Identification of a novel autoantigen eukaryotic initiation factor 3 associated with polymyositis.

OBJECTIVES: To describe the prevalence and clinical associations of autoantibodies to a novel autoantigen, eukaryotic initiation factor 3 (eIF3), detected in idiopathic inflammatory myositis. METHODS: Sera or plasma from 678 PM patients were analysed for autoantigen specificity by radio-labelled protein immunoprecipitation (IPP). Samples immunoprecipitating the same novel autoantigens were further analysed by indirect immunofluorescence and IPP using pre-depleted cell extracts. The autoantigen was identified through a combination of IPP and MALDI-TOF mass spectrometry, and confirmed using commercial antibodies and IPP-western blots. Additional samples from patients with DM (668), DM-overlap (80), PM-overlap (191), systemic sclerosis (150), systemic lupus erythematosus (200), Sjogren's syndrome (40), rheumatoid arthritis (50) and healthy controls (150) were serotyped by IPP as disease or healthy controls. RESULTS: IPP revealed a novel pattern in three PM patients (0.44%) that was not found in disease-specific or healthy control sera. Indirect immunofluorescence demonstrated a fine cytoplasmic speckled pattern for all positive patients. Mass spectrometry analysis of the protein complex identified the target autoantigen as eIF3, a cytoplasmic complex with a role in the initiation of translation. Findings were confirmed by IPP-Western blotting. The three anti-eIF3-positive patients had no history of malignancy or interstitial lung disease, and had a favourable response to treatment. CONCLUSION: We report a novel autoantibody in 0.44% of PM patients directed against a cytoplasmic complex of proteins identified as eIF3. Although our findings need further confirmation, anti-eIF3 appears to correlate with a good prognosis and a favourable response to treatment.

Characteristics of Children with Acute Rheumatic Carditis from a High-Incidence Region: Importance of Unexplained Worsening of Functional Class.

BACKGROUND: Acute rheumatic fever (ARF) and acute rheumatic carditis (ARC) continue to be a major public health problem in developing countries. OBJECTIVE: To study the characteristics of children with ARC being treated at a tertiary centre. METHODS AND RESULTS: We studied 126 children (mean age 10.4 ± 2.3 years, range 5-15 years, 60% males) diagnosed with ARC by treating cardiologists. Most had lower socio-economic status. Fifty of 126 (40%) presented with a first episode of ARC. Joint symptoms were present in 29% and fever in 25%. Only 2.4% had subcutaneous nodules and none had erythema marginatum or chorea. Fifty-one percent presented in NYHA class II and 29% in NYHA class III or IV. Tachycardia and heart failure were present in 53% and 21%, respectively. Recent worsening of NYHA class (dyspnoea) was the commonest feature (48%). Laboratory investigations showed raised antistreptolysin O titres (>333 units) in only 36.7% of patients. Raised C-reactive protein (CRP) was present in 70%, while raised erythrocyte sedimentation rate was found in only 37% of patients. On the basis of above findings, the modified Jones criteria (2015) for the diagnosis of ARF were satisfied only in 46% of children. Echocardiography showed mitral valve thickening in 77% and small nodules on the tip of the leaflets in 43% (27 and 8%, respectively for aortic valve). Left ventricular ejection fraction was <50% in only 3 patients. The dominant valve lesion was mitral regurgitation (MR) (present in 95% of patients; severe in 78%, moderate in 15%), while aortic regurgitation was present in 44% (severe in 14%). CONCLUSIONS: The criteria are often not satisfied by patients being treated for ARC. Recent unexplained worsening of dyspnoea, young age, significant MR, echocardiographic nodules, and elevated CRP are important indicators.

Oxidative stress parameters in children with acute rheumatic fever.

BACKGROUND: The aim of this study was to investigate of the role of oxidative stress (OS) in acute rheumatic fever (ARF) and its relationship with the progress of the disease. METHODS: Thirty patients with ARF and 31 age-sex-matched healthy children were enrolled in this study. Serum malondialdehyde (MDA), protein carbonyl (PCO), high-sensitivity C-reactive protein (hs-CRP), cytokines (tumor necrosis factor-α and interleukin-6) and total antioxidant capacity (TAC) were measured. The diagnosis of ARF was based on the Jones criteria. RESULTS: Patients with ARF had significantly higher serum MDA, PCO, hs-CRP and cytokine levels and lower TAC than healthy controls. On Pearson's correlation analysis we found that oxidative stress markers were positively correlated with hs-CRP and cytokines, while TAC was negatively correlated with MDA, PCO, hs-CRP and cytokines. The number of valves involved as well as the level of mitral valve involvement was also significantly related to the oxidative stress parameters and TAC. All oxidative stress parameters decreased significantly with anti-inflammatory therapy while TAC increased. CONCLUSION: Malondialdehyde and PCO, as biomarkers, as well as hs-CRP together with the other available diagnostic tools, can be used in the evaluation of patients with ARF.

Sydenham's Chorea.

BACKGROUND: Sydenham's chorea is the most common acquired movement disorder of adolescence. This clinical manifestation of acute rheumatic fever has a clear and documented relationship with Group A streptococcal infections. The symptoms are involuntary choreiform movements that can affect the face and all extremities. The pathophysiology remains unclear. CASE REPORT: A 12-year-old female was brought to the emergency department with a 2-week history of involuntary muscle spasms of her right arm and leg. Her parents reported intermittent slurred speech and difficulty grasping utensils. Physical examination revealed an awake, alert, age-appropriate female with normal cranial nerves. Patient was found to have choreoathetoid movements on the right extremities with dystonia of right leg with ambulation. Neurology consultation, computed tomography of the head, and magnetic resonance imaging of the brain did not show any acute pathology. Echocardiogram did show mild tricuspid regurgitation, suggestive of rheumatic fever. Anti-streptolysin O titer was markedly elevated, along with DNAse-B antibodies. The patient had marked improvement of movement disorder at just over 1 week later. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Sydenham's chorea is a rare but important movement disorder often related to Group A streptococcus and rheumatic fever. The incidence of rheumatic fever has been decreasing in North America but continues to be much more prevalent in developing countries as well as immigrant populations. This diagnosis is rare and can occasionally be misdiagnosed as a "fidgety" child or as a psychiatric manifestation. Sydenham's chorea is important to diagnose because acute treatment and prophylactic antibiotics can help improve symptoms and minimize cardiac damage.

Heart Involvement in Inflammatory Rheumatic Diseases: A Systematic Literature Review.

Introduction: Patients with inflammatory rheumatic diseases have an increased risk of developing cardiovascular manifestations. The high risk of cardiovascular pathology in these patients is not only due to traditional cardiovascular risk factors (age, gender, family history, smoking, sedentary lifestyle, cholesterol), but also to chronic inflammation and autoimmunity. Aim: In this review, we present the mechanisms of cardiovascular comorbidities associated with inflammatory rheumatic diseases, as they have recently been reported by different authors, grouped in electrical abnormalities, valvular, myocardial and pericardial modifications and vascular involvement. Methods: We conducted a systematic search of published literature on the following online databases: EBSCO, ScienceDirect, Scopus and PubMed. Searches were limited to full-text English-language journal articles published between 2010 and 2017 using the following key words: heart, systemic inflammation, autoimmunity, rheumatic diseases and disease activity. After the primary analysis we included 50 scientific articles in this review. Results: The results showed that cardiac manifestations of systemic inflammation can occur frequently with different prevalence in rheumatoid arthritis (RA), systemic lupus erythematosus(SLE), systemic sclerosis(SSc) and ankylosing spondylitis(AS). Rheumatologic diseases can affect the myocardium, cardiac valves, pericardium, conduction system and arterial vasculature. Conclusions: Early detection, adequate management and therapy of specific cardiac involvement are essential in rheumatic disease. Electrocardiographic and echocardiographic evaluation should be performed as routine investigations in patients with inflammatory rheumatic diseases.

Poststreptococcal Illness: Recognition and Management.

Group A beta-hemolytic streptococcus can cause several postinfectious, nonsuppurative immune- mediated diseases including acute rheumatic fever, poststreptococcal reactive arthritis, pediatric autoimmune neuropsychiatric disorders, and poststreptococcal glomerulonephritis. Except for sporadic outbreaks, poststreptococcal autoimmune syndromes occur most commonly in sub-Saharan Africa, India, Australia, and New Zealand. Children younger than three years are rarely affected by group A streptococcus pharyngitis or rheumatic fever, and usually do not require testing. Rheumatic fever is a rare condition that presents as a febrile illness characterized by arthritis, carditis or valvulitis, and neurologic and cutaneous disease, followed many years later by acquired valvular disease. Recurrence rates are high. In addition to evidence of recent streptococcal infection, two major or one major and two minor Jones criteria are required for diagnosis. Electrocardiography, chest radiography, erythrocyte sedimentation rate, and an antistreptolysin O titer are the most useful initial tests. Echocardiography is recommended to identify patients with subclinical carditis. The arthritis usually responds within three days to nonsteroidal anti-inflammatory drugs. Poststreptococcal reactive arthritis is nonmigratory, can affect any joint, and typically does not respond to aspirin. Pediatric autoimmune neuropsychiatric disorders affect the basal ganglia and are manifested by obsessive-compulsive and tic disorders. The presentation of poststreptococcal glomerulonephritis ranges from asymptomatic microscopic hematuria to gross hematuria, edema, hypertension, proteinuria, and elevated serum creatinine levels.

Pain management in rheumatology research, training, and practice.

The Pain Management Task Force of the American College of Rheumatology published a report in 2010 highlighting pain management as a fundamental aspect of clinical practice, training and research. In the interim, the consideration of pain as a focus of attention of rheumatologists and rheumatology health professionals has become even more challenging than in 2010 because of the epidemic of opiate addiction and overdose death. The characterisation of categories of pain by mechanism (e.g., inflammation, joint degeneration, abnormalities of central pain processing) can help guide treatment. However, such categorisation can overlook the overlap of these processes and their interaction to create mixed pain states. Further complicating the assessment of pain, outcome measures in rheumatic disease often assess the degree of pain indirectly while concentrating on the quantification of inflammation. Non-inflammatory pain often persists despite treatment, highlighting the need for alternative analgesic therapies. Recommended therapies include acetaminophen, nonsteroidal anti-inflammatory drugs, and stimulators of the pain inhibitory pathway. Each of these non-opioid therapies has incomplete efficacy and potential toxicities that can limit their utility. Non-pharmacologic therapies can show efficacy that rivals or surpasses pharmacologic therapies in the control of pain and improving function in a variety of rheumatic disorders including chronic low back pain and fibromyalgia. A limitation of the use of these therapies is inadequate training and appreciation of their benefits. Furthermore, the supply of trained practitioners to provide non-pharmacological care and support patient efforts for self-management is often limited. Together, these considerations suggest the importance of a renewed effort to implement task force recommendations.

Ventricular dyssynchrony as a marker of latent carditis in children with acute rheumatic fever: A tissue Doppler imaging.

OBJECTIVE: We aimed to investigate the hypothesis that the presence of left ventricular (LV) dyssynchrony in children with acute rheumatic fever (ARF) children may be a predictor of latent rheumatic carditis. METHODS: Eighty-nine children with ARF and 45 healthy control children were included the study. LV dyssynchrony was investigated by color-coded tissue Doppler imaging. RESULTS: LV dyssynchrony parameters including Ts-SD-12, Ts-12, Ts-SD-6, and Ts-6 were found to be prolonged in children with ARF than in controls (P < .001). We found that 45.2% in children with ARF without carditis had LV dyssynchrony (Ts-SD-12 ≥ 34.4 ms), while 63.4% in children with ARF with carditis had LV dyssynchrony. Follow-up analysis demonstrated that children with arthritis and without dyssynchrony had no adverse events (recurrent rheumatic activity, development of valvular diseases; heart failure and atrial fibrillation), while those with LV dyssynchrony had events rate of 40.9% (P < .001). Likewise, children with carditis had event rates of 63.4%. Ts-SD-12 was found to be correlated with hs-CRP (r = .63; P < .001). Receiver-operating characteristic (ROC) curve analysis showed that a Ts-SD-12 ≥ 36.5 was the optimal cutoff value in predicting unfavorable outcome in patients with ARF, with a sensitivity of 95% and specificity of 82%. CONCLUSIONS: We found that children with ARF without any evidence of carditis had a significant LV systolic dyssynchrony spite of normal EF. LV dyssynchrony in those children had a significant event rates on follow-up. These results highlighted the incremental value of LV dyssynchrony as a marker of subclinical carditis in children with ARF.

Correlation between Pulmonary Artery Pressure Measured by Echocardiography and Right Heart Catheterization in Patients with Rheumatic Mitral Valve Stenosis (A Prospective Study).

INTRODUCTION: Right heart catheterization (RHC) remains the gold standard for hemodynamic assessment of the right heart and pulmonary artery. However, this is an invasive tool, and noninvasive alternatives such as transthoracic echocardiography (TTE) are preferable. Nonetheless, the correlation between measurements by TTE and RHC are debated. In this study, we prospectively examined the correlation between systolic and mean pulmonary artery pressures (sPAP and mPAP) measured by RHC and TTE in patients with hemodynamically significant rheumatic mitral stenosis (MS). MATERIAL AND METHODS: Three hundred patients with hemodynamically significant MS undergoing TTE who were scheduled to undergo RHC within 24 hours were analyzed. PAP measurements were taken for all patients by RHC (sPAP(RHC), mPAP(RHC)). Maximum velocity of tricuspid regurgitation (TR) jet obtained by continuous-wave Doppler with adding right atrial (RA) pressure was used for measuring sPAP by TTE (sPAP(TRVmax)). Mean PAP was measured using either pulmonary artery acceleration time (mPAP(PAAT)) method or by adding RA pressure to velocity-time integral of TR jet (mPAP(TRVTI)). RESULTS: A good correlation between sPAP(RHC) and sPAP(TRVmax) (r = 0.89, P < 0.001), between mPAP(RHC) and mPAP(PAAT) (r = 0.9, P < 0.001), and between mPAP(RHC) and mPAP(TRVTI) (r = 0.92, P < 0.001) was found. Sensitivity and specificity of sPAP(TRV) max in detecting pulmonary hypertension (PH) were 92.8% and 86.6% and of mPAP(PAAT) were 94.1% and 73.3%, respectively. CONCLUSION: The noninvasive assessment of sPAP and mPAP by TTE correlates well with invasive measurements and has an acceptable specificity and sensitivity in detecting PH in patients with hemodynamically significant MS.

Fifteen-minute consultation: rheumatic fever.

OBJECTIVE: To present a structured approach for an outpatient consultation or inpatient assessment of a child with possible rheumatic fever. METHOD: Review of literature and description of diagnostic and therapeutic approach. CONCLUSIONS: A focused history and examination is key to establish the cause and draw a management plan for rheumatic fever.

Clinical Profile of Acute Rheumatic Fever Patients in a Tertiary Care Institute in Present Era.

INTRODUCTION: Rheumatic heart disease (RHD) is still a common cause of morbidity and mortality in India. Rheumatic fever commonly occurs between 5-15 yrs of age. Rheumatic activity is a common cause of deterioration of symptoms in a stable or undiagnosed case of RHD. MATERIAL AND METHODS: 41 consecutive patients of acute rheumatic activity were studied. Presenting symptoms were noted. Physical examination was done for major and minor Jone's criteria. Detailed cardiac examination was done. All underwent echocardiography. RESULTS: Mean age was 14.80 ± 7.01 yrs, 26 were female and 15 were male. Joint pain was the commonest present complaint (29 patients), followed by fever in 17 patients, 32 had carditis, 26 had arthritis, 13 had subcutaneous nodules, 7 had chorea and one had erythema marginatum. In patients with carditis, 30 had mitral regurgitation (MR) only, 15 had MR with aortic regurgitation (AR). Out of 32 patients with carditis, 10 patients did not have any clinical evidence of carditis and were detected by echocardiography only. Six patients were known cases of rheumatic fever but had stopped penicillin prophylaxis. CONCLUSION: Commonest complaint in patients with rheumatic fever was joint pain followed by fever. In patients with carditis, all had MR, with 1/3rd of these patients having associated AR. 1/3rd of patients with carditis were detected by echo only and therefore, echo should be included in diagnostic criteria for acute rheumatic fever. None of the patients who developed rheumatic fever was on penicillin prophylaxis.

Carotid intima media thickness and arterial stiffness in children with acute rheumatic fever.

Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) constitute important public health problems in developing countries. Inflammation is present both in the early and late stages of the diseases. Chronic inflammation is known to be associated with atherosclerosis. We hypothesize that subclinical atherosclerosis and arterial stiffness may increase due to the ongoing inflammation as well as the increased pulse pressure and left-ventricular systolic dysfunction in RHD. The purpose of the present study was to investigate carotid intima media thickness (CIMT) and carotid artery stiffness in patients with ARF. Forty patients in follow-up due to ARF in the age group of 7-16 years (disease duration 1-10 years) and 36 volunteered subjects with similar body mass index were included in the study. The subjects included in the present study were compared regarding M-mode echocardiographic parameters and CIMT as well as carotid arterial strain (CAS), carotid artery distensibility (CAD), beta stiffness index (ßSI), and pressure-strain elasticity modulus (Ep) as carotid artery stiffness parameters. CIMT (0.52 ± 0.08 and 0.48 ± 0.07 mm, p = 0.01), ßSI (5.29 ± 2.98 and 3.02 ± 1.30, p < 0.001), and Ep (426.53 ± 210.50 and 254.44 ± 104.69 p < 0.001) were increased, whereas CAS (0.11 ± 0.01 and 0.19 ± 0.09, p < 0.001) and CAD (10.27 ± 4.69 and 17.76 ± 14.41, p < 0.001) were decreased in patients with ARF compared with the control group. There was a positive correlation between pulse pressure and ßSI (r = 0.25, p = 0.02) and Ep (r = 0.28, p = 0.01) in addition to a correlation between left atrial dilatation and CIMT (r = 0.55 p < 0.001) in patients with ARF. CIMT and carotid artery stiffness were increased in patients with ARF. Patients with ARF may have an increased risk of subclinical atherosclerosis and cardiovascular events.

Accelerated junctional rhythm in children with acute rheumatic fever: is it specific to the disease?

OBJECTIVE: During the course of acute rheumatic fever, some electrocardiographic changes are seen. First-degree atrioventricular block is the most common electrocardiographic abnormality. Second- and third-degree atrioventricular block, ventricular tachycardia, and junctional acceleration are also seen. In the present study, the specificity of accelerated junctional rhythm to acute rheumatic fever was INVESTIGATED. METHODS: The study included patients with acute rheumatic fever (Group 1), healthy children who had suffered from recent group A ß-haemolytic streptococcal upper respiratory tract infection but did not develop acute rheumatic fever (Group 2), and patients who had other diseases that may affect the joints and/or heart (Group 3). RESULTS: Accelerated junctional rhythm was detected in 10 patients in Group 1, but in none of the patients from Group 2 or 3. Specificity of accelerated junctional rhythm for acute rheumatic fever was 100% and the positive predictive value was 100%. CONCLUSION: Accelerated junctional rhythm is specific to acute rheumatic fever. Although its frequency is low, it seems that it can be used in the differential diagnosis of acute rheumatic fever, especially in patients with isolated polyarthritis.

Assessment of atrial electromechanical delay in children with acute rheumatic fever.

PURPOSE: There may be an increase in the risk of atrial arrhythmia due to left atrial enlargement and the influence on conduction system in acute rheumatic fever. The aim of this study is to investigate atrial electromechanical delay and P-wave dispersion in patients with acute rheumatic fever. PATIENTS: A total of 48 patients diagnosed with acute rheumatic fever and 40 volunteers of similar age, sex, and body mass index were included in the study. The study groups were compared for M-mode echocardiographic parameters, interatrial electromechanical delay, intra-atrial electromechanical delay, and P-wave dispersion. RESULTS: Maximum P-wave duration, P-wave dispersion, and interatrial electromechanical delay were significantly higher in patients with acute rheumatic fever compared with the control group (p < 0.001). However, there was no difference in terms of intra-atrial electromechanical delay (p > 0.05). For patients with acute rheumatic fever, a positive correlation was identified between the left atrium diameter and the P-wave dispersion and interatrial electromechanical delay (r = 0.524 and p < 0.001, and r = 0.351 and p = 0.014, respectively). Furthermore, an important correlation was also identified between the P-wave dispersion and the interatrial electromechanical delay (r = 0.494 and p < 0.001). CONCLUSION: This study shows the prolongation of P-wave dispersion and interatrial electromechanical delay in acute rheumatic fever. Left atrial enlargement can be one of the underlying reasons for the increase in P-wave dispersion and interatrial electromechanical delay.

Antibiotics prescription in Nigerian dental healthcare services.

INTRODUCTION: Inappropriate antibiotics prescription in dental healthcare delivery that may result in the emergence of antibiotic-resistant bacteria, is a worldwide concern. The objective of the study was to determine the antibiotics knowledge and prescription patterns among dentists in Nigeria. MATERIALS AND METHODS: A total of 160 questionnaires were distributed to dentists attending continuing education courses organized by two organizations in Southern and Northern parts of Nigeria. Data analysis was done using SPSS version 17.0. RESULTS: A total of 146 questionnaires were returned, properly filled, out of 160 questionnaires, giving an overall response rate 91.3%. The clinical factors predominantly influenced the choice of therapeutic antibiotics among the respondents. In this study, the most commonly prescribed antibiotics among the respondents was a combination of amoxicillin and metronidazole. Of the respondents, 136 (93.2%) of them considered antibiotic resistance as a major problem in Nigeria and 102 (69.9%) have experienced antibiotics resistance in dental practice. The major reported conditions for prophylactic antibiotics among the respondents were diabetic mellitus, HIV/AIDS, history of rheumatic fever, other heart anomalies presenting with heart murmur and presence of prosthetic hip. The knowledge of adverse effects of antibiotics was greatest for tooth discoloration which is related to tetracycline. CONCLUSION: Data from this study revealed the most commonly prescribed antibiotics as a combination of amoxicillin and metronidazole. There existed gaps in prophylactic antibiotic prescription, consideration in the choice of therapeutic antibiotics and knowledge of adverse effects of antibiotics among the studied dentists.

Sydenham's Chorea in Children with Acute Rheumatic Fever: An Echocardiographic Survey of Pediatric Patients in Northwestern Iran.

Background: Although infrequent, Sydenham's chorea (SC) may occur as a result of injury to the basal ganglia in children with acute rheumatic fever (ARF) secondary to group A Streptococcal infection. Certain hallmarks of SC, such as movement disorders, could be utilized as a predictive marker for carditis. The present study aimed to investigate neurologic and cardiologic symptoms in children with suspected SC after ARF. Methods: All children aged 5-16 who were admitted at Shahid Madani Pediatric Hospital (Tabriz, Iran), with an initial diagnosis of ARF and SC between 2009 and 2022 were included for echocardiographic assessment and prospective follow-up within 6 and 12 months after the start point. The pattern and severity of valvulopathy, as well as the prevalence of Jones criteria for rheumatic fever, were used to assess the effect. The collected data were analyzed using SPSS Statistics software (version 22.0) using Chi square and Fisher's exact tests. P<0.05 was considered statistically significant. Results: The study enrolled 85 children, 36 girls and 49 boys, with a mean age of 9.7±2.7. On the first echocardiography, 42.4% of patients had mitral valve regurgitation (MR), with a predominance of female patients (P=0.04). Of those diagnosed with SC (12 girls and 6 boys), 66.7% showed cardiac involvement, with a higher prevalence of MR in both sexes (P=0.04). The pattern of cardiac involvement after 6 months was significantly different between the groups (P=0.04). However, no such difference was observed during the one-year follow-up (P=0.07). Female sex was found to have a significant relationship with SC localization (P=0.01). Conclusion: In addition to its neurological manifestations, SC can be associated with clinical or subclinical cardiac valve dysfunction that might last for more than a year. In addition to attempting early detection and appropriate management, a precise cardiac and neurologic assessment during admission and follow-up is recommended.A preprint version of this manuscript is available at DOI: 10.21203/rs.3.rs-772662/v1 (https://www.researchsquare.com/article/rs-772662/v1).

Protective effect of allograft inflammatory factor-1 on the apoptosis of fibroblast-like synoviocytes in patients with rheumatic arthritis induced by nitro oxide donor sodium nitroprusside.

OBJECTIVES: Inadequate apoptosis of rheumatic arthritis (RA) fibroblast-like synoviocytes (FLS) plays a crucial role in the immunopathogenesis of RA. Allograft inflammatory factor-1 (AIF-1) is a novel member of the cytokine network that has been found to be involved in the immunological process underlying RA. This study was undertaken to investigate the potential effects of AIF-1 on nitric oxide donor (NO) sodium nitroprusside (SNP)-induced RA-FLS apoptosis, and the possible molecular mechanisms underlying these effects. METHOD: FLS obtained from patients with active RA were cultured in vitro and treated with SNP in the present or absence of AIF-1. RA-FLS viability was tested by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. RA-FLS apoptosis was analysed by flow cytometry and terminal dUTP nick-end labeling (TUNEL). The levels of phospho-Akt (p-Akt) and phospho-BAD (p-BAD) protein were detected by Western blot. RESULTS: A 24-h AIF-1 pretreatment at concentrations ranging from 10 to 100 ng/mL increased the viability of RA-FLS and prevented RA-FLS apoptosis in a dose-dependent manner in the presence of SNP. AIF-1 induced phosphorylation of Akt and BAD in a time- and concentration-dependent manner. The effect was reversed by treatment with the PI3K inhibitor LY2940042 (LY) and the nuclear factor kappa B (NF-κB) inhibitor pyrrolidine dithiocarbamate (PDTC). CONCLUSIONS: AIF-1 can protect RA-FLS from apoptosis induced by NO by upregulating the expression of p-Akt and p-BAD.