**Preclinical and Predictive Algorithms in Monitoring Patients with Autoimmune Diseases and Their Relatives-at-Risks**

Sergey Suchkov1,2, Dmitry Kostyushev1, Dmitry Gnatenko1, Sevindzh Gadzhieva1 and Mikhail Paltsev3 *1I.M. Sechenov First Moscow State Medical University 2Moscow State Medical Dentistry University, National 3Research Center "Kurchatov Institute" Russia* 

#### **1. Introduction**

190 Autoimmune Disorders – Current Concepts and Advances from Bedside to Mechanistic Insights

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Dec 12, 19057-19062.

Millions of people all round the world suffer from various autoimmune disorders. T1D, MS, SLE, autoimmune diseases of the heart, liver, intestine and other internal organs, etc., all represent severe manifestations, which deteriorate the quality of life and cause physical disability and even death in patients with chronic illnesses. Every year, the largest world economies incur megabuck losses associated with medical services, insurance and drug procurement, not to mention the ever decreasing size of the able-bodied population. The development of preclinical diagnostic algorithms for autoimmune diseases, their implementation and introduction into routine clinical practice will help detect tissue or organ pathologies at the stages where their reversal is still possible. Early implementation of causal therapy allows the physician to compensate for the lack of one or another organ and ensures complete recovery or significant improvement of the patient's health status. However, in developing updated preventive protocols, the investigator is faced with a necessity to solve fundamental problems in order to understand:


While constructing preclinical monitoring algorithms, one should also take into consideration the diseases suffered by patients' relatives. One of the cornerstones in preventive and predictive medicine is screening for genetic abnormalities or hereditary predisposition. All-encompassing analysis of gene units and construction of individual genetic maps not only facilitate the assessment of individual risks for each concrete patient, but also allows prediction of disease development in first-degree-relatives. Therefore, today's objective demands include not only large-scale monitoring of definite cohorts of the general population, but, rather, identification of high risk cohorts coupled with genetic abnormalities and/or shifts and social factors (residence, place of employment, occupation, living conditions, etc.). However, even a comprehensive analysis is inadequate without a set

Preclinical and Predictive Algorithms in Monitoring

postscreening management of patients, which includes:

with regimen and other preventive measures, etc.);

cellular pools *in vivo*.

treatment;

standards;

**etiology** 

Patients with Autoimmune Diseases and Their Relatives-at-Risks 193

Taking into consideration the foregoing and being guided by the Major Preventive and Preventive Medicine Principle, we developed an original protocol for screening and

Comprehensive genetic analysis for estimating potential risks for patient's (or his/her relatives') individuality and design of protocols for diagnostic assessment and preventive

Proteomic analysis and detection of metabolic shifts including identification of biomarkers (e.g., autoAbs in case of autoimmune disorders); monitoring of evolutional and spectral characteristics of biomarkers; control over emergence of new biomarkers for updating prophylactic and preventive treatment protocols and maintenance of high curability

Persistent control over predisposing factors including identification of factors potentiating specific pathologies (analysis of bacterial and virus-borne infections, monitoring compliance

Psychologic doctor-patient cooperation, strict compliance with doctor's recommendations and requirements through elucidation of disease severity (including the preclinical stage). The use of advanced screening strategies and early implementation of specific therapy ensure substantial reduction of morbidity and mortality from autoimmune disorders and, as a consequence, significant improvement of life quality and minimization of economic losses. The same principles are embodied in the guidelines of preventive and predictive medicine. Their practical realization may culminate in the establishment of an international research network, development of novel criteria for preclinical diagnosis and treatment and

validation of uniform specifications and standards for laboratory diagnostics.

specific *biopredictors* and valuable tools for *preclinical diagnosis* of T1D.

**2. The preclinical diagnosis algorithm and a new conceptual model of T1D** 

T1D is an autoimmune disease induced by a vast variety of triggering factors. In individuals with genetic predisposition to T1D, these factors initiate autoimmune processes culminating in the appearance of autoAbs and infiltration of the pancreas with self-reactive T cells. In its turn, progressive deterioration of pancreatic functional activity leads to systemic metabolic and immune failures. These processes show a tendency for self-acceleration, aggravation by associated diseases or numerous adverse factors and formation of new linkages between immunoregulatory and immunoeffector compartments within the immune system. T1D is also distinguished for alterations at the cellular level including pathological changes in cell to-cell interactions, incompatibility of packages of secreted humoral factors, and so on. Intracellular events provoked by specific uncongenial conditions in the cell environment also play a role. Therefore, humoral factors secreted at any (cellular, tissue or organic) level and pathological changes in any link of the metabolic cascade can be regarded as highly

In the course of the autoimmune process, T1D goes through a number of sequential stages, which differ from one another by the degree of severity of the underlying pathology, functional peculiarities of affected organs and clinical manifestations of the disease. A *personalized* therapeutic approach must be based on a detailed analysis of the immune status with special reference to the patient's genetic map and is prerequisite to the construction of

acquisition of high-quality material *in vitro* and control over differentiation into desired

of criteria providing high accuracy and reliability of state-of-health data. By illustration, it has long been believed that the same gene loci are specific for definite diseases including integer disease-related clusters. T1D, celiac disease, rheumatoid arthritis, multiple sclerosis, etc., they exist in close linkage with one another and often form polyglandular syndromes. Being a positively provisional discipline, genetics provides a fairly accurate prognosis for an individual; however, genetic tributes cannot always be adequately understood by reason of their ability to provoke extremely severe diseases. It should be taken into consideration that deleterious environmental (exogenous or endogenous) factors may strongly destabilize the physiological status of the organism by triggering pathological processes even in the presence of protective genes, and *vice versa*.

Therefore, screening of patients for the presence and evolution of biomarkers should be included into all preventive medicine protocols alongside with the patient's individual genetic map.

Even an unambiguous allocation of patients into risk groups, selection of basic state-of-art (additional, individual, etc.) screening criteria and personalized approaches to every new patient will hardly be successful without selection of optimal conditions and methods for obtaining reliable and reproducible clinical data on a mass scale.

The practical realization of these principles will enable the physician to diagnose abnormalities and/or disorders at the very earliest stages and to predict their outcome. However, suspension or blockade of pathological processes presents a formidable challenge to the medical community. In designing therapeutic strategies for autoimmune diseases, two important issues, namely, targets for autoimmune attacks and depth of morphofunctional deficiency of an organ or a tissue, should be taken into consideration. The first issue is more or less clear, since immunosuppressors with specific or nonspecific activities have long been used in the clinical practice, while the second one is not so apparent. Restoration of the structure and function of affected tissues can successfully be achieved through practical realization of the following strategies:


of criteria providing high accuracy and reliability of state-of-health data. By illustration, it has long been believed that the same gene loci are specific for definite diseases including integer disease-related clusters. T1D, celiac disease, rheumatoid arthritis, multiple sclerosis, etc., they exist in close linkage with one another and often form polyglandular syndromes. Being a positively provisional discipline, genetics provides a fairly accurate prognosis for an individual; however, genetic tributes cannot always be adequately understood by reason of their ability to provoke extremely severe diseases. It should be taken into consideration that deleterious environmental (exogenous or endogenous) factors may strongly destabilize the physiological status of the organism by triggering pathological processes even in the

Therefore, screening of patients for the presence and evolution of biomarkers should be included into all preventive medicine protocols alongside with the patient's individual

Even an unambiguous allocation of patients into risk groups, selection of basic state-of-art (additional, individual, etc.) screening criteria and personalized approaches to every new patient will hardly be successful without selection of optimal conditions and methods for

The practical realization of these principles will enable the physician to diagnose abnormalities and/or disorders at the very earliest stages and to predict their outcome. However, suspension or blockade of pathological processes presents a formidable challenge to the medical community. In designing therapeutic strategies for autoimmune diseases, two important issues, namely, targets for autoimmune attacks and depth of morphofunctional deficiency of an organ or a tissue, should be taken into consideration. The first issue is more or less clear, since immunosuppressors with specific or nonspecific activities have long been used in the clinical practice, while the second one is not so apparent. Restoration of the structure and function of affected tissues can successfully be achieved through practical

 allogeneic or xenogeneic transplantation. The main challenges include high risk of socalled "graft-versus-host" responses and rejection of transplanted tissues (graft

 medical products with regenerative resources. This technology seems to hold especially great promise in modern medicine. Some medicinal drugs (e.g., IgM for MS) are widely employed in the clinical practice, while others (e.g., peptide-based drugs for MS, rheumatoid arthritis, T1D) are under intensive development. The main obstacles on the way to large-scale application of such drugs are low efficiency, particularly due to organism's addiction to their active substances (reduced number of receptors, downregulation, etc.), and hyperactivation of the excretory system (augmented synthesis of liver microsomal enzymes, hyperexcretion with urine, faeces or sweat, etc.); stem cell technology. This trend is especially actively debated by the medical community because of its high relevance to ethic problems and legal prohibitions, on the one hand, and inability to maintain "stemness" for sufficiently long periods of time and differentiation of stem cells into "undesirable" pools, on the other. Similar problems arise at virtually every stage, viz.: search for and isolation of stem cells from the organism; enhanced accumulation of biological material, which may be critical under conditions of fulminant progression of the disease and pronounced deficit of time; necessity to maintain the pluripotent state of cells for sufficiently long periods of time without malignization *in vitro;* delivery of SC; provisional differentiation and

presence of protective genes, and *vice versa*.

realization of the following strategies:

rejection);

obtaining reliable and reproducible clinical data on a mass scale.

genetic map.

acquisition of high-quality material *in vitro* and control over differentiation into desired cellular pools *in vivo*.

Taking into consideration the foregoing and being guided by the Major Preventive and Preventive Medicine Principle, we developed an original protocol for screening and postscreening management of patients, which includes:

Comprehensive genetic analysis for estimating potential risks for patient's (or his/her relatives') individuality and design of protocols for diagnostic assessment and preventive treatment;

Proteomic analysis and detection of metabolic shifts including identification of biomarkers (e.g., autoAbs in case of autoimmune disorders); monitoring of evolutional and spectral characteristics of biomarkers; control over emergence of new biomarkers for updating prophylactic and preventive treatment protocols and maintenance of high curability standards;

Persistent control over predisposing factors including identification of factors potentiating specific pathologies (analysis of bacterial and virus-borne infections, monitoring compliance with regimen and other preventive measures, etc.);

Psychologic doctor-patient cooperation, strict compliance with doctor's recommendations and requirements through elucidation of disease severity (including the preclinical stage).

The use of advanced screening strategies and early implementation of specific therapy ensure substantial reduction of morbidity and mortality from autoimmune disorders and, as a consequence, significant improvement of life quality and minimization of economic losses. The same principles are embodied in the guidelines of preventive and predictive medicine. Their practical realization may culminate in the establishment of an international research network, development of novel criteria for preclinical diagnosis and treatment and validation of uniform specifications and standards for laboratory diagnostics.
