1 3057 157 GENOME-WIDE DNA METHYLATION ANALYSIS IN ANKYLOSING SPONDYLITIS IDENTIFIES HLA-B*27 DEPENDENT AND INDEPENDENT DNA METHYLATION CHANGES IN WHOLE BLOOD. BACKGROUND AND OBJECTIVE: ANKYLOSING SPONDYLITIS IS A CHRONIC INFLAMMATORY DISEASE CHARACTERIZED BY INFLAMMATION OF THE SACROILIAC JOINTS AND THE SPINE THAT CAN LEAD TO SIGNIFICANT PAIN, IMMOBILITY, AND DISABILITY. THE ETIOLOGY AND PATHOGENESIS OF ANKYLOSING SPONDYLITIS ARE INCOMPLETELY UNDERSTOOD, THOUGH MOST PATIENTS CARRY THE HLA-B*27 ALLELE. THE OBJECTIVE OF THIS STUDY WAS TO EVALUATE DNA METHYLATION CHANGES IN ANKYLOSING SPONDYLITIS WITH THE GOAL OF REVEALING NOVEL MECHANISTIC INSIGHTS INTO THIS DISEASE. METHODS: GENOME-WIDE DNA METHYLATION ANALYSIS WAS PERFORMED IN WHOLE BLOOD DNA SAMPLES USING THE INFINIUM METHYLATIONEPIC ARRAY IN PATIENTS WITH ANKYLOSING SPONDYLITIS COMPARED TO AGE, SEX, AND RACE MATCHED PATIENTS WITH OSTEOARTHRITIS AS A NON-INFLAMMATORY DISEASE CONTROL. WE STUDIED 24 PATIENTS WITH ANKYLOSING SPONDYLITIS, INCLUDING 12 PATIENTS WHO CARRY HLA-B*27 AND 12 PATIENTS WHO ARE HLA-B*27 NEGATIVE. DNA METHYLATION ANALYSIS WAS PERFORMED WITH ADJUSTMENT FOR BLOOD CELL COMPOSITION IN EACH SAMPLE. RESULTS: WE IDENTIFIED A TOTAL OF 67 DIFFERENTIALLY METHYLATED SITES BETWEEN ANKYLOSING SPONDYLITIS PATIENTS AND OSTEOARTHRITIS CONTROLS. HYPERMETHYLATED GENES FOUND INCLUDED GTPASE-RELATED GENES, WHILE HYPOMETHYLATED GENES INCLUDED HCP5, WHICH ENCODES A LNCRNA WITHIN THE MHC REGION, PREVIOUSLY ASSOCIATED WITH GENETIC RISK FOR PSORIASIS AND TOXIC EPIDERMAL NECROLYSIS. CARRYING HLA-B*27 WAS ASSOCIATED WITH ROBUST HYPOMETHYLATION OF HCP5, TUBULIN FOLDING COFACTOR A (TBCA) AND PHOSPHOLIPASE D FAMILY MEMBER 6 (PLD6) IN ANKYLOSING SPONDYLITIS PATIENTS. HYPOMETHYLATION WITHIN HCP5 INVOLVES A CPG SITE THAT CONTAINS A SINGLE NUCLEOTIDE POLYMORPHISM IN LINKAGE DISEQUILIBRIUM WITH HLA-B*27 AND THAT CONTROLS DNA METHYLATION AT THIS LOCUS IN AN ALLELE-SPECIFIC MANNER. CONCLUSIONS: A GENOME-WIDE DNA METHYLATION ANALYSIS IN ANKYLOSING SPONDYLITIS IDENTIFIED DNA METHYLATION PATTERNS THAT COULD PROVIDE POTENTIAL NOVEL INSIGHTS INTO THIS DISEASE. OUR FINDINGS SUGGEST THAT HLA-B*27 MIGHT PLAY A ROLE IN ANKYLOSING SPONDYLITIS IN PART THROUGH INDUCING EPIGENETIC DYSREGULATION. 2019 2 555 29 AXIAL SPONDYLOARTHRITIS: RESHAPE THE FUTURE-FROM THE "2022 GISEA INTERNATIONAL SYMPOSIUM". THE TERM "AXIAL SPONDYLOARTHRITIS" (AXSPA) REFERS TO A GROUP OF CHRONIC RHEUMATIC DISEASES THAT PREDOMINANTLY INVOLVE THE AXIAL SKELETON AND CONSIST OF ANKYLOSING SPONDYLITIS, REACTIVE ARTHRITIS, ARTHRITIS/SPONDYLITIS ASSOCIATED WITH PSORIASIS (PSA) AND ARTHRITIS/SPONDYLITIS ASSOCIATED WITH INFLAMMATORY BOWEL DISEASES (IBD). MOREOVER, PAIN IS AN IMPORTANT AND COMMON SYMPTOM OF AXSPA. IT MAY PROGRESS TO CHRONIC PAIN, A MORE COMPLICATED BIO-PSYCHOSOCIAL PHENOMENA, LEADING TO A SIGNIFICANT WORSENING OF QUALITY OF LIFE. THE DEVELOPMENT OF THE AXSPA INFLAMMATORY PROCESS IS GROUNDED IN THE COMPLEX INTERACTION BETWEEN GENETIC (SUCH AS HLA B27), EPIGENETIC, AND ENVIRONMENTAL FACTORS ASSOCIATED WITH A DYSREGULATED IMMUNE RESPONSE. CONSIDERING THE PIVOTAL CONTRIBUTION OF IL-23 AND IL-17 IN AXSPA INFLAMMATION, THE INHIBITION OF THESE CYTOKINES HAS BEEN EVALUATED AS A POTENTIAL THERAPEUTIC STRATEGY. WITH THIS CONTEXT, HERE WE DISCUSS THE MAIN PATHOGENETIC MECHANISMS, THERAPEUTIC APPROACHES AND THE ROLE OF PAIN IN AXSPA FROM THE 2022 INTERNATIONAL GISEA/OEG SYMPOSIUM. 2022 3 3033 44 GENETICS, EPIGENETICS, AND GENDER IMPACT IN AXIAL-SPONDYLOARTHRITIS SUSCEPTIBILITY: AN UPDATE ON GENETIC POLYMORPHISMS AND THEIR SEX RELATED ASSOCIATIONS. SPONDYLOARTHRITIS (SPA) IS A GROUP OF CHRONIC INFLAMMATORY RHEUMATIC DISEASE THAT CAN BE DIVIDED INTO PREDOMINANTLY AXIAL OR PREDOMINANTLY PERIPHERAL INVOLVEMENT, WITH OR WITHOUT ASSOCIATED PSORIASIS, INFLAMMATORY BOWEL DISEASE OR PREVIOUS INFECTION. AXIAL SPA (AXSPA) ENCOMPASSES ANKYLOSING SPONDYLITIS (AS) WITH RADIOLOGICAL SACROILIITIS, AND A TYPE WITHOUT RADIOGRAPHIC SACROILIITIS, CALLED "NON-RADIOGRAPHIC AXIAL SPA" (NR-AXSPA). MALES AND FEMALES SHOW LARGE DIFFERENCES IN THEIR SUSCEPTIBILITY TO SPA, SUCH AS DISTINCTIONS IN CLINICAL PATTERNS, PHENOTYPES AND IN THERAPEUTICAL RESPONSE, PARTICULARLY TO TNF INHIBITORS (TNFI). SEVERAL STUDIES INDICATE THAT AS WOMEN HAVE DOUBLED RISK TO FAILURE TNFI COMPARED WITH MALES. THIS DIVERSITY IN DRUGS' EFFICACY AMONG WOMEN AND MEN MAY BE CAUSED BY DIFFERENCES IN THE BALANCE OF SEX HORMONES AND IN GENE-SPECIFIC EXPRESSION LIKELY TRIGGERED BY X-CHROMOSOME INSTABILITY AND GENE-SPECIFIC EPIGENETIC MODIFICATIONS. EVIDENCE REPORTED THAT POLYMORPHISMS IN MICRORNAS ON X- AND OTHER CHROMOSOMES, SUCH AS MIR-146A, MIR-155, MIR-125A-5P, MIR-151A-3P AND MIR-22-3P, MIR-199A-5P COULD BE INVOLVED IN THE DIFFERENT CLINICAL PRESENTATION OF SPA, AS WELL AS DISEASE ACTIVITY. IN ADDITION, ASSOCIATION WITH NON-RESPONSE TO TNFI TREATMENT AND PRESENCE OF IRAK3 AND CHUCK GENES IN SPA PATIENTS WAS RECENTLY DETECTED. FINALLY, POLYMORPHISMS IN GENES INVOLVED IN IL-23/IL-17 PATHWAY, SUCH AS IN DRUG PHARMACODYNAMICS AND PHARMACOKINETICS MAY HAVE A ROLE IN RESPONSE TO TNFI, IL17I, AND IL23I. A MAJOR UNDERSTANDING OF GENOMIC VARIABILITY COULD HELP IN THE DEVELOPMENT OF NEW THERAPEUTIC TARGETS OR IN TAKING ADVANTAGES OF DIFFERENT MECHANISMS OF ACTION OF BIOLOGICAL DRUGS. MOVING FROM THE MULTIFACTORIAL ETIOLOGY OF DISEASE, THE PRESENT REVIEW AIMS AT EVALUATING GENETIC AND EPIGENETIC FACTORS AND THEIR RELATIONSHIP WITH SEX AND BDMARDS RESPONSE, HELPING TO INVESTIGATE THE DIFFERENT EXPRESSION AMONG MALES AND FEMALES OF GENES ON X- AND OTHER CHROMOSOMES, AS WELL AS MI-RNA, TO HIGHLIGHT RELATIONSHIPS BETWEEN SEX AND OCCURRENCE OF SPECIFIC PHENOTYPES AND SYMPTOMS OF THE DISEASE. MOREOVER, THE ROLE OF THE EPIGENETIC MODIFICATION IN RELATION TO IMMUNE-REGULATORY MECHANISMS WILL BE EVALUATED. 2021 4 2989 42 GENETIC FACTORS INVOLVED IN THE CO?OCCURRENCE OF ENDOMETRIOSIS WITH ANKYLOSING SPONDYLITIS (REVIEW). PREVIOUS RESEARCH HAS REVEALED AN ASSOCIATION BETWEEN ENDOMETRIOSIS AND VARIOUS AUTOIMMUNE DISEASES, WHILE RECENT DATA SUGGEST, FOR THE FIRST TIME, AN ASSOCIATION BETWEEN ENDOMETRIOSIS AND THE RISK OF DEVELOPING ANKYLOSING SPONDYLITIS (AS). AS, THE PROTOTYPE OF SPONDYLOARTHRITIDES DISEASES, IS A SYSTEMIC, CHRONIC, IMMUNE?MEDIATED INFLAMMATORY ARTHRITIS, WHICH PRIMARILY AFFECTS THE SPINE AND SACROILIAC JOINTS, AS WELL AS THE AXIAL SKELETON WITH OR WITHOUT EXTRASPINAL MANIFESTATIONS. AS IS OF POLYGENIC INHERITANCE AND NUMEROUS IMMUNOLOGICALLY RELEVANT GENES CONTRIBUTE TO ITS DEVELOPMENT. ENDOMETRIOSIS IS AN ENIGMATIC, RELATIVELY COMMON, BENIGN, ESTROGEN?DEPENDENT, HETEROGENEOUS GYNECOLOGICAL DISEASE, INFLUENCED BY MULTIPLE GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS. IT IS CHARACTERIZED BY THE GROWTH OF ENDOMETRIAL TISSUE OCCURRING IN SITES OTHER THAN THE UTERINE CAVITY, MOST COMMONLY IN THE PELVIC CAVITY, INCLUDING THE OVARIES AND THE UTEROSACRAL LIGAMENTS, AFFECTING UP TO 10% OF THE FEMALE POPULATION OF CHILDBEARING AGE, CAUSING PAIN AND INFERTILITY. THE PRESENT REVIEW DISCUSSES WHETHER A PARTIALLY SHARED GENETIC BACKGROUND MAY EXPLAIN THE CO?OCCURRENCE OF THESE DISORDERS, AS WELL AS POTENTIAL SIMILARITIES REGARDING THE UNDERLYING PATHOGENETIC MECHANISMS AND SPECIFIC MOLECULAR AND CELLULAR PATHWAYS. 2023 5 3173 27 GUT MICROBIOTA-MICRORNA INTERACTIONS IN ANKYLOSING SPONDYLITIS. ANKYLOSING SPONDYLITIS (AS) IS A CHRONIC AUTOIMMUNE INFLAMMATORY DISABILITY THAT IS PART OF THE RHEUMATIC DISEASE GROUP OF SPONDYLOARTHROPATHIES. AS COMMONLY INFLUENCES THE JOINTS OF THE AXIAL SKELETON. THE CONTRIBUTIONS TO AS PATHOGENESIS OF GENETIC SUSCEPTIBILITY (PARTICULARLY HLA-B27 AND ERAP-1) AND EPIGENETIC MODIFICATIONS, LIKE NON-CODING RNAS, AS WELL AS ENVIRONMENTAL FACTORS, HAVE BEEN INVESTIGATED OVER THE LAST FEW YEARS. BUT THE FUNDAMENTAL ETIOLOGY OF AS REMAINS ELUSIVE TO DATE. THE EVIDENCE SUMMARIZED HERE INDICATES THAT IN THE IMMUNOPATHOGENESIS OF AS, MICRORNAS AND THE GUT MICROBIOME PERFORM CRITICAL FUNCTIONS. WE DISCUSS SIGNIFICANT ADVANCES IN THE IMMUNOLOGICAL MECHANISMS UNDERLYING AS AND ADDRESS POTENTIAL CROSS-TALK BETWEEN THE GUT MICROBIOME AND HOST MICRORNAS. THIS CRITICAL INTERACTION IMPLICATES A CO-EVOLUTIONARY SYMBIOTIC LINK BETWEEN HOST IMMUNITY AND THE GUT MICROBIOME. 2021 6 2569 35 EPIGENETICS OF ANKYLOSING SPONDYLITIS: RECENT DEVELOPMENTS. ANKYLOSING SPONDYLITIS (AS) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE WHICH MAINLY AFFECTS THE SPINE, SACROILIAC JOINT AND PERIPHERAL JOINTS. TO DATE, THE EXACT CAUSES AND PATHOGENESIS OF AS STILL REMAIN UNKNOWN. IT IS CONSIDERED THAT THE PATHOGENESIS OF AS IS ASSOCIATED WITH GENETIC, INFECTION, ENVIRONMENT, IMMUNITY AND OTHER FACTORS. AMONG THEM, THE ROLE OF GENETIC FACTORS IN THE PATHOGENESIS OF AS HAS BEEN STUDIED MOST DEEPLY. HOWEVER, OVER THE PAST FEW YEARS, THE FUNCTION OF ENVIRONMENTAL PREDISPOSITION AND EPIGENETIC MODIFICATION IN THE PATHOGENESIS OF AS HAS RECEIVED EXTENSIVE ATTENTION. THIS PAPER SUMMARIZES THE RECENT PROGRESS IN THE EPIGENETICS OF AS, INCLUDING ABNORMAL EPIGENETIC MODIFICATIONS AT AS-ASSOCIATED GENOMIC LOCI, SUCH AS DNA METHYLATION, HISTONE MODIFICATION, MICRORNA, AND SO ON. IN SUMMARY, THE FINDINGS OF THIS REVIEW ATTEMPT TO EXPLAIN THE ROLE OF EPIGENETIC MODIFICATION IN THE OCCURRENCE AND DEVELOPMENT OF AS. NEVERTHELESS, THERE ARE STILL UNKNOWN AND COMPLICATED ASPECTS WORTH EXPLORING TO DEEPEN OUR UNDERSTANDING OF THE PATHOGENESIS OF AS. 2021 7 6289 31 THE POTENTIAL ROLE OF GENETICS, ENVIRONMENTAL FACTORS, AND GUT DYSBIOSIS IN THE ABERRANT NON-CODING RNA EXPRESSION TO MEDIATE INFLAMMATION AND OSTEOCLASTOGENIC/OSTEOGENIC DIFFERENTIATION IN ANKYLOSING SPONDYLITIS. ANKYLOSING SPONDYLITIS (AS) OR RADIOGRAPHIC AXIAL SPONDYLOARTHRITIS IS A CHRONIC IMMUNE-MEDIATED RHEUMATIC DISORDER CHARACTERIZED BY THE INFLAMMATION IN THE AXIAL SKELETON, PERIPHERAL JOINTS, AND SOFT TISSUES (ENTHESIS, FASCIA, AND LIGAMENT). IN ADDITION, THE EXTRA-SKELETAL COMPLICATIONS INCLUDING ANTERIOR UVEITIS, INTERSTITIAL LUNG DISEASES AND AORTITIS ARE FOUND. THE PATHOGENESIS OF AS IMPLICATES AN INTRICATE INTERACTION AMONG HLA (HLA-B27) AND NON-HLA LOCI [ENDOPLASMIC RETICULUM AMINOPEPTIDASE 1 (ERAP1), AND INTERLEUKIN-23 RECEPTOR (IL23R), GUT DYSBIOSIS, IMMUNE PLASTICITY, AND NUMEROUS ENVIRONMENTAL FACTORS (INFECTIONS, HEAVY METALS, STRESS, CIGARETTE SMOKING, ETC.) THE LATTER MULTIPLE NON-GENETIC FACTORS MAY EXERT A POWERFUL STRESS ON EPIGENETIC REGULATIONS. THESE EPIGENETIC REGULATIONS OF GENE EXPRESSION CONTAIN DNA METHYLATION/DEMETHYLATION, HISTONE MODIFICATIONS AND ABERRANT NON-CODING RNAS (NCRNAS) EXPRESSION, LEADING TO INFLAMMATION AND IMMUNE DYSFUNCTIONS. IN THE PRESENT REVIEW, WE SHALL DISCUSS THESE CONTRIBUTORY FACTORS THAT ARE INVOLVED IN AS PATHOGENESIS, ESPECIALLY THE ABERRANT NCRNA EXPRESSION AND ITS EFFECTS ON THE PROINFLAMMATORY CYTOKINE PRODUCTIONS (TNF-ALPHA, IL-17 AND IL-23), T CELL SKEWING TO TH1/TH17, AND OSTEOCLASTOGENIC/OSTEOGENIC DIFFERENTIATION. FINALLY, SOME POTENTIAL INVESTIGATORY APPROACHES ARE RAISED FOR SOLVING THE PUZZLES IN AS PATHOGENESIS. 2021 8 4319 27 MICRORNAS IN AXIAL SPONDYLARTHRITIS: AN OVERVIEW OF THE RECENT PROGRESSES IN THE FIELD WITH A FOCUS ON ANKYLOSING SPONDYLITIS AND PSORIATIC ARTHRITIS. PURPOSE OF REVIEW: TO HIGHLIGHT THE RECENT DISCOVERIES AND LINES OF EVIDENCE ON THE ROLE OF MICRORNAS IN ANKYLOSING SPONDYLITIS (AS) AND PSORIATIC ARTHRITIS (PSA), FOCUSING ON THEIR EXPRESSION PROFILING AND MECHANISMS OF ACTION. RECENT FINDINGS: AS AND PSA ARE CHRONIC INFLAMMATORY MUSCULOSKELETAL DISEASES WITH AXIAL MANIFESTATIONS AND REPRESENT AN EXCELLENT MODEL FOR STUDYING MICRORNAS CONTRIBUTION TO THE DISEASE PATHOGENESIS, PARTICULARLY THROUGH IMMUNOMODULATION, INFLAMMATION, AND BONE REMODELLING, OR THEIR VALUE AS CANDIDATE DIAGNOSTIC AND PROGNOSTIC BIOMARKERS. MICRORNAS ARE SINGLE-STRANDED NUCLEOTIDES ABLE TO REGULATE GENE EXPRESSION. THEY ARE A KEY COMPONENT OF THE EPIGENETIC MACHINERY, INVOLVED IN PHYSIOLOGICAL AND PATHOLOGICAL PROCESSES. THE CONTRIBUTION OF MICRORNAS IN AS AND PSA (SUCH AS MIR-29A IN REGULATING BONE METABOLISM) IS HIGHLIGHTED BY SEVERAL WORKS IN THE FIELD BUT THEIR UTILITY AS POSSIBLE MARKERS MUST BE STILL CONFIRMED, PARTICULARLY IN LARGER PATIENTS' COHORTS. 2021 9 4676 39 NEW INSIGHTS TOWARD THE PATHOGENESIS OF ANKYLOSING SPONDYLITIS; GENETIC VARIATIONS AND EPIGENETIC MODIFICATIONS. ANKYLOSING SPONDYLITIS (AS) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE, CHARACTERIZED BY TYPICALLY AN AXIAL ARTHRITIS. AS IS THE PROTOTYPE OF A GROUP OF DISORDERS CALLED SPONDYLOARTHROPATHIES, WHICH IS BELIEVED TO HAVE COMMON CLINICAL MANIFESTATIONS AND GENETIC PREDISPOSITION. TO DATE, THE EXACT ETIOLOGY OF AS REMAINS UNCLEAR. OVER THE PAST FEW YEARS, HOWEVER, THE ROLE OF GENETIC SUSCEPTIBILITY AND EPIGENETIC MODIFICATIONS CAUSED THROUGH ENVIRONMENTAL FACTORS HAVE BEEN EXTENSIVELY SURVEYED WITH RESPECT TO THE PATHOGENESIS OF AS, RESULTED IN IMPORTANT ADVANCES. THIS REVIEW ARTICLE FOCUSES ON THE RECENT ADVANCES IN THE FIELD OF AS RESEARCH, INCLUDING HLA AND NON-HLA SUSCEPTIBILITY GENES IDENTIFIED IN GENOME-WIDE ASSOCIATION STUDIES (GWAS), AND ABERRANT EPIGENETIC MODIFICATIONS OF GENE LOCI ASSOCIATED WITH AS. HLA GENES MOST SIGNIFICANTLY LINKED WITH AS SUSCEPTIBILITY INCLUDE HLA-B27 AND ITS SUBTYPES. NUMEROUS NON-HLA GENES SUCH AS THOSE IN UBIQUITINATION, AMINOPEPTIDASES AND MHC CLASS I PRESENTATION MOLECULES LIKE ERAP-1 WERE ALSO REPORTED. MOREOVER, EPIGENETIC MODIFICATIONS OCCURRED IN AS HAS BEEN SUMMARIZED. TAKEN TOGETHER, THE FINDINGS PRESENTED IN THIS REVIEW ATTEMPT TO EXPLAIN THE CIRCUMSTANCE BY WHICH BOTH GENETIC VARIATIONS AND EPIGENETIC MODIFICATIONS ARE INVOLVED IN TRIGGERING AND DEVELOPMENT OF AS. NONETHELESS, SEVERAL UNANSWERED DARK SIDES CONTINUE TO CLOG OUR EXHAUSTIVE UNDERSTANDING OF AS. FUTURE RESEARCHES IN THE FIELD OF EPIGENETICS SHOULD BE CARRIED OUT TO EXTEND OUR VISION OF AS ETIOPATHOGENESIS. 2017 10 3989 49 LONGITUDINAL ANALYSIS OF BLOOD DNA METHYLATION IDENTIFIES MECHANISMS OF RESPONSE TO TUMOR NECROSIS FACTOR INHIBITOR THERAPY IN RHEUMATOID ARTHRITIS. BACKGROUND: RHEUMATOID ARTHRITIS (RA) IS A CHRONIC, IMMUNE-MEDIATED INFLAMMATORY DISEASE OF THE JOINTS THAT HAS BEEN ASSOCIATED WITH VARIATION IN THE PERIPHERAL BLOOD METHYLOME. IN THIS STUDY, WE AIM TO IDENTIFY EPIGENETIC VARIATION THAT IS ASSOCIATED WITH THE RESPONSE TO TUMOR NECROSIS FACTOR INHIBITOR (TNFI) THERAPY. METHODS: PERIPHERAL BLOOD GENOME-WIDE DNA METHYLATION PROFILES WERE ANALYZED IN A DISCOVERY COHORT OF 62 RA PATIENTS AT BASELINE AND AT WEEK 12 OF TNFI THERAPY. DNA METHYLATION OF INDIVIDUAL CPG SITES AND ENRICHMENT OF BIOLOGICAL PATHWAYS WERE EVALUATED FOR THEIR ASSOCIATION WITH DRUG RESPONSE. USING A NOVEL CELL DECONVOLUTION APPROACH, ALTERED DNA METHYLATION ASSOCIATED WITH TNFI RESPONSE WAS ALSO TESTED IN THE SIX MAIN IMMUNE CELL TYPES IN BLOOD. VALIDATION OF THE RESULTS WAS PERFORMED IN AN INDEPENDENT LONGITUDINAL COHORT OF 60 RA PATIENTS. FINDINGS: TREATMENT WITH TNFI WAS ASSOCIATED WITH SIGNIFICANT LONGITUDINAL PERIPHERAL BLOOD METHYLATION CHANGES IN BIOLOGICAL PATHWAYS RELATED TO RA (FDR<0.05). 139 BIOLOGICAL FUNCTIONS WERE MODIFIED BY THERAPY, WITH METHYLATION LEVELS CHANGING SYSTEMATICALLY TOWARDS A SIGNATURE SIMILAR TO THAT OF HEALTHY CONTROLS. DIFFERENCES IN THE METHYLATION PROFILE OF T CELL ACTIVATION AND DIFFERENTIATION, GTPASE-MEDIATED SIGNALING, AND ACTIN FILAMENT ORGANIZATION PATHWAYS WERE ASSOCIATED WITH THE CLINICAL RESPONSE TO THERAPY. CELL TYPE DECONVOLUTION ANALYSIS IDENTIFIED CPG SITES IN CD4+T, NK, NEUTROPHILS AND MONOCYTES THAT WERE SIGNIFICANTLY ASSOCIATED WITH THE RESPONSE TO TNFI. INTERPRETATION: OUR RESULTS SHOW THAT TREATMENT WITH TNFI RESTORES HOMEOSTATIC BLOOD METHYLATION IN RA. THE CLINICAL RESPONSE TO TNFI IS ASSOCIATED TO METHYLATION VARIATION IN SPECIFIC BIOLOGICAL PATHWAYS, AND IT INVOLVES CELLS FROM BOTH THE INNATE AND ADAPTIVE IMMUNE SYSTEMS. FUNDING: THE INSTITUTO DE SALUD CARLOS III. 2022 11 4318 32 MICRORNAS IN ANKYLOSING SPONDYLITIS: FUNCTION, POTENTIAL AND CHALLENGES. EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS AND NON-CODING RNA, ARE CONSIDERED THE ESSENTIAL CONNECTION BETWEEN A DISORDER'S ONSET AND THE ENVIRONMENT, ON A PERMISSIVE GENETIC BACKGROUND. AMONG AUTOIMMUNE AND INFLAMMATORY-MEDIATED DISORDERS, ANKYLOSING SPONDYLITIS (AS), A CHRONIC ARTHRITIS OF THE SPINE, IS A VERY GOOD EXAMPLE FOR THE WEIGHT OF EPIGENETICS' CONTRIBUTION. MICRORNAS (MIRNAS) ARE SINGLE-STRANDED NUCLEOTIDES WHICH REGULATE GENE EXPRESSION AND ARE INVOLVED IN PATHOLOGICAL AND PHYSIOLOGICAL PROCESSES. IN THIS MANUSCRIPT WE PROVIDE A CLARIFICATION ON THE ROLE OF MICRORNAS IN AS, WITH A FOCUS ON THE MECHANISMS OF PATHOGENESIS. IN SPECIFIC, WE HAVE EXAMINED THE CONTRIBUTION OF MIRNAS IN THE PROCESSES OF INFLAMMATION, NEW BONE FORMATION AND T-CELL FUNCTION, AND THE PATHWAYS (I.E. WNT, BMP, TGFBETA SIGNALLING ETC.) THEY REGULATE. THE UTILITY OF MIRNAS IN BETTER UNDERSTANDING AS PATHOGENESIS IS UNDISPUTED AND THEIR UTILITY AS THERAPEUTIC OPPORTUNITY IS STRONGLY INCREASING. 2020 12 1114 32 COMMONALITIES AND DISPARITIES BETWEEN ENDOMETRIOSIS AND CHRONIC ENDOMETRITIS: THERAPEUTIC POTENTIAL OF NOVEL ANTIBIOTIC TREATMENT STRATEGY AGAINST ECTOPIC ENDOMETRIUM. CHRONIC ENDOMETRITIS (CE) IS A LOCAL MUCOSAL INFLAMMATORY DISORDER OF THE UTERINE LINING, WHICH IS HISTOPATHOLOGICALLY RECOGNIZED AS THE UNUSUAL INFILTRATION OF CD138(+) PLASMACYTES INTO THE ENDOMETRIAL STROMAL COMPARTMENT. ACCUMULATING BODY OF RESEARCH DOCUMENTED THAT CE IS ASSOCIATED WITH FEMALE INFERTILITY AND SEVERAL OBSTETRIC/NEONATAL COMPLICATIONS. THE MAJOR CAUSE OF CE IS THOUGHT TO BE INTRAUTERINE INFECTION REPRESENTED BY COMMON BACTERIA (ESCHERICHIA COLI, ENTEROCOCCUS FAECALIS, STREPTOCOCCUS, AND STAPHYLOCOCCUS), MYCOPLASMA/UREAPLASMA, AND MYCOBACTERIUM. ADDITIONALLY, LOCAL DYSBIOSIS IN THE FEMALE REPRODUCTIVE TRACT MAY BE INVOLVED IN THE ONSET AND DEVELOPMENT OF CE. ANTIBIOTIC TREATMENTS AGAINST THESE MICROORGANISMS ARE EFFECTIVE IN THE ELIMINATION OF ENDOMETRIAL STROMAL PLASMACYTES IN THE AFFECTED PATIENTS. MEANWHILE, ENDOMETRIOSIS IS A COMMON FEMALE REPRODUCTIVE TRACT DISEASE CHARACTERIZED BY ENDOMETRIOTIC TISSUES (ECTOPIC ENDOMETRIUM) GROWING OUTSIDE THE UTERUS AND POTENTIALLY CAUSES CHRONIC PELVIC SYMPTOMS (DYSMENORRHEA, DYSPAREUNIA, DYSCHEZIA, AND DYSURIA), INFERTILITY, AND OVARIAN CANCERS. ENDOMETRIOSIS INVOLVES ENDOCRINOLOGICAL, GENETIC, AND EPIGENETIC FACTORS IN ITS ETIOLOGY AND PATHOGENESIS. RECENT STUDIES FOCUS ON IMMUNOLOGICAL, INFLAMMATORY, AND INFECTIOUS ASPECTS OF ENDOMETRIOSIS AND DEMONSTRATE SEVERAL COMMON CHARACTERISTICS BETWEEN ENDOMETRIOSIS AND CE. THIS REVIEW AIMED TO BETTER UNDERSTAND THE IMMUNOLOGICAL AND MICROBIAL BACKGROUNDS UNDERLYING ENDOMETRIOSIS AND CE AND LOOK INTO THE THERAPEUTIC POTENTIAL OF THE NOVEL ANTIBIOTIC TREATMENT STRATEGY AGAINST ENDOMETRIOSIS IN LIGHT OF ENDOMETRIAL INFECTIOUS DISEASE. 2023 13 4962 33 PATHOGENESIS OF PSORIATIC ARTHRITIS. PSORIATIC ARTHRITIS (PSA) IS A CHRONIC INFLAMMATORY ARTHROPATHY INVOLVING SYNOVIAL AND ENTHESEAL STRUCTURES, ASSOCIATED WITH PSORIASIS OR SIMILAR CONDITIONS. THE ETIOPATHOGENETIC MECHANISMS UNDERLYING PSA REMAIN UNCLARIFIED. THE MOST ACCREDITED HYPOTHESIS INVOLVES A COMPLEX INTERACTION AMONG GENETIC, ENVIRONMENTAL, AND IMMUNOLOGICAL FACTORS. ENVIRONMENTAL AGENTS, PARTICULARLY TRAUMA, MECHANICAL STRESS, AND SMOKE HAVE BEEN CITED AS POSSIBLE FACTORS IN TRIGGERING THE DISEASE IN GENETICALLY PREDISPOSED SUBJECTS. LIKE OTHER FORMS OF SPONDYLOARTHROPATHIES, PSA SHOWS SEVERAL GENETIC ASSOCIATIONS WITH THE MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) CLASS I ALLELES LOCATED ON CHROMOSOME 6P21.3, PARTICULARLY THE HUMAN LEUKOCYTE ANTIGEN (HLA)-B27 IN AXIAL PHENOTYPES. RECENT STUDIES HAVE DEMONSTRATED THAT THE MOST COMMON EPIGENETIC MECHANISMS THAT REGULATE GENE EXPRESSION IN PSA ARE REPRESENTED BY DNA METHYLATION, PARENT OF ORIGIN EFFECT OR GENOMIC IMPRINTING, EXPRESSION OR ACTIVITY OF EPIGENETIC MODIFYING ENZYMES, AND RNA INTERFERENCE (RNAI) BY MICRORNAS (MIRNAS). THE MECHANISMS UNDERLYING PSA PATHOGENESIS ACTIVATE THE INNATE AND ADAPTIVE IMMUNE SYSTEM AND OVEREXPRESSION OF TNF ASSOCIATED WITH AMPLIFICATION OF THE IL-23/IL-17 AXIS. IN RECENT YEARS, MORE PSA SUSCEPTIBILITY GENES AND EPIGENETIC MECHANISMS HAVE BEEN IDENTIFIED. ADVANCES IN THE KNOWLEDGE OF INNATE AND ADAPTIVE IMMUNE MECHANISMS UNDERLYING PSA HAVE CONTRIBUTED TO A BETTER UNDERSTANDING OF THE HETEROGENEOUS CLINICAL EXPRESSION OF THE DISEASE AND, THUS, TO THERAPY STRATEGIES. THE COMPLEXITY OF THE PATHOGENETIC ASPECTS INVOLVING MULTIPLE CYTOKINES, CELL LINES, AND MOLECULES NEEDS TO BE FURTHER INVESTIGATED TO ADVANCE PERSONALIZED THERAPEUTIC STRATEGIES AND TO IMPROVE OUTCOMES OF PATIENTS AFFECTED BY PSA. 2019 14 986 32 CHRONIC RECURRENT MULTIFOCAL OSTEOMYELITIS (CRMO) AND JUVENILE SPONDYLOARTHRITIS (JSPA): TO WHAT EXTENT ARE THEY RELATED? CHRONIC RECURRENT MULTIFOCAL OSTEOMYELITIS (CRMO) IS AN AUTOINFLAMMATORY DISEASE OCCURRING MAINLY IN THE PEDIATRIC AGE GROUP (BEFORE 16 YEARS) AND GENERALLY PRESENTS AS A SEPARATE ENTITY. SYNOVITIS, ACNE, PUSTULOSIS, HYPEROSTOSIS AND OSTEITIS (SAPHO) SYNDROME COMBINES OSTEOARTICULAR AND CUTANEOUS INVOLVEMENT, SIMILAR TO CRMO, AND FALLS INTO THE SPECTRUM OF SPONDYLOARTHRITIS (SPA). THE FACT THAT A PATIENT CAN PROGRESS FROM ONE DISEASE TO ANOTHER RAISES THE QUESTION OF WHETHER CRMO, LIKE SAPHO, COULD FALL WITHIN THE SPECTRUM OF SPA, RANGING FROM A PREDOMINANTLY OSTEOARTICULAR FORM TO AN ENTHESITIC FORM WITH MORE OR LESS MARKED SKIN INVOLVEMENT. IN THIS REVIEW, WE SET OUT TO DISCUSS THIS HYPOTHESIS BY HIGHLIGHTING THE DIFFERENCES AND SIMILARITIES BETWEEN CRMO AND JUVENILE SPA IN CLINICAL, RADIOLOGICAL AND PATHOPHYSIOLOGICAL ASPECTS. A COMMON HYPOTHESIS COULD POTENTIALLY CONSIDER INTESTINAL DYSBIOSIS AS THE ORIGIN OF THESE DIFFERENT INFLAMMATORY DISEASES. INTERINDIVIDUAL FACTORS SUCH AS GENDER, ENVIRONMENT, GENETICS AND/OR EPIGENETIC BACKGROUND COULD ACT AS COMBINED DISEASE MODIFIERS. THIS IS WHY WE SUGGEST THAT PATHOPHYSIOLOGY, RATHER THAN CLINICAL PHENOTYPE, BE USED TO RECLASSIFY THESE DISEASES. 2023 15 6237 26 THE MAIN THEORIES ON THE PATHOGENESIS OF ENDOMETRIOSIS. ENDOMETRIOSIS IS A COMPLEX DISEASE, WHICH IS DEFINED BY ABNORMAL GROWTH OF ENDOMETRIAL TISSUE OUTSIDE THE UTERUS. IT AFFECTS ABOUT 10% OF WOMEN OF REPRODUCTIVE AGE ALL OVER THE WORLD. ENDOMETRIOSIS CAUSES SYMPTOMS THAT NOTABLY WORSEN PATIENT'S WELL-BEING-SUCH AS SEVERE PELVIC PAIN, DYSFUNCTION OF THE ORGANS OF PELVIC CAVITY, INFERTILITY AND SECONDARY MENTAL ISSUES. THE DIAGNOSIS OF ENDOMETRIOSIS IS QUITE OFTEN DELAYED BECAUSE OF NONSPECIFIC MANIFESTATIONS. SINCE THE DISEASE WAS DEFINED, SEVERAL DIFFERENT PATHOGENETIC PATHWAYS HAVE BEEN CONSIDERED, INCLUDING RETROGRADE MENSTRUATION, BENIGN METASTASIS, IMMUNE DYSREGULATION, COELOMIC METAPLASIA, HORMONAL DISBALANCE, INVOLVEMENT OF STEM CELLS AND ALTERATIONS IN EPIGENETIC REGULATION, BUT THE TRUE PATHOGENESIS OF ENDOMETRIOSIS REMAINS POORLY UNDERSTOOD. THE KNOWLEDGE OF THE EXACT MECHANISM OF THE ORIGIN AND PROGRESSION OF THIS DISEASE IS SIGNIFICANT FOR THE APPROPRIATE TREATMENT. THEREFORE, THIS REVIEW REPORTS THE MAIN PATHOGENETIC THEORIES OF ENDOMETRIOSIS BASED ON CURRENT STUDIES. 2023 16 2595 41 EPIGENETICS OF SPONDYLOARTHRITIS. SPONDYLOARTHRITIS (SPA) IS A CHRONIC INFLAMMATORY DISORDER RESULTING FROM A COMBINATION OF GENETIC PREDISPOSITION AND ENVIRONMENTAL FACTORS. DESPITE RECENT ADVANCES, A SUBSTANTIAL FRACTION OF ITS GENETIC BASIS REMAINS POORLY UNDERSTOOD. SEVERAL MECHANISMS HAVE BEEN PROPOSED TO ACCOUNT FOR THIS UNEXPLAINED HERITABILITY, INCLUDING EPIGENETICS WHICH CAN PLAY A ROLE AT THE INTERFACE BETWEEN GENETIC AND ENVIRONMENTAL SUSCEPTIBILITY FACTORS. EPIGENETICS REFERS TO CHANGES IN GENE EXPRESSION THAT ARE NOT ENCODED IN THE DNA SEQUENCE ITSELF. SUCH MECHANISMS MAY INCLUDE DNA METHYLATION, HISTONE MODIFICATIONS AND NON-CODING RNAS. DISRUPTION OF ONE OF THESE SYSTEMS CAN LEAD TO INAPPROPRIATE GENE EXPRESSION, WHICH IN TURN MIGHT FAVOUR THE DEVELOPMENT OF DISEASE. THANKS TO RECENT TECHNOLOGICAL PROGRESS, THERE HAS BEEN A GROWING INTEREST IN THE FIELD OF EPIGENETICS IN COMPLEX DISEASES, INCLUDING SPA. HOWEVER, EPIGENETIC STUDIES FACE SOME METHODOLOGICAL LIMITATIONS THAT HAMPER INTERPRETATION OF THEIR RESULTS: SMALL SAMPLE SIZE, ABSENCE OF BIOLOGICAL REPLICATION, LACK OF ADEQUATE CONTROLS FOR POTENTIAL CONFOUNDERS, STUDIES NOT PERFORMED IN THE MOST RELEVANT CELL/TISSUES. IN THE FUTURE, INTEGRATION OF EPIGENETICS WITH OTHER "OMICS" DATA WILL PROBABLY BE NECESSARY TO IMPROVE OUR UNDERSTANDING OF SPA PATHOGENESIS. THESE ISSUES NEED TO BE ADDRESSED BEFORE CONSIDERING THE USE OF EPIGENETIC MARKS IN CLINICAL ROUTINE, AS BIOMARKERS OR AS DRUG TARGETS. 2020 17 4956 24 PATHOGENESIS OF ENDOMETRIOSIS: FOCUS ON ADENOGENESIS-RELATED FACTORS. ENDOMETRIOSIS CAN BE DEFINED AS THE PRESENCE OF THE ENDOMETRIUM OUTSIDE THE UTERINE CAVITY. IT AFFECTS APPROXIMATELY 10% OF WOMEN OF REPRODUCTIVE AGE AND CAUSES INFERTILITY, CHRONIC PAIN, AND DETERIORATION OF THE QUALITY OF LIFE. SINCE THE IDENTIFICATION OF THE DISEASE, VARIOUS PATHOGENETIC MECHANISMS HAVE BEEN PROPOSED, SUCH AS RETROGRADE MENSTRUATION, COELOMIC METAPLASIA, HORMONAL IMBALANCE, STEM CELL INVOLVEMENT, AND ALTERATIONS IN EPIGENETIC REGULATION. HOWEVER, THE UNDERLYING PATHOGENESIS OF ENDOMETRIOSIS REMAINS INADEQUATELY UNDERSTOOD. ELUCIDATION OF THE PRECISE MECHANISM OF THE DEVELOPMENT AND PROGRESSION OF ENDOMETRIOSIS IS CRUCIAL FOR EFFECTIVE TREATMENT. THIS REVIEW PRESENTS THE MAJOR PATHOGENETIC THEORIES OF ENDOMETRIOSIS BASED ON CURRENT RESEARCH STUDIES WITH A MAJOR FOCUS ON THE POTENTIAL ROLE OF UTERINE FACTORS. 2023 18 2556 23 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 19 406 32 ANALYSIS OF FIVE CHRONIC INFLAMMATORY DISEASES IDENTIFIES 27 NEW ASSOCIATIONS AND HIGHLIGHTS DISEASE-SPECIFIC PATTERNS AT SHARED LOCI. WE SIMULTANEOUSLY INVESTIGATED THE GENETIC LANDSCAPE OF ANKYLOSING SPONDYLITIS, CROHN'S DISEASE, PSORIASIS, PRIMARY SCLEROSING CHOLANGITIS AND ULCERATIVE COLITIS TO INVESTIGATE PLEIOTROPY AND THE RELATIONSHIP BETWEEN THESE CLINICALLY RELATED DISEASES. USING HIGH-DENSITY GENOTYPE DATA FROM MORE THAN 86,000 INDIVIDUALS OF EUROPEAN ANCESTRY, WE IDENTIFIED 244 INDEPENDENT MULTIDISEASE SIGNALS, INCLUDING 27 NEW GENOME-WIDE SIGNIFICANT SUSCEPTIBILITY LOCI AND 3 UNREPORTED SHARED RISK LOCI. COMPLEX PLEIOTROPY WAS SUPPORTED WHEN CONTRASTING MULTIDISEASE SIGNALS WITH EXPRESSION DATA SETS FROM HUMAN, RAT AND MOUSE TOGETHER WITH EPIGENETIC AND EXPRESSED ENHANCER PROFILES. THE COMORBIDITIES AMONG THE FIVE IMMUNE DISEASES WERE BEST EXPLAINED BY BIOLOGICAL PLEIOTROPY RATHER THAN HETEROGENEITY (A SUBGROUP OF CASES GENETICALLY IDENTICAL TO THOSE WITH ANOTHER DISEASE, POSSIBLY OWING TO DIAGNOSTIC MISCLASSIFICATION, MOLECULAR SUBTYPES OR EXCESSIVE COMORBIDITY). IN PARTICULAR, THE STRONG COMORBIDITY BETWEEN PRIMARY SCLEROSING CHOLANGITIS AND INFLAMMATORY BOWEL DISEASE IS LIKELY THE RESULT OF A UNIQUE DISEASE, WHICH IS GENETICALLY DISTINCT FROM CLASSICAL INFLAMMATORY BOWEL DISEASE PHENOTYPES. 2016 20 4452 29 MOLECULAR MECHANISMS AND MANAGEMENT OF A CUTANEOUS INFLAMMATORY DISORDER: PSORIASIS. PSORIASIS IS A COMPLEX CHRONIC INFLAMMATORY CUTANEOUS DISORDER. TO DATE, ROBUST MOLECULAR MECHANISMS OF PSORIASIS HAVE BEEN REPORTED. AMONG DIVERSE ABERRANT IMMUNOPATHOGENETIC MECHANISMS, THE CURRENT MODEL EMPHASIZES THE ROLE OF TH1 AND THE IL-23/TH17 AXIS, SKIN-RESIDENT IMMUNE CELLS AND MAJOR SIGNAL TRANSDUCTION PATHWAYS INVOLVED IN PSORIASIS. THE MULTIPLE GENETIC RISK LOCI FOR PSORIASIS HAVE BEEN RAPIDLY REVEALED WITH THE ADVENT OF A NOVEL TECHNOLOGY. MOREOVER, IDENTIFYING EPIGENETIC MODIFICATIONS COULD BRIDGE THE GAP BETWEEN GENETIC AND ENVIRONMENTAL RISK FACTORS IN PSORIASIS. THIS REVIEW WILL PROVIDE A BETTER UNDERSTANDING OF THE PATHOGENESIS OF PSORIASIS BY UNRAVELING THE COMPLICATED INTERPLAY AMONG IMMUNOLOGICAL ABNORMALITIES, GENETIC RISK FOCI, EPIGENETIC MODIFICATION AND ENVIRONMENTAL FACTORS OF PSORIASIS. WITH ADVANCES IN MOLECULAR BIOLOGY, DIVERSE NEW TARGETS ARE UNDER INVESTIGATION TO MANAGE PSORIASIS. THE RECENT ADVANCES IN TREATMENT MODALITIES FOR PSORIASIS BASED ON TARGETED MOLECULES ARE ALSO DISCUSSED. 2017