectiveness of anti-IL-6 receptor and anti-IL-6 mAbs, as well as prospects for personalized therapy of the cytokine storm syndrome in COVID-19.

Revisiting hydroxychloroquine and chloroquine for patients with chronic immunity-mediated inflammatory rheumatic diseases

Hydroxychloroquine and chloroquine, also known as antimalarial drugs, are widely used in the treatment of rheumatic diseases and have recently become the focus of attention because of the ongoing COVID-19 pandemic. Rheumatologists have been using antimalarials to manage patients with chronic immune-mediated inflammatory rheumatic diseases for decades. It is an appropriate time to review their immunomodulatory and anti-inflammatory mechanisms impact on disease activity and survival of systemic lupus erythematosus patient, including antiplatelet effect, metabolic and lipid benefits. We also discuss possible adverse effects, adding a practical and comprehensive approach to monitoring rheumatic patients during treatment with these drugs.

COVID-19: the new challenge for rheumatologists

Currently, the infection caused by the new coronavirus COVID-19 is considered by the global community as an emergency of international concern. Rheumatologists are particularly concerned about this problem, since patients with immune-mediated inflammatory rheumatic diseases (IMIRDs) are at higher risk for infectious diseases and receive immunosuppressive treatment. The use of disease-modifying antirheumatic drugs and biological agents increases the incidence of serious infections, but insufficient/no monitoring of IMIRD activity is an even greater risk factor for infectious complications. In addition, the role of vaccination mainly against influenza and pneumococcal infection is substantially increasing in modern conditions, since the risk of death from respiratory tract infections is quite high in patients with IMIRDs, which is very important in the context of the current COVID-19 pandemic.The paper presents an update on the incidence of viral infections in patients with IMIRDs and also discusses whether antirheumatic drugs can be used to treat COVID-19.

Cancer alertness in patients with rheumatic diseases

The processes that vary in nature and underlie the pathogenesis of malignant neoplasms (MNs) and immune-mediated inflammatory rheumatic diseases (RDs) share just the same some common features. Thus, many early-stage neoplasias can mask autoimmune diseases, requiring that physicians of various specialties should comply with the principle of cancer alertness. When specific cancer treatments (immunotherapy, cytostatic therapy, radiotherapy) are performed, there may be certain rheumatic syndromes (arthritis, myalgia, serositis, etc.) that require a differential diagnosis. At the same time, the course of a number of RDs (rheumatoid arthritis, Sjögren's syndrome, and polymyositis) can be accompanied by the development of MNs, which is relevant for real clinical practice and calls for further investigation.The community of etiological factors and a genetic predisposition in the development of RDs and MNs remain to be of no less importance. At the same time, therapists should pay attention to the presence of rheumatic masks in many MNs, which undoubtedly prolongs the time between onset of the first symptoms and correct diagnosis.

Lower concentration of vitamin D is associated with lower DAS28 and VAS-pain scores in patients with inflammatory rheumatic diseases treated with infliximab: a pilot study.

Vitamin D is beneficial in patients with immune-mediated rheumatic diseases as it has been shown that it lowers the incidence risk and the level of inflammation. To examine the association between clinical outcomes and initial 25-hydroxyvitamin D [25(OH)D] concentrations in patients with the immune-mediated rheumatic diseases treated with infliximab for 9months. This study was performed in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) treated with infliximab for at least 38weeks. Disease activity was assessed using Disease Activity Score (DAS28) for RA and PsA and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for AS, while the global assessment was performed using the Visual Analogue Scale (VAS). Patients were divided into 2 groups according to 25(OH)D concentration which was classified as deficient or non-deficient (below and above 50nmol/L, respectively). Concentrations of infliximab (IFX) and C-reactive protein (CRP) were measured according to the manufacturer's instructions.This study was performed in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) treated with infliximab for at least 38weeks. Disease activity was assessed using Disease Activity Score (DAS28) for RA and PsA and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for AS, while the global assessment was performed using the Visual Analogue Scale (VAS). Patients were divided into 2 groups according to 25(OH)D concentration which was classified as deficient or non-deficient (below and above 50nmol/L, respectively). Concentrations of infliximab (IFX) and C-reactive protein (CRP) were measured according to the manufacturer's instructions. The study included 23 patients (14 with RA, 6 with AS and 3 with PsA), median age 54years, 15 females. Vitamin D deficient and non-deficient groups had median initial concentrations of 38 and 61nmol/L, respectively. DAS28 and pain on VAS calculated at the 2nd and 38th week showed a statistically significant decrease only in RA and PsA patients with vitamin D deficiency (P = 0.02 and 0.06, respectively). Lower initial concentration of 25(OH)D in patients treated with infliximab was associated with better improvement of clinical measures (DAS28 and VAS) of disease after 9months of therapy.

Vaccination in Rheumatology: New Data (Based on Recommendations of the European League Against Rheumatism)

Comorbid infections have a significant effect on morbidity and mortality in modern rheumatology, especially in immune-mediated inflammatory rheumatic diseases (IMIRD). In this regard, vaccination is becoming increasingly important in the prevention of infections in IMIRD. The article analyzes an updated version of the recommendations for vaccination of adult patients with IMIRD, proposed by experts of the European League Against Rheumatism at the end of 2019. The safety and immunogenicity of vaccination associated with the prevention of various infections in patients with IMIRD are discussed. The main directions of future research on this issue are outlined.

CORONAVIRUS DISEASE 2019 (COVID-19): A RHEUMATOLOGIST’S THOUGHTS

In December 2019, an outbreak of a novel infection under the working name 2019-nCoV was registered in Wuhan (the Hubei Province located in China's central region), which has quickly spread throughout almost the entire world and become pandemic. The World Health Organization (WHO) proposed a new name coronavirus disease (COVID-19) for this disease, whereas the International Committee on Virus Taxonomy renamed 2019-nCov as SARS-Cov-2 (Severe Acute Respiratory Syndrome Coronavirus-2). The development of the COVID-19 pandemic is not only of great social importance, but also draws the attention of a medical community to the fundamentally new clinical and fundamental problems of the immunopathology of human diseases that are yet to be formulated. The unique experience gained in rheumatology from studies of the pathogenetic mechanisms and pharmacotherapy of immune-mediated inflammatory rheumatic diseases (IMIRDs) can be of great importance for deciphering the nature of the pathological processes that underlie the severe, potentially fatal complications of COVID-19, and may assist in improving their therapy. As for prospects in patients with IMIRDs, although the development of COVID-19 in the presence of IMIRDs has not yet fortunately been described, infection with SARS-CoV-2, like other viruses, can be assumed to cause an exacerbation of the pathological process, whereas severe immune system pathology and comorbidities can worsen the course of infection. Since, according to the current concepts, it is the «hyperimmune» response, and not just the effect only of the virus itself, that underlies lung damage and deaths from COVID-19, special attention is drawn to the effects of antirheumatic therapy that includes glucocorticoids, disease-modifying anti-rheumatic drugs (DMARDs), biological agents, and targeted DMARDs, which can have a multidirectional effect on the course of COVID-19. There are significant theoretical prerequisites for the repurposing of some drugs widely used in rheumatology for the treatment of COVID-19 and its complications. Consideration is given to the prospects of studying the immunopathology of COVID-19 and to the theoretical justifications for the use of antimalarial 4-aminoquinolines, anti-cytokine monoclonal antibodies (mAbs), and Janus kinase inhibitors for the prevention of complications and for the treatment of COVID-19.

EFFICACY AND SAFETY OF TOFACITINIB FOR IMMUNEMEDIATED INFLAMMATORY RHEUMATIC DISEASES (PART II)

The design of targeted oral anti-inflammatory drugs, such as Janus kinase (JAK) inhibitors, the first representative of which is tofacitinib (TOFA), is considered a major achievement in biology and medicine early in the 21 st century. Part I of the review considers the materials of studies evaluating the efficacy and safety of TOFA in rheumatoid arthritis (RA). The expansion of ideas about the mechanisms of development and chronicity of inflammation and the antiinflammatory and immunomodulatory effects of TOFA using a RA model has created theoretical and clinical prerequisites for studying the efficacy of TOFA in other immune-mediated inflammatory rheumatic diseases (IMIRDs) and chronic inflammatory non-rheumatic diseases. Part II of the review summarizes new data that allow one to formulate main areas of further clinical and fundamental studies, the objective of which is to expand indications for and to personalize therapy with JAK inhibitors in patients with IMIRDs.

HEPATITIS B VIRUS AND RHEUMATIC DISEASES

Hepatitis B virus (HBV) is often found and associated with immune-mediated inflammatory rheumatic diseases (IMIRDs), necessitating the modification of both antiviral and antirheumatic therapies. The review provides basic information about the structure of HBV, the course of chronic HBV infection, and the prevention of HBV reactivation in patients with IMIRDs who receive immunosuppressive therapy.

Efficacy and safety of tofacitinib for immune-mediated inflammatory rheumatic diseases (Part I)

Efficacy and safety of tofacitinib for immune-mediated inflammatory rheumatic diseases (Part I)

The role of the procalcitonin test in the diagnosis of infections in immune-mediated inflammatory rheumatic diseases

Objective: to evaluate the role of the procalcitonin (PC) test in the diagnosis of infections in immune-mediated inflammatory rheumatic diseases (IIRDs). Subjects and methods. The investigation enrolled 325 patients (216 women, 109 men) aged 2 to 82 years with different IIRDs. The serum PC concentration was determined by the quantitative electrochemiluminescence method using a Cobas E 411 analyzer (Roche, Switzerland). Results and discussion . The infectious process was detected in 145 (44.6%) patients: generalized and local infections in 11 and 134 cases, respectively. Local infections were regarded as severe and mild in 61 and 73 cases, respectively. In patients with generalized infection, the median (Me) PC level was 3.6 [0.88; 11.3] ng/ml. In this group, the PC values exceeded 2 and 10 ng/ml in 73% and 27%, respectively. In severe local infection, the Me PC level was 0.33 [0.23; 0.88] ng/ml, in mild infection — 0.12 [0.05; 0.16] ng/ml. In 180 patients without infection, it was 0.11 [0.05; 0.17] ng/ml, whereas higher PC levels were found in adult onset Still's disease (0.39 [0.14; 0.51] ng/ml), systemic juvenile arthritis (0.17 [0.11; 0.56] ng/ml) and systemic lupus erythematosus (0.11 [0.06; 0.15] ng/ml). The level of PC was significantly higher in the patients with generalized infection than that in those without infection (p<0.0001), as well as in those with mild (p<0.0001) and severe (p<0.0001) local infection. The PC level was higher in patients with severe local infection than in those without infection (p<0.001) and in those with mild local infection (p=0.004). There were no significant differences in PC levels in the patients with mild local infection and in those without infection. The ROC analysis showed that the diagnostic significance of PC determination was excellent in generalized infection, very good in severe local infection, and very good when differentiating generalized from local infection. Conclusion. Measuring PC is sure to contribute to the diagnosis of generalized and severe local infections in patients with IIRDs. However, when interpreting the PC values, it is necessary to take into account the pooled data: a specific rheumatic nosological entity and clinical, laboratory, and instrumental findings. The multimarker approach can be considered as a promising way to diagnose infections in IIRDs.

The development of rheumatology at the stage of formation of a new technological paradigm

Using rheumatology as an example, the paper considers current trends in the development of medical science in the 21st century. It is emphasized that biochemistry, genetics, and molecular biology are becoming the central research priority site attracting to clinical medicine and rheumatology, neuroscience (including cognitive and computational neurobiology, neuroinformatics), and psychology. Modern rheumatology effectively adapts current scientific achievements, which contributes to the significant progress of fundamental and clinical medicine. Deciphering the key immune mechanisms of the pathogenesis of immune-mediated inflammatory rheumatic diseases (IIRD) has allowed biotechnology techniques to be used to design fundamentally new drugs, such as biological agents, small molecules that are able to selectively affect certain pathogenetic constituents and to minimize the overall functioning of the immune system. This could substantially enhance the efficiency of treatment for IIRDs, by achieving a long-term stable remission in many patients and contributed to a significant expansion of ideas on human pathology. It is assumed that most promising studies of pharmacotherapy for IIRDs towards personalized medicine will be based on postgenomic technologies, including proteomics, transcriptomics, metabolomics, epigenomics, as well as the integrated use of digital methods.