Treatment Of Autoimmune Rheumatic Diseases Research Articles

Hepatitis B reactivation in PsA patients: an SLR and meta-analysis for IL-17, IL-23 and JAK inhibitors.

Hepatitis B reactivation (HBVr) constitutes a side effect of the treatment of autoimmune rheumatic diseases. Even though HBVr risk of conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) and anti-tumor necrosis factor (anti-TNF) agents has long been established, the risk of targeted synthetic (ts)DMARDs and anti-interleukin (anti-IL) agents remains largely unknown. We conducted a SLR (PubMed, Scopus and EMBASE) and metanalysis to examine the HBVr risk for the following: anti-IL17, anti-IL12/23, anti-IL23 and JAK-inhibitors in patients with chronic HBV infection (HBsAg presence or detectable HBV-DNA) and in patients with prior HBV infection (HBcAb-positive and HBsAg-negative). Meta-analysis was performed using both the fixed and random effects method and was conducted using the R computing language. Overall, our study revealed a low HBVr risk of < 6% in all agents; the risk was significantly higher for people having chronic compared with those with resolved HBV (14,4% vs 5.1%, respectively p< 0.01). There was no difference among different drugs in the HBVr rates [anti-IL-17: 4% (95% CI: 1-9%), anti-IL-12/IL-23: 2% (95% CI: 0-5%), JAK-inhibitors: 4% (95% CI: 1-8%), anti-IL23: 0%]. Of note, HBVr rate reached 28% in patients with chronic HBV who did not receive anti-viral treatment. For patients with resolved hepatitis the respective percentage was 4.7%. Overall, our meta-analysis shows that patients with chronic HBV receiving anti-IL-17, anti-IL-12/23, anti-IL-23 and JAK-inhibitors have significant risk for HBVr, especially if they are not under anti-viral treatment. In contrast, resolved HBV seems to offer minor risk for HBVr even without anti-viral treatment.

The Potential Role of Butyrate in the Pathogenesis and Treatment of Autoimmune Rheumatic Diseases.

The gut microbiota is a complex ecosystem of microorganisms residing in the human gastrointestinal tract, playing a crucial role in various biological processes and overall health maintenance. Dysbiosis, an imbalance in the composition and function of the gut microbiota, is linked to systemic autoimmune diseases (SAD). Short-chain fatty acids (SCFAs), especially butyrate, produced by the gut microbiota through the fermentation of dietary fibers, play a significant role in immunomodulation and maintaining intestinal homeostasis. Butyrate is essential for colonocyte energy, anti-inflammatory responses, and maintaining intestinal barrier integrity. Studies show reduced butyrate-producing bacteria in SAD patients, suggesting that increasing butyrate levels could have therapeutic benefits. Butyrate's anti-inflammatory effects and its potential therapeutic role have been studied in rheumatoid arthritis, Sjogren's syndrome, systemic lupus erythematosus, systemic sclerosis, and Behçet's disease. Despite promising in vitro and animal model results, human studies are limited, and the optimal strategies for modulating dysbiosis in SADs remain elusive. This review explores the current evidence on the immunoregulatory role of butyrate and its potential therapeutic effects in SAD.

Activation Markers on B and T Cells and Immune Checkpoints in Autoimmune Rheumatic Diseases.

In addition to identifying the major B- and T-cell subpopulations involved in autoimmune rheumatic diseases (ARDs), in recent years special attention has been paid to studying the expression of their activation markers and immune checkpoints (ICPs). The activation markers on B and T cells are a consequence of the immune response, and these molecules are considered as sensitive specific markers of ARD activity and as promising targets for immunotherapy. ICPs regulate the activation of the immune response by preventing the initiation of autoimmune processes, and they modulate it by reducing immune cell-induced organ and tissue damage. The article considers the possible correlation of ICPs with the activity of ARDs, the efficacy of specific ARD treatments, and the prospects for the use of activation molecules and activation/blocking ICPs for the treatment of ARDs.

Treating Autoimmune-Related Interstitial Lung Disease With B Cell Depletion.

Autoimmune rheumatic diseases may affect vital organs with lung involvement being severe and difficult to treat manifestation. Systemic sclerosis (SSc) commonly affects the lung in the form of interstitial lung disease (ILD). ILD may be also seen in patients with rheumatoid arthritis (RA), Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), inflammatory myositis (IM), antisynthetase syndrome (AS), and the ANCA-associated vasculitides (AAV). Rituximab (RTX) is an anti-CD20 B lymphocyte depleting mAb, often administered in the treatment of autoimmune rheumatic diseases. Although RTX is an off-label treatment for CTD–ILD, there are numerous reports providing data that is effective in improving both pulmonary function tests (PFTs) and chest computed tomography findings consistent with ILD. There are retrospective uncontrolled studies that assess RTX as a treatment of ILD in autoimmune diseases. These studies, apart from one, do not include patients with AAV-ILD. In SSc-ILD, in particular, there are both controlled and uncontrolled studies displaying encouraging results following B cell depletion. In addition, a number of retrospective uncontrolled studies and fewer prospective studies evaluate RTX in connective tissue diseases CTD–ILD. Although RTX is an approved treatment for AAV there are scarce only data focusing on patients with AAV-ILD specifically. The results of a handful of studies comparing treatment of CTD-ILD with RTX to treatment with other agents are in favor of RTX. Results from large, still ongoing controlled trials are awaited to ascertain RTX effects in ILD encountered in autoimmune rheumatic diseases. We review herein the results of the different RTX trials in patients with autoimmune disease–associated with ILD. Despite the heterogeneity of these studies, RTX may be considered an alternative and safe but still off-label treatment for patients with refractory CTD–ILD.

Autologous ATG-free hematopoietic stem cell transplantation for refractory autoimmune rheumatic diseases: a Latin American cohort.

Autologous hematopoietic stem cell transplantation (HSCT) has been recognized as treatment alternative for patients with severe, refractory autoimmune rheumatic diseases (ARDs). Usually, anti-thymocyte globulin (ATG)-containing conditioning regimens are employed; however, ATG is unavailable in some developing nations. We report our 15-year clinical experience autografting patients with ARDs with an ATG-free conditioning regimen and a brief assessment of patient-reported outcomes post-HSCT. All patients had active disease and were resistant to multiple lines of treatment. Event-free survival (EFS) was assessed using the Kaplan-Meier method. Eight patients underwent autologous HSCT. Diagnoses included juvenile idiopathic arthritis (n = 3), systemic lupus erythematosus (n = 2), systemic sclerosis (n = 2), and rheumatoid arthritis (n = 1). Median time from diagnosis to HSCT was 3years (0.75-19). Hematological recovery was documented in all recipients, and 4 patients (50%) completed the procedure in a completely ambulatory setting. Five (62.5%) patients achieved complete response and 3 (37.5%) partial response. The median EFS was 7months (95% CI, 4.97-9.02), and the 1-year EFS rate was 21.9% (95% CI, 18.25-25.76). Transplant-related mortality was 0%, and 1 recipient died 8years post-HSCT due to chronic kidney disease. Six (75%) patients presented steroid dosage reduction post-HSCT, and 2 (25%) perceived improvement in functionality despite having relapsed. HSCT is a viable treatment alternative for selected patients with severe therapy-resistant ARDs, as an improvement in disease management and quality of life was documented. The need remains to elucidate the characteristics of the optimal HSCT candidate, as well as the adequate conditioning regimen when ATG is not available. Key Points • Despite advances in the treatment of autoimmune rheumatic diseases, some patients remain refractory. In this context, autologous hematopoietic stem cell transplantation (HSCT) rises as a viable alternative. • Of 8 HSCT recipients with autoimmune rheumatic diseases, 5 (62.5%) patients achieved complete response and 3 (37.5%) partial response, with a 1-year event-free survival of 21.9%. • Transplant-related mortality was 0%, with 4 (50%) patients autografted in a completely outpatient setting. • Even when relapse presented, patients reported an improvement in functionality and quality of life; also, a better response to DMARDs and a reduction in steroid dependency post-HSCT were documented.

The role of the cholinergic anti-inflammatory pathway in autoimmune rheumatic diseases.

The cholinergic anti-inflammatory pathway (CAP) is a classic neuroimmune pathway, consisting of the vagus nerve, acetylcholine (ACh)-the pivotal neurotransmitter of the vagus nerve-and its receptors. This pathway can activate and regulate the activities of immune cells, inhibit cell proliferation and differentiation, as well as suppress cytokine release, thereby playing an anti-inflammatory role, and widely involved in the occurrence and development of various diseases; recent studies have demonstrated that the CAP may be a new target for the treatment of autoimmune rheumatic diseases. In this review, we will summarize the latest progress with the view of figuring out the role of the cholinergic pathway and how it interacts with inflammatory reactions in several autoimmune rheumatic diseases, and many advances are results from a wide range of experiments performed in vitro and in vivo.

Biologic Therapies and Autoimmune Phenomena.

The use of biologic medications has represented a great advancement in the treatment of autoimmune rheumatic diseases. Despite their excellent efficacy, during the last years, a growing number of reports of autoimmune phenomena and paradoxical inflammation has emerged. These phenomena may range from the discovery of an isolated autoantibody to full-blown autoimmune diseases, organ-specific and systemic. This review has been carried out in order to underline the multitude of the potential adverse manifestations from the use of biologic medications. Thus, early recognition of specific types of autoimmune phenomena is an imperative for the physicians allowing them to have an accurate diagnosis and treatment.

Storage Conditions of Immunobiologicals and their Influence on the Efficacy and Safety in the Treatment of Autoimmune Rheumatic Diseases

Objective: The study aimed to evaluate the influence of storage temperature on immunobiological efficacy and safety in autoimmune rheumatic disease treatment. Methods: This observational study included adult patients with autoimmune rheumatic diseases who used immunobiologicals stored at home and were followed up at the rheumatology outpatient clinic of the General University Hospital of Cuiabá, Mato Grosso, Brazil, in 2017/2018. Patients were evaluated regarding disease activity and occurrence of adverse events, and a household survey of the temperature of the storage environment of these drugs was conducted. Results: Sixty patients with a mean age of 50.4 years were evaluated. Of these, 39 patients (65%) stored their biological drugs outside the recommended temperature range. Storage of the immunobiological at the incorrect temperature was 76% higher among patients with moderate/high rheumatic disease activity (p=0.003). Conclusion: Most patients stored their immunobiologicals outside the temperature range recommended in the package insert, and there was an association between incorrect storage temperature and moderate/high autoimmune rheumatic disease activity.

Mesenchymal stem cell treatment in autoimmune diseases

Mesenchymal stromal or stem cells (MSC) possess strong immunomodulatory properties. Due to their impressive potential to differentiate into various cell types they are capable of inducing mechanisms of tissue repair. Experimental data have demonstrated impaired MSC function in several rheumatic diseases in vitro; however, the relevance of these phenomena for the pathogenesis of rheumatic disorders has not been convincingly demonstrated. Nevertheless, allogeneic MSC transplantation (MSCT), and possibly autologous MSCT as well, could prove to be an interesting instrument for the treatment of autoimmune rheumatic diseases. The first clinical trials have demonstrated positive effects in systemic lupus erythematosus, systemic sclerosis and Sjogren's syndrome; however, questions regarding the long-term benefits and safety as well as the best source, the optimal cultivation technique and the most effective way of application of MSC are still unanswered.

Application potential of bacterial flagellin in treatment of autoimmune rheumatic diseases with Treg epitope peptides

Immunization with regulatory T cell (Treg) epitope peptides to activate and induce Tregs, by which to suppress pathological autoimmune responses and reconstitute a new homeostasis, is a promising therapeutic regimen for autoimmune rheumatic diseases. However, it is usually hard to induce potent peptide-specific immune responses in vivo with small molecular peptides. Bacterial flagellin is one of the agonists triggering innate immune responses. When used as carrier, it shows strong adjuvant activity to its conjugated antigens. In some particular situations, bacterial flagellin can also activate and induce Tregs. Thus if Treg epitope peptides are covalently conjugated to a bacterial flagellin, the conjugates should be able to effectively enhance the Treg-based immune responses via flagellin itself and the adjuvanticity of flagellin to Treg epitope peptides, and thereby enhance the immunotherapeutic effects on autoimmune rheumatic diseases. Key words: Bacterial flagellin; Treg epitope; Autoimmune rheumatic disease; Conjugate; Vaccine efficacy

Pathogenesis and treatment of autoimmune rheumatic diseases.

Autoimmune diseases are of unknown origin, and they represent significant causes of morbidity and mortality. Here, we review new developments in the understanding of their pathogenesis that have led to development of well tolerated and effective treatments. In addition to the long-recognized genetic impact of the HLA locus, interferon regulatory factors, PTPN22, STAT4, and NOX have been implicated in pathogenesis of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Smoking, ultraviolet light, diet, and microbiota exert strong environmental influence on development of RA and SLE. Metabolism has been recognized as a critical integrator of genetic and environmental factors, and it controls immune cell differentiation both under physiological and pathological conditions. With the advent of high-throughput genetic, proteomic, and metabolomic technologies, the field of medicine has been shifting towards systems-based and personalized approaches to diagnose and treat common conditions, including rheumatic diseases. Regulatory checkpoints of metabolism and signal transduction, such as glucose utilization, mitochondrial electron transport, JAK, mTOR, and AMPK pathway activation, and production of pro-inflammatory cytokines IL-1, IL-6, and IL-17 have presented new targets for therapeutic intervention. This review amalgamates recent discoveries in genetics and metabolomics with immunological pathways of pathogenesis in rheumatic diseases.

Medication adherence and persistence in patients with autoimmune rheumatic diseases: a narrative review.

BackgroundSeveral drugs are available for the treatment of autoimmune rheumatic diseases; however, their effectiveness may be negatively influenced by inappropriate adherence. Low adherence and persistence rates have a significant impact on patient quality of life and are associated with health-related expenses.PurposeTo provide an up-to-date narrative review on treatment adherence and persistence rates, and discuss the factors that influence them, in patients with autoimmune rheumatic diseases.Materials and methodsWe searched the PubMed database for studies among patients with a diagnosis of rheumatoid arthritis (RA), ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), or psoriatic arthritis (PsA), published from January 2015 to February 2017. Only studies with a well-defined measurement of adherence/persistence and those that carried out an evaluation of the influencing factors were included.ResultsFifteen relevant studies that evaluated adherence and/or persistence were included. Adherence rates varied between 9.3% and 94%, and persistence rates between 23% and 80%. Most of the studies used one method to evaluate adherence or persistence (different questionnaire scores, proportion of days covered, and mean treatment duration). A high concordance was found between the adherence measurements of the Medication Event Monitoring System and Visual Analog Scale. Factors of economic, demographic, and clinical nature were only moderately linked to treatment adherence or persistence. However, patient-related factors – such as positive and increased beliefs in medication necessity, strong views of the chronic nature of the diseases, and increased knowledge of the disease – were related to better treatment adherence.ConclusionOwing to the heterogeneity of the study results, we consider that the use of more than one method to assess adherence/persistence should yield more comprehensive and accurate data about patient adherence behavior. Patient-related factors should be included and analyzed more often in adherence studies as the former may be modified to improve patient adherence.

Anti-malarials: Are There Benefits Beyond Mild Disease?

Therapeutic applications for hydroxychloroquine, a quinine compound originally used as an anti-malarial, have evolved and expanded over the years to include the treatment of autoimmune rheumatic diseases. In systemic lupus erythematosus (SLE), hydroxychloroquine has emerged as a cornerstone medication for not only mild disease but also severe disease as adjunctive therapy. With the advent of highly effective biologic disease-modifying agents over the last two decades for treatment of rheumatoid arthritis (RA), hydroxychloroquine’s future in RA is less clear. However, hydroxychloroquine’s pleiotropic benefits in rheumatic diseases have been increasingly recognized, supporting its place in the therapeutic armamentarium. These benefits include but are not limited to its beneficial impact on glycemic and lipid profiles and its anti-thrombotic effects. These are of major significance in light of the great burden of cardiovascular morbidity and mortality in patients with lupus and RA. This relatively safe, inexpensive, and generally well-tolerated medication’s uncommon but serious risk is retinal toxicity which can be minimized by following screening and monitoring guidelines and using appropriate weight-based dosage. In this review article, we present an overview of hydroxychloroquine’s potential role beyond its anti-rheumatic benefits.

Epigenetic Modulation as a Therapeutic Prospect for Treatment of Autoimmune Rheumatic Diseases.

Systemic inflammatory rheumatic diseases are considered as autoimmune diseases, meaning that the balance between recognition of pathogens and avoidance of self-attack is impaired and the immune system attacks and destroys its own healthy tissue. Treatment with conventional Disease Modifying Antirheumatic Drugs (DMARDs) and/or Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) is often associated with various adverse reactions due to unspecific and toxic properties of those drugs. Although biologic drugs have largely improved the outcome in many patients, such drugs still pose significant problems and fail to provide a solution to all patients. Therefore, development of more effective treatments and improvements in early diagnosis of rheumatic diseases are badly needed in order to increase patient's functioning and quality of life. The reversible nature of epigenetic mechanisms offers a new class of drugs that modulate the immune system and inflammation. In fact, epigenetic drugs are already in use in some types of cancer or cardiovascular diseases. Therefore, epigenetic-based therapeutics that control autoimmunity and chronic inflammatory process have broad implications for the pathogenesis, diagnosis, and management of rheumatic diseases. This review summarises the latest information about potential therapeutic application of epigenetic modification in targeting immune abnormalities and inflammation of rheumatic diseases.

AUTOIMMUNE RHEUMATIC DISEASES: RESULTS AND PROSPECTS FOR RESEARCHES

According to the present-day views, autoimmunity is a complex pathological process, the essence of which is intolerance and hence a pathological immune response to intrinsic tissue components (autoantigens), which underlies the pathogenesis of a broad spectrum of human autoimmune diseases. Recently, diverse immune disorders underlying autoimmune rheumatic diseases (ARD) and syndromes have been revealed; an association has been found between the development of ARD and autoinflammatory diseases and syndromes; a classification of human immunoinflammatory diseases has been elaborated. The paper considers the results of the authors’ investigations of ARD treatment with innovative biologics, the pathogenetic mechanisms and diagnosis of ARD, by conducting immunological and molecular biological studies of a wide range of molecular and cellular biomarkers (autoantibodies, acute phase proteins, cytokines, chemokines, vascular endothelial activation markers, complement system components, lymphocyte subpopulations, bone and cartilage tissue metabolic products, genetic, epigenetic, transcriptomic markers), and approaches to personalized treatment of ARD.

B Cell Therapies, Approved and Emerging: a Review of Infectious Risk and Prevention During Use.

The development of B cell-targeted biologics represents a major advance in the treatment of autoimmune rheumatic diseases. As with other immunosuppressive agents, risk of infection is a key clinical concern. This review summarises safety data from 15years of experience of rituximab in autoimmune diseases with a particular focus on opportunistic infection and class-specific complications and infection risk. Rarely, cases of progressive multifocal leucoencephalopathy in rituximab-treated patients (5/100 000) have accumulated over time although no proven causal association has yet been shown. With repeat cycles of therapy, hypogammaglobulinaemia has been observed in a larger proportion of patients and is associated with increased risk of serious infections. The infection profile of the newer B cell-targeted agent, belimumab, in patients with active systemic lupus erythematosus is also discussed. Data from registries are needed to extend insights further and also to evaluate for any impact with the difference in mode of action of belimumab and infection risk in this population.

Safe use of biological therapies for the treatment of rheumatoid arthritis and spondyloarthritides

The treatment of autoimmune rheumatic diseases has gradually improved over the last half century, which has been expanded with the contribution of biological therapies or immunobiopharmaceuticals. However, we must be alert to the possibilities of undesirable effects from the use of this class of medications. The Brazilian Society of Rheumatology (Sociedade Brasileira de Reumatologia) produced a document based on a comprehensive literature review on the safety aspects of this class of drugs, specifically with regard to the treatment of rheumatoid arthritis and spondyloarthritides. The themes selected by the participating experts, on which considerations have been established as the safe use of biological drugs, were: occurrence of infections (bacterial, viral, tuberculosis), infusion reactions, hematological, neurological, gastrointestinal and cardiovascular reactions, neoplastic events (solid tumors and hematologic neoplasms), immunogenicity, other occurrences and vaccine response. For didactic reasons, we opted by elaborating a summary of safety assessment in accordance with the previous themes, by drug class/mechanism of action (tumor necrosis factor antagonists, T-cell co-stimulation blockers, B-cell depletors and interleukin-6 receptor blockers). Separately, general considerations on safety in the use of biologicals in pregnancy and lactation were proposed. This review seeks to provide a broad and balanced update of that clinical and experimental experience pooled over the last two decades of use of immunobiological drugs for RA and spondyloarthritides treatment.

Segurança do uso de terapias biológicas para o tratamento de artrite reumatoide e espondiloartrites

The treatment of autoimmune rheumatic diseases has gradually improved over the last half century, which has been expanded with the contribution of biological therapies or immunobiopharmaceuticals. However, we must be alert to the possibilities of undesirable effects from the use of this class of medications. The Brazilian Society of Rheumatology (Sociedade Brasileira de Reumatologia/SBR) produced a document based on a comprehensive literature review on the safety aspects of this class of drugs, specifically with regard to the treatment of rheumatoid arthritis (RA) and spondyloarthritides. The themes selected by the participating experts, on which considerations have been established as the safe use of biological drugs, were: occurrence of infections (bacterial, viral, tuberculosis), infusion reactions, hematological, neurological, gastrointestinal and cardiovascular reactions, neoplastic events (solid tumors and hematologic neoplasms), immunogenicity, other occurrences and vaccine response. For didactic reasons, we opted by elaborating a summary of safety assessment in accordance with the previous themes, by drug class/mechanism of action (tumor necrosis factor antagonists, T‐cell co‐stimulation blockers, B‐cell depletors and interleukin‐6 receptor blockers). Separately, general considerations on safety in the use of biologicals in pregnancy and lactation were proposed. This review seeks to provide a broad and balanced update of that clinical and experimental experience pooled over the last two decades of use of immunobiological drugs for RA and spondyloarthritides treatment.

Overview of biologic therapies in autoimmune rheumatic diseases

First-line treatment of autoimmune rheumatic diseases (ARD) ranging from systemic lupus erythematosus (SLE), through small and large vessel vasculitides to Behçet's syndrome, is still based upon the use of traditional immunosuppressive drugs. Increasingly, the newly developed biologic agents are used as second-line treatments of these diseases. This summary article highlights the biologic agents that are used in clinical practice as well as their indications, contraindications and adverse effect profiles. Efficacy of these biologic agents is tabulated in accordance with current evidence of open-label studies and trials, and new advances in the biologic treatment of several ARDs are also discussed. Overall, this paper highlights the contribution that the biologic therapies have made to progressive advancements in the treatment of ARD.

THU0270 The Effect of Hydroxychloroquine to the Lipid Profile of Greek Patients with Sjogren’s Syndrome

ObjectivesHydroxychloroquine (HCQ) is a widely used medicine in the treatment of autoimmune rheumatic diseases. Many scientific studies have highlighted its hypolipidemic effect. We investigated the effect of HCQ to the...