Signs Of Rheumatoid Arthritis Research Articles

Indicative features of tissue and microbial sensitization in the pathogenesis of generalized parodontitis associated with rheumatoid arthritis

In the literature, there are not enough studies that reflect the role and place of tissue and microbial sensitization in patients with generalized parodontitis (GP) associated with rheumatoid arthritis (RA). In our opinion, the research of these components will help to better understand the etiopathogenetic mechanisms of development of GP against the background of RA, which will improve the formation of preventive and therapeutic measures for this disease treatment. The purpose of the research was to determine the location and integration features of tissue and microbial sensitization in the pathogenesis of generalized parodontitis associated with rheumatoid arthritis. Immunological studies were carried out in 335 people, who were divided into 4 groups: Group 1 – the main – consisted of 136 patients with GP on the background of RA; Group 2 – control – 71 people with GP without signs of RA; Group 3 – comparison – 128 people without GP, but with diseases of the musculoskeletal system not related to RA and Group 4 – 30 practically healthy people. To determine microbial and tissue sensitization, we used inhibition reaction of migrating lymphocytes with microbial antigens of streptococci and staphylococci, tissue antigens (bone and synovial). A high frequency of microbial sensitization to streptococcal and staphylococcal antigens was established in patients with GP on the background of RA and in patients with GP without signs of RA. The parodontal focus turned out to be an active focus of microbial sensitization in patients with GP associated with RA and in patients with GP without signs of RA. Established sensitization to bone antigen in a small number of patients (27-33%) with GP, which was significantly more frequent (61-80%) in patients with GP associated with RA, indicates that in the latter, allergy is to a greater extent due to tissue systemic damage to connective tissue than GP. However, a certain allergy to bone tissue in GP may indicate the inclusion of an immune component in the pathogenesis of GP. The presence of microbial and tissue sensitization in patients with GP and RA indicates that similar and cross antigens of streptococcal and staphylococcal microorganisms with connective tissue are a potential trigger for the development of both GP and RA, which is a reason to consider GP and RA comorbid diseases with similar pathogenetic mechanisms of development.

Identification of Risk Factors for Relapse in Childhood Leukemia Using Penalized Semi-parametric Mixture Cure Competing Risks Model.

Leukemia is the most common childhood malignancy. Identifying prognostic factors of patient survival and relapse using more reliable statistical models instead of traditional variable selection methods such as stepwise regression is of great importance. The present study aimed to apply a penalized semi-parametric mixture cure model to identify the prognostic factors affecting short-term and long-term survival of childhood leukemia in the presence of competing risks. The outcome of interest in this study was time to relapse. Study Design: A retrospective cohort study. A total of 178 patients (0‒15 years old) with leukemia participated in this study (September 1997 to September 2016, followed up to June 2021) at Golestan University of Medical Sciences, Iran. Demographic, clinical, and laboratory data were collected, and then a penalized semi-parametric mixture cure competing risk model with smoothly clipped absolute deviation (SCAD) and least absolute shrinkage and selection operator (LASSO) regularizations was used to analyze the data. Important prognostic factors of relapse patients selected by the SCAD regularization method were platelets (150000‒400000 vs.>400000; odds ratio=0.31) in the cure part and type of leukemia (ALL vs. AML, hazard ratio (HR)=0.08), mediastinal tumor (yes vs. no, HR=16.28), splenomegaly (yes vs. no; HR=2.94), in the latency part. In addition, significant prognostic factors of death identified by the SCAD regularization method included white blood cells (<4000 vs.>11000, HR=0.25) and rheumatoid arthritis signs (yes vs. no, HR=5.75) in the latency part. Several laboratory factors and clinical side effects were associated with relapse and death, which can be beneficial in treating the disease and predicting relapse and death time.

P26 Felty’s syndrome as the first presentation of rheumatoid arthritis

Abstract Introduction Felty's syndrome (FS) is a rare, autoimmune disease occurring in &amp;lt; 1% of patients with rheumatoid arthritis (RA) and comprising a triad of persistent idiopathic neutropenia, splenomegaly and RA. In some affected individuals, FS may develop when the symptoms and signs of RA have subsided or are absent. In this case, FS may remain undiagnosed. In rare instances, the development of FS may precede the development of the clinical manifestation of RA. Case description A 73-year-old Caucasian gentleman presented in October 2017 with pancytopenia and splenomegaly. He was investigated by the haematology team with multiple bone marrow biopsies showing no underlying haematological causes for his pancytopenia. He was also investigated by the hepatologists for the possibility of liver cirrhosis as he had a heavy alcohol intake. His liver ultrasound showed fatty liver with splenomegaly, his fibro-scan showed fibrosis with no evidence of cirrhosis and his OGD showed no oesophageal varies. At this point, he was treated with blood transfusions, weekly erythropoietin and filgrastim as needed under the haematologists. In October 2022, he was admitted with febrile neutropenia and he gave a 20-year history of palindromic rheumatism with no evidence of synovitis or previous DMARD treatment. His rheumatoid factor (RF) was &amp;gt;120 iu/ml, anti-cyclic citrullinated peptide (ACCPA) was &amp;gt;340 u/ml and ANA by CIA was weakly positive (20.6 CU) with Hep-2 IFF being homogenous. ENA and dsDNA were negative. His hand X-ray showed evidence of osteoarthritis with no erosion. He subsequently had multiple admissions due to infections. CT chest, abdomen, and pelvis showed splenomegaly with portal vein dilatation suggestive of portal hypertension, normal liver appearance, and left lower lung bronchiectasis. Liver biopsy showed non-specific portal and sinusoidal inflammation, mild fibrosis, and architectural features suggestive of nodular regenerative hyperplasia indicative of FS. Furthermore, his HLA-DRB1*04 was positive. Together, these factors allowed us to diagnose FS. He was started on a tapered course of prednisolone, 30mg daily decreased by 10mg every two weeks, and methotrexate (10mg orally weekly) with careful blood monitoring. Two weeks later, he developed a mild rise in the ALT and alkaline phosphatase. Therefore, the methotrexate dose was reduced to 5mg weekly. Four weeks later, he reported feeling much better, with improvement in all his cell counts and liver function. Discussion While persistent idiopathic neutropenia and splenomegaly (present in 90% of FS patients) are salient features of FS, patients can also present with other extra-articular manifestations such as rheumatoid nodules (74%), hepatomegaly (68%), lymphadenopathy (42%), Sjögren's syndrome (48%), pulmonary fibrosis (50%), pleuritis (22%), peripheral neuropathy (14%) and leg ulcers (16%). Systemic symptoms include fever and weight loss. They also present with idiopathic non-cirrhotic portal hypertension, which can lead to variceal bleeding. The exact pathophysiology of FS is unclear, making the diagnosis and treatment of FS very challenging. A large multi-central cohort study found that FS is associated with HLA-DRB1*0401 and, in two other studies into the pathophysiology of FS, they found that 73% of patients with FS had IgG Anti-G-CSF and autoantibodies that bind to deaminated histones and neutrophil extracellular chromatin traps (NETs), leading to neutrophil sequestration. Therefore, treatment aims to control the underline RA, improve the neutrophil count, and prevent infection. The first challenge, in this case, was to confirm the diagnosis of FS in the absence of any obvious RA joint involvement and a history of heavy alcohol intake. Following an extensive investigation, we discussed his case at the Rare Disease MDT meeting and liaised with the haematology, hepatology, and histopathology teams to exclude the other differential diagnoses. The clues to the diagnosis of FS were the strongly positive RF and ACCPA, the positive HLA-DRB1*04, the liver biopsy, and the exclusion of other causes of neutropenia. The second challenge in this case was to safely start methotrexate, given his mild liver fibrosis and recurrent infections. With close blood test monitoring and follow-up, he achieved improvement in his cell count (WBC from 0.8 to 1.1x10 9/L, HB from 86 to 104 g/L, platelet from 70 to 91X109/L) with stable liver function. Key learning points Rheumatoid arthritis is a multisystem disease with variable presentations. Rarely, FS can occur in the absence of clinical manifestations of the erosive joint involvement of RA. In this situation, careful, thorough investigation to exclude other causes of neutropenia and prove the diagnosis of FS is imperative to justify immunosuppressive treatment. A multidisciplinary team working across specialties was pivotal in the safe diagnosis and treatment of this gentleman.

Periodontal Health as Perceived by Rheumatologists and Rheumatoid Arthritis Patients

The aim of the present study is to assess the knowledge and attitudes towards periodontal health among rheumatologists and rheumatoid arthritis (RA) patients. Two questionnaires comprising questions on demographics, knowledge, and attitudes towards periodontal health were created via Qualtrics survey software. A link to the survey was sent via email to rheumatologists registered under the Australian Rheumatology Association (ARA) practising in Western Australia, and a separate survey was distributed to patients via Arthritis and Osteoporosis WA social media pages. Seven and 76 responses were received from rheumatologists and RA patients, respectively. Statistically significant results (p &lt; 0.05) were found between the length of RA diagnosis and signs of periodontal disease, as well as the type of RA diagnosis and knowledge levels. Employed and retired participants attended the dentist more regularly, and a higher percentage believed that maintaining good oral hygiene is important for overall health. A significant correlation was found between patients who thought improving oral hygiene would impact their RA and whether they received periodontal treatment. No significant differences were found for rheumatologists; however, younger practitioners more frequently asked about their patients’ oral health and performed oral exams. There is a deficit in knowledge about the relationship between periodontal disease and RA among both rheumatoid patients and rheumatologists. The high prevalence of periodontitis and the two-way relationship between RA and periodontal disease would benefit from improved knowledge in relation to their association and could have significant benefits in their clinical and public health implications.

Combination of Two Monoclonal Anti-Citrullinated Protein Antibodies Induced Tenosynovitis, Pain, and Bone Loss in Mice in a Peptidyl Arginine Deiminase-4-Dependent Manner.

The appearance of anti-citrullinated protein antibodies (ACPAs) in the circulation represents a major risk factor for developing rheumatoid arthritis (RA). Patient-derived ACPAs have been shown to induce pain and bone erosion in mice, suggesting an active role in the pathogenicity of RA. We undertook this study to investigate whether ACPAs can induce tenosynovitis, an early sign of RA, in addition to pain and bone loss and whether these symptoms are dependent on peptidyl arginine deiminase 4 (PAD4). Monoclonal ACPAs generated from plasma cells of RA patients were transferred to wild-type and PAD4-deficient mice. Pain-like behavior and macroscopic inflammation were monitored for a period of 4 weeks, followed by the analyses of tenosynovitis in the ankle joints using magnetic resonance imaging (MRI) and bone microarchitecture in the tibia using an X-ray microscope. Microscopic changes in the tendon sheath were analyzed in decalcified ankle joint sections. The combination of 2 monoclonal ACPAs (1325:04C03 and 1325:01B09) induced long-lasting pain-like behavior and trabecular bone loss in mice. Although no synovitis was observed macroscopically, we detected tenosynovitis in the ACPA-injected mice by MRI. Microscopic analyses of the joints revealed a cellular hyperplasia and a consequent enlargement of the tendon sheath in the ACPA-treated group. In PAD4-/- mice, the effects of ACPAs on pain-like behavior, tenosynovitis, and bone loss were significantly reduced. Monoclonal ACPAs can induce tenosynovitis in addition to pain and bone loss via mechanisms dependent on PAD4-mediated citrullination.

Novel Treatment Option for Rheumatoid Arthritis through Bone‐Targeted Delivery of Novokinin

ObjectiveRheumatoid arthritis (RA) is an autoimmune inflammatory disorder affecting about 1‐2% of the world population. RA is known to be a major cause of disability which progresses eventually to systemic complexities with high chances of early morbidity. This complex dynamic situation of inflammation is orchestrated by multiple systems in the body, including the Renin‐Angiotensin System (RAS). Angiotensin II (Ang II), a main effector peptide in the RAS, predominantly binds to Angiotensin II Type (I) receptor (AT1R). When it overproduced can result in inflammation, vasoconstriction, and oxidative stress. Ang II also binds to Angiotensin II Type (II) receptor (AT2R), which provides functional antagonism to AT1R activation. Novokinin, a synthetic peptide, promotes beneficial effects through activation of AT2R, and can be considered a potential drug candidate for alternative therapy in RA if its plasma stability and half‐life could be improved. Here, we developed a novel bone‐targeting novokinin Conjugate (Novo Conj), which binds to the bone, utilizes it as a reservoir while protecting it from enzymatic and hydrolytic degradation. We hypothesized that this delivery approach would extend the peptide half‐life and provide sustained plasma levels to elicit anti‐inflammatory activity.MethodHealthy male, Sprague Dawley rats, were induced adjuvant arthritis (AA) by administering 0.2mL of 50mg/mL of Mycobacterium butyricum through the tail base injection. Arthritic rats were divided into three groups (n=5/group) and dosed with saline (Inflamed), novokinin of 400 µg/kg (Novokinin), or an equivalent dose of 400 µg/kg of novokinin (Novo Conj). A group of healthy rats (n=5) received saline and was taken as a healthy control (Control) group. After the emergence of arthritis (i.e., 10‐12 days after adjuvant arthritis induction), animals were dosed with assigned treatment every other day for two weeks. Animals were monitored three times a week for their body weight, paw, and joint diameters. At the end of the experiment, rats were euthanized, plasma/tissues were harvested and analyzed for plasma nitric oxide (NO) and the RAS components by western blot.ResultsThe induction of AA led to a significant reduction in percent body weight gain over time, increased paws and joints swelling, and elevated plasma NO levels. AA brought an imbalance in the RAS enzymatic inflammatory axis indicator, i.e., Angiotensin‐Converting Enzyme (ACE) and ACE2 causing a reduction in ACE2/ACE and AT2R/AT1R ratio. The treatment of arthritic rats by novokinin and Novo Conj restored their body weight gain, reduced paws and joints' swelling, lowered the plasma NO level, and reinstated the imbalanced ratios of enzymes and receptors. These observed anti‐inflammatory effects were significantly higher in the Novo Conj group.ConclusionThis result indicates that the novokinin and its bone‐targeted conjugate shows anti‐inflammatory effects through the RAS. The observed enhanced impacts could be attributed to improved stability and extension of the half‐life of novokinin through its conjugation and binding to the bone. Our novel bone‐targeting delivery of novokinin offers effective alternative therapy for managing RA signs and symptoms and could be further utilized for various RAS disorders.

Зв’язок реологічних властивостей сироватки крові зі станом вегетативної нервової системи при ревматоїдному артриті

Актуальність. Ревматоїдний артрит (РА) належить до найбільш частих запальних хвороб суглобів, і численність таких пацієнтів всюди збільшується, завдаючи величезного медико-соціального й економічного збитку. Важлива роль у патогенезі РА відводиться порушенням функції вегетативної нервової системи (ВНС), стан якої тісно пов’язаний із реологічними властивостями сироватки крові (РВСК). Мета дослідження: оцінити співвідношення «вегетативного паспорта» хворих на РА і вегетативної дисфункції з РВСК при різних варіантах перебігу хвороби. Матеріали та методи. Обстежено 173 хворих на РА у віці від 18 до 79 років (в середньому 46 років), серед яких було 21 % чоловіків та 79 % жінок. Тривалість маніфестації захворювання становила 10 років, серопозитивний за ревматоїдним фактором і антицитруліновими антитілами варіант РА встановлено в 3/4 випадків, позасуглобову (системну) форму хвороби діагностовано в 37 % спостережень. З використанням комп’ютерного тензіометру «PAT2-Sinterface» (Німеччина) визначали поверхневі показники сироватки крові — в’язкість, пружність, натяг, релаксацію й модуль в’язкоеластичності. Результати. «Вегетативний паспорт» визначав інтегральні клініко-лабораторні та інструментальні ознаки РА, при цьому тяжкість вегетативної дисфункції прямо корелювала з темпами прогресування патології суглобів, а у симпатотоніків — з початковими параметрами ревматоїдного фактора в крові й ступенем активності РА. Зміни РВСК супроводжувались збільшенням рівноважного (статичного) поверхневого натягу, що реєструвалося в 70 % випадків. Інтегральний стан міжфазної активності, релаксаційних та в’язкоеластичних характеристик крові визначав тип ВНС і наявність у хворих вегетативної дисфункції (ваготонікам властиві підвищення модуля в’язкоеластичності й зниження поверхневого натягу, симпатотонікам — підвищення поверхневого натягу та зниження поверхневої в’язкості). Параметри РВСК пов’язані з вираженістю вегетативних розладів, а показник поверхневої в’язкості має прогностичну значущість. Висновки. Розвиток вегетативної дисфункції пов’язаний не лише з особливостями перебігу суглобового синдрому і екстраартикулярних ознак РА, а й зі станом ВНС, що бере участь в порушеннях РВСК. У майбутньому буде корисною оцінка стану ВНС для подальших своєчасних реабілітаційних заходів щодо захворювання.

Filgotinib in Rheumatoid Arthritis: A Profile of Its Use

Filgotinib (Jyseleca®), an oral Janus kinase (JAK) inhibitor, is approved as monotherapy or in combination with methotrexate to treat moderate to severe active rheumatoid arthritis (RA) in adults who have an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs). In phase 3 trials, once-daily filgotinib was generally well tolerated and associated with an improvement in RA signs and symptoms as well as physical function in patients with an inadequate response to ongoing methotrexate, an inadequate response to ongoing conventional synthetic DMARDs plus an inadequate response or intolerance to prior biologic DMARDs, or limited or no prior exposure to methotrexate. In addition, filgotinib was noninferior to adalimumab in terms of low disease activity response rate (DAS28-CRP ≤ 3.2) in patients with an inadequate response to methotrexate. Filgotinib also appeared to inhibit the radiographic progression of joint damage and led to low disease activity or disease remission (DAS28-CRP < 2.6). Filgotinib showed sustained efficacy, and the safety profile of filgotinib longer term was similar to that in the phase 2 and 3 trials.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40261-021-01055-0.

POS1455-HPR RELATIONSHIP BETWEEN PSYCHOLOGICAL FACTORS AND MEASURES OF RHEUMATOID ARTHRITIS ACTIVITY

Background:The patient-reported outcomes are important components of quantitative methods of rheumatoid arthritis (RA) activity assessment which are used to choose the appropriate drug therapy. The value of these parameters can be significantly affected not only by the inflammatory process, but also by the psychological characteristics of the patient and, in particular, by hardiness [1].Objectives:To study the relationship between psychological factors and signs of RA activity.Methods:Patients with RA who met the EULAR/ACR 2010 criteria, and observed at the V. A. Nasonova Research Institute of Rheumatology were included. Clinical examination was performed including patient global assessment (PGA), physician global assessment (PhGA), pain measurement on a visual analog scale, tender joint count (TJC), swollen joint count (SJC). The functional status was determined by HAQ, the quality of life – by SF-36 EQ-5D, the nature of pain – by painDETECT, the presence of anxiety and depression – by HADS. Patients also completed Hardiness Survey questionnaire to assess hardiness (HDS) and 3 components of the HDS – commitment (CMT), control (CT) and challenge (CLN). Disease activity was evaluated with DAS28, CDAI, and RAPID3. All patients signed informed consent to participate in the study. Analysis of the data was performed using Spearman’s rank test, Fisher exact test, qui-square and t-tests.Results:85 patients with RA were included. There were 69 women and 16 men. Mean age was 56.7±13.1 years, disease duration – 7.6±2.7 years. 72 patients were positive for rheumatoid factor, 75 – for anti-cyclic citrullinated peptide antibody. CDAI showed high activity in 15, moderate – in 37, low – in 30, and remission in 3 patients, DAS 28 – in 10, 55, 12, and 8, and RAPID3 – in 24, 25, 15, and 21, respectively. 24 patients had subclinically or clinically expressed anxiety and 15 –subclinically or clinically expressed depression (≥8 according to HADS). In 31 patients, the painDETECT questionnaire revealed possible or probable neuropathic pain. Mean HDS was 84.8±21.7, CMT – 38.9±9.2, CT – 29.4±8.6, CLN – 17.3±7.1. These values were comparable with the corresponding population data for this age group. There was a significant inverse correlation between HDS and RA activity measures, including SJC, TJC, DAS28 (p&lt;0.05), pain, PGA, PhGA, CDAI, RAPID3, and HAQ (p&lt;0.01). In addition, HDS and all its components positively correlated with quality of life, assessed by SF-36 and EQ-5D (p&lt;0.01). In patients with subclinically and clinically expressed anxiety and depression, HDS, CMT, and CT were significantly lower than in patients without anxiety and depression (p&lt;0.01), while the values of CLN in these groups did not differ significantly.Conclusion:The results of the present study suggest that low HDS may be one of the significant factors determining RA activity level because it does not allow patients to adapt adequately to a stressful situation produced by the disease.

Efficacy of Rituximab on Rheumatoid Leptomeningitis as the First Symptom of Rheumatoid Arthritis

Rheumatoid meningitis may occur in the disease course of rheumatoid arthritis with varied and non-specific symptoms.Cerebrospinal fluid examination, MRI and tests for rheumatoid factor or anti-citrullinated protein antibodies in serum or in cerebrospinal fluid are key examinations for diagnosing rheumatoid meningitis.Rituximab has good efficacy in rheumatoid meningitis.

Filgotinib versus placebo or adalimumab in patients with rheumatoid arthritis and inadequate response to methotrexate: a phase III randomised clinical trial

ObjectiveTo evaluate the efficacy and safety of the Janus kinase-1-preferential inhibitor filgotinib versus placebo or tumour necrosis factor-α inhibitor therapy in patients with active rheumatoid arthritis (RA) despite ongoing treatment...

Long-term safety and efficacy of sirukumab for patients with rheumatoid arthritis who previously received sirukumab in randomised controlled trials (SIRROUND-LTE)

ObjectiveInterleukin (IL)-6 is a pleiotropic cytokine involved in the pathophysiology of rheumatoid arthritis (RA). Sirukumab is a human monoclonal antibody that binds to IL-6 with high affinity and specificity.MethodsThis long-term...

Chronological effects of non-steroidal anti-inflammatory drug therapy on oxidative stress and antioxidant status in patients with rheumatoid arthritis

Non-steroidal anti-inflammatory drugs (NSAIDs) are effective in reducing pain and inflammation in rheumatoid arthritis and other joint- and muscle-associated diseases. However, the extensive, long-term, and over the counter administration of NSAIDs may cause various side effects in the patients. In the present study, the chronological effect of NSAIDs on oxidative stress and antioxidant status in patients with rheumatoid arthritis was studied. The study included 100 female individuals categorized in four major groups: (1) control group consisting of age- and gender-matched healthy individuals, (2) NRA-NSAID individuals taking NSAIDs without any history of RA, (3) RA individuals with a history of RA but not taking NSAIDs, and (4) RA-NSAID individuals with chronic RA and taking NSAIDs for a long period. The sera of the participants were analyzed for the oxidative stress and antioxidant status. The RA-NSAID group showed the significantly highest oxidative stress, in terms of malondialdehyde content and lipid-reducing ability as determined in thiocyanate and hemoglobin-induced linoleic acid systems. However, the free radical scavenging ability of the RA-NSAID group, against 2,2-diphenyl-1-picrylhydrazyl, hydroxyl, superoxide, and 2,2-azino-bis-tetrazolium sulfate radicals, was found to be lower than those of the other study groups. The regression analysis of the experimental data showed a significant positive relationship between duration of NSAID intake and malondialdehyde production, lipid-reducing ability, and metal chelating ability in the RA-NSAID patients. The free radical scavenging abilities of the RA-NSAID group were negatively correlated with the duration of NSAID intake. The prolonged use of NSAIDs significantly increased the oxidative stress and decrease the antioxidant potential of both the RA patients and NRA individuals. The study provides awareness to the public particularly the RA patients regarding the risk of oxidative stress-associated abnormalities caused by the frequent and prolonged use of NSAIDs for temporary relief from pain. Key Points • The study presents the effects of long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) on antioxidant status of patients with rheumatoid arthritis. • The continuous administration of NSAIDs has been found to significantly increase the oxidative stress of the patients with rheumatoid arthritis as well as the individuals with no signs of rheumatoid arthritis. • The prolonged NSAID therapy also decreased the antioxidant potential of the patients with rheumatoid arthritis as well as the individuals with no signs of rheumatoid arthritis. • The study would be a significant and valuable contribution to the literature for the awareness regarding the use of NSAIDs.

The Role of the Microbiome in Driving RA-Related Autoimmunity.

Once referred to as “normal commensal flora” the human microbiome plays an integral role between health and disease. The host mucosal surface replete with a multitude of immune cells is a vast arena constantly sensing and responding to antigen presentation and microbial by-products. It is this key role that may allow the microbiome to prime or protect the host from autoimmune disease. Rheumatoid arthritis (RA) is a chronic, disabling inflammatory condition characterized by a complex multifactorial etiology. The presence of certain genetic markers has been proven to increase susceptibility to RA however it does not guarantee disease development. Given low concordance rates demonstrated in monozygotic twin studies there is a clear implication for the involvement of external players in RA pathogenesis. Since the historical description of rheumatoid factor, numerous additional autoantibodies have been described in the sera of RA patients. The presence of anti-cyclic citrullinated protein antibody is now a standard test, and is associated with a more severe disease course. Interestingly these antibodies are detectable in patient’s sera long before the clinical signs of RA occur. The production of autoantibodies is driven by the lack of tolerance of the immune system, and how tolerance is broken is a crucial question for understanding RA development. Here we review current literature on the role of the microbiome in RA development including periodontal, gut and lung mucosa, with particular focus on proposed mechanisms of host microbiome interactions. We discuss the use of Mendelian randomization to assign causality to the microbiome and present considerations for future studies.

Comparison of Some Physiological Parameters in Female Rheumatoid Arthritis Patients in Pre- and Postmenopausal Stages

Rheumatoid arthritis is an autoimmune disorder that is highly prevalent, leading to gradual cartilage distraction, and therefore is important to diagnose in the early stage. This study aimed to estimate the level of rheumatoid factor (RF) and Anti-citrullinated protein (Anti-ccp) in the serum of female patients. We also investigated several female reproductive hormones in the patients and compared their levels in the premenopausal and postmenopausal phases. The study included 88 female subjects, 50 suffering from signs of rheumatoid arthritis who were attending AL-Yarmouk teaching hospital, Baghdad, Iraq, and 38 without clinical signs of RA as a control group. The ELISA technique was used to estimate all the studied parameters. The results showed a significant elevation in the levels of RF (103.6 ± 227.0 vs. 22.1 ± 111.0 U/ml) and Anti-ccp (158.0 ± 170.0 vs. 0.51 ± 1.69 U/ml) in patient’s serum as compared to the control. The percentage of overweight and obese patients was higher than that of those with normal weight. Also, the current results showed significant differences in the serum concentrations of the reproductive hormones between the premenopausal and postmenopausal phases in the patients group. The level of FSH in postmenopausal female patients was higher than that in premenopausal ones (33.5 ± 17.9 vs. 9.01 ± 9.31 U/ml). Also, the level of luteinizing hormone (LH) in the postmenopausal patients was higher than that in the premenopausal patients (26.4 ± 12.3 vs. 12.7 ± 10.2 U/ml). While the level of prolactin (PRL) in RA postmenopausal female patients was lower than that in the premenopausal patients (8.60 ± 7.07 vs. 14.8 ± 10.6 ng/ml). In addition, the level of Anti-mullerian hormone (AMH) in post-menopausal patients was lower than that in the pre-menopausal ones (0.034 ± 0.023 vs. 0.635 ± 0.683 ng/ml). Finally, the concentration of estradiol (E2) in the post-menopausal female patients was lower than that in the pre-menopausal ones (32.9 ± 18.6 vs. 76.5 ± 43.6 ng/ml).

Systemic bee venom exerts anti-arthritic and anti-inflammatory properties in a rat model of arthritis.

Bee venom (BV) is widely used as a traditional China medicine to treat various conditions, including rheumatoid arthritis (RA). The aim of the present study was to evaluate the effects of systemic BV (60 mg/kg) as an anti-arthritic natural product, compare it with Methotrexate and determine the possible underlying mechanisms of BV action using complete Freund's adjuvant-induced arthritic rats. The development of signs of RA signs (knee joint circumference and arthritis scoring index) was evaluated. Erythrocyte sedimentation rate, serum tumor necrosis factor-α (TNF-α) and serum interleukin-1β (IL-1β) levels were measured at the end of the study. Histopathological examination followed by immunostaining of NF-κB (P65) was performed on the affected knee joints. Additionally, in vitro cyclooxygenase (COX) inhibition activity, carrageenan paw edema test and acetic acid writhing tests were performed to evaluate the anti-inflammatory and analgesic effects of the assessed dose and compared with diclofenac. An acute toxicity test was performed to establish the safety of BV at high doses. The results of the present study highlighted the potential of systemic BV on preventing the development of signs of RA. BV also significantly reduced serum levels of TNF-α, IL-1β and NF-κB in the affected joints. In addition to its potent analgesic activity, BV exhibited favorable inhibitory activity of the COX pathway in both in vivo and in vitro models. Therefore, high dose administration of systemic BV displayed safe and promising anti-arthritic, anti-inflammatory and analgesic properties through regulation of different mechanisms associated with the pathogenesis of RA.

The Role of Magnetic Resonance Imaging in Diagnosis and Prognosis of Rheumatoid Arthritis

Abstract Background: Rheumatoid arthritis (RA) is one of the most common forms of arthritis. A progressive joint damage occurs early in the disease course even before being detected in conventional imaging, and eventually leads to irreversible joint deformity and severe functional impairment. Routinely, clinical assessment and laboratory investigations as well as conventional radiology are used for diagnosis of RA, however; they are not fair enough to establish early diagnosis and can't provide information about the disease activity. Estimating the disease activity at onset is fundamental to identify the prognosis of RA. Aim of Study: The aim of this study was to demonstrate the importance of MRI in detecting early signs of arthritis helping in early diagnosis of rheumatoid arthritis, and its ability to assess the degree of inflammatory activity as a prognostic parameter for the development of subsequent bone destruction. Patients and Methods: The twenty-five patients included in this study (14 females, 56%, and 11 males, 44%), were diagnosed with rheumatoid arthritis according to the 2010 ACR/EULA classification criteria. The clinically dominant wrist and hand joints were examined by MRI study for detec-tion of pathological signs of RA that include synovitis, BME, and erosions. Twenty (20) patients (80%) were found to have synovial thickening. Of which, 12 wrist joints (60%) were active, among them 5 joints (25%) had mild activity, 4 (20%) had moderate activity and 3 wrist joints had severe activity (15%). 17 patients had bone marrow edema (68%), more frequently at the radius and the lunate. Erosions was seen in 8 joints (32 %). The total positive MRI inflammatory findings, as well as each one of them alone, were compared and corre-lated with the 2010 ACR/EULA scoring system. Results: We found significant correlation and agreement between the total MRI positive findings and the 2010 ACR/EULAR criteria used for diagnosing RA, and MRI was more sensitive in detecting synovitis and BME in patients who didn't meet the criteria. Conclusion: The high sensitivity of MRI in detecting inflammatory signs, and the significant correlation with clinical and laboratory findings, indicates the potential importance of MRI study in diagnosing RA early in its course, and the assessment of disease activity that helps in prediction of joint destruction.

Phthalate Exposure During the Prenatal and Lactational Period Increases the Susceptibility to Rheumatoid Arthritis in Mice.

The prenatal and early postnatal period is highly sensitive to environmental exposures that may interfere with the developmental programming of the immune system leading to an altered disease risk in later life. To clarify the role of early influences in activation or exacerbation of autoimmune diseases like rheumatoid arthritis (RA) we investigated the effect of maternal exposure during the prenatal and lactational period of DBA/1 mice to the plasticizer benzyl butyl phthalate (BBP) on the development of RA in the offspring. Using a mild collagen-induced arthritis (CIA) model, maternal BBP-exposure increased both the prevalence and the severity of RA in the progeny compared to un-exposed dams. Additionally, maternal BBP exposure led to elevated serum IgG1 and IgG2a level in the offspring and increased the IFN-γ and IL-17 release from collagen-re-stimulated spleen cells. Transcriptome analysis of splenocytes isolated from 3-week-old pups before RA-induction revealed considerable changes in gene expression in the offspring from BBP-exposed dams. Among them were regulator of G-protein signaling 1 (rgs1), interleukin-7 receptor (il-7r) and CXC chemokine 4 (cxcr4), all genes that have previously been described as associated with RA pathology. In summary, our results demonstrate that perinatal exposure to BBP increases the susceptibility of the offspring to RA, probably via a phthalate-induced disturbed regulation of RA-relevant genes or signaling pathways.

P217 Efficacy and safety of filgotinib for patients with RA naïve to MTX therapy: FINCH3 primary outcome results

Abstract Background Filgotinib (FIL), an orally administered, potent, selective inhibitor of janus kinase 1 (JAK1), has shown good efficacy and was well tolerated for treatment of rheumatoid arthritis (RA). The objectives of this study were to compare efficacy and safety of FIL with and without methotrexate (MTX) in patients with RA who were naïve to MTX therapy. Methods This Phase 3, double-blind, active-controlled study randomised patients with moderately to severely active RA (2:1:1:2) to FIL 200mg daily+MTX, FIL 100mg+MTX, FIL 200mg (+placebo [PBO]), or MTX (+PBO) up to 52 weeks; results are through week 24. Primary endpoint was proportion achieving ACR20 response at week 24. Safety endpoints included adverse events types and rates. Results Of 1,252 randomised patients, 1,249 received study drug (416 FIL 200mg+MTX; 207 FIL 100mg+MTX; 210 FIL 200mg monotherapy; 416 MTX monotherapy) and were analysed; 1,130 completed week 24. Most (76.9%) were female; mean time since RA diagnosis was 2.2 years (median 0.4 years); mean (standard deviation [SD]) DAS28-CRP was 5.7 (1.0); and 35.9% were using oral steroids at baseline. At week 24, significantly more patients in the FIL 200mg+MTX (81.0%; P&amp;lt;0.001) and FIL 100mg+MTX (80.2%; P&amp;lt;0.05) arms achieved an ACR20 response compared to MTX monotherapy (71.4%)(Table 1). Compared to MTX monotherapy, more patients receiving FIL with or without MTX achieved ACR50 and ACR70 responses, DAS28-CRP &amp;lt;2.6 and ≤3.2, and reported improvements in SF-36 PCS (Table 1). The onset of activity was rapid, with significantly more patients achieving ACR50 and DAS28-CRP &amp;lt;2.6 with FIL than MTX at week 2. The FIL safety profile was consistent with prior studies through week 24. Serious AEs were observed in 4.1%, 2.4%, 4.8%, and 2.9% of patients in the FIL 200mg+MTX, FIL 100mg+MTX, FIL 200mg monotherapy, and MTX monotherapy groups, respectively. There was 1 death from lupus cardiomyopathy. Conclusion The JAK1 inhibitor FIL in combination with MTX led to significant improvements in RA signs and symptoms, physical function, and patient-reported outcomes compared to MTX alone and was well tolerated in patients with early active RA naïve to MTX. Clinically meaningful response to FIL occurred as early as 2 weeks after treatment initiation. Disclosures N. McKay: None. D. van der Heijde: Corporate appointments; Director of Imaging Rheumatology bv. Consultancies; Consultant for AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Daiichi, Eli Lilly, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda Pharmaceutical Company Ltd., UCB. R. Westhovens: Corporate appointments; Advisor for Celltrion and Galapagos/Gilead. Other; Advisor for Celltrion and Galapagos/Gilead. W.F.C. Rigby: Consultancies; Consultant for Gilead. D.W.T. Ching: Corporate appointments; Speaker for AbbVie. Member of speakers’ bureau; Speaker for AbbVie. B. Bartok: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. F. Matzkies: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. Z. Yin: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. Y. Guo: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. C. Tasset: Corporate appointments; Employee of Galapagos NV. J.S. Sundy: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. N. Mozaffarian: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. O.D. Messina: Honoraria; Received Honoraria from Pfizer, Amgen, and Americas Health Foundation (AHF). R.B.M. Landewé: Consultancies; Consultant for AbbVie, AstraZeneca, BMS, Galapagos, Pfizer, Eli Lilly, Novartis, and UCB. T. Atsumi: None. G.R. Burmester: Honoraria; Received Honoraria from AbbVie, Gilead, Eli Lilly, and Pfizer.

Immunomodulatory benefits of mesenchymal stem cells treated with Caffeine in adjuvant-induced arthritis

PurposeWe intend to assess the effect of the conditioned medium of Caffeine pulsed MSCS in the amelioration of rheumatoid arthritis (RA)-afflicted rats. MethodsMSCs were incubated with 0, 0.1, 0.5 or 1 mM Caffeine for 2 weeks. RA was induced by the injection of complete Freund's adjuvant (CFA) into the base of the tail of Wistar rats. According to in vitro studies, RA rats were intraperitoneally treated with MSCs, Caffeine (0.5 mM) pulsed MSCs or vehicle on day 14 when all rats had shown signs of RA. ResultsOur results suggest that the least effective dose concentration of Caffeine that can induce potent anti-inflammatory property in the MSC population is 0.5 mM. Without any significant impact on the vitality or MScs' marker, Caffeine at this concentration could induce lower levels of IFN-γ, IL-6, and IL-1β and a higher level of IDO, TGF-β, and IL-10 compared to other groups. Therefore, MSCs pulsed with Caffeine at 0.5 mM concentration was selected for in vitro studies. Caffeine pulsed MSCs could reduce the severity of the disease and improve weight-gaining more profoundly than treatment with MSCs alone. Furthermore, Caffeine pulsed MSCs caused a significant reduction in the serum levels C-reactive protein, Nitric oxide, Myeloperoxidase, TNF-α and conversely led a significant increase in the levels of IL-10 more prominent than the similar findings brought about by MSCs alone. ConclusionIn general, caffeine-treated MSCs may be a promising strategy for cell-based therapy of RA.