Treatment Of Inflammatory Rheumatic Diseases Research Articles

The subanalysis of Rheuma-VOR demonstrates aconsiderable need for rheumatological care

Early diagnosis and treatment of inflammatory rheumatic diseases can prevent consequential damage such as permanently limited mobility and joint or organ damage. Simultaneously, there is an increasing deficit in medical care owing to the lack of rheumatological capacity. Rural regions are particularly affected. The available unconfirmed diagnoses of the study Rheuma-VOR were analysed regarding another definitive inflammatory rheumatic disease. The returned questionnaires of the rheumatologists participating in Rheuma-VOR were screened for definitive inflammatory rheumatic diseases other than the required diagnosis of rheumatoid arthritis, psoriatic arthritis or spondyloarthritis. Of 910 unconfirmed diagnoses, in 245 patients another definitive diagnosis could be confirmed. A total of 29.8% of thediagnoses corresponded to degenerative joint changes or chronic pain syndrome, whereas 26.1% involved different forms of inflammatory arthritis. The majority of diagnoses (40.5%) were collagenosis or vasculitis, DISCUSSION: The available data show that a rheumatological presentation was indicated for the majority of patients. Owing to the increasing deficits in medical care aprior selection of the patients is crucial to make optimal use of restricted rheumatological capacities.

JAK inhibition in the treatment of inflammatory rheumatic diseases.

The most common immune-mediated inflammatory rheumatic diseases, rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis and have reached significant advances in recent years with the introduction of biological therapies against cytokines and immune cells, but also against intracellular enzymes, specifically Janus kinases (JAKs). Intracellular JAK signalling is activated by binding of various cytokines or growth factors to the respective cellular receptors, allowing the activation of STAT (Signal Transducers and Activators of Transcription) transcription factors and ultimately the transcription of genes with important roles during the innate and adaptive immune response. Four Janus kinases have been described: JAK1, JAK2, JAK3 and tyrosine kinase-2 (TYK2). Four JAK inhibitors (tofacitinib, baricitinib, upadacitinib and filgotinib) are currently approved for the treatment of rheumatoid arthritis, and some for the treatment of psoriatic arthritis and axial spondyloarthritis. JAK inhibitors have varying selectivity against individual kinases. Some JAK inhibitors are being tested in other rarer systemic connective tissue diseases. The general advantages of JAK inhibitors are oral administration, rapid onset of action, and efficacy in monotherapy. The safety profile of JAK inhibitors compared with biologic therapy appears to be comparable, with a higher incidence of herpes zoster, and an increased incidence of major cardiovascular disease, thromboembolic complications, and cancer in at-risk patients is discussed. The aim of this paper will be to summarize the latest findings on JAK inhibitors in approved indications for the most common rheumatic diseases.

Gender-specific differences in the diagnosis and treatment of inflammatory rheumatic diseases

Gender differences in the diagnosis and treatment of various diseases are increasingly being researched with the aim of optimizing treatment strategies and improving individual treatment success. This paper summarizes the existing literature for gender differences in inflammatory rheumatic diseases. Many, but not all, inflammatory rheumatic diseases occur more frequently in women than in men. Women more often have alonger duration of symptoms until diagnosis than men, which may be due to different clinical and radiological presentations. Across diseases, women more often have lower remission and treatment response rates to antirheumatic medication compared to men. Discontinuation rates are also higher in women than in men. Whether women are more likely to develop anti-drug antibodies to biologic disease-modifying antirheumatic drugs is still unclear. For Janus kinase inhibitors, there is no evidence of differential treatment response to date. Whether individual dosing regimens and gender-adapted remission criteria are also required in rheumatology cannot be deduced from the evidence available to date.

Points to consider for cost-effective use of biological and targeted synthetic DMARDs in inflammatory rheumatic diseases: results from an umbrella review and international Delphi study

ObjectivesTo develop evidence-based points to consider for cost-effective use of biological and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in the treatment of inflammatory rheumatic diseases, specifically rheumatoid arthritis, psoriatic arthritis...

Hydroxychloroquine as an Immunomodulatory and Antithrombotic Treatment in Antiphospholipid Syndrome.

Antiphospholipid syndrome (APS) is an acquired highly prothrombotic disorder in which thrombo-inflammatory antiphospholipid antibodies (aPL) cause thrombosis via multiple mechanisms, including endothelial damage and activation. Obstetric complications in APS are caused by placental thrombosis, inflammation and complement activation. Anticoagulation is poorly effective in some patients especially those with triple positive aPL who are at ~30% risk of thrombosis recurrence within 10 years. Increasing therapeutic anticoagulation intensity may be beneficial but leads to excess bleeding with serious complications, such as intracerebral haemorrhage. Nonetheless, anticoagulation is still the mainstay of treatment despite the autoimmune nature of APS. The antimalarial immunomodulatory drug hydroxychloroquine (HCQ) has been used for many years for the treatment of inflammatory rheumatic diseases. HCQ has complex pleiotropic mechanisms of action upon multiple cell types. The proposed biological processes that HCQ regulates support the hypothesis that it may be a successful adjunctive treatment in the prevention of recurrent thrombosis and pregnancy complications.

Epigenetic changes in inflammatory arthritis monocytes contribute to disease and can be targeted by JAK inhibition.

How the local inflammatory environment regulates epigenetic changes in the context of inflammatory arthritis remains unclear. Here we assessed the transcriptional and active enhancer profile of monocytes derived from the inflamed joints of JIA patients, a model well-suited for studying inflammatory arthritis. RNA sequencing and H3K27me3 chromatin immunoprecipitation sequencing (ChIP-seq) were used to analyse the transcriptional and epigenetic profile, respectively, of JIA synovial fluid-derived monocytes. Synovial-derived monocytes display an activated phenotype, which is regulated on the epigenetic level. IFN signalling-associated genes are increased and epigenetically altered in synovial monocytes, indicating a driving role for IFN in establishing the local inflammatory phenotype. Treatment of synovial monocytes with the Janus-associated kinase (JAK) inhibitor ruxolitinib, which inhibits IFN signalling, transformed the activated enhancer landscape and reduced disease-associated gene expression, thereby inhibiting the inflammatory phenotype. This study provides novel insights into epigenetic regulation of inflammatory arthritis patient-derived monocytes and highlights the therapeutic potential of epigenetic modulation for the treatment of inflammatory rheumatic diseases.

Possible relationship between hydroxychloroquine and electrocardiographic and echocardiographic abnormalities in patients with inflammatory rheumatic diseases--a monocentric study.

Hydroxychloroquine (HCQ) is used in the treatment of inflammatory rheumatic diseases and is considered a safe drug. The role of HCQ in the COVID-19 pandemic highlighted some deleterious cardiac effects of HCQ. We aim to evaluate the prevalence and development of cardiac-adverse events in HCQ-treated patients with inflammatory rheumatic diseases. We performed a cross-sectional study where patients aged ≥18years with a diagnosis of inflammatory rheumatic disease currently exposed or not to hydroxychloroquine underwent electrocardiogram (ECG) and echocardiogram. Comparisons between groups were evaluated using chi-square, t test, and Mann-Whitney U test. Logistic regression was performed to determine predictors of changes in ECG and echocardiography. Eighty patients were included, 75 (93.8%) female, aged 52 ± 13years. ECG changes were seen in higher proportion in patients with hypertension (40.6% vs 12.5%, p = .004) and higher median potassium levels-4.5 (4.1-4.8) versus 4.2 (4.0-4.4), p = .023. Echocardiography changes were seen in older patients (59 ± 11 vs 50 ± 13years, p = .003) and in patients with higher cumulative dose-1752 (785-2190) versus 438 (328-1022) g, p = 0.008 - and time of exposure to HCQ - 12 (6-15) versus 4 (2-9) years, p = 0.028. HCQ cumulative dose (OR 1.001, CI95% 1.000-1.002, p = .033) and exposure time (OR 1.136, CI95% 1.000-1.289, p = .049) were predictors of echocardiography changes, but when adjusted for age, neither HCQ cumulative dose nor exposure time were predictors of echocardiography changes. No association was found between changes in ECG and echocardiogram in patients under HCQ, which remains a safe drug in patients with inflammatory rheumatic diseases.

Busting the myth of methotrexate chronic hepatotoxicity.

Methotrexate is a key component of the treatment of inflammatory rheumatic diseases and the mainstay of therapy in rheumatoid arthritis. Hepatotoxicity has long been a concern for prescribers envisaging long-term treatment with methotrexate for their patients. However, the putative liver toxicity of methotrexate should be evaluated in the context of advances in our knowledge of the pathogenesis and natural history of liver disease, especially non-alcoholic fatty liver disease (NAFLD). Notably, patients with NAFLD are at increased risk for methotrexate hepatotoxicity, and methotrexate can worsen the course of NAFLD. Understanding the mechanisms of acute hepatotoxicity can facilitate the interpretation of elevated concentrations of liver enzymes in this context. Liver fibrosis and the mechanisms of fibrogenesis also need to be considered in relation to chronic exposure to methotrexate. A number of non-invasive tests for liver fibrosis are available for use in patients with rheumatic disease, in addition to liver biopsy, which can be appropriate for particular individuals. On the basis of the available evidence, practical suggestions for pretreatment screening and long-term monitoring of methotrexate therapy can be made for patients who have (or are at risk for) chronic liver disease.

Evidence-based non-pharmacological treatment of inflammatory rheumatic diseases

Evidence-based non-pharmacological treatment of inflammatory rheumatic diseases

Coexistence of fibromyalgia syndrome and inflammatory rheumatic diseases, and autonomic cardiovascular system involvement in fibromyalgia syndrome.

The spectrum of symptoms represented by fibromyalgia syndrome (FMS) has a profound effect on daily activities and impairs the quality of life. A considerable proportion of patients with inflammatory rheumatic diseases (IRDs) fulfill the FMS criteria, which can complicate the diagnosis, treatment, and follow-ups of IRD. In addition, the coexistence of FMS may cause unnecessary laboratory and radiological assessments. Several mechanisms have been proposed that may have a role in the etiopathogenesis of FMS, one of which is autonomic dysregulation. In studies evaluating cardiac autonomic dysfunction based on heart rate variability (HRV), there has been found to be a decrease in HRV and dominance of the sympathetic nervous system. Autonomic reactivity reflects modulations of several functions to overcome the existing state and conditions. Blunted autonomic reactivity has been found in some FMS patients, which makes it difficult for these patients to respond appropriately to unexpected stress sources that occur during daily living activities. Baroreceptor signals have an inhibitory influence on the central nervous system, and these impulses cause pain suppression. From this perspective, there are studies that have suggested the involvement of diminished baroreflex sensitivity in the etiology of FMS. The risk of endothelial dysfunction and increased arterial stiffness have been shown to occur in FMS patients due to autonomic dysfunction, sympathetic nervous system dominance, chronic stress, and pain. There is also evidence linking FMS with the risk of atrial and ventricular arrhythmias. Considering all these cardiovascular autonomic dysfunctions, tests that can confirm abnormalities should be performed when suspicion arises. There is a need for specific pharmacological and non-pharmacological treatment alternatives to be identified for subgroups of patients with cardiovascular system abnormalities. Key points • The frequency of FMS accompanying inflammatory rheumatic diseases is considerable and this coexistence leads to troubles in evaluating treatment response and determining appropriate medical treatment options in inflammatory rheumatic diseases. • Various cardiovascular autonomic abnormalities have been described in FMS patients. Among these, the most emphasized are autonomic dysfunction, the disruption of the balance between the sympathetic-parasympathetic nervous systems, blunted autonomic reactivity to acute stress, changes in baroreflex sensitivity, increased arterial stiffness, and electrophysiological alterations. • Autonomic cardiovascular dysfunction may be involved in the complex etiopathogenesis of the fibromyalgia syndrome and may trigger at least some symptoms.

PHARAO study: drug treatment of inflammatory rheumatic diseases : Guideline-conform treatment with biologics follows availability of biosimilars

With the introduction of tumor necrosis factor (TNF) alpha inhibitors, the treatment of inflammatory rheumatic diseases (IRD) has undergone afundamental change. Several of the originally high-priced biologics are now accessible as lower cost biosimilars, removing asignificant impediment to prescription. The present study investigated whether the availability of biosimilars is associated with an improvement in the care of IRD. Moreover, the subjective acceptance of biosimilars by physicians and patients was investigated and compared with objectifiable parameters. Pseudonymized claims data of the Bavarian Association of Statutory Health Insurance Physicians from 2014 to 2019 as well as apaper and pencil survey of patients and rheumatologists formed the data basis of the study. During the observation period, the proportion of diagnosed patients receiving drug therapy increased from 38.5% to 43.2%. Also, the care changed in terms of the prescribed agents. Conventional drug therapy declined overall and, in particular, glucocorticoid prescriptions decreased from 39.3% in 2014 to 34.3% in 2019. At the same time, the proportion of targeted treatments increased from 12.3% to 20.4%. The median duration of basic treatment before first-time bDMARD use dropped from 3.15years in 2014 to 2.17years in 2019. Over the observation period, in which three biosimilars entered the market, the care of patients with IRD improved both quantitatively and qualitatively. The market share of biosimilars increased in parallel with this development. With an overall high acceptance of biosimilars, the assessment of the disease course by physicians and patients indicates aslight subjectively perceived advantage of therapy with originals compared to biosimilars, which, however, is not confirmed when standardized scores are applied. Apossible explanation for this might be anocebo effect, which could be minimized by suitable communication strategies.

The safety of glucocorticoids in the treatment of inflammatory rheumatic disease: new evidence.

Glucocorticoids justifiably remain a cornerstone in the treatment of many inflammatory rheumatic diseases but many are opposed to their use because of the side effects, most of them known to be dose-dependent. Most concerns regarding glucocorticoids stem from observational studies which are affected by several forms of bias, mainly confounding by indication, that may result in overestimation of harm. Solid evidence regarding the safety of low-dose glucocorticoids remains remarkably scarce. Several observational studies showed heterogeneous results and two 6-month trials showed no increase of harm. The GLORIA trial of 5 mg/day prednisolone vs. placebo in patients aged 65+ is the first randomized control trial with glucocorticoids safety as coprimary outcome. The benefits of glucocorticoids in terms of symptoms and structural damage were confirmed, but the proportion of patients with at least one adverse event of special interest (serious or glucocorticoids-related) was increased by 24%, mostly due to nonsevere infections. Based on current evidence the benefit-risk balance of low-dose glucocorticoids in rheumatoid arthritis, and probably in other rheumatic diseases is generally favourable. Physicians should be aware of the risks and mitigate them, but avoid the negative effects of unfounded fear.

Dietary recommendations of the French Society for Rheumatology for patients with chronic inflammatory rheumatic diseases.

This article presents the 1st set of dietary recommendations of the French Society for Rheumatology for patients suffering from chronic inflammatory rheumatic diseases (IRD) made by a working group consisting of 12 rheumatology experts, 3 physician nutrition specialists, 1 internal medicine specialist, 1 registered dietician and 3 representatives from patient associations. This group relied on a systematic literature review and on expert opinions, while taking into consideration not only the joint effects of diet in IRD but also the extra-articular ones. Eight general principles and nine recommendations were established. The general principles emphasize that nutritional advice is not a substitute for pharmacological treatment of IRD and that it is an integral part of the patients' overall care, which could help the patient actively participate in their care. The recommendations propose supporting weight loss in subjects who are overweight or obese, a Mediterranean-type diet and supplementation in polyunsaturated fatty acids, mainly omega-3. Conversely, gluten-free diets (in the absence of celiac disease), vegetarian/vegan diets, fasting and elimination of dairy products should not be proposed. Supplementation with vitamins or trace elements is not indicated for controlling chronic IRD activity, while the use of probiotics or spices is not recommended given the limited or disparate data.

Risk of tuberculosis is increased in Behçet’s disease compared to other rheumatological disorders after anti-TNFα treatments: a case series and review of the literature

Background/aimTumor necrosis factor-alfa (TNF-a) antagonists are extensively utilized in the treatment of inflammatory rheumatic diseases and also shown to be effective in Behçet’s disease (BD) patients with major organ involvement. In this study, we aimed to re-evaluate the incidence of tuberculosis (TB) infection after anti-TNFa treatments and to reveal the risk of TB in BD.MethodsData of patients who received anti-TNFa treatment between 2005 and 2018 were assessed retrospectively. Demographic features, TNF-a antagonist type/treatment time, tuberculosis skin test (TST) and QuantiFERON results, isoniazid prophylaxis status, and concomitant corticosteroid (CS) treatments were collected. ResultsA total of 1277 (male/female = 597/680; median age = 49 years) patients were treated with TNF-a antagonist for a median of 33 months (Q1:12, Q3:62). Thirteen (1%) patients developed TB during the follow-up period. Within 13 TB-positive patients, 7 of them had pulmonary, and 7 had extrapulmonary TB. Although, the median time of (month) TNF-a antagonist treatment was higher in TB-positive patients than negative ones, the difference was not statistically significant (48 and 33 months, respectively, p = 0.47). Similarly, TB-positive patients were treated with CSs more than TB-negative patients (80% vs. 60%). Time from the initiation of TNF-a antagonist treatment to the diagnosis of TB had a median of 40 months (Q1-Q3: 22-56). There was a statistically significant increase of TB development in BD patients than non-BD patients after TNF-a antagonists (7.5% vs. 0.8%, respectively, p = 0.007). When we combined our patients with the other series from Turkey, among 12928 patients who received TNF-a antagonists, TB was positive in 12 (3.9%) of 305 BD patients compared to 112 (0.9%) of 12623 non-BD patients (p < 0.00001).ConclusionOur results suggest a higher frequency of TB infections in BD patients with TNF-a antagonists. As biologic agents are increasingly used for major organ involvement in current practice for BD, screening mechanisms should be carefully implemented.

Sports and exercise therapy in inflammatory rheumatic diseases

Physical therapy has always been apillar of the treatment of inflammatory rheumatic diseases in addition to targeted drug treatment; nevertheless, it is only established in the treatment guidelines for afew diseases. Within the last two decades the discovery of myokines has uncovered the physiological correlations of the anti-inflammatory effect of physical activity. For rheumatoid arthritis and spondylarthritis, several randomized controlled trials provide sufficient evidence to make well-founded recommendations. For connective tissue diseases (CTD) the data situation is clearly sparser but nevertheless shows that the positive effects of physical activity prevail. In the following article the authors present the most important clinical studies on sport and inflammatory rheumatic diseases and from these derive possible therapeutic recommendations.

Ultrasound-Guided Biopsies: Medium and Large Joints.

Ultrasound-guided needle synovial biopsies are useful for clinical practice and research in rheumatology. With the emergence of personalized medicine for the treatment of inflammatory rheumatic diseases, it is predicted that this technique will be increasingly used in the near future. Standardized characterization of the technical aspects of ultrasound-guided needle synovial biopsies is needed in order to produce solid evidence on the safety and effectiveness of the technique.

Identification of new biomarkers to promote personalised treatment of patients with inflammatory rheumatic disease: protocol for an open cohort study

IntroductionThe introduction of biological disease-modifying antirheumatic drugs (bDMARDs) has improved the treatment of inflammatory rheumatic diseases dramatically. However, bDMARD treatment failure occurs in 30%–40% of patients due to lack of...

Biologics registers in RA: methodological aspects, current role and future applications.

The beginning of the 21st century saw a biopharmaceutical revolution in the treatment of inflammatory rheumatic diseases, particularly rheumatoid arthritis. The fast-evolving use of biologic therapies highlighted the need to develop registers at national and international levels with the aim of collecting long-term data on patient outcomes. Over the past 15 years, many biologics registers have contributed a wealth of data and provided robust and reliable evidence on the use, effectiveness and safety of these therapies. The unavoidable challenges posed by the continuous introduction of new therapies, particularly with regard to understanding their long-term safety, highlights the importance of learning from experience with established biologic therapies. In this Perspectives article, the role of biologics registers in bridging the evidence gap between efficacy in clinical trials and real-world effectiveness is discussed, with a focus on methodological aspects of registers, their unique features and challenges and their role going forward.

Role of non-coding regulatory ribonucleic acids in chronic inflammatory diseases

Non-coding regulatory ribonucleic acids (RNA), including microRNA, long non-coding RNA and circular RNA, can influence the expression of genes mediating inflammatory processes and therefore affect the course and progression of chronic inflammatory diseases. Recent studies using antisense oligonucleotides suggest that such non-coding regulatory RNAs are suitable as novel therapeutic target molecules for the treatment of inflammatory rheumatic diseases.

Non-surgical management of knee osteoarthritis: where are we now and where do we need to go?

After the successful treatment of inflammatory rheumatic diseases with targeted therapies, the greatest challenge in rheumatic diseases remains the treatment of the most common chronic joint disorder, osteoarthritis. Osteoarthritis (OA) commonly affects the knee, with an age-standardised and sex-standardised incidence of 240 per 100.000 person-years. With the aging of the population and rising obesity throughout the world, it is anticipated that the burden of OA will increase and become a major problem for health systems globally. Given this background, proper guidance on the management of OA is needed. This issue has been addressed over recent months in updated guidelines or recommendations detailing three treatment modalities: non-pharmacological, pharmacological and surgical. It should be noted, that OA is not a uniform disease entity. In some patients, progression of the disease seems to be driven by cartilage factors, in others by bone factors or by inflammatory factors. Ongoing research aims to identify potential biomarkers for these different forms of OA. Research is also underway into disease modifying OA drugs (DMOADs) that target different aspects of the disease, treatments for OA pain, and cell-based therapies.