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Abstract Background Activated fibroblast-like synoviocytes (FLS) are drivers of synovitis and structural joint damage in rheumatoid arthritis (RA). Despite the use of disease-modifying drugs, only about 50% of RA patients reach remission in real-world settings. We used an unbiased approach to investigate the effects of standard-of-care methotrexate (MTX) and a Janus kinase inhibitor, tofacitinib (TOFA), on gene expression in RA-FLS, in order to identify untargeted disease mediators. Methods Primary RA-FLS were activated by stimulation with interleukin-1β (IL-1β) or platelet-derived growth factor + IL-1β in the presence or absence of MTX or TOFA, with or without additional inhibitors. Co-cultures of synovial cells were performed in direct and indirect systems. Cells were collected for RNA sequencing or qPCR, and supernatants were analyzed for protein concentrations. Results Six thousand three hundred fifty genes were differentially expressed, the majority being upregulated, in MTX-treated activated RA-FLS and 970 genes, the majority being downregulated, in TOFA-treated samples. Pathway analysis showed that MTX had largest effects on ‘Molecular mechanisms of cancer’ and TOFA on ‘Interferon signaling’. Targeted analysis of disease-associated genes revealed that MTX increased the expression of cell cycle-regulating genes but also of pro-inflammatory mediators like IL-1α (IL1A) and granulocyte–macrophage colony-stimulating factor, GM-CSF (CSF2). The MTX-promoted expression of CSF2 in activated RA-FLS peaked at 48 h, could be mediated via either NF-κB or AP-1 transcription factors, and was abrogated by IL-1 inhibitors (IRAK4 inhibitor and anakinra). In a co-culture setting, MTX-treatment of activated RA-FLS induced IL1B expression in macrophages. Conclusions MTX treatment induces secretion of IL-1 from activated RA-FLS which by autocrine signaling augments their release of GM-CSF. This unexpected effect of MTX might contribute to the persistence of synovitis.

Monocytes are innate immune cells that play a dual role in protection of host against pathogens and initiation and perpetuation of inflammatory disorders including joint diseases. During inflammation, monocytes migrate from peripheral blood to tissues via chemokine receptors where they produce inflammatory factors. Monocytes are classified into three subsets, namely: classical, intermediate and non-classical, each subset has particular function. Synovium of patients with inflammatory joint diseases, such as rheumatoid arthritis and psoriatic arthritis as well as osteoarthritis, is enriched by monocytes that differ from circulatory ones by distinct subsets distribution. Several therapeutic agents used systemically or locally through intra-articular injections in arthritis management modulate monocyte subsets. This scoping review summarized the existing literature delineating the effect of common therapeutic agents used in arthritis management on circulating and synovial monocytes/macrophages. As certain agents have an inhibitory effect on monocytes, we propose to test their potential to inhibit synovial monocytes via an ex-vivo platform based on cultured synovial fluid mononuclear cells derived from patients with rheumatic diseases. Information obtained from the ex-vivo platform can be applied to explore the therapeutic potential of medications in clinical practice. [ABSTRACT FROM AUTHOR]

Background/Aim: Women with rheumatic and musculoskeletal disorders often discontinue using their medications prior to conception or during the few early weeks of pregnancy because drug use during pregnancy frequently results in anxiety. Pregnant women have reported seeking out health-related information from a variety of sources, particularly the Internet, in an attempt to ease their concerns about the use of such medications during pregnancy. The objective of this study was to evaluate the accuracy and completeness of health-related information concerning the use of anti-rheumatic medications during pregnancy as provided by Open Artificial Intelligence (AI's) Chat Generative Pre-trained Transformer (ChatGPT) versions 3.5 and 4, which are widely known AI tools. Methods: In this prospective cross-sectional study, the performances of OpenAI's ChatGPT versions 3.5 and 4 were assessed regarding health information concerning anti-rheumatic drugs during pregnancy using the 2016 European Union of Associations for Rheumatology (EULAR) guidelines as a reference. Fourteen queries from the guidelines were entered into both AI models. Responses were evaluated independently and rated by two evaluators using a predefined 6-point Likert-like scale (1 – completely incorrect to 6 – completely correct) and for completeness using a 3-point Likert-like scale (1 – incomplete to 3 – complete). Inter-rater reliability was evaluated using Cohen’s kappa statistic, and the differences in scores across ChatGPT versions were compared using the Mann–Whitney U test. Results: No statistically significant difference between the mean accuracy scores of GPT versions 3.5 and 4 (5 [1.17] versus 5.07 [1.26]; P=0.769), indicating the resulting scores were between nearly all accurate and correct for both models. Additionally, no statistically significant difference in the mean completeness scores of GPT 3.5 and GPT 4 (2.5 [0.51] vs 2.64 [0.49], P=0.541) was found, indicating scores between adequate and comprehensive for both models. Both models had similar total mean accuracy and completeness scores (3.75 [1.55] versus 3.86 [1.57]; P=0.717). In the GPT 3.5 model, hydroxychloroquine and Leflunomide received the highest full scores for both accuracy and completeness, while methotrexate, Sulfasalazine, Cyclophosphamide, Mycophenolate mofetil, and Tofacitinib received the highest total scores in the GPT 4 model. Nevertheless, for both models, one of the 14 drugs was scored as more incorrect than correct. Conclusions: When considering the safety and compatibility of anti-rheumatic medications during pregnancy, both ChatGPT versions 3.5 and 4 demonstrated satisfactory accuracy and completeness. On the other hand, the research revealed that the responses generated by ChatGPT also contained inaccurate information. Despite its good performance, ChatGPT should not be used as a standalone tool to make decisions about taking medications during pregnancy due to this AI tool’s limitations. [ABSTRACT FROM AUTHOR]

Aim:The aim of this study is to determine the screening rates for hepatitis B (HBV) and C virus (HCV) in patients with rheumatologic diseases who receive immunosuppressive therapies, to evaluate the prevalence of HBV reactivation during the regimens and also to reveal the frequency of vaccination.Materials and Methods:This retrospective study included the patients who were followed-up with different rheumatologic diseases in two rheumatology outpatient clinics. The immunosuppressive regimens were categorized into two groups as biologic (bDMARDs) and conventional synthetic disease modifying anti rheumatic drugs (csDMARDs). The markers of HBsAg, anti-HBs, anti-HBc-IgM and anti-HBc-IgG, HBV DNA, anti-HCV levels were all taken from the patients’ charts checked prior and during the immunosuppressive treatments.Results:There were 451 patients [61.9% female, mean age 41.1 years, (standard deviation: 13.78)] who were taking bDMARDs (n=348) and csDMARDs (n=103). The data for HBV for 20 (4.4%) patients and HCV for 23 (5%) patients were missing, all in the csDMARDs group. Also, HBV serology tests were found to be incomplete in 51 patients (14.7%) in the bDMARDs group, as not checking the anti-HBc-IgM and anti-HBc-IgG. During the follow-up, HBV reactivation was not observed in the whole cohort. In the bDMARDs group, there were 39 patients who did not receive prophylaxis despite having HBsAg negative phase of chronic HBV infection; no HBV reactivation was observed also in this group. One hundred twenty nine (28.6%) of the patients were evaluated as never infected and unvaccinated prior to immunosuppressive therapies. Recurrent HBV serology controls were performed in nearly half (n=75) of them during their follow-up and it was observed that all were still non-immune.Conclusion:The screening rates of HBV and HCV serology were detected as successful in rheumatology patients under immunosuppressive therapies. No HBV reactivation was observed in the entire group. Also, the study showed that there was a significant deficiency in immunizing patients against HBV in follow-up.

Coronavirus infection can have various degrees of severity and outcomes. In some cases, it causes excessive production of pro-inflammatory cytokines, a so-called cytokine storm, leading to acute respiratory distress syndrome. Unfortunately, the exact pathophysiology and treatment, especially for severe cases of COVID-19, are still uncertain. Results of preliminary studies showed that immunosuppressive therapy, such as interleukin (IL)-6, IL-1, and TNF-α antagonists commonly used in rheumatology, can be considered as treatment options for COVID-19, especially in severe cases. The review focused on the most common and currently studied monoclonal antibody drugs, as well as up-to-date data on the pathogenesis of COVID-19, host immune response against SARS-CoV-2 and its association with cytokine storm. It also covered effects of interleukin (IL)-6, IL-1, and TNF-α blockers on the course of coronavirus infection and outcome in patients treated for the main autoimmune disease and subsequently infected with COVID-19. [ABSTRACT FROM AUTHOR]

Copyright of Namık Kemal Tıp Dergisi is the property of Galenos Yayinevi Tic. LTD. STI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Purpose: We aimed to assess the characteristics of inflammatory rheumatic disease (IRD) patients in Kuwait diagnosed with COVID‐19 and the factors linked with hospitalization, complications, and mortality. Methods: Data of IRD patients from Kuwait diagnosed with COVID‐19 between March 2020 and March 2021, submitted to the COVID‐19 Global Rheumatology Alliance physician‐reported registry, were included in our analysis. Data on patients' age, gender, smoking, diagnosis, IRD activity, and other comorbidities were collected. Statistical Package for the Social Sciences (SPSS), version 25, was used for statistical analysis. Results: A total of 52 patients were included, with a mean age of 55 years (±14). The majority of patients were ≤65 years (77%), female (77%), non‐smokers (80.8%), and diagnosed with rheumatoid arthritis (67.0%). Of the included patients, 19.2%, 9.6%, and 7.7% reported having methotrexate monotherapy, antimalarials monotherapy, and interleukin‐6 inhibitors monotherapy immediately before COVID‐19, respectively. Most of the included patients (92.3%) were either in remission or had minimal/low disease activity, while others (7.7%) had moderate disease activity. Forty‐three patients (82.7%) were hospitalized, while 11 patients (25.6%) required ventilation (invasive or non‐invasive). Ten of the ventilated patients (90.9%) received glucocorticoids as part of the local protocol to treat severe COVID symptoms, and 4 patients (7.69%) died. The duration till symptom‐free ranged between 0 to 30 days, with a mean value of 10 days (±6.5). Conclusion: The current study provides timely real‐world evidence regarding characteristics and potential risk factors linked to poor COVID‐19‐related outcomes in the IRD population in Kuwait. [ABSTRACT FROM AUTHOR]

Abstract Background Anti-rheumatic drugs can increase the predisposition to infection, and patients may be unaware of continuing their treatment during the COVID-19 pandemic. Objective This study aimed to assess whether patients maintain their treatment for rheumatic conditions during the pandemic period and determine the factors responsible for discontinuation. Methods Patients were randomly selected from the prospectively collected database of our tertiary referral center. The patients were interviewed by telephone through a standardized closed-ended questionnaire, which is targeting the continuity of the treatment plan and the considerations related to the individual choice. The patients were asked whether they hesitated to visit the hospital for follow-up or intravenous drug administration. Results A total of 278 patients completed the questionnaire. While 62 of the patients (22.3%) had reduced or interrupted the treatment, only 11 patients (3.9%) stopped the treatment completely. A significant difference was observed between the duration of illness and the discontinuation of treatment. (p = 0.023) There was a significant difference in disease activity between the group that stopped treatment and continued treatment. (p = 0.001) There was no statistically significant difference in other demographic characteristics. One hundred thirty-five patients (48.6%) made the treatment decision by themselves, and 80% continued the treatment. Reasons for stopping the treatment were anxiety (48.4%), not being able to go to the hospital for intravenous treatment (45.1%), and not being able to find the drug (6.5%). Conclusion Since patients with long-term illnesses were found to be significantly more likely to stop their treatment, this group of patients should be monitored.

Objective: To determine the contraceptive awareness and practices in patients with rheumatic diseases using disease modifying anti-rheumatic drugs. Study Design: Cross-sectional study. Place and Duration of Study: Outpatient of Rheumatology, Department at Pakistan Institute of Medical Sciences, Islamabad Pakistan, from Jan to Apr 2021. Methodology: Patients with any rheumatic disease and taking teratogenic disease modifying anti-rheumatic drugs were included in the study. Patients were asked about if they were counseled regarding the risk of teratogenicity with the antirheumatic drugs and when to stop the drug before pregnancy. Results: Out of total 150 patients, 87 (58.0%) female patients had Rheumatoid arthritis and 26 (17.3%) had Systemic lupus erythematosus. The majority of female patients (104, 69.3%) were using Methotrexate and 21 (14.0%) females were using Leflunomide. Only 53 (35.3%) females were counseled about drug teratogenicity. Most of the female patients (102, 68.0%) were never counseled about the use of contraception while taking anti-rheumatic drugs. The rate of use of contraceptives was even worse and merely 15 (10.0%) females were using contraceptives. Conclusion: Majority of the patients with rheumatic diseases being treated with teratogenic disease modifying anti-rheumatic drugs, were not using any form of contraception. The rate of contraceptive use and counseling regarding contraceptives was noted to be very low. [ABSTRACT FROM AUTHOR]

World Health Organization declared coronavirus disease-19 (COVID-19) as pandemic since 11 March 2020. Herein, new human coronavirus, SARS-CoV2 is the etiologic agent of the disease. Also, it has been a global health problem since it was detected in Chinese province of Wuhan at December 2019. COVID-19 has several different clinical variations from mild disease to acute respiratory distress syndrome. For the treatment of the disease, several remedies have been administered. Even though, anecdotal data showed somewhat effectiveness of those drugs for the treatment of the disease, there has been no accurate scientific knowledge proofing these. Therefore, main purpose of this review was discussing how the physicians arrange the therapies of the rheumatologic diseases during COVID-19, especially while patients are under immunosuppressive drugs. Also, we summarized the current data about the effectiveness of immunosuppressive drugs on COVID-19.

Şiddetli akut solunum yolu sendromu koronavirüsü 2 (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) solunum sistemini en çok etkileyen ve akciğerdeki çok sayıda ACE2 reseptörü nedeniyle hızla yayılan bulaşıcı bir ajandır. Artralji ve miyalji en sık görülen romatolojik bulgulardır, ancak artrit nadirdir. Sitokin fırtınası adı verilen hiperinflamatuar durum, akut solunum sıkıntısı sendromu (acute respiratory distress syndrome, ARDS)’na neden olarak ölüme neden olur. Koronavirüs hastalığı 2019 (coronavirus disease 2019, COVID-19) çoğu durumda hafif veya asemptomatik olmasına rağmen, özellikle ileri yaş ve komorbiditeleri olan hastalarda pnömoni ve ARDS'ye ilerleyebilir. Enflamatuar yanıtı baskılayan ve sitokin fırtınasını azaltan tosiluzumab gibi ilaçlar, COVID-19 pnömonisinin tedavisinde etkili olabilir. Nedeni tam olarak anlaşılamayan ve bağışıklık sistemindeki birçok yapının birbiriyle etkileşime girdiği sitokin fırtınası oldukça karmaşıktır ve buna katkıda bulunan farklı mekanizmalara sahiptir. Tedavide hidroksiklorokin gibi antimalaryal ilaçlar kullanılsa da etkili olduklarına dair kesin bir kanıt yoktur. Romatizmal hastalıklarda COVID-19 sıklığının ve seyrinin genel popülasyona benzer olduğu, artan yaş ve ek komorbid durumların mortalite riskini artırdığı gösterilmiştir. Romatizmal hastalıkların tedavisinde kullanılan anti-romatizmal ilaçların, hasta COVID-19 ile enfekte olmadıkça kesilmemesi önerilmektedir.

Contemporary rheumatology is a field dealing with the phenomena of autoimmune states and inflammation. Rheumatic diseases cover a wide spectrum of diseases of the musculoskeletal system, connective tissue and vessels. The occurrence of an immune, autoimmune and autoinflammatory response is often linked to different kinds of infections. Which aspects of the coronavirus infection relate to rheumatological therapy and practice? In order to answer this question one needs to look at the pathogenesis of the SARS-CoV-2 infection. Antimalarial drugs may block antigen presentation of the viral peptides from antigen presenting cells, as they may alter the lysosomal proteases that mediate the viral entry in the cells and have demonstrated efficacy in improving the infection. Anti-IL-6 may interfere with cytokine storm in severe cases and use of tocilizumab has had good results in a small cohort. Baricitinib not only plays a role in inhibiting the synthesis of cytokines but it also has a function in suppressing receptor-mediated endocytosis. The constantly new and tested concepts in the treatment of COVID testify to the growing knowledge about the virus, but also to the need for more targeted therapy. Treatment regimens have been developed for both patients with COVID-19 and those with symptomatic SARS-CoV infection and rheumatic disease. This article is an attempt to discuss the management of COVID-19 and coexisting rheumatic disease.

The pharmacotherapy of Takayasu arteritis (TAK) with disease-modifying anti-rheumatic drugs (DMARDs) is an evolving area. A systematic review of Scopus, Web of Science, Pubmed Central, clinical trial databases and recent international rheumatology conferences for interventional and observational studies reporting the effectiveness of DMARDs in TAK identified four randomized controlled trials (RCTs, with another longer-term follow-up of one RCT) and 63 observational studies. The identified trials had some concern or high risk of bias. Most observational studies were downgraded on the Newcastle-Ottawa scale due to lack of appropriate comparator groups. Studies used heterogenous outcomes of clinical responses, angiographic stabilization, normalization of inflammatory markers, reduction in vascular uptake on positron emission tomography, reduction in prednisolone doses and relapses. Tocilizumab showed benefit in a RCT compared to placebo in a secondary per-protocol analysis but not the primary intention-to-treat analysis. Abatacept failed to demonstrate benefit compared to placebo for preventing relapses in another RCT. Pooled data from uncontrolled observational studies demonstrated beneficial clinical responses and angiographic stabilization in nearly 80% patients treated with tumour necrosis factor alpha inhibitors, tocilizumab or leflunomide. Certainty of evidence for outcomes from RCTs ranged from moderate to very low and was low to very low for all observational studies. There is a paucity of high-quality evidence to guide the pharmacotherapy of TAK. Future observational studies should attempt to include appropriate comparator arms. Multicentric, adequately powered RCTs assessing both clinical and angiographic responses are necessary in TAK. [ABSTRACT FROM AUTHOR]

Copyright of Namık Kemal Tıp Dergisi is the property of Galenos Yayinevi Tic. LTD. STI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Rheumatoid arthritis (RA) is an autoimmune disease that principally attacks synovial joints. RA also cause inflammation in the joints and associated regions. There is an unmet medical need for RA as well as for the targetted drug delivery of anti‐rheumatic drugs to improve its efficacy at a much lower doses while decreasing its side effects. Hence, in this Letter, the authors report the development and characterisation of glucosamine sulphate magnetic nanoparticles for magnetically targetted RA chemotherapy. [ABSTRACT FROM AUTHOR]

As of June 10th 2020 about 7.2 million individuals have tested positive for, and more than 410,000 have died due to COVID-19. In this review we outline the pathophysiology that underpins the potential use of anti-rheumatic therapies for severe COVID-19 infection and summarize the current evidence regarding the risk and outcome of COVID-19 in patients with systemic autoimmune diseases. Thus far there is no convincing evidence that any disease-modifying anti-rheumatic drug (conventional synthetic, biologic or targeted synthetic) including hydroxychloroquine, may protect against severe COVID-19 infection; answers about their possible usefulness in the management of the cytokine storm associated with severe COVID-9 infection will only arise from ongoing randomized controlled trials. Evidence on COVID-19 risk and outcome in patients with systemic autoimmune diseases is extremely limited; thus, any conclusions would be unsafe and should be seen with great caution. At present, the risk and severity (hospitalization, intensive care unit admission and death) of COVID-19 infection in people with autoimmune diseases do not appear particularly dissimilar to the general population, with the possible exception of hospitalization in patients exposed to high glucocorticoid doses. At this stage it is impossible to draw any conclusions for differences in COVID-19 risk and outcome between different autoimmune diseases and between the various immunomodulatory therapies used for them. More research in the field is obviously required, including as a minimum careful and systematic epidemiology and appropriately controlled clinical trials. [ABSTRACT FROM AUTHOR]

Contemporary rheumatology is a field dealing with the phenomena of autoimmune states and inflammation. Rheumatic diseases cover a wide spectrum of diseases of the musculoskeletal system, connective tissue and vessels. The occurrence of an immune, autoimmune and autoinflammatory response is often linked to different kinds of infections. Which aspects of the coronavirus infection relate to rheumatological therapy and practice? In order to answer this question one needs to look at the pathogenesis of the SARS-CoV-2 infection. Antimalarial drugs may block antigen presentation of the viral peptides from antigen presenting cells, as they may alter the lysosomal proteases that mediate the viral entry in the cells and have demonstrated efficacy in improving the infection. Anti-IL-6 may interfere with cytokine storm in severe cases and use of tocilizumab has had good results in a small cohort. Baricitinib not only plays a role in inhibiting the synthesis of cytokines but it also has a function in suppressing receptor-mediated endocytosis. The constantly new and tested concepts in the treatment of COVID testify to the growing knowledge about the virus, but also to the need for more targeted therapy. Treatment regimens have been developed for both patients with COVID-19 and those with symptomatic SARS-CoV infection and rheumatic disease. This article is an attempt to discuss the management of COVID-19 and coexisting rheumatic disease. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an infectious agent affecting respiratory system the most and spreads rapidly due to large number of ACE2 receptors in the lung. Arthralgia and myalgia are the most common rheumatologic findings, but arthritis is rare. Hyperinflammatory condition called cytokine storm causes acute respiratory distress syndrome (ARDS) leading to death. Although coronavirus disease 2019 (COVID-19) is mild or asymptomatic in most cases, it may progress to pneumonia and ARDS, especially in elderly patients who have comorbidities. Drugs such as tocilizumab which suppress inflammatory response and reduce cytokine storm may be effective on treating COVID-19 pneumonia. Cytokine storm, the cause of which is not fully understood and in which many structures of immune system interact with each other, is quite complex and has different mechanisms contributing to it. Although antimalarial drugs such as hydroxychloroquine are used in the treatment, there is no definite evidence that they are effective. It has been shown that the prevalence and course of COVID-19 in rheumatic diseases is similar to the general population, and that increasing age and additional comorbid conditions increase the risk of mortality. It is recommended that anti-rheumatic drugs used in the treatment of rheumatic diseases should not be stopped unless the patient is infected with COVID-19. [ABSTRACT FROM AUTHOR]

Hyperactivation of immune responses resulting in excessive release of pro-inflammatory mediators in alveoli/lung structures is the principal pathological feature of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The cytokine hyperactivation in COVID-19 appears to be similar to those seen in rheumatoid arthritis (RA), an autoimmune disease. Emerging evidence conferred the severity and risk of COVID-19 to RA patients. Amid the evidence of musculoskeletal manifestations involving immune-inflammation-dependent mechanisms and cases of arthralgia and/or myalgia in COVID-19, crosstalk between COVID-19 and RA is often debated. The present article sheds light on the pathological crosstalk between COVID-19 and RA, the risk of RA patients in acquiring SARS-CoV-2 infection, and the aspects of SARS-CoV-2 infection in RA development. We also conferred whether RA can exacerbate COVID-19 outcomes based on available clinical readouts. The mechanistic overlapping in immune-inflammatory features in both COVID-19 and RA was discussed. We showed the emerging links of angiotensin-converting enzyme (ACE)-dependent and macrophage-mediated pathways in both diseases. Moreover, a detailed review of immediate challenges and key recommendations for anti-rheumatic drugs in the COVID-19 setting was presented for better clinical monitoring and management of RA patients. Taken together, the present article summarizes available knowledge on the emerging COVID-19 and RA crosstalk and their mechanistic overlaps, challenges, and therapeutic options.

Autoimmune rheumatic diseases are often seen in individuals at reproductive age. Medications used in case of unplanned pregnancy and/or active rheumatic disease may increase the risk of obstetric complications. Knowledge about the medications used during pregnancy is limited and it is usually accumulated over the years as a result of medications exposure during unplanned pregnancies. Recently, European League Against Rheumatology (EULAR) and the British Society of Rheumatology (BSR) and the British Health Professionals in Rheumatology (BHPR) updated and published the guidelines for the management of rheumatic diseases during pregnancy. As Turkish Society for Rheumatology (TRD), we have decided to develop national treatment recommendations for the proper management of anti-rheumatic drugs during pregnancy and lactation in rheumatic diseases. The aim here is to establish guiding "recommendations" on significant matters such as preg-nancy plan and the use of antirheumatic drugs during conception, gestation and lactation periods and vaccination. This guideline was created by a multidisciplinary working group consist of rheumatology, obstetrics and pediatrics physicians. These recommendations are based on the current recommendations of rheumatic drug use during pregnancy by the EULAR, BSR and BHPR. A literature review was conducted by the working group to update existing international recommendations and its references. The draft of recommendations was submitted to TRD members for their preliminary evaluation. After the revised recommendations were created, the final version was submitted to TRD members and voted [scoring 0-10 (0: Strongly disagree, 10: Strongly agree)]. Two meetings were held with the participation of the working group, one on April 7, 2017 for the preliminary evaluation and the planning, and the other on May 6, 2017 for consensus and writing planning on "the draft of recommendations". The draft recommendations prepared were reviewed by TRD members on September 2018. The final version of the recommendations were voted by the members on April 2019. [ABSTRACT FROM AUTHOR]

Statement of the Problem: Rheumatoid arthritis and periodontitis are chronic inflammatory diseases with a possible bidirectional relationship. This link may be affected by many factors like drug consumption. Purpose: This study was designed to evaluate the periodontal condition in patients with rheumatoid arthritis, considering the effect of disease modifying anti-rheumatic drugs. Materials and Method: This case-control study included 25 newly diagnosed rheumatoid arthritis patients with negative history of taking anti-rheumatic drugs, 25 patients who received anti-rheumatic drugs for more than three years and 50 healthy individuals as a control group. Periodontal indices, including plaque index, gingival index, probing depth, clinical attachment loss, and rheumatologic indices were recorded and compared between these groups. Results: Rheumatoid arthritis patients were significantly more affected by periodontitis compared with healthy subjects (p= 0.006). There was no significant difference in rheumatologic indices between patients with and without periodontitis. Clinical attachment loss in old rheumatoid arthritis patients and gingival index in newly diagnosed ones were significantly more compared to the control group (p= 0.003 and p< 0.001 respectively). We could not find a linear relationship between the severity of rheumatoid arthritis and chronic periodontitis (p= 0.1, r= -0.224). Conclusion: Periodontitis and clinical attachment loss were more in patients with rheumatoid arthritis than the healthy group, especially in drug consumers. Gingival index in patients without the history of consuming anti-rheumatic drugs was significantly higher than those who were drug consumers, indicating the effect of the medications on the signs of inflammation. [ABSTRACT FROM AUTHOR]

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The past decade has seen a major change in the treatment options and strategies for rheumatoid arthritis (RA) and the other immune-mediated arthritic diseases. The disease modifying antirheumatic drugs (DMARDs) are now used in early stages of the disease in order to preserve joint architecture. There are two groups of DMARDs, the small molecules, like methotrexate, and the biological DMARDs, which are frequently referred to as “magic bullets” since they target specific cytokines and immune cells associated with arthritic conditions. They are monoclonal antibodies or fusion proteins designed to bind and inactivate immune targets. Tumour necrosis factor-alpha (TNF-α) plays an important role in the pathogenesis of rheumatoid disorders and is the target of four biological DMARDs, etanercept, infliximab, golimumab and adalimumab. The other biological DMARDs include abatacept, rituximab and tocilizumab and these prevent T-cell costimulation, cause the depletion of mature CD20 positive B cells or prevent the activation of the interleukin-6 receptor molecule, respectively. Ustekinumab, a monoclonal antibody against IL12/IL23 is effective in psoriatic arthritis. Biological agents are indicated when patients do not respond adequately to the traditional DMARDs. Numerous clinical trials have shown that the biological agents reduce joint inflammation and erosive damage, especially when used in combination with methotrexate. Apart from their prohibitive cost, the biological agents are not without potentially serious adverse effects with infections being the main concern. The TNF-α inhibitors increase the risk for tuberculosis and other opportunistic infections, whereas the non-TNF-α immune inhibitors increase the risk for opportunistic viral, fungal and bacterial infections. This review provides an overview of the biological agents currently available in South Africa.

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Background and aims In rheumatoid arthritis, the control of both disease activity and standard cardiovascular (CV) risk factors is expected to attenuate the increased CV risk. Evidence that brain-derived neurotrophic factor (BDNF) plays a role in vascular biology led us to investigate the vascular BDNF pathway in arthritis rats as well as the interaction between endothelial nitric oxide (NO) and BDNF production. Methods The aortic BDNF pathway was studied in rats with adjuvant-induced arthritis, (AIA) using Western blot and immunohistochemical analysis. Control of arthritis score was achieved by administration (for 3 weeks) of an equipotent dosage of etanercept, prednisolone, methotrexate, celecoxib or diclofenac. Aortas were exposed to an NO donor or an NO synthase inhibitor and vasoreactivity experiments were performed using LM22A-4 as a TrkB agonist. Results Vascular BDNF and full length tropomyosin-related kinase B receptor (TrkB-FL) were higher in AIA than in control rats. These changes coincided with decreased endothelial immunoreactivity in BDNF and pTrkB tyr816 and were disconnected from arthritis score. Among anti-rheumatic drugs, only prednisolone and methotrexate prevented AIA-induced vascular BDNF loss. The effect of AIA on aortic BDNF levels was reversed by an NO donor and reproduced by an NOS inhibitor. Finally, LM22A-4 induced both NO-dependent vasodilation and phosphorylation of endothelial NO synthase at serine 1177. Conclusions Our study identified changes in the BDNF/TrkB pathway as a disease activity-independent component of AIA-associated changes in endothelial phenotype. It provides new perspectives in the understanding and management of the high CV risk reported in rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

To analyse the level of consistency and updating of the information on pregnancy and lactation provided by patient information leaflets (PILs) of the antirheumatic drugs approved in Argentina. Inconsistencies between the 2016 EULAR Task Force recommendations on the use of anti-rheumatic drugs during pregnancy and lactation and the information provided by PILs of the same drugs approved in Argentina were analysed along with inconsistencies within the PILs of different registered trademarks of these drugs. Eighty-eight PILs of 32 drugs were analysed. Out of the 88 PILs, 50% presented information inconsistencies as to pregnancy. Medications comprised in this group were: hydroxychloroquine, sulfasalazine, azathioprine, tacrolimus, cyclosporine, NSAIDs (during the first two trimesters), celecoxib, some glucocorticoids, colchicine, and some anti-TNF drugs (etanercept, adalimumab and infliximab) during part of the pregnancy. As for lactation, 56% had information inconsistencies. Medications encompassed in this group were: hydroxychloroquine, chloroquine, sulfasalazine, azathioprine, tacrolimus, cyclosporine, NSAIDs, celecoxib, meprednisone, prednisone, colchicine, and anti-TNF drugs. Out of 17 drugs that had more than one registered trademark, information inconsistencies on pregnancy were found in the PILs of sulfasalazine, diclofenac, ibuprofen and methylprednisolone. Concerning lactation, inconsistencies were present in the PILs of hydroxychloroquine, sulfasalazine, diclofenac, ibuprofen, meprednisone, and colchicine. At least half of the PILs of anti-rheumatic drugs analysed in this study had information inconsistencies on pregnancy and lactation. This is a serious state of affairs because the consensual decision-making process between patient and professional may be compromised, which, in turn, may give rise to medical-legal issues. [ABSTRACT FROM AUTHOR]

This article gives a brief overview of rheumatoid arthritis and psoriatic arthritis focusing on the treatment and management of these conditions. The toxicity of drugs used to treat these conditions requires careful monitoring and for those patients whose condition is stable and well, this may well be done in the primary care setting. This article hopes to give practice nurses more knowledge and understanding of shared care arrangements and when referral back to secondary care is needed with the aim of giving them more confidence if asked to help in this area of patient care. [ABSTRACT FROM AUTHOR]

As doenças reumáticas podem causar distúrbios sexuais e reprodutivos. As razões destes distúrbios são multifatoriais. Manifestações e sintomas das doenças podem reduzir a libido e interferir no sucesso da reprodução, como ocorre na artrite reumatóide (AR), lúpus eritematoso sistêmico (LES), espondilite anquilosante (EA) e esclerose sistêmica (ES). A atividade da doença pode levar a uma alteração do eixo hipotálamo-hipófise, acarretando períodos de disfunção gonadal. Os auto-anticorpos e os distúrbios de hormônios sexuais, que podem estar presentes em muitas doenças reumáticas, podem influenciar negativamente na fertilidade. Além disso, algumas drogas usadas no tratamento de doenças reumatológicas por vezes representam um risco para a reprodução masculina, devido aos efeitos adversos que podem causar, como defeitos cromos-sômicos e gonadotoxicidade, prejudicando a espermatogênese e a motilidade dos espermatozóides. Conseqüentemente, há falência gonadal transitória ou permanente. Este trabalho faz uma revisão de um assunto pouco abordado na literatura brasileira.Rheumatic diseases affect all aspects of life, including sexuality and reproduction. The reasons for disturbing sexual functioning and reproduction are multifactorial. Manifestations and symptoms of disease can reduce libido and interfere with successful reproduction, for example, in rheumatoid arthritis (AR), systemic lupus erythematosus (SLE), ankylosing spondylitis (AS) and systemic sclerosis (SSc). Active disease disturbs the hypothalamic-pituitary-axis, giving rise to periods of gonadal dysfunction. Autoantibodies, which are present in most of the rheumatic diseases, and disturbances of sex hormone status can negatively influence the fertilization. Furthermore, some antirheumatic drugs carry a risk for male reproduction, because can present adverse effects, which includes chromosomal defects and gonadotoxicity, damaging the spermatogenesis and sperm motility. It results in transient or permanent gonadal failure. We are presenting a review of this aspect.

Chronic inflammation associated with autoimmune activation is characteristic of rheumatic diseases from childhood to adulthood. In recent decades, significant improvements in the treatment of these types of disease have been achieved using disease modifying anti-rheumatic drugs (DMARDs), such as methotrexate (MTX) and, more recently, using biologic inhibitors. The recent introduction of kinase inhibitors (for example, tofacitinib; Tofa) further increases the available ARDs. However, there are patients that do not respond to any treatment strategies, for whom combination therapies are proposed. The data regarding the combined action of different drugs is lacking and the knowledge of the mechanisms of ARDs and their actions upon pathogenic lymphocytes, which are hypothesized to sustain disease, is poor. An in vitro model of inflammation was developed in the current study, in which stimulated and unstimulated lymphocytes were cultured together, but tracked separately, to investigate the action of MTX and Tofa on the two populations. By analysing lymphocyte proliferation and activation, and cytokine secretion in the culture supernatants, it was established that, due to the presence of activated cells, unstimulated cells underwent a bystander activation that was modulated by the ARDs. Additionally, varying administration schedules were demonstrated to affect lymphocytes differently in vitro, either directly or via bystander activation. Furthermore, MTX and Tofa exerted different effects; while MTX showed an antiproliferative effect, Tofa marginally effected activation, although only a slight antiproliferative action, which could be potentiated by sequential treatment with MTX. Thus, it was hypothesized that these differences may be exploited in sequential therapeutic strategies, to maximize the anti-rheumatic effect. These findings are notable and must be accounted for, as bystander-activated cells in vivo could contribute to the spread of autoimmune activation and disease progression. [ABSTRACT FROM AUTHOR]

Development of novel drugs for treatment of chronic inflammatory diseases is to a large extent dependent on the availability of good experimentalin vivomodels in order to perform preclinical tests of new drugs and for the identification of novel drug targets. Here, we review a number of existing rodent models for Rheumatoid Arthritis in the context of how these models have been utilized for developing established therapy in Rheumatoid Arthritis and, furthermore, the present use of animal models for studies of novel drug candidates. We have studied the literature in the field for the use ofin vivomodels during development of anti-rheumatic drugs; from Methotrexate to various antibody treatments, to novel drugs that are, or have recently been, in clinical trials. For novel drugs, we have explored websites for clinical trials. Although a single Rheumatoid Arthritisin vivomodel cannot mirror the complexity of disease development, there exist a number of good animal models for Rheumatoid Arthritis, each defining some parts in disease development, which are useful for studies of drug response. We find that many of the established drugs were not tested inin vivomodels before being used in the clinic, but rather animal models have been subsequently used to find mechanisms for efficacy. Finally, we report a number of novel drugs, tested in preclinicalin vivomodels, presently in clinical trials. [ABSTRACT FROM AUTHOR]

Autoimmune rheumatic diseases (ARD) can affect women and men during fertile age, therefore reproductive health is a priority issue in rheumatology. Many topics need to be considered during preconception counselling: fertility, the impact of disease-related factors on pregnancy outcomes, the influence of pregnancy on disease activity, the compatibility of medications with pregnancy and breastfeeding. Risk stratification and individualized treatment approach elaborated by a multidisciplinary team minimize the risk of adverse pregnancy outcomes (APO). Research has been focused on identifying biomarkers that can be predictive of APO. Specifically, preeclampsia and hypertensive disorders of pregnancy tend to develop more frequently in women with ARD. Placental insufficiency can lead to intrauterine growth restriction and small-for-gestational age newborns. Such APO have been shown to be associated with maternal disease activity in different ARD. Therefore, a key message to be addressed to the woman wishing for a pregnancy and to her family is that treatment with compatible drugs is the best way to ensure maternal and fetal wellbeing. An increasing number of medications have entered the management of ARD, but data about their use in pregnancy and lactation are scarce. More information is needed for most biologic drugs and their biosimilars, and for the so-called small molecules, while there is sufficient evidence to recommend the use of TNF inhibitors if needed for keeping maternal disease under control. Other issues related to the reproductive journey have emerged as "unmet needs", such as sexual dysfunction, contraception, medically assisted reproduction techniques, long-term outcome of children, and they will be addressed in this review paper. Collaborative research has been instrumental to reach current knowledge and the future will bring novel insights thanks to pregnancy registries and prospective studies that have been established in several Countries and to their joint efforts in merging data., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Regarding the pregnancy outcome in patients with Rheumatoid Arthritis (RA), most concerns are linked to pharmacological therapies. In order to manage the disease and obtain a favourable outcome of the pregnancy, there are several remissive or biological therapies that may be used, with minimal precautions. The anti-rheumatic drugs that may be used in RA are classified into 4 pregnancy risk categories according to the risk of inducing fetal injury: minimal risks, medium risks, high risks, and unknown risks. For many biological therapies, the lack of extensive studies is limiting the therapeutic recommendations in this sensitive area; recommendations are coming from experts in this field. However, if the preconceptual period and all the pregnancy conducts comply with the general recommendations, we may conclude that medication and pregnancy in rheumatoid arthritis may be combined with minimal risks. [ABSTRACT FROM AUTHOR]

This drug utilization study aimed to investigate prescription patterns and trends for anti-rheumatic drug use in Japanese patients with rheumatoid arthritis (RA), clarifying if patients with RA in Japan are being treated according to EULAR recommendations and ACR guidelines. We used a large-scale claims database consisting of the medical claims of employee health insurance recipients, which included approximately one million insured people. The claims data for incident 5,126 patients with diagnosis codes of RA between January 1, 2005 and October 31, 2011 were analyzed. The number of patients who received disease modifying anti-rheumatic drugs (DMARDs) including biologics as initial therapy was 629 (12.3 %), while the others received non-DMARD therapy only. During the study period, use of methotrexate (MTX) and biologics as first-line drugs increased from 1.9 to 8.0 % and from 0 to 1.6 %, respectively ( p < 0.001 for both), while that of non-steroidal anti-inflammatory drugs (NSAIDs) decreased ( p = 0.004). Time from first RA diagnosis to the start of treatment with DMARDs decreased significantly from 2005 to 2010. These findings suggest that many early RA patients in Japan do not yet receive aggressive treatment, albeit that this prescribing practice has gradually changed to better comply with clinical recommendations. The current, obsolete Japanese RA guidelines require urgent updating to reflect the most recent knowledge and care with effective treatment modalities. [ABSTRACT FROM AUTHOR]

ABSTRACT Purpose Previous studies suggest that disease-modifying anti-rheumatic drugs (DMARDs) increase tuberculosis (TB) risk. The accuracy of pharmacy and coded-diagnosis information to identify persons with TB is unclear. Methods Within a cohort of rheumatoid arthritis (RA) patients (2000-2005) enrolled in Tennessee Medicaid, we identified those with potential TB using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD9-CM) diagnosis codes and/or pharmacy claims. Using the Tennessee TB registry as the gold standard for identification of TB, we estimated the sensitivity, specificity, predictive values, and the respective 95% confidence intervals for each TB case-ascertainment strategy. Results Ten of 18 094 RA patients had confirmed TB during 61 461 person-years of follow-up (16.3 per 100 000 person-years). The sensitivity and positive predictive value (PPV) and respective 95% confidence intervals were low for confirmed TB based on ICD9-CM codes alone (60.0% (26.2-87.8) and 1.3% (0.5-2.9)), pharmacy data alone (20% (2.5-55.6) and 4.1% (0.5-14.3)), and both (20% (2.5-55.6) and 25.0% (3.2-65.1)). Conclusions Algorithms that use administrative data alone to identify TB have a poor PPV that results in a high false positive rate of TB detection. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: Thermal analysis of antirheumatic drugs, parecoxib sodium (PCX) and valdecoxib (VCX) was achieved. Thermogravimetry (TG), derivative thermogravimetry (DTG), and differential thermal analysis (DTA) were used through the work. The results led to thermal stability data, and also to the determination of kinetic parameters such as activation energy and frequency factor. The differential scanning calorimetry (DSC) was suitable for the purity determination of the compounds. The simplicity, speed, and low operational costs of thermal analysis justify its application in the quality control of pharmaceutical drugs. [Copyright &y& Elsevier]

Abstract: Biologics are highly effective in the treatment of rheumatoid arthritis (RA), but they are very expensive. The costs of biologics should limit their usage in patients with RA, especially in the developing countries. Therefore, it is necessary to develop suitable strategies for treating RA patients in these countries. In this article, the efficacy, toxicity, and cost-effectiveness of conventional DMARDs and biologics will be investigated. The therapeutic strategies for treating early RA will also be proposed. [Copyright &y& Elsevier]

We have previously shown that the gold-containing disease-modifying anti-rheumatic drugs, auranofin (AF) and gold sodium aurothiomalate (GSTM) reduce human umbilical vein endothelial cell (HUVEC) adhesion molecule expression and neutrophil (PMN) adherence. AF diminishes E-selectin and intercellular adhesion molecule-1 (ICAM-1) on cytokine-activated HUVEC, while GSTM decreases only E-selectin. Since tight adhesion is critical for PMN to damage EC, we tested whether these drugs modulated human PMN-mediated injury to TNF-α-activated HUVEC in vitro (as measured by 51Cr release). Here we show that TNF-α caused a prominent PMN-mediated cytotoxicity that was dose-dependently reduced when AF and GSTM were added to the assay system. We also found that a potent inhibitor of NF-κB, pyrrolidine dithiocarbamate (PDTC) in a dose-dependent manner impaired TNF-α-induced cytotoxicity, indicating a role of NF-κB activation in cytokine-induced endothelial injury. To examine the effects of AF and GSTM on TNF-α-induced NF-κB activation this was measured in HUVEC nuclear extracts by an electrophoretic mobility shift assay. AF, but not GSTM, decreased TNF-α-induced NF-κB activation in HUVEC. Thus, in this in vitro model of vasculitis, AF and GSTM dose dependently reduced TNF-α-mediated neutrophil-dependent cytotoxicity for HUVEC, and AF, but not GSTM, inhibited NF-κB mobilization, thereby providing possible mechanisms for effects of AF and GSTM. [ABSTRACT FROM AUTHOR]