1 5739 95 SMOKING AND RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY DISEASE CAUSED BY BOTH GENETIC AND ENVIRONMENTAL FACTORS. SMOKING HAS BEEN IMPLICATED AS ONE OF THE MOST IMPORTANT EXTRINSIC RISK FACTORS FOR ITS DEVELOPMENT AND SEVERITY. RECENT DEVELOPMENTS HAVE SHED LIGHT ON THE PATHOPHYSIOLOGY OF RA IN SMOKERS, INCLUDING OXIDATIVE STRESS, INFLAMMATION, AUTOANTIBODY FORMATION AND EPIGENETIC CHANGES. THE ASSOCIATION OF SMOKING AND THE DEVELOPMENT OF RA HAVE BEEN DEMONSTRATED THROUGH EPIDEMIOLOGIC STUDIES, AS WELL AS THROUGH IN VIVO AND ANIMAL MODELS OF RA. WITH INCREASED USE OF BIOLOGICAL AGENTS IN ADDITION TO STANDARD DISEASE-MODIFYING ANTIRHEUMATIC DRUGS (DMARDS), THERE HAS BEEN INTEREST IN HOW SMOKING AFFECTS DRUG RESPONSE IN RA TREATMENT. RECENT EVIDENCE SUGGESTS THE RESPONSE AND DRUG SURVIVAL IN PEOPLE TREATED WITH ANTI-TUMOUR NECROSIS FACTOR (ANTI-TNF) THERAPY IS POORER IN HEAVY SMOKERS, AND POSSIBLE IMMUNOLOGICAL MECHANISMS FOR THIS EFFECT ARE PRESENTED IN THE CURRENT PAPER. 2014 2 4844 32 ONE YEAR IN REVIEW 2019: PATHOGENESIS OF RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE INFLUENCED BY BOTH GENETIC AND ENVIRONMENTAL FACTORS. OVER THE LAST FEW YEARS, PARTICULAR ATTENTION HAS BEEN GIVEN TO NOVEL GENES AND TO THE CLOSE INTERACTION BETWEEN GENETIC FACTORS AND EPIGENETIC MECHANISMS. RESEARCH HAS ALSO FOCUSED ON THE INFLUENCE OF ENVIRONMENTAL FACTORS ON DISEASE DEVELOPMENT, AND ON NEW MECHANISMS OF THE INNATE AND ADAPTIVE IMMUNE SYSTEM THAT CAN INFLUENCE THE DIFFERENT STAGES OF RA. HOWEVER, THERE ARE STILL SEVERAL ASPECTS OF THE DISEASE THAT NEED FURTHER INVESTIGATION. SHEDDING SOME LIGHT ON THE DIFFERENT ASPECTS OF RA PATHOGENESIS WILL HELP TO IMPROVE THE CURRENT DIAGNOSTIC TOOLS AND TO IDENTIFY NEW TARGETS FOR THE DEVELOPMENT OF DISEASE-MODIFYING THERAPIES. THUS, IN THIS REVIEW WE SUMMARISE THE NEW INSIGHTS IN RA PATHOGENESIS, RESULTING FROM LITERATURE RESEARCH DATA PUBLISHED IN THE LAST YEAR. 2019 3 1608 32 DNA METHYLATION-GOVERNED GENE EXPRESSION IN AUTOIMMUNE ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE HALLMARKED BY PROGRESSIVE AND IRREVERSIBLE JOINT DESTRUCTION. RA PATHOGENESIS IS A T CELL-REGULATED AND B CELL-MEDIATED PROCESS IN WHICH ACTIVATED LYMPHOCYTE-PRODUCED CHEMOKINES AND CYTOKINES PROMOTE LEUKOCYTE INFILTRATION THAT ULTIMATELY LEADS TO DESTRUCTION OF THE JOINTS. THERE IS AN OBVIOUS NEED TO DISCOVER NEW DRUGS FOR RA TREATMENT THAT HAVE DIFFERENT BIOLOGICAL TARGETS OR MODES OF ACTION THAN THE CURRENTLY EMPLOYED THERAPEUTICS. ENVIRONMENTAL FACTORS SUCH AS CIGARETTE SMOKE, CERTAIN DIET COMPONENTS, AND ORAL PATHOGENS CAN SIGNIFICANTLY AFFECT GENE REGULATION VIA EPIGENETIC FACTORS. EPIGENETICS OPENED A NEW FIELD FOR PHARMACOLOGY, AND DNA METHYLATION AND HISTONE MODIFICATION-IMPLICATED FACTORS ARE FEASIBLE TARGETS FOR RA THERAPY. EXPLORING RA PATHOGENESIS INVOLVED EPIGENETIC FACTORS AND MECHANISMS IS CRUCIAL FOR DEVELOPING MORE EFFICIENT RA THERAPIES. HERE WE REVIEW EPIGENETIC ALTERATIONS ASSOCIATED WITH RA PATHOGENESIS INCLUDING DNA METHYLATION AND INTERACTING FACTORS. ADDITIONALLY, WE WILL SUMMARIZE THE LITERATURE REVEALING THE INVOLVED MOLECULAR STRUCTURES AND INTERACTIONS. FINALLY, POTENTIAL EPIGENETIC FACTOR-BASED THERAPIES WILL BE DISCUSSED THAT MAY HELP IN BETTER MANAGEMENT OF RA IN THE FUTURE. 2019 4 4845 31 ONE YEAR IN REVIEW 2020: PATHOGENESIS OF RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE INFLUENCED BY BOTH GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS. THE DISCOVERY OF NEW GENE POLYMORPHISMS AND THEIR ASSOCIATION WITH DISEASE SUSCEPTIBILITY HAVE ADDED NEW ELEMENTS TO BETTER CLARIFY RA PATHOGENESIS. IN THE LAST YEAR, IMPORTANT ELEMENTS HAVE BEEN ADDED TO THE CURRENT KNOWLEDGE OF MECHANISMS REGULATING INNATE AND ADAPTIVE IMMUNITY IN RA, LEADING TO DISCOVERING NEW TARGETS FOR THE DEVELOPMENT OF DISEASE-MODIFYING THERAPIES. THUS, IN THIS REVIEW WE SUMMARISE THE NEW INSIGHTS RESULTING FROM A LITERATURE RESEARCH DATA PUBLISHED IN THE LAST YEAR. 2020 5 5372 33 RECENT ADVANCES IN UNDERSTANDING THE PATHOGENESIS OF RHEUMATOID ARTHRITIS: NEW TREATMENT STRATEGIES. RHEUMATOID ARTHRITIS (RA) IS CONSIDERED A CHRONIC SYSTEMIC, MULTI-FACTORIAL, INFLAMMATORY, AND PROGRESSIVE AUTOIMMUNE DISEASE AFFECTING MANY PEOPLE WORLDWIDE. WHILE PATIENTS SHOW VERY INDIVIDUAL COURSES OF DISEASE, WITH RA FOCUSING ON THE MUSCULOSKELETAL SYSTEM, JOINTS ARE OFTEN SEVERELY AFFECTED, LEADING TO LOCAL INFLAMMATION, CARTILAGE DESTRUCTION, AND BONE EROSION. TO PREVENT JOINT DAMAGE AND PHYSICAL DISABILITY AS ONE OF MANY SYMPTOMS OF RA, EARLY DIAGNOSIS IS CRITICAL. AUTO-ANTIBODIES PLAY A PIVOTAL CLINICAL ROLE IN PATIENTS WITH SYSTEMIC RA. AS BIOMARKERS, THEY COULD HELP TO MAKE A MORE EFFICIENT DIAGNOSIS, PROGNOSIS, AND TREATMENT DECISION. BESIDES AUTO-ANTIBODIES, SEVERAL OTHER FACTORS ARE INVOLVED IN THE PROGRESSION OF RA, SUCH AS EPIGENETIC ALTERATIONS, POST-TRANSLATIONAL MODIFICATIONS, GLYCOSYLATION, AUTOPHAGY, AND T-CELLS. UNDERSTANDING THE INTERPLAY BETWEEN THESE FACTORS WOULD CONTRIBUTE TO A DEEPER INSIGHT INTO THE CAUSES, MECHANISMS, PROGRESSION, AND TREATMENT OF THE DISEASE. IN THIS REVIEW, THE LATEST RA RESEARCH FINDINGS ARE DISCUSSED TO BETTER UNDERSTAND THE PATHOGENESIS, AND FINALLY, TREATMENT STRATEGIES FOR RA THERAPY ARE PRESENTED, INCLUDING BOTH CONVENTIONAL APPROACHES AND NEW METHODS THAT HAVE BEEN DEVELOPED IN RECENT YEARS OR ARE CURRENTLY UNDER INVESTIGATION. 2021 6 1047 31 CLINICAL EFFECT AND BIOLOGICAL MECHANISM OF EXERCISE FOR RHEUMATOID ARTHRITIS: A MINI REVIEW. RHEUMATOID ARTHRITIS (RA) IS A COMMON SYSTEMATIC, CHRONIC INFLAMMATORY, AUTOIMMUNE, AND POLYARTICULAR DISEASE, CAUSING A RANGE OF CLINICAL MANIFESTATIONS, INCLUDING JOINT SWELLING, REDNESS, PAIN, STIFFNESS, FATIGUE, DECREASED QUALITY OF LIFE, PROGRESSIVE DISABILITY, CARDIOVASCULAR PROBLEMS, AND OTHER COMORBIDITIES. STRONG EVIDENCE HAS SHOWN THAT EXERCISE IS EFFECTIVE FOR RA TREATMENT IN VARIOUS CLINICAL DOMAINS. EXERCISE TRAINING FOR RELATIVELY LONGER PERIODS (E.G., >/= 12 WEEKS) CAN DECREASE DISEASE ACTIVITY OF RA. HOWEVER, THE MECHANISM UNDERLYING THE EFFECTIVENESS OF EXERCISE IN REDUCING RA DISEASE ACTIVITY REMAINS UNCLEAR. THIS REVIEW FIRST SUMMARIZES AND HIGHLIGHTS THE EFFECTIVENESS OF EXERCISE IN RA TREATMENT. THEN, WE INTEGRATE CURRENT EVIDENCE AND PROPOSE BIOLOGICAL MECHANISMS RESPONSIBLE FOR THE POTENTIAL EFFECTS OF EXERCISE ON IMMUNE CELLS AND IMMUNITY, INFLAMMATORY RESPONSE, MATRIX METALLOPROTEINASES, OXIDATIVE STRESS, AND EPIGENETIC REGULATION. HOWEVER, A LARGE BODY OF EVIDENCE WAS OBTAINED FROM THE NON-RA POPULATIONS. FUTURE STUDIES ARE NEEDED TO FURTHER EXAMINE THE PROPOSED BIOLOGICAL MECHANISMS RESPONSIBLE FOR THE EFFECTIVENESS OF EXERCISE IN DECREASING DISEASE ACTIVITY IN RA POPULATIONS. SUCH KNOWLEDGE WILL CONTRIBUTE TO THE BASIC SCIENCE AND STRENGTHEN THE SCIENTIFIC BASIS OF THE PRESCRIPTION OF EXERCISE THERAPY FOR RA IN THE CLINICAL ROUTINE. 2022 7 1136 34 COMPREHENSIVE OVERVIEW OF MICRORNA FUNCTION IN RHEUMATOID ARTHRITIS. MICRORNAS (MIRNAS), A CLASS OF ENDOGENOUS SINGLE-STRANDED SHORT NONCODING RNAS, HAVE EMERGED AS VITAL EPIGENETIC REGULATORS OF BOTH PATHOLOGICAL AND PHYSIOLOGICAL PROCESSES IN ANIMALS. THEY DIRECT FUNDAMENTAL CELLULAR PATHWAYS AND PROCESSES BY FINE-TUNING THE EXPRESSION OF MULTIPLE GENES AT THE POSTTRANSCRIPTIONAL LEVEL. GROWING EVIDENCE SUGGESTS THAT MIRNAS ARE IMPLICATED IN THE ONSET AND DEVELOPMENT OF RHEUMATOID ARTHRITIS (RA). RA IS A CHRONIC INFLAMMATORY DISEASE THAT MAINLY AFFECTS SYNOVIAL JOINTS. THIS COMMON AUTOIMMUNE DISORDER IS CHARACTERIZED BY A COMPLEX AND MULTIFACETED PATHOGENESIS, AND ITS MORBIDITY, DISABILITY AND MORTALITY RATES REMAIN CONSISTENTLY HIGH. MORE IN-DEPTH INSIGHTS INTO THE UNDERLYING MECHANISMS OF RA ARE REQUIRED TO ADDRESS UNMET CLINICAL NEEDS AND OPTIMIZE TREATMENT. HEREIN, WE COMPREHENSIVELY REVIEW THE DEREGULATED MIRNAS AND IMPAIRED CELLULAR FUNCTIONS IN RA TO SHED LIGHT ON SEVERAL ASPECTS OF RA PATHOGENESIS, WITH A FOCUS ON EXCESSIVE INFLAMMATION, SYNOVIAL HYPERPLASIA AND PROGRESSIVE JOINT DAMAGE. THIS REVIEW ALSO PROVIDES PROMISING TARGETS FOR INNOVATIVE THERAPIES OF RA. IN ADDITION, WE DISCUSS THE REGULATORY ROLES AND CLINICAL POTENTIAL OF EXTRACELLULAR MIRNAS IN RA, HIGHLIGHTING THEIR PROSPECTIVE APPLICATIONS AS DIAGNOSTIC AND PREDICTIVE BIOMARKERS. 2023 8 4842 32 ONE YEAR IN REVIEW 2017: PATHOGENESIS OF RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE INFLUENCED BY BOTH GENETIC AND ENVIRONMENTAL FACTORS. IT HAS BEEN POSTULATED THAT A HIGH-RISK GENETIC BACKGROUND, IN COMBINATION WITH EPIGENETIC MARKS AND ENVIRONMENTAL EXPOSURES, LEADS TO A CASCADE OF EVENTS INDUCING SYNOVITIS AND CONSEQUENT DESTRUCTIVE ARTHRITIS. THE CLINICAL PICTURE OF JOINT INVOLVEMENT IN RA IS THE RESULT OF CHRONIC INFLAMMATION OF THE SYNOVIUM, CHARACTERISED BY INTERACTIONS OF RESIDENT CELLS SUCH AS FIBROBLAST-LIKE SYNOVIOCYTES (FLS) WITH CELLS OF THE INNATE (E.G. MACROPHAGES, DENDRITIC CELLS, MAST CELLS AND NK CELLS, NEUTROPHILS) AND ADAPTIVE IMMUNE SYSTEM (E.G. B AND T LYMPHOCYTES). CURRENTLY, OUR UNDERSTANDING OF THE ROLE OF INNATE AND ADAPTIVE IMMUNITY IN THE PATHOGENESIS OF RA IS EXPANDING. THE CONCEPT OF HOW IMMUNE RESPONSES CONTRIBUTE TO THE DISEASE HAS DRAMATICALLY EVOLVED OVER THE LAST 50 YEARS. SHEDDING SOME LIGHT ON THE DIFFERENT ASPECTS OF RA PATHOGENESIS WILL HELP TO IDENTIFY NEW TARGETS FOR THE DEVELOPMENT OF DISEASE-MODIFYING THERAPIES. THUS, IN THIS REVIEW WE REPORT NEW INSIGHTS IN RA PATHOGENESIS, RESULTING FROM A LITERATURE RESEARCH DATE PUBLISHED IN THE LAST YEAR. 2017 9 1812 38 EFFECTS OF BIOLOGICAL THERAPIES ON MOLECULAR FEATURES OF RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS AN AUTOIMMUNE AND CHRONIC INFLAMMATORY DISEASE PRIMARILY AFFECTING THE JOINTS, AND CLOSELY RELATED TO SPECIFIC AUTOANTIBODIES THAT MOSTLY TARGET MODIFIED SELF-EPITOPES. RELEVANT FINDINGS IN THE FIELD OF RA PATHOGENESIS HAVE BEEN DESCRIBED. IN PARTICULAR, NEW INSIGHTS COME FROM STUDIES ON SYNOVIAL FIBROBLASTS AND CELLS BELONGING TO THE INNATE AND ADAPTIVE IMMUNE SYSTEM, WHICH DOCUMENTED THE ABERRANT PRODUCTION OF INFLAMMATORY MEDIATORS, OXIDATIVE STRESS AND NETOSIS, ALONG WITH RELEVANT ALTERATIONS OF THE GENOME AND ON THE REGULATORY EPIGENETIC MECHANISMS. IN RECENT YEARS, THE ADVANCES IN THE UNDERSTANDING OF RA PATHOGENESIS BY IDENTIFYING KEY CELLS AND CYTOKINES ALLOWED THE DEVELOPMENT OF NEW TARGETED DISEASE-MODIFYING ANTIRHEUMATIC DRUGS (DMARDS). THESE DRUGS CONSIDERABLY IMPROVED TREATMENT OUTCOMES FOR THE MAJORITY OF PATIENTS. MOREOVER, NUMEROUS STUDIES DEMONSTRATED THAT THE PHARMACOLOGICAL THERAPY WITH BIOLOGIC DMARDS (BDMARDS) PROMOTES, IN PARALLEL TO THEIR CLINICAL EFFICACY, SIGNIFICANT IMPROVEMENT IN ALL THESE ALTERED MOLECULAR MECHANISMS. THUS, CONTINUOUS UPDATING OF THE KNOWLEDGE OF MOLECULAR PROCESSES ASSOCIATED WITH THE PATHOGENESIS OF RA, AND ON THE SPECIFIC EFFECTS OF BDMARDS IN THE CORRECTION OF THEIR DYSREGULATION, ARE ESSENTIAL IN THE EARLY AND CORRECT APPROACH TO THE TREATMENT OF THIS COMPLEX AUTOIMMUNE DISORDER. THE PRESENT REVIEW DETAILS BASIC MECHANISMS RELATED TO THE PHYSIOPATHOLOGY OF RA, ALONG WITH THE CORE MECHANISMS OF RESPONSE TO BDMARDS. 2020 10 3039 27 GENOME ENGINEERING FOR PERSONALIZED ARTHRITIS THERAPEUTICS. ARTHRITIS REPRESENTS A FAMILY OF COMPLEX JOINT PATHOLOGIES RESPONSIBLE FOR THE MAJORITY OF MUSCULOSKELETAL CONDITIONS. NEARLY ALL DISEASES WITHIN THIS FAMILY, INCLUDING OSTEOARTHRITIS, RHEUMATOID ARTHRITIS, AND JUVENILE IDIOPATHIC ARTHRITIS, ARE CHRONIC CONDITIONS WITH FEW OR NO DISEASE-MODIFYING THERAPEUTICS AVAILABLE. ADVANCES IN GENOME ENGINEERING TECHNOLOGY, MOST RECENTLY WITH CRISPR-CAS9, HAVE REVOLUTIONIZED OUR ABILITY TO INTERROGATE AND VALIDATE GENETIC AND EPIGENETIC ELEMENTS ASSOCIATED WITH CHRONIC DISEASES SUCH AS ARTHRITIS. THESE TECHNOLOGIES, TOGETHER WITH CELL REPROGRAMMING METHODS, INCLUDING THE USE OF INDUCED PLURIPOTENT STEM CELLS, PROVIDE A PLATFORM FOR HUMAN DISEASE MODELING. WE SUMMARIZE NEW EVIDENCE FROM GENOME-WIDE ASSOCIATION STUDIES AND GENOMICS THAT SUBSTANTIATES A GENETIC BASIS FOR ARTHRITIS PATHOGENESIS. WE ALSO REVIEW THE POTENTIAL CONTRIBUTIONS OF GENOME ENGINEERING IN THE DEVELOPMENT OF NEW ARTHRITIS THERAPEUTICS. 2017 11 2238 29 EPIGENETIC MODULATION AS A THERAPEUTIC PROSPECT FOR TREATMENT OF AUTOIMMUNE RHEUMATIC DISEASES. SYSTEMIC INFLAMMATORY RHEUMATIC DISEASES ARE CONSIDERED AS AUTOIMMUNE DISEASES, MEANING THAT THE BALANCE BETWEEN RECOGNITION OF PATHOGENS AND AVOIDANCE OF SELF-ATTACK IS IMPAIRED AND THE IMMUNE SYSTEM ATTACKS AND DESTROYS ITS OWN HEALTHY TISSUE. TREATMENT WITH CONVENTIONAL DISEASE MODIFYING ANTIRHEUMATIC DRUGS (DMARDS) AND/OR NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) IS OFTEN ASSOCIATED WITH VARIOUS ADVERSE REACTIONS DUE TO UNSPECIFIC AND TOXIC PROPERTIES OF THOSE DRUGS. ALTHOUGH BIOLOGIC DRUGS HAVE LARGELY IMPROVED THE OUTCOME IN MANY PATIENTS, SUCH DRUGS STILL POSE SIGNIFICANT PROBLEMS AND FAIL TO PROVIDE A SOLUTION TO ALL PATIENTS. THEREFORE, DEVELOPMENT OF MORE EFFECTIVE TREATMENTS AND IMPROVEMENTS IN EARLY DIAGNOSIS OF RHEUMATIC DISEASES ARE BADLY NEEDED IN ORDER TO INCREASE PATIENT'S FUNCTIONING AND QUALITY OF LIFE. THE REVERSIBLE NATURE OF EPIGENETIC MECHANISMS OFFERS A NEW CLASS OF DRUGS THAT MODULATE THE IMMUNE SYSTEM AND INFLAMMATION. IN FACT, EPIGENETIC DRUGS ARE ALREADY IN USE IN SOME TYPES OF CANCER OR CARDIOVASCULAR DISEASES. THEREFORE, EPIGENETIC-BASED THERAPEUTICS THAT CONTROL AUTOIMMUNITY AND CHRONIC INFLAMMATORY PROCESS HAVE BROAD IMPLICATIONS FOR THE PATHOGENESIS, DIAGNOSIS, AND MANAGEMENT OF RHEUMATIC DISEASES. THIS REVIEW SUMMARISES THE LATEST INFORMATION ABOUT POTENTIAL THERAPEUTIC APPLICATION OF EPIGENETIC MODIFICATION IN TARGETING IMMUNE ABNORMALITIES AND INFLAMMATION OF RHEUMATIC DISEASES. 2016 12 5002 40 PERIODONTITIS AND PERIODONTOPATHIC BACTERIA AS RISK FACTORS FOR RHEUMATOID ARTHRITIS: A REVIEW OF THE LAST 10 YEARS. RHEUMATOID ARTHRITIS (RA) IS CHARACTERIZED BY CHRONIC INFLAMMATORY DESTRUCTION OF JOINT TISSUE AND IS CAUSED BY AN ABNORMAL AUTOIMMUNE RESPONSE TRIGGERED BY INTERACTIONS BETWEEN GENETICS, ENVIRONMENTAL FACTORS, AND EPIGENETIC AND POSTTRANSLATIONAL MODIFICATIONS. RA HAS BEEN SUGGESTED TO BE INTERRELATED WITH PERIODONTITIS, A SERIOUS FORM OR STAGE OF CHRONIC INFLAMMATORY PERIODONTAL DISEASE ASSOCIATED WITH PERIODONTOPATHIC BACTERIAL INFECTIONS, GENETIC PREDISPOSITION, ENVIRONMENTAL FACTORS, AND EPIGENETIC INFLUENCES. OVER THE LAST DECADE, A NUMBER OF ANIMAL AND CLINICAL STUDIES HAVE BEEN CONDUCTED TO ASSESS WHETHER OR NOT PERIODONTITIS AND ASSOCIATED PERIODONTOPATHIC BACTERIA CONSTITUTE RISK FACTORS FOR RA. THE PRESENT REVIEW INTRODUCES RECENT ACCUMULATING EVIDENCE TO SUPPORT THE ASSOCIATIONS OF PERIODONTITIS AND PERIODONTOPATHIC BACTERIA WITH THE RISK OF RA OR THE OUTCOME OF RA PHARMACOLOGICAL TREATMENT WITH DISEASE-MODIFYING ANTIRHEUMATIC DRUGS. IN ADDITION, THE RESULTS FROM INTERVENTION STUDIES HAVE SUGGESTED AN IMPROVEMENT IN RA CLINICAL PARAMETERS AFTER NONSURGICAL PERIODONTAL TREATMENT. FURTHERMORE, THE POTENTIAL CAUSAL MECHANISMS UNDERLYING THE LINK BETWEEN PERIODONTITIS AND PERIODONTOPATHIC BACTERIA AND RA ARE SUMMARIZED. 2023 13 2294 30 EPIGENETIC REGULATION IN THE PATHOGENESIS OF SJOGREN SYNDROME AND RHEUMATOID ARTHRITIS. AUTOIMMUNE RHEUMATIC DISEASES, SUCH AS SJOGREN SYNDROME (SS) AND RHEUMATOID ARTHRITIS (RA), ARE CHARACTERIZED BY CHRONIC INFLAMMATION AND AUTOIMMUNITY, WHICH CAUSE JOINT TISSUE DAMAGE AND DESTRUCTION BY TRIGGERING REDUCED MOBILITY AND DEBILITATION IN PATIENTS WITH THESE DISEASES. INITIATION AND MAINTENANCE OF CHRONIC INFLAMMATORY STAGES ACCOUNT FOR SEVERAL MECHANISMS THAT INVOLVE IMMUNE CELLS AS KEY PLAYERS AND THE INTERACTION OF THE IMMUNE CELLS WITH OTHER TISSUES. INDEED, THE OVERLAPPING OF CERTAIN CLINICAL AND SEROLOGIC MANIFESTATIONS BETWEEN SS AND RA MAY INDICATE THAT NUMEROUS IMMUNOLOGIC-RELATED MECHANISMS ARE INVOLVED IN THE PHYSIOPATHOLOGY OF BOTH THESE DISEASES. IT IS WIDELY ACCEPTED THAT EPIGENETIC PATHWAYS PLAY AN ESSENTIAL ROLE IN THE DEVELOPMENT AND FUNCTION OF THE IMMUNE SYSTEM. ALTHOUGH MANY PUBLISHED STUDIES HAVE ATTEMPTED TO ELUCIDATE THE RELATION BETWEEN EPIGENETIC MODIFICATIONS (E.G. DNA METHYLATION, HISTONE POST-TRANSLATIONAL MODIFICATIONS, MIRNAS) AND AUTOIMMUNE DISORDERS, THE CONTRIBUTION OF EPIGENETIC REGULATION TO THE PATHOGENESIS OF SS AND RA IS AT PRESENT POORLY UNDERSTOOD. THIS REVIEW ATTEMPTS TO SHED LIGHT FROM A CRITICAL POINT OF VIEW ON THE IDENTIFICATION OF THE MOST RELEVANT EPIGENETIC MECHANISMS RELATED TO RA AND SS BY EXPLAINING INTRICATE REGULATORY PROCESSES AND PHENOTYPIC FEATURES OF BOTH AUTOIMMUNE DISEASES. MOREOVER, WE POINT OUT SOME EPIGENETIC MARKERS WHICH CAN BE USED TO MONITOR THE INFLAMMATION STATUS AND THE DYSREGULATED IMMUNITY IN SS AND RA. FINALLY, WE DISCUSS THE INCONVENIENCE OF USING EPIGENETIC DATA OBTAINED FROM BULK IMMUNE CELL POPULATIONS INSTEAD SPECIFIC IMMUNE CELL SUBPOPULATIONS. 2019 14 783 24 CELL-SPECIFIC EPIGENETIC DRIVERS OF PATHOGENESIS IN RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS IS A COMPLEX, INFLAMMATORY AUTOIMMUNE DISEASE, WHICH IS CHARACTERIZED BY PAIN, SWELLING AND JOINT DAMAGE DRIVEN BY THE ALTERED BEHAVIOR OF A NUMBER OF DIFFERENT CELL TYPES SUCH AS SYNOVIAL FIBROBLASTS MACROPHAGES AND LYMPHOCYTES. THE MECHANISM UNDERLYING PATHOGENESIS IS UNCLEAR BUT INCREASING EVIDENCE POINTS TO ALTERED EPIGENETIC REGULATION WITHIN THESE CELL TYPES WHICH PROMOTES THE ACTIVATED DESTRUCTIVE BEHAVIOR THAT UNDERLIES DISEASE PATHOGENESIS. THIS REVIEW SUMMARIZES THE KEY EPIGENETIC MODIFICATIONS IN THE MOST IMPORTANT CELLS TYPES IN RHEUMATOID ARTHRITIS, WHICH ARE ASSOCIATED WITH DISEASE ACTIVITY. WE ALSO DISCUSS EMERGING AVENUES OF RESEARCH FOCUSING ON READERS OF EPIGENETIC MARKERS WHICH MAY SERVE TO BE POTENTIAL THERAPEUTIC TARGETS. 2021 15 4685 28 NEW TARGETS AND STRATEGIES FOR RHEUMATOID ARTHRITIS: FROM SIGNAL TRANSDUCTION TO EPIGENETIC ASPECT. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC AUTOIMMUNE DISEASE THAT CAN LEAD TO JOINT DAMAGE AND EVEN PERMANENT DISABILITY, SERIOUSLY AFFECTING PATIENTS' QUALITY OF LIFE. AT PRESENT, THE COMPLETE CURE FOR RA IS NOT ACHIEVABLE, ONLY TO RELIEVE THE SYMPTOMS TO REDUCE THE PAIN OF PATIENTS. FACTORS SUCH AS ENVIRONMENT, GENES, AND SEX CAN INDUCE RA. PRESENTLY, NON-STEROIDAL ANTI-INFLAMMATORY DRUGS, DRMADS, AND GLUCOCORTICOIDS ARE COMMONLY USED IN TREATING RA. IN RECENT YEARS, SOME BIOLOGICAL AGENTS HAVE ALSO BEEN APPLIED IN CLINICAL PRACTICE, BUT MOST HAVE SIDE EFFECTS. THEREFORE, FINDING NEW MECHANISMS AND TARGETS FOR TREATING RA IS NECESSARY. THIS REVIEW SUMMARIZES SOME POTENTIAL TARGETS DISCOVERED FROM THE PERSPECTIVE OF EPIGENETICS AND RA MECHANISMS. 2023 16 2556 24 EPIGENETICS IN RHEUMATOID ARTHRITIS. EPIGENETICS IS A STEADILY GROWING RESEARCH AREA. IN MANY HUMAN DISEASES, ESPECIALLY IN CANCERS, BUT ALSO IN AUTOIMMUNE DISEASES, EPIGENETIC ABERRATIONS HAVE BEEN FOUND. RHEUMATOID ARTHRITIS IS AN AUTOIMMUNE DISEASE CHARACTERIZED BY CHRONIC INFLAMMATION AND DESTRUCTION OF SYNOVIAL JOINTS. EVEN THOUGH THE ETIOLOGY IS NOT YET FULLY UNDERSTOOD, RHEUMATOID ARTHRITIS IS GENERALLY CONSIDERED TO BE CAUSED BY A COMBINATION OF GENETIC PREDISPOSITION, DEREGULATED IMMUNOMODULATION, AND ENVIRONMENTAL INFLUENCES. TO GAIN A BETTER UNDERSTANDING OF THIS DISEASE, RESEARCHERS HAVE BECOME INTERESTED IN STUDYING EPIGENETIC CHANGES IN RHEUMATOID ARTHRITIS. HERE, WE WANT TO REVIEW THE CURRENT KNOWLEDGE ON EPIGENETICS IN RHEUMATOID ARTHRITIS. 2010 17 3038 29 GENOME ENGINEERING FOR OSTEOARTHRITIS: FROM DESIGNER CELLS TO DISEASE-MODIFYING DRUGS. BACKGROUND: OSTEOARTHRITIS (OA) IS A HIGHLY PREVALENT DEGENERATIVE JOINT DISEASE INVOLVING JOINT CARTILAGE AND ITS SURROUNDING TISSUES. OA IS THE LEADING CAUSE OF PAIN AND DISABILITY WORLDWIDE. AT PRESENT, THERE ARE NO DISEASE-MODIFYING OA DRUGS, AND THE PRIMARY THERAPIES INCLUDE EXERCISE AND NONSTEROIDAL ANTI-INFLAMMATORY DRUGS UNTIL TOTAL JOINT REPLACEMENT AT THE END-STAGE OF THE DISEASE. METHODS: IN THIS REVIEW, WE SUMMARIZED THE CURRENT STATE OF KNOWLEDGE IN GENETIC AND EPIGENETIC ASSOCIATIONS AND RISK FACTORS FOR OA AND THEIR POTENTIAL DIAGNOSTIC AND THERAPEUTIC APPLICATIONS. RESULTS: GENOME-WIDE ASSOCIATION STUDIES AND ANALYSIS OF EPIGENETIC MODIFICATIONS (SUCH AS MIRNA EXPRESSION, DNA METHYLATION AND HISTONE MODIFICATIONS) CONDUCTED ACROSS VARIOUS POPULATIONS SUPPORT THE NOTION THAT THERE IS A GENETIC BASIS FOR CERTAIN SUBSETS OF OA PATHOGENESIS. CONCLUSION: WITH RECENT ADVANCES IN THE DEVELOPMENT OF GENOME EDITING TECHNOLOGIES SUCH AS THE CRISPR-CAS9 SYSTEM, THESE GENETIC AND EPIGENETIC ALTERNATIONS IN OA CAN BE USED AS PLATFORMS FROM WHICH POTENTIAL BIOMARKERS FOR THE DIAGNOSIS, PROGNOSIS, DRUG RESPONSE, AND DEVELOPMENT OF POTENTIAL PERSONALIZED THERAPEUTIC TARGETS FOR OA CAN BE APPROACHED. FURTHERMORE, GENOME EDITING HAS ALLOWED THE DEVELOPMENT OF "DESIGNER" CELLS, WHEREBY THE RECEPTORS, GENE REGULATORY NETWORKS, OR TRANSGENES CAN BE MODIFIED AS A BASIS FOR NEW CELL-BASED THERAPIES. 2019 18 2309 31 EPIGENETIC REGULATION OF CHONDROCYTES AND SUBCHONDRAL BONE IN OSTEOARTHRITIS. THE AIM OF THIS REVIEW IS TO PROVIDE AN UPDATED REVIEW OF THE EPIGENETIC FACTORS INVOLVED IN THE ONSET AND DEVELOPMENT OF OSTEOARTHRITIS (OA). OA IS A PREVALENT DEGENERATIVE JOINT DISEASE CHARACTERIZED BY CHRONIC INFLAMMATION, ECTOPIC BONE FORMATION WITHIN THE JOINT, AND PHYSICAL AND PROTEOLYTIC CARTILAGE DEGRADATION WHICH RESULT IN CHRONIC PAIN AND LOSS OF MOBILITY. AT PRESENT, NO DISEASE-MODIFYING THERAPEUTICS EXIST FOR THE PREVENTION OR TREATMENT OF THE DISEASE. RESEARCH HAS IDENTIFIED SEVERAL OA RISK FACTORS INCLUDING MECHANICAL STRESSORS, PHYSICAL ACTIVITY, OBESITY, TRAUMATIC JOINT INJURY, GENETIC PREDISPOSITION, AND AGE. RECENTLY, THERE HAS BEEN INCREASED INTEREST IN IDENTIFYING EPIGENETIC FACTORS INVOLVED IN THE PATHOGENESIS OF OA. IN THIS REVIEW, WE DETAIL SEVERAL OF THESE EPIGENETIC MODIFICATIONS WITH KNOWN FUNCTIONS IN THE ONSET AND PROGRESSION OF THE DISEASE. WE ALSO REVIEW CURRENT THERAPEUTICS TARGETING ABERRANT EPIGENETIC REGULATION AS POTENTIAL OPTIONS FOR PREVENTIVE OR THERAPEUTIC TREATMENT. 2022 19 1565 24 DNA METHYLATION OF T LYMPHOCYTES AS A THERAPEUTIC TARGET: IMPLICATIONS FOR RHEUMATOID ARTHRITIS ETIOLOGY. RHEUMATOID ARTHRITIS (RA) IS AN AUTOIMMUNE DISEASE THAT CAN CAUSE JOINT DAMAGE AND DISABILITY. EPIGENETIC VARIATION, ESPECIALLY DNA METHYLATION, HAS BEEN SHOWN TO BE INVOLVED IN ALMOST ALL THE STAGES OF THE PATHOLOGY OF RA, FROM AUTOANTIBODY PRODUCTION TO VARIOUS SELF-EFFECTOR T CELLS AND THE DEFECTS OF PROTECTIVE T CELLS THAT CAN LEAD TO CHRONIC INFLAMMATION AND EROSION OF BONES AND JOINTS. GIVEN THE CRITICAL ROLE OF T CELLS IN THE PATHOLOGY OF RA, THE REGULATORY FUNCTIONS OF DNA METHYLATION IN T CELL BIOLOGY REMAIN UNCLEAR. IN THIS REVIEW, WE ELABORATE ON THE RELATIONSHIP BETWEEN RA PATHOGENESIS AND DNA METHYLATION IN THE CONTEXT OF DIFFERENT T CELL POPULATIONS. WE SUMMARIZE THE RELEVANT METHYLATION EVENTS IN T CELL DEVELOPMENT, DIFFERENTIATION, AND T CELL-RELATED GENES IN DISEASE PREDICTION AND DRUG EFFICACY. UNDERSTANDING THE EPIGENETIC REGULATION OF T CELLS HAS THE POTENTIAL TO PROFOUNDLY TRANSLATE PRECLINICAL RESULTS INTO CLINICAL PRACTICE AND PROVIDE A FRAMEWORK FOR THE DEVELOPMENT OF NOVEL, INDIVIDUALIZED RA THERAPEUTICS. 2022 20 3031 35 GENETICS OF RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS AN INFLAMMATORY AUTOIMMUNE DISEASE INVOLVING SYMMETRIC JOINTS AND IS GENERALLY CHARACTERIZED BY PERSISTENT PAIN, TENDERNESS, AND DESTRUCTION OF JOINTS. THE VAST MAJORITY OF RA PATIENTS PRODUCE AUTOANTIBODIES, AND IMMUNE CELL INVOLVEMENT IN DISEASE DEVELOPMENT IS WELL RECOGNIZED, AS IS THE CONTRIBUTION OF OTHER TYPES OF CELLS IN SYNOVIAL TISSUE, LIKE FIBROBLASTS. IT IS KNOWN THAT THERE ARE MAJOR GENETIC ASSOCIATIONS WITH THE HLA LOCUS, WHILE MULTIPLE NON-HLA GENETIC VARIANTS DISPLAY RELATIVELY LOW RISK OF RA. BOTH HLA AND NON-HLA ASSOCIATIONS SUGGEST THAT THE PROFILES OF GENETIC ASSOCIATIONS FOR AUTOANTIBODY-POSITIVE VS. AUTOANTIBODY-NEGATIVE RA ARE DIFFERENT. SEVERAL ALLELES OF HLA-DRB1 ARE ASSOCIATED WITH HIGH RISK FOR AUTOANTIBODY-POSITIVE RA, WITH THE STRONGEST RISK CHARACTERIZED BY VALINE AT POSITION 11 OF THE PROTEIN SEQUENCE (HLA-DRB1*04 AND *10 ALLELES). THERE IS A STRONG PROTECTIVE EFFECT FOR THE RISK OF AUTOANTIBODY-POSITIVE RA ASSOCIATED WITH HLA-DRB1*13 ALLELES. ALTHOUGH MAJOR GENETIC ASSOCIATIONS HAVE BEEN KNOWN FOR SEVERAL YEARS, UNDERSTANDING OF THE SPECIFIC MECHANISMS IN THE DEVELOPMENT OF INCREASED RISK OF RA FOR THESE VARIATIONS IS WORK IN PROGRESS. CURRENT STUDIES FOCUS ON THE BINDING OF IMMUNE RECEPTORS INVOLVED IN RECOGNITION OF PUTATIVE PEPTIDES IN ACTIVATION OF T CELLS, AS WELL AS INVESTIGATION OF CELL SIGNALING MECHANISMS. AT LEAST A PART OF RA RISK COULD BE EXPLAINED BY GENE-GENE AND GENE-ENVIRONMENT INTERACTIONS. THERE ARE CURRENTLY MORE THAN 150 CANDIDATE LOCI WITH POLYMORPHISMS THAT ASSOCIATE WITH RA, MAINLY RELATED TO SEROPOSITIVE DISEASE, AND NEW DISCOVERIES ARE ANTICIPATED IN THE FUTURE FROM INVESTIGATION OF DIVERSE HUMAN POPULATIONS. THIS NEW RESEARCH WILL HELP CREATE A STRONG FOUNDATION FOR THE CONTINUING PROCESS OF INTEGRATING GENETIC, EPIGENETIC, TRANSCRIPTOMIC, AND PROTEOMIC DATA IN STUDIES OF RA. 2022