The Value of Ultrasound for Detecting and Following Subclinical Interstitial Lung Disease in Systemic Sclerosis.

BACKGROUND: Interstitial lung disease (ILD) is a complication in patients with systemic sclerosis (SSc). Accurate strategies to identify its presence in early phases are essential. We conducted the study aiming to determine the validity of ultrasound (US) in detecting subclinical ILD in SSc, and to ascertain its potential in determining the disease progression. METHODS: 133 patients without respiratory symptoms and 133 healthy controls were included. Borg scale, Rodnan skin score (RSS), auscultation, chest radiographs, and respiratory function tests (RFT) were performed. A rheumatologist performed the lung US. High-resolution CT (HRCT) was also performed. The patients were followed every 12 weeks for 48 weeks. RESULTS: A total of 79 of 133 patients (59.4%) showed US signs of ILD in contrast to healthy controls (4.8%) (p = 0.0001). Anti-centromere antibodies (p = 0.005) and RSS (p = 0.004) showed an association with ILD. A positive correlation was demonstrated between the US and HRCT findings (p = 0.001). The sensitivity and specificity of US in detecting ILD were 91.2% and 88.6%, respectively. In the follow-up, a total of 30 patients out of 79 (37.9%) who demonstrated US signs of ILD at baseline, showed changes in the ILD score by US. CONCLUSIONS: US showed a high prevalence of subclinical ILD in SSc patients. It proved to be a valid, reliable, and feasible tool to detect ILD in SSc and to monitor disease progression.

Role of the MicroRNAs in the Pathogenic Mechanism of Painful Symptoms in Long COVID: Systematic Review.

The ongoing pandemic of COVID-19 has caused more than 6.7 million tragic deaths, plus, a large percentage of people who survived it present a myriad of chronic symptoms that last for at least 6 months; this has been named as long COVID. Some of the most prevalent are painful symptoms like headache, joint pain, migraine, neuropathic-like pain, fatigue and myalgia. MicroRNAs are small non-coding RNAs that regulate genes, and their involvement in several pathologies has been extensively shown. A deregulation of miRNAs has been observed in patients with COVID-19. The objective of the present systematic review was to show the prevalence of chronic pain-like symptoms of patients with long COVID and based on the expression of miRNAs in patients with COVID-19, and to present a proposal on how they may be involved in the pathogenic mechanisms of chronic pain-like symptoms. A systematic review was carried out in online databases for original articles published between March 2020 to April 2022; the systematic review followed the PRISMA guidelines, and it was registered in PROSPERO with registration number CRD42022318992. A total of 22 articles were included for the evaluation of miRNAs and 20 regarding long COVID; the overall prevalence of pain-like symptoms was around 10 to 87%, plus, the miRNAs that were commonly up and downregulated were miR-21-5p, miR-29a,b,c-3p miR-92a,b-3p, miR-92b-5p, miR-126-3p, miR-150-5p, miR-155-5p, miR-200a, c-3p, miR-320a,b,c,d,e-3p, and miR-451a. The molecular pathways that we hypothesized to be modulated by these miRNAs are the IL-6/STAT3 proinflammatory axis and the compromise of the blood-nerve barrier; these two mechanisms could be associated with the prevalence of fatigue and chronic pain in the long COVID population, plus they could be novel pharmacological targets in order to reduce and prevent these symptoms.

Rheumatoid Arthritis and Oxidative Stress.

Rheumatoid arthritis (RA) is an autoimmune disease that affects approximately 1% of the worldwide population. In recent decades, oxidative stress (OS) has been shown to be involved in the progression of this disease through DNA, lipid and protein damage, resulting in synovial inflammation. There are many causes of OS; metabolism is involved in the production of reactive oxygen species (ROS) but pollution, diet and microbiota imbalances could lead to the overproduction of these ROS. A decade of research focused on understanding how OS is promoted by known RA risk factors is described herein. The use of antioxidants represents an integrative treatment for patients with rheumatoid arthritis, given the evidence of the damage caused by oxidative stress in this disease. Understanding the different factors that contribute to the development and progression of RA, such as OS, will pave the way not only for better pharmacological treatments but also for recommendations for dietary and health behaviours that will benefit patients with this disease.

Inflammasome Genes Polymorphisms and Susceptibility to Gout. Is There a Link?

ABSTRACT Background: The inflammatory response in gout disease is induced by the activation of NLR family pyrin domain-containing 3 (NLPR3) signaling pathway mediated by IL-1β release. Objective: The objective of the study was to determine the association between single nucleotide polymorphisms (SNPs) within NLRP3 inflammasome genes and gout susceptibility. Methods: Mexican patients with gout from the National Rehabilitation Institute and General Hospital of Mexico were enrolled. A healthy control group was also included. We analyzed the frequency and allelic distribution of eight SNPs from seven different genes within the NLRP3 inflammasome signaling pathway: TLR4 rs2149356, CD14 rs2569190, NLRP3 rs3806268, NLRP3 rs10754558, CARD8 rs2043211, IL-1β rs1143623, P2RX7 rs3751142, and PPARGC1B rs45520937 SNPs. Results: We found that the SNP rs45520937 of PPARGC1B was associated with the risk of developing gout when it was analyzed using the dominant model (Odds ratio [OR] = 2.30; 95% confidence interval [CI]: 1.09-4.86; p = 0.030), and it is proposed that the adaptor molecule CD14 rs2569190 polymorphism could be associated with a lower risk of gout under an additive model (OR= 0.41;95% CI: 0.16-1.05; p = 0.064). No significant associations were identified for the remaining SNPs. Conclusion: Our findings suggest that the PPARGC1B rs45520937 SNP is associated with gout susceptibility.

The emerging role of ultrasound in detecting interstitial lung disease in patients with rheumatoid arthritis.

OBJECTIVE: To investigate the potential role of US in the detection of ILD in a cohort of patients with RA. METHODS: Patients with diagnosis of RA were consecutively enrolled. All patients underwent pulmonary examination, laboratory data, DLCO measure, chest HRCT and radiographs, and US examination. A healthy group was included as control group. US was performed according the 14-intercostal space scanning protocol using the following semiquantitative scale [0=normal (≤5 B-lines); 1=slight (≥6 and ≤15 B-lines); 2=moderate, (≤16 and ≥30 B-lines); 3=severe (≥30 B-lines)]. RESULTS: A total of 74 RA patients and 74 healthy controls were included. Thirty of 74 patients (40.5%) showed US signs of ILD with respect to the healthy controls (3 subjects, 4.1%) (P<0.001); whereas HRCT showed ILD in 27 (36.4%) of 74 patients. Among the 30 patients that showed US findings of ILD, 17 (56.6%) were asymptomatic from respiratory view-point. The sensitivity and specificity of US were 92% and 89% respectively. A positive correlation between US and HRCT findings were found (P<0.001) whereas no correlation was found with chest radiographs and DLCO findings. Positive association between US findings and DAS28-ESR, anti-CCP and RF (P<0.01 for each respectively) was found. Feasibility, represented by the mean time spent to perform the pulmonary US assessment was 7.8minutes (±SD 1.2, range 6 to 10minutes). CONCLUSIONS: Our results support the potential of US in detect accurately ILD in patients with RA and provide a rationale to consider it as a friendly screening tool to be implemented in early phases of the disease.

Inflammasome genes polymorphisms and susceptibility to gout. Is there a link?

Background: The inflammatory response in gout disease is induced by the activation of NLR family pyrin domain-containing 3 (NLPR3) signaling pathway mediated by IL-1ß release. Objective: The objective of the study was to determine the association between single nucleotide polymorphisms (SNPs) within NLRP3 inflammasome genes and gout susceptibility. Methods: Mexican patients with gout from the National Rehabilitation Institute and General Hospital of Mexico were enrolled. A healthy control group was also included. We analyzed the frequency and allelic distribution of eight SNPs from seven different genes within the NLRP3 inflammasome signaling pathway: TLR4 rs2149356, CD14 rs2569190, NLRP3 rs3806268, NLRP3 rs10754558, CARD8 rs2043211, IL-1ß rs1143623, P2RX7 rs3751142, and PPARGC1B rs45520937 SNPs. Results: We found that the SNP rs45520937 of PPARGC1B was associated with the risk of developing gout when it was analyzed using the dominant model (Odds ratio [OR] = 2.30; 95% confidence interval [CI]: 1.09-4.86; p = 0.030), and it is proposed that the adaptor molecule CD14 rs2569190 polymorphism could be associated with a lower risk of gout under an additive model (OR= 0.41;95% CI: 0.16-1.05; p = 0.064). No significant associations were identified for the remaining SNPs. Conclusion: Our findings suggest that the PPARGC1B rs45520937 SNP is associated with gout susceptibility.

Update of the current role of ultrasound in asymptomatic hyperuricemia. A systematic literature review.

Ultrasound (US) is a recognized imaging modality for the assessment of gout. Recently it is being explored for its potential role in the evaluation of subjects with asymptomatic hyperuricemia (AH). Preliminary reports demonstrated the presence of monosodium urate (MSU)-crystal deposits including aggregates, double contour sign and/or tophi in both intra-articular and periarticular tissues of AH individuals. Although these results are exciting, the value and potential application of US in AH remain to be clearly delineated. In this systematic literature review, we aim to summarise the recent publications regarding the role of US in the assessment of AH. We analyzed possible application of US in the daily clinical practice and its future clinical and research potential in the evaluation of AH individuals.

The current role of NLRP3 inflammasome polymorphism in gout susceptibility.

INTRODUCTION: The NLR family pyrin domain containing 3 (NLRP3) signaling pathway has an important role in inflammation mediated by monosodium urate crystals in gout, and the characterization of single nucleotide polymorphisms (SNPs) have helped to recognize disease susceptibility. OBJECTIVE: The aim of this review is to provide an overview of the potential role of the inflammasome gene SNPs as a susceptibility factor for gout, discussing the current evidence available. METHODS: This review analyzes the relevant literature in the field of inflammasome SNPs and gout published in the last 10 years. The systematic research was performed in 16 articles, including both the SNPs associated and those not associated with gout, with the goal to have a complete overview. RESULTS: Sixty-nine SNPs from 10 different genes have been reported in the literature. Of these, 13 SNPs present association with gout susceptibility in different populations, while 56 have been established as not being associated with the disease. CONCLUSIONS: This review is a summary of the potential role of inflammasome gene SNPs and their association with gout risk, all of them related with NLRP3 inflammasome signaling, suggesting these polymorphisms are susceptibility candidates and genetic markers for gout. From the 69 SNPs analyzed in the literature, 13 of them have been associated with gout as follows: NLRP3 (rs3806268 and rs10754558), CARD8 (rs2043211), TLR4 (rs2149356), CD14 (rs2569190), IL-1ß (rs1143623), P2RX7 (rs2230911, rs1653624, rs7958316 and rs17525809) and PPARGC1B (rs45520937, rs10491360 and rs7712296) in different populations.

HGF/c-Met regulates p22phox subunit of the NADPH oxidase complex in primary mouse hepatocytes by transcriptional and post-translational mechanisms.

INTRODUCTION AND OBJECTIVES: It is well-known that signaling mediated by the hepatocyte growth factor (HGF) and its receptor c-Met in the liver is involved in the control of cellular redox status and oxidative stress, particularly through its ability to induce hepatoprotective gene expression by activating survival pathways in hepatocytes. It has been reported that HGF can regulate the expression of some members of the NADPH oxidase family in liver cells, particularly the catalytic subunits and p22phox. In the present work we were focused to characterize the mechanism of regulation of p22phox by HGF and its receptor c-Met in primary mouse hepatocytes as a key determinant for cellular redox regulation. MATERIALS AND METHODS: Primary mouse hepatocytes were treated with HGF (50 ng/mL) at different times. cyba expression (gene encoding p22phox) or protein content were addressed by real time RT-PCR, Western blot or immunofluorescence. Protein interactions were explored by immunoprecipitation and FRET analysis. RESULTS: Our results provided mechanistic information supporting the transcriptional repression of cyba induced by HGF in a mechanism dependent of NF-κB activity. We identified a post-translational regulation mechanism directed by p22phox degradation by proteasome 26S, and a second mechanism mediated by p22phox sequestration by c-Met in plasma membrane. CONCLUSION: Our data clearly show that HGF/c-Met exerts regulation of the NADPH oxidase by a wide-range of molecular mechanisms. NADPH oxidase-derived reactive oxygen species regulated by HGF/c-Met represents one of the main mechanisms of signal transduction elicited by this growth factor.

Subclinical Interstitial Lung Disease in Patients with Systemic Sclerosis. A Pilot Study on the Role of Ultrasound. / Intersticiopatía pulmonar subclínica en pacientes con esclerosis sistémica. Estudio piloto sobre el papel del ultrasonido.

INTRODUCTION: Interstitial lung disease (ILD) is a common comorbidity present in patients with systemic sclerosis (SSc). Employment of high-resolution computed tomography (HRCT) is very limited and lung ultrasound (LUS) can be an alternative tool for the early evaluation of ILD. OBJECTIVE: To determine the validity of LUS in the early detection of ILD in patients with SSc. METHODS: Sixty-eight patients with SSc ≥18 years without respiratory symptoms were included. A rheumatologist rated the subclinical respiratory condition, another rheumatologist blinded to the clinical assessment performed the LUS. To determine validity HRCT was performed as well. RESULTS: Prevalence of ILD in SSc patients was 41.2% in contrast to the 4.8% healthy controls (P=.0001). Variables associated with LUS and HRCT findings were anti-centromere antibodies (P=.005) and the Rodnan skin score (P=.004). A positive correlation was present between the findings of HRCT and LUS (P=.001). Sensitivity and specificity were 91.2% and 88.6% respectively. Good reliability in the LUS findings was found between observers (k=.72). CONCLUSIONS: By proving to be a valid, trustworthy and feasible alternative tool, we consider that LUS can be implemented for the early detection of ILD in SSc.

Criterion validity of ultrasound in the identification of calcium pyrophosphate crystal deposits at the knee: an OMERACT ultrasound study.

OBJECTIVE: To evaluate the discriminatory ability of ultrasound in calcium pyrophosphate deposition disease (CPPD), using microscopic analysis of menisci and knee hyaline cartilage (HC) as reference standard. METHODS: Consecutive patients scheduled for knee replacement surgery, due to osteoarthritis (OA), were enrolled. Each patient underwent ultrasound examination of the menisci and HC of the knee, scoring each site for presence/absence of CPPD. Ultrasound signs of inflammation (effusion, synovial proliferation and power Doppler) were assessed semiquantitatively (0-3). The menisci and condyles, retrieved during surgery, were examined microscopically by optical light microscopy and by compensated polarised microscopy. CPPs were scored as present/absent in six different samples from the surface and from the internal part of menisci and cartilage. Ultrasound and microscopic analysis were performed by different operators, blinded to each other's findings. RESULTS: 11 researchers from seven countries participated in the study. Of 101 enrolled patients, 68 were included in the analysis. In 38 patients, the surgical specimens were insufficient. The overall diagnostic accuracy of ultrasound for CPPD was of 75%-sensitivity of 91% (range 71%-87% in single sites) and specificity of 59% (range 68%-92%). The best sensitivity and specificity were obtained by assessing in combination by ultrasound the medial meniscus and the medial condyle HC (88% and 76%, respectively). No differences were found between patients with and without CPPD regarding ultrasound signs of inflammation. CONCLUSION: Ultrasound demonstrated to be an accurate tool for discriminating CPPD. No differences were found between patents with OA alone and CPPD plus OA regarding inflammation.

Acute administration of levetiracetam in tonic pain model modulates gene expression of 5HT1A and 5HT7 receptors in the thalamus of rats (Rattus norvergicus).

The nociceptive effect of Levetiracetam (LEV) on the expression of 5-HT1A and 5-HT7 receptors found in the thalamus was evaluated. Thirty-six male rats (Wistar) were randomized into six groups: in the Control group without treatment; LEV50 group LEV was administered in a single dose of 50 mg/kg i.g.; in the LEV300 group LEV dose of 300 mg/kg i.g.; in the FORMALIN group the formalin test was performed; in the LEV50/FORMALIN group LEV dose of 50 mg/kg i.g and the formalin test was performed; in the LEV300/FORMALIN group LEV dose of 300 mg/kg i.g and the formalin test was performed, subsequently the thalamus was dissected in all groups. In the formalin tests LEV exhibited an antinociceptive effect in the LEV300/FORMALIN group (p < 0.05) and a pronociceptive effect in the LEV50/FORMALIN group (p < 0.001). The results obtained by Real-time PCR confirmed the expression of the 5-HT1A and 5-HT7 receptors in the thalamus, 5-HT1A receptors increased significantly in the FORMALIN group and the LEV300/FORMALIN group (p < 0.05). 5-HT7 receptors are only over expressed at a dose of 300 mg/Kg of LEV with formalin (p < 0.05). This suggests that LEV modulates the sensation of pain by controlling the expression of 5-HT1A and 5-HT7 in a tonic pain model, and that changes in the expression of 5-HT1A and 5-HT7 receptors are associated with the sensation of pain, furthermore its possibility to be used in clinical treatments for pain.

Chemical Mediators' Expression Associated with the Modulation of Pain in Rheumatoid Arthritis.

BACKGROUND: The management of pain in patients with rheumatoid arthritis (RA) is a complex subject due to the autoimmune nature of the pathology. Studies have shown that chemical mediators play a fundamental role in the determination, susceptibility and modulation of pain at different levels of the central and peripheral nervous system, resulting in interesting novel molecular targets to mitigate pain in patients with RA. However, due to the complexity of pain physiology in RA cand the many chemical mediators, the results of several studies are controversial. OBJECTIVE: The aim of this study was to identify the chemical mediators that are able to modulate pain in RA. METHOD: In this review, a search was conducted on PubMed, ProQuest, EBSCO, and the Science Citation index for studies that evaluated the expression of chemical mediators on the modulation of pain in RA. RESULTS: Few studies have highlighted the importance of the expression of some chemical mediators that modulate pain in patients with rheumatoid arthritis. The expression of TRPV1, ASIC-3, and TDV8 encode ionic channels in RA and modulates pain, likewise, the transcription factors in RA, such as TNFα, TGF-ß1, IL-6, IL-10, IFN-γ, IL-1b, mTOR, p21, caspase 3, EDNRB, CGRPCALCB, CGRP-CALCA, and TAC1 are also directly involved in pain perception. CONCLUSION: The expression of all chemical mediators is directly related to RA and the modulation of pain by a complex intra and extracellular signaling pathway, however, transcription factors are involved in modulating acute pain, while the ionic channels are involved in chronic pain in RA.

Impact of cadmium toxicity on cartilage loss in a 3D in vitro model.

Osteoarthritis (OA) is the gradual loss of articular cartilage and decrease in subchondral space. One of the risk factors Exposure to cadmium (Cd) through tobacco smoke has been identified as a major OA risk factor. There are no reports addressing the role of Cd in OA progression at the molecular level. Our findings revealed that Cd can promote the activation of metalloproteinases (MMP1, MMP3, MMP9 y MMP13), affecting the expression of COL2A1 and ACAN, and decreasing the presence of glycosaminoglycans and proteoglycans through an inflammatory response related to IL-1ß y a IL-6, as well as oxidative by producing ROS like O2-• and H2O2. In conclusion, our findings suggest a cytotoxic role of Cd in the articular cartilage, which could affect OA development.

Ultrasound as a potential tool for the assessment of interstitial lung disease in rheumatic patients. Where are we now?

Lung ultrasound (LUS) achieved an intriguing role in the management of pulmonary involvement in patients affected by connective tissues diseases (CTDs). Few studies have been performed to support its usefulness in the evaluation of the presence and the severity of interstitial lung disease (ILD), relating it to the information obtained with chest high-resolution computed tomography (HRCT). These results open up new fields of research in order to demonstrate the utility of LUS as screening tool to evaluate ILD in CTD. The aim of this review is to provide the "state of the art" of the role of LUS in the management of ILD associated with CTD.

Prevalence of chondrocalcinosis in a Mexican tertiary care institution of musculoskeletal disorders.

INTRODUCTION/OBJECTIVES: The prevalence of chondrocalcinosis (CC) was reported as variable according to the geographic populations. However, there are no data regarding its prevalence in Mexico. Thus, we decided to investigate the Mexican prevalence of CC in a cohort of patients from a tertiary health care institution. METHODS: A retrospective analysis of radiographs of knees and wrists from our institution was performed. Inclusion criteria included patients > 50 years old having radiographs of knees and wrists. Radiographic presence of CC was classified according to a dichotomous evaluation assayed by two rheumatologists experts on the area. RESULTS: A total of 3.350 radiographs from 1.602 patients were evaluated. Forty-seven patients showed calcifications in at least one knee or wrist for an overall prevalence of 3%, of which 23.4% were men and 76.6% women. The knee was more commonly affected than the wrist (85.1% and 14.9% respectively). The prevalence according to gender was 2.9% in women, whereas, it was 3.2% in men. Only two patients (4.3%) showed a contemporaneous presence of CC in both hands and both knees. At knee level, the prevalence was 2.7%, whereas at the wrist, we reported a prevalence of 4.9%. CONCLUSIONS: The prevalence of CC for Mexican population had not been reported so far. This a starting point to break the silence and encourage the knowledge of how this disease is associated with possible risk factors in Mexican population. Key Points •The prevalence of chondrocalcinosis in Mexico was 3%. •The prevalence of knee chondrocalcinosis increases according to the age in women's. •The nixtamalized meals could be a protective factor for CC in Mexican population.

Ultrasound as a Useful Tool in the Diagnosis of Rheumatoid Arthritis in Patients With Undifferentiated Arthritis.

BACKGROUND: Nowadays, rheumatologists face challenges in finding an effective method to classify and treat patients with undifferentiated arthritis (UA). There is a need for new tools that could ensure accurate characterization of inflammatory processes in these patients. OBJECTIVE: The aim of this study was to investigate if a characterization of UA patients using ultrasound (US) may help to fulfill the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) rheumatoid arthritis (RA) classification criteria in a real-life cohort. METHODS: We conducted a cross-sectional study in 2 rheumatology care clinics. Patients not fulfilling the 2010 ACR/EULAR RA criteria were included. On the examination day, all patients underwent a physical examination, radiography, and US. The 7-joint US score was adopted to scan all patients. The US was performed according to EULAR criteria and interpreted by Outcome Measures in Rheumatology definitions. Gray-scale and power Doppler synovitis and tenosynovitis were scored. Bone erosions were also evaluated during the US examination. RESULTS: A total of 204 patients were included. The diagnosis was modified from UA to RA in 86 patients (42.1%). Also, the final score of the 2010 ACR/EULAR RA classification criteria changed from a mean of 4.6 to 6.5 after the US examination. In addition to synovitis, a wide range of tenosynovitis and bone erosions were detected by US. Synovitis was more frequently detected in second metacarpophalangeal joint followed by second metatarsophalangeal joint (MTPj) and fifth MTPj. The tendons of the wrist and second and third fingers were the most affected. In relation to bone erosions, second metacarpophalangeal joint and fifth MTPj were the joints with more proportion of anatomical damage. CONCLUSIONS: The US demonstrated to be useful to help accurately classify as RA patients previously diagnosed with UA.

The current role of capillaroscopy in vasculitides.

Nailfold capillaroscopy (NFC) has gained remarkable interest among rheumatologists because of its utility in both clinical practice and research activity. Nevertheless, there has been scarce attention on its potential in other rheumatic disorders such as vasculitis. We perform a systematic review of literature on NFC in noninfectious vasculitides, with the aim to provide an overview of the main NFC changes described, to discuss the current evidence supporting its clinical impact and applications in daily practice and to provide future research fields.

Fast Morphological Gallbladder Changes Triggered by a Hypercholesterolemic Diet.

INTRODUCTION AND AIM: Obesity is a worldwide epidemic problem, described as a risk factor for hepatic diseases, such as non-alcoholic fatty liver disease and other pathologies related to development of cholesterol crystals and cholesterol gallbladder stones. It has been reported that cholesterol overload may cause hepatic damage; however, little is known about the effects of an acute hypercholesterolemic diet on the gallbladder. The aim of this manuscript was to evaluate the impact of a cholesterol-rich diet on the gallbladder. MATERIAL AND METHODS: The study included ten eight-week-old C57BL6 male mice, which were divided into two study groups and fed different diets for 48 h: a hypercholesterolemic diet and a balanced Chow diet. After 48 h, the mice were analyzed by US with a Siemens Acuson Antares equipment. Mice were subsequently sacrificed to carry out a cholesterol analysis with a Refloton System (Roche), a crystal analysis with a Carl Zeiss microscope with polarized light, and a histological analysis with Hematoxylin-eosin staining. RESULTS: The hypercholesterolemic diet induced an increase in gallbladder size and total cholesterol content in the bile, along with important histological changes. CONCLUSION: Cholesterol overloads not only trigger hepatic damage, but also affect the gallbladder significantly.

The association of AKNA gene polymorphisms with knee osteoarthritis suggests the relevance of this immune response regulator in the disease genetic susceptibility.

Recent studies have identified AKNA as a potential susceptibility gene for several inflammatory diseases. Here, we aimed to assess the potential association of AKNA polymorphisms with knee osteoarthritis (KOA) susceptibility in a Mexican population, following STREGA recommendations. From a DNA bank of 181 KOA patients and 140 healthy controls, two AKNA SNPs were genotyped using TaqMan probes. The association between KOA susceptibility and AKNA polymorphisms genotypes was evaluated by multivariated logistic regression analysis. Information regarding patients' inflammatory biomarkers levels was obtained and their association with AKNA polymorphisms genotypes was assessed by lineal regression. We found a positive association with the recessive inheritance model of both AKNA polymorphisms (A/A genotype for both) and KOA susceptibility adjusting by age, body mass index (BMI), gender and place of birth (OR = 2.48, 95% CI 1.09-5.65 for rs10817595 polymorphism; and OR = 4.96; 95% CI 2.421-10.2 for rs3748176 polymorphism). Additionally these associations were also seen after stratifying patients by KOA severity and age. Furthermore the total leukocyte count was positively associated with rs10817595 AKNA polymorphism (ß = 1.39; 95% CI 0.44-2.34) adjusting by age, BMI, gender, place of birth and disease severity. We suggest that regulatory and coding polymorphisms of the inflammatory modulator gene AKNA can influence the development of KOA. Further structural and functional studies might reveal the role of AKNA in OA and other rheumatic diseases.