Immune-mediated Rheumatic Diseases Research Articles

Glucagon-like peptide-1 receptor agonists: Prospects for use in rheumatology

Glucagon-like peptide-1 receptor agonists (ArGLP-1) are effective drugs for the treatment of type 2 diabetes mellitus and obesity. Recent studies in patients with a wide range of immunoinflammatory diseases suggest important pleiotropic mechanisms of action of these drugs, primarily related to the suppression of inflammation. The article presents new data indicating the prospects for the use of ArGLP-1 in immunoinflammatory rheumatic diseases, which dictates the need for clinical studies. GLP-1 receptor agonists are effective drugs for the treatment of type 2 diabetes mellitus and obesity. Recent studies in patients with a wide range of immune-mediated diseases suggest important pleiotropic mechanisms of action of these drugs, primarily related to the suppression of inflammation. The article presents new data indicating the prospects for the use of ArGLP-1 in immune-mediated rheumatic diseases, which dictates the need for clinical studies.

Calcinosis in Rheumatic Disease Is Still an Unmet Need: A Retrospective Single-Center Study.

Patients with immune-mediated rheumatic disease-related calcinosis comprise a subgroup at risk of encountering a more severe clinical outcome. Early assessment is pivotal for preventing overall disease progression, as calcinosis is commonly overlooked until several years into the disease and is considered as a 'non-lethal' manifestation. This single-center retrospective study explored the prevalence, clinical associations, and impact on survival of subcutaneous calcinosis in 86 patients with immune-mediated rheumatic diseases (IMRD). Calcinosis predominantly appeared in individuals with longstanding disease, particularly systemic sclerosis (SSc), constituting 74% of cases. Smaller calcinosis lesions (≤1 cm) were associated with interstitial lung disease, musculoskeletal involvement, and digital ulcerations, while larger lesions (≥4 cm) were associated with malignancy, severe peripheral artery disease, and systemic arterial hypertension. The SSc calcinosis subgroup exhibited a higher mean adjusted European Scleroderma Study Group Activity Index score than those without. However, survival rates did not significantly differ between the two groups. Diltiazem was the most commonly used treatment, and while bisphosphonates reduced complications related to calcinosis, complete resolution was not achieved. The findings underscore current limitations in diagnosing, monitoring, and treating calcinosis, emphasizing the need for further research and improved therapeutic strategies to improve patient care and outcomes.

Coronavirus disease 2019 (COVID-19) pandemic and autoimmune rheumatic diseases: Outcomes and prospects

The pandemic of coronavirus disease 2019 (COVID-19), etiologically related to the SARS-CoV-2 virus (severe acute respiratory syndrome coronavirus-2), has drawn attention to new clinical and fundamental problems in the immunopathology of human diseases associated with virus-induced autoimmunity and autoinflammation. The provision that “the experience gained in rheumatology in the process of studying the pathogenetic mechanisms and pharmacotherapy of immunoinflammatory rheumatic diseases as the most common and severe forms of autoimmune and autoinflammatory pathology in humans will be in demand for deciphering the nature of the pathological processes underlying COVID-19 and developing approaches to effective pharmacotherapy” was confirmed in numerous studies conducted over the next 3 years in the midst of the COVID-19 pandemic. The main focus will be on a critical analysis of data regarding the role of autoimmune inflammation, which forms the basis of the pathogenesis of immune-mediated rheumatic diseases in the context of the immunopathology of COVID-19.

Regulatory T cells in spondyloarthropathies: genetic evidence, functional role, and therapeutic possibilities.

Regulatory T cells (Tregs) are a very specialized subset of T lymphocytes: their main function is controlling immune responses during inflammation. T-regs involvement in autoimmune and immune-mediated rheumatic diseases is well-described. Here, we critically review the up-to-date literature findings on the role of Tregs in spondyloarthropathies, particularly in ankylosing spondylitis (AS), a polygenic inflammatory rheumatic disease that preferentially affects the spine and the sacroiliac joints. Genetics discoveries helped in elucidating pathogenic T-regs gene modules and functional involvement. We highlight T-regs tissue specificity as crucial point, as T-regs might have a distinct epigenomic and molecular profiling depending on the different site of tissue inflammation. Furthermore, we speculate about possible therapeutic interventions targeting, or enhancing, Treg cells in spondyloarthropathies.

Position statement on infection screening, prophylaxis, and vaccination of pediatric patients with rheumatic diseases and immunosuppressive therapies, part 3: precautions in situations of surgery, fever, and opportunistic infections

The objective of this study is to provide practical recommendations on the management of pediatric patients with immune-mediated rheumatic diseases receiving immunosuppressive therapies. The recommendations specifically address the cases of surgery, fever, and opportunistic infections (varicella, herpes-zoster, tuberculosis, invasive fungal disease). A qualitative approach was applied. A narrative literature review was performed via Medline. Primary searches were conducted using MeSH terms and free text to identify publications on infections and vaccinations in pediatric patients with immune-mediated rheumatic diseases receiving immunosuppressive therapies. The results were presented and discussed in a nominal group meeting, comprising a committee of 12 pediatric rheumatologists from the Infection Prevention and Treatment Working Group of the Spanish Society of Pediatric Rheumatology. Several recommendations were generated. A consensus procedure was implemented via a Delphi process; this was extended to members of the Spanish Society of Pediatric Rheumatology and Spanish Society of Pediatric Infectious Disease of the Spanish Association of Pediatrics. Participants produced a score ranging from 0 (totally disagree) to 10 (totally agree). Agreement was defined as a vote ≥ 7 by at least 70% of participants. The literature review included more than 400 articles. Overall, 63 recommendations (19 on surgery, fever, and opportunistic infections) were generated and voted by 59 pediatric rheumatologists and other pediatric specialists. Agreement was reached for all 63 recommendations. The recommendations on special situations cover management in cases of surgery, fever, and opportunistic infections (varicella, herpes-zoster, tuberculosis, and invasive fungal disease). Conclusions: Hereby, we provided consensus and updated of recommendations about the management of special situations such as surgery, fever, and opportunistic in children with immune-mediated rheumatic diseases receiving immunosuppressive therapies. Several of the recommendations depend largely on clinical judgement and specific balance between risk and benefit for each individual and situation. To assess this risk, the clinician should have knowledge of the drugs, the patient’s previous situation as well as the current infectious disease, in addition to experience.What is Known:• Infectious diseases and related complications are a major cause of morbidity and mortality in patients with immune-mediated rheumatic diseases.• Information on how to manage the treatment in situations of fever, opportunistic infections, and surgery in children is limited, and guidelines for action are often extrapolated from adults.What is New:• In the absence of strong evidence, a literature review and a Delphi survey were conducted to establish a series of expert recommendations that could support the clinical practice, providing a practical and simple day-to-day approach to be used by pediatric rheumatologists.

Imbalanced machine learning classification models for removal biosimilar drugs and increased activity in patients with rheumatic diseases.

Predict long-term disease worsening and the removal of biosimilar medication in patients with rheumatic diseases. Observational, retrospective descriptive study. Review of a database of patients with immune-mediated inflammatory rheumatic diseases who switched from a biological drug (biosimilar or non-biosimilar) to a biosimilar drug for at least 6 months. We selected the most important variables, from 18 variables, using mutual information tests. As patients with disease worsening are a minority, it is very difficult to make models with conventional machine learning techniques, where the best models would always be trivial. For this reason, we computed different types of imbalanced machine learning models, choosing those with better f1-score and mean ROC AUC. We computed the best-imbalanced machine learning models to predict disease worsening and the removal of the biosimilar, with f1-scores of 0.52 and 0.63, respectively. Both models are decision trees. In the first one, two important factors are switching of biosimilar and age, and in the second, the relevant variables are optimization and the value of the initial PCR. Biosimilar drugs do not always work well for rheumatic diseases. We obtain two imbalanced machine learning models to detect those cases, where the drug should be removed or where the activity of the disease increases from low to high. In our decision trees appear not previously studied variables, such as age, switching, or optimization.

HLA-B27 did not protect against COVID-19 in patients with axial spondyloarthritis – data from the ReumaCov-Brasil Registry

BackgroundSome studies have suggested the HLA-B27 gene may protect against some infections, as well as it could play a benefit role on the viral clearance, including hepatitis C and HIV. However, there is lack of SARS-CoV-2 pandemic data in spondyloarthritis (SpA) patients.AimTo evaluate the impact of HLA-B27 gene positivity on the susceptibility and severity of COVID-19 and disease activity in axial SpA patients.MethodsThe ReumaCoV-Brasil is a multicenter, observational, prospective cohort designed to monitor immune-mediated rheumatic diseases patients during SARS-CoV-2 pandemic in Brazil. Axial SpA patients, according to the ASAS classification criteria (2009), and only those with known HLA-B27 status, were included in this ReumaCov-Brasil’s subanalysis. After pairing them to sex and age, they were divided in two groups: with (cases) and without (control group) COVID-19 diagnosis. Other immunodeficiency diseases, past organ or bone marrow transplantation, neoplasms and current chemotherapy were excluded. Demographic data, managing of COVID-19 (diagnosis, treatment, and outcomes, including hospitalization, mechanical ventilation, and death), comorbidities, clinical details (disease activity and concomitant medication) were collected using the Research Electronic Data Capture (REDCap) database. Data are presented as descriptive analysis and multiple regression models, using SPSS program, version 20. P level was set as 5%.ResultsFrom May 24th, 2020 to Jan 24th, 2021, a total of 153 axial SpA patients were included, of whom 85 (55.5%) with COVID-19 and 68 (44.4%) without COVID-19. Most of them were men (N = 92; 60.1%) with mean age of 44.0 ± 11.1 years and long-term disease (11.7 ± 9.9 years). Regarding the HLA-B27 status, 112 (73.2%) patients tested positive. There were no significant statistical differences concerning social distancing, smoking, BMI (body mass index), waist circumference and comorbidities. Regarding biological DMARDs, 110 (71.8%) were on TNF inhibitors and 14 (9.15%) on IL-17 antagonists. Comparing those patients with and without COVID-19, the HLA-B27 positivity was not different between groups (n = 64, 75.3% vs. n = 48, 48%, respectively; p = 0.514). In addition, disease activity was similar before and after the infection. Interestingly, no new episodes of arthritis, enthesitis or extra-musculoskeletal manifestations were reported after the COVID-19. The mean time from the first symptoms to hospitalization was 7.1 ± 3.4 days, and although the number of hospitalization days was numerically higher in the B27 positive group, no statistically significant difference was observed (5.7 ± 4.11 for B27 negative patients and 13.5 ± 14.8 for B27 positive patients; p = 0.594). Only one HLA-B27 negative patient died. No significant difference was found regarding concomitant medications, including conventional or biologic DMARDs between the groups.ConclusionsNo significant difference of COVID-19 frequency rate was observed in patients with axial SpA regarding the HLA-B27 positivity, suggesting a lack of protective effect with SARS-CoV-2 infection. In addition, the disease activity was similar before and after the infection.Trial registrationThis study was approved by the Brazilian Committee of Ethics in Human Research (CONEP), CAAE 30186820.2.1001.8807, and was registered at the Brazilian Registry of Clinical Trials – REBEC, RBR-33YTQC. All patients read and signed the informed consent form before inclusion.

Factors Associated With Mortality in Patients With Immune-Mediated Rheumatic Diseases and COVID-19 From Latin America: Data From Argentina, Mexico, and Brazil.

To describe characteristics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with rheumatic immune-mediated inflammatory diseases (IMIDs) from Argentina, Mexico and Brazil, and to assess factors associated with mortality in this population. Data from 3 national registries, SAR-COVID (Argentina), CMR-COVID (Mexico), and ReumaCoV-Brasil (Brazil), were combined. Adult patients with IMIDs and SARS-CoV-2 infection were recruited. Sociodemographic data, comorbidities, IMID clinical characteristics and treatment, and SARS-CoV-2 infection presentation and outcomes were recorded. A total of 4827 individuals were included: 2542 (52.7%) from SAR-COVID, 1167 (24.2%) from CMR-COVID, and 1118 (23.1%) from ReumaCoV-Brasil. Overall, 82.1% were female with a mean age of 49.7 (SD, 14.3) years; 22.7% of the patients were hospitalized, and 5.3% died because of COVID-19 (coronavirus disease 2019). Argentina and Brazil had both 4% of mortality and Mexico 9.4%. In the multivariable analysis, older age (≥60 years; odds ratio [OR], 7.4; 95% confidence interval [CI], 4.6-12.4), male sex (OR, 1.5; 95% CI, 1.1-2.1), living in Mexico (OR, 3.0; 95% CI, 2.0-4.4), comorbidity count (1 comorbidity: OR, 1.5; 95% CI, 1.0-2.1), diagnosis of connective tissue disease or vasculitis (OR, 1.8; 95% CI, 1.3-2.4), and other diseases (OR, 2.6; 95% CI, 1.6-4.1) compared with inflammatory joint disease, high disease activity (OR, 4.2; 95% CI, 2.5-7.0), and treatment with glucocorticoids (OR, 1.9; 95% CI, 1.4-2.5) or rituximab (OR, 4.2; 95% CI, 2.7-6.6) were associated with mortality. Mortality in patients with IMIDs was particularly high in Mexicans. Ethnic, environmental, societal factors, and different COVID-19 mitigation measures adopted have probably influenced these results.

The role of NETosis in the pathogenesis of immunoinflammatory rheumatic diseases

Uncontrolled activation of neutrophils is considered an important mechanism of thromboinflammation and fibrosis in immunemediated rheumatic diseases (IMRD), malignant neoplasms, atherosclerosis, COVID-19 and many other acute and chronic inflammatory diseases of humans. Particular attention has been drawn to the ability of neutrophils to form “network” (web-like) structures, called “neutrophil extracellular traps” NETs. The process associated with the formation of NETs and the weakening of their degradation is called “NETosis”. The publication summarizes data on the role of NETosis in the pathogenesis of IMRD and discusses the prospects for pharmacotherapy aimed at preventing the formation and destruction of NETs.

Long-term golimumab persistence: Five-year treatment retention data pooled from pivotal Phase III clinical trials in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis

IntroductionGolimumab, a monoclonal antibody against tumor necrosis factor–α (TNF-α), is used widely for treatment of rheumatic diseases. Long-term persistence is an important factor influencing therapeutic benefit and is a surrogate measure of efficacy. We compared five-year golimumab treatment persistence across studies, indications, and lines of therapy using pooled data from pivotal golimumab Phase III clinical trials.MethodsThis post-hoc analysis evaluated use of golimumab administered subcutaneously (50 or 100 mg every four weeks) for up to five years in 2228 adult participants with rheumatoid arthritis (RA; GO-BEFORE, GO-AFTER, and GO-FORWARD studies), psoriatic arthritis (PsA; GO-REVEAL study), or ankylosing spondylitis (AS; GO-RAISE study). Retention rate differences were evaluated by study, indication, and line of therapy using log-rank tests, and probability of treatment persistence was estimated by Kaplan–Meier analysis.ResultsGolimumab retention rates at Year 5 were consistently high when used as 1st-line therapy (69.8%) and did not differ significantly across the three indications tested (p = 0.5106) or across 1st-line studies (p = 0.2327). Retention at Year 5 was better in participants using golimumab as 1st-line than in those using it as 2nd-line (41.6%) therapy. Participants on 2nd-line golimumab therapy had a longer disease duration (median 9.2 years versus 3.7 years) than those on 1st-line golimumab therapy.ConclusionsThese data support the value of long-term golimumab therapy in patients with chronic, immune-mediated rheumatic diseases when used as 1st-line (RA, PsA, AS) or 2nd-line (RA) therapy.Key Points• Golimumab is a human monoclonal antibody directed against tumor necrosis factor–α (TNF-α) and is approved widely for the treatment of rheumatic autoimmune diseases.• We compared the probability of treatment persistence, or the time of continuous drug use, for golimumab across five Phase III studies spanning multiple rheumatic indications over five years.• Treatment persistence was favorable and did not differ significantly for participants with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, but persistence was greater when golimumab was used as 1st-line than as 2nd-line biologic therapy.

New insights at the interface between leprosy and immune-mediated rheumatic diseases.

Leprosy is an infectious and contagious disease of slow evolution, triggered by Mycobacterium leprae. Arthritis is its third most common manifestation, after cutaneous and peripheral nerve involvement. Since musculoskeletal symptoms may be the initial presentation of the disease, it is important for health professionals to recognize its rheumatic manifestations for early diagnosis and appropriate treatment, especially in endemic areas. In addition, cases of leprosy have increased globally, notably in patients undergoing treatment with TNF-α blockers and due to the increase in migration and travel of people from developing countries to developed countries. This review proposes to discuss the main scenarios of mimicry of different rheumatic diseases by leprosy, as well as the role of immunosuppressive drugs used in rheumatology practice in the treatment of reactional states and in the risk of developing the infection.

The role of immune aging in Giant Cell Arteritis

Giant cell arteritis (GCA) is a granulomatous vasculitis with a predilection for medium and large calibre arteries. The most significant risk factor for its development is advancing age, with a peak incidence in the seventh and eighth decades of life. Despite this, until recently, the role of aging in disease pathogenesis has been largely overlooked. Advancing age is associated with numerous alterations in both the innate and adaptive immune system. Indeed, there is significant overlap in the cellular and molecular pathways involved in immune aging and those observed in the pathogenesis of GCA. In this review we explore these similarities and further expand the discussion on the postulated role of accelerated immune ageing in the pathogenesis of GCA. With the dramatic increase in lifespan in recent decades, elucidating the potential role of early immune aging in disease pathogenesis is extremely pertinent, with the potential to offer a new therapeutic avenue not only for those with GCA, but all immune mediated rheumatic diseases.

Specific Cellular and Humoral Response after the Third Dose of Anti-SARS-CoV-2 RNA Vaccine in Patients with Immune-Mediated Rheumatic Diseases on Immunosuppressive Therapy.

Data on cellular and humoral immunogenicity after the third dose of anti-SARS-CoV-2 vaccines in patients with immune-mediated rheumatic diseases (IMRDs) are scarce. Herein, we evaluated the adaptive immune response in IMRD patients treated with different immunosuppressive therapies (conventional synthetic disease-modifying antirheumatic drugs [csDMARDs], biological disease-modifying antirheumatic drugs [bDMARDs], and targeted synthetic disease-modifying antirheumatic drugs [tsDMARDs]) after the booster of the anti-SARS-CoV-2 vaccine to determine whether any drug reduced the vaccine's response. A single-center prospective study was conducted, including patients presenting with IMRD and healthy controls (HC). Specific anti-SARS-CoV-2 interferon-gamma (IFN-γ) production was evaluated between 8-12 weeks after the third dose of the SARS-CoV-2 vaccine. In addition, anti-Spike IgG antibody titers were also measured. Samples were obtained from 79 IMRD patients (51 women, 28 men; mean age 57 ± 11.3 years old): 43 rheumatoid arthritis, 10 psoriatic arthritis, 14 ankylosing spondylitis, 10 undifferentiated spondyloarthritis, and 2 inflammatory bowel disease-associated spondyloarthritis (IBD-SpA). In total, 31 HC (mean age 50.9 ± 13.1 years old, 67.7% women) were included in the study. Post-vaccine results displayed positive T-cell immune responses in 68 out of 79 (86.1%) IMRD patients (82.3% of those without prior COVID-19). All HC and IMRDs patients had an antibody response against the SARS-CoV-2 receptor-binding domain; however, the HC response was significantly higher (median of 18,048 AU/mL) than in IMRDs patients (median of 6590.3 AU/mL, p < 0.001). MTX and leflunomide were associated with lower titers of IgG and IFN-γ responses. Among bDMARDs, adalimumab, etanercept, and guselkumab are associated with reduced cellular responses. Our preliminary data show that the majority of our IMRD patients develop cellular and humoral responses after the SARS-CoV-2 booster vaccination, emphasizing the relevance of vaccination in this group. However, the magnitude of specific responses was dependent on the immunosuppressive therapy administered. Specific vaccination protocols and personalized decisions about boosters are essential for these patients.

Rheumatic complications of checkpoint inhibitors: Lessons from autoimmunity.

Immune checkpoint inhibitors are now an established treatment in the management of a range of cancers. Their success means that their use is likely to increase in future in terms of the numbers of patients treated, the indications and the range of immune checkpoints targeted. They function by counteracting immune evasion by the tumor but, as a consequence, can breach self-tolerance at other sites leading to a range of immune-related adverse events. Included among these complications are a range of rheumatologic complications, including inflammatory arthritis and keratoconjunctivitis sicca. These superficially resemble immune-mediated rheumatic diseases (IMRDs) such as rheumatoid arthritis and Sjogren's disease but preliminary studies suggest they are clinically and immunologically distinct entities. However, there appear to be common processes that predispose to the development of both that may inform preventative interventions and predictive tools. Both groups of conditions highlight the centrality of immune checkpoints in controlling tolerance and how it can be restored. Here we will discuss some of these commonalities and differences between rheumatic irAEs and IMRDs.

Long COVID in inflammatory rheumatic diseases-what's in a name?

Long COVID in inflammatory rheumatic diseases-what's in a name?

Particularities regarding Clinical-biological and Evolutive Parameters of Immune-mediated Rheumatic Diseases in Patients with COVID-19 – systematic literature review

Background: Since its outbreak in 2019, Coronavirus disease 2019 (COVID-19)/Severe Acu-te Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was a serious medical threat and was declared Global Pandemic, triggering fear, panic and uncertainty for people around the Globe. Among those individuals, there is a specific category of patients – the ones with immune-mediated rheumatic diseases (IMIDs) – whose mantra from the diagnosis was to avoid infections at all costs because of the additional negative impact on the immune sys-tem and overall reactivity. Objective: Considering the aforementioned, our objective is to understand the in-depth relation of the immune system of patients with IMIDs in the set-ting of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), and the real bur-den of the disease and vaccination against COVID-19. Materials and Methods: In this res-pect, we have conducted a thoroughly systematic literature review according to the “Prefer-red Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)” concept. Following its five-steps algorithm, we first selected 745 articles that were published in re-putable international medical databases, ISI-indexed, for the period 1 January, 2021–31 December, 2022. After consequent elimination of duplicates, of articles that were not En-glish-written and “open access” and then applying PEDro classification/scoring-inspired, only 58 articles were selected for in-depth full qualitative reading. In the last stage,20 arti-cles were “excluded with reasons”, because they didn’t offer significant information. The-refore, in our systematic literature review, 38 articles were included.Results: In the data gathered in this review we described the molecular pathways of activation of the immune system triggered by COVID-19, with significance on the clinical and paraclinical aspects of IMID patients infected with the new Coronavirus. Patients with IMIDs are at higher risk for hospitalization if diagnosed with SARS-CoV2 and more prone to severe outcomes and death. Risk factors associated with severe outcomes and death are: age, comorbidities, un-derlying disease activity, therapies used (“the good” being anti-tumor necrosis factor α, “the bad” – Methotrexate, Sulfasalazine, Azathioprine and “the ugly” – anti CD20 mono-clonal antibodies). There were several reports of flares and new-onset of IMIDs after CO-VID-19 and after vaccination against this disease, but data from larger studies and registri-es do not confirm higher incidence of flare-ups or new-onset IMIDs. Regarding vaccination, of mounting importance is the timing between immunomodulatory and immunosuppres-sive agents and the administration of the vaccine. And last but not the least, we discussed about Long COVID and the role of artificial intelligence in the pandemic and related-drug development. Discussion and Conclusion: The data in our systematic literature review is consistent with the expertise from our clinical practice. This article is the first part of the doctoral study that is centralized on the same topics, with the current objective of deepe-ning the knowledge about the intersection of COVID-19/SARS-CoV2 and immune-mediated rheumatic diseases and a future objective: to compare information we have synthetized here with our database of almost 170 Romanian patients with a IMID and COVID-19/SARS-CoV2. The next objective is to extend the study to a multicenter control one. Keywords: SARS-CoV2, COVID-19, Immune Mediated Rheumatic Diseases, Rheumatoid Arthri-tis, Systemic Lupus Erythematosus, COVID-19 Vaccine, Long COVID

Particularities regarding Clinical-biological and Evolutive Parameters of Immune-mediated Rheumatic Diseases in Patients with COVID-19 – systematic literature review

Background: Since its outbreak in 2019, Coronavirus disease 2019 (COVID-19)/Severe Acu-te Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was a serious medical threat and was declared Global Pandemic, triggering fear, panic and uncertainty for people around the Globe. Among those individuals, there is a specific category of patients – the ones with immune-mediated rheumatic diseases (IMIDs) – whose mantra from the diagnosis was to avoid infections at all costs because of the additional negative impact on the immune sys-tem and overall reactivity. Objective: Considering the aforementioned, our objective is to understand the in-depth relation of the immune system of patients with IMIDs in the set-ting of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), and the real bur-den of the disease and vaccination against COVID-19. Materials and Methods: In this res-pect, we have conducted a thoroughly systematic literature review according to the “Prefer-red Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)” concept. Following its five-steps algorithm, we first selected 745 articles that were published in re-putable international medical databases, ISI-indexed, for the period 1 January, 2021–31 December, 2022. After consequent elimination of duplicates, of articles that were not En-glish-written and “open access” and then applying PEDro classification/scoring-inspired, only 58 articles were selected for in-depth full qualitative reading. In the last stage,20 arti-cles were “excluded with reasons”, because they didn’t offer significant information. The-refore, in our systematic literature review, 38 articles were included.Results: In the data gathered in this review we described the molecular pathways of activation of the immune system triggered by COVID-19, with significance on the clinical and paraclinical aspects of IMID patients infected with the new Coronavirus. Patients with IMIDs are at higher risk for hospitalization if diagnosed with SARS-CoV2 and more prone to severe outcomes and death. Risk factors associated with severe outcomes and death are: age, comorbidities, un-derlying disease activity, therapies used (“the good” being anti-tumor necrosis factor α, “the bad” – Methotrexate, Sulfasalazine, Azathioprine and “the ugly” – anti CD20 mono-clonal antibodies). There were several reports of flares and new-onset of IMIDs after CO-VID-19 and after vaccination against this disease, but data from larger studies and registri-es do not confirm higher incidence of flare-ups or new-onset IMIDs. Regarding vaccination, of mounting importance is the timing between immunomodulatory and immunosuppres-sive agents and the administration of the vaccine. And last but not the least, we discussed about Long COVID and the role of artificial intelligence in the pandemic and related-drug development. Discussion and Conclusion: The data in our systematic literature review is consistent with the expertise from our clinical practice. This article is the first part of the doctoral study that is centralized on the same topics, with the current objective of deepe-ning the knowledge about the intersection of COVID-19/SARS-CoV2 and immune-mediated rheumatic diseases and a future objective: to compare information we have synthetized here with our database of almost 170 Romanian patients with a IMID and COVID-19/SARS-CoV2. The next objective is to extend the study to a multicenter control one. Keywords: SARS-CoV2, COVID-19, Immune Mediated Rheumatic Diseases, Rheumatoid Arthri-tis, Systemic Lupus Erythematosus, COVID-19 Vaccine, Long COVID

Elevated serum levels of TNF-α and IL-17 in psoriatic and rheumatoid arthritis

Psoriatic arthritis (PsA) and rheumatoid arthritis (RA) are chronic inflammatory immune-mediated rheumatic diseases, in which cytokine dysregulation is key for pathogenesis. In terms of the specific processes involved in predominantly enthesopathic inflammation and predominantly synovial inflammation, PsA and RA are distinct disease entities. The aim of the present study was to investigate the serum cytokine expression profiles of TNF-α and IL-17 in the two inflammatory arthropathies, discussing their role in the context of disease activity assessed by means of DAS28-CRP, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). The study included 32 patients with PsA, 30 with RA and 20 healthy subjects. In patients with RA and PsA, higher serum levels of both cytokines were measured compared to healthy controls, with the difference being significant, except for TNF-α for patients with PsA, whose concentration was numerically but not significantly higher compared to healthy individuals. We also recorded a significant increase in circulating TNF-α in RA versus PsA, with no difference for IL-17 in the two inflammatory joint diseases. The two studied cytokines did not show a significant difference in serum concentrations according to the state of the disease activity (DAS28- CRP &lt; 3.2 vs. DAS28- CRP ≥ 3.2) in both PsA and RA, as well as association with clinical and laboratory parameters of activity from correlation analyses, supporting the claim that they are not useful markers for its assessment. In conclusion, both cytokines are clearly abundant in the circulation in conditions of both inflammatory arthropathies. The TNF-α and IL-17 pathways are important links and an active participant in these types of rheumatic inflammation.

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.

The impact of immunomodulating treatment on the immunogenicity of COVID-19 vaccines in patients with immune-mediated inflammatory rheumatic diseases compared to healthy controls. A Swedish nationwide study (COVID19-REUMA).

To elucidate antibody responses after the second and third dose of COVID-19 vaccine in patients with inflammatory rheumatic diseases (IRD) treated with biologic/targeted disease modifying anti-rheumatic drugs (b/ts DMARDs). Antibody levels to antigens representing spike full length protein and spike S1 were measured before vaccination, 2-12weeks after the second dose, before and after the third dose using multiplex bead-based serology assay. Positive antibody response was defined as antibody levels over cut off (seropositivity) in seronegative individuals or≥4-fold increase in antibodies in individuals seropositive for both spike proteins. Patients (n=414) receiving b/ts DMARDs (283 had arthritis, 75 systemic vasculitis and 56 other autoimmune diseases) and controls (n=61) from five Swedish regions participated. Treatments groups were: rituximab (n=145); abatacept (n=22); Interleukin 6 receptor inhibitors [IL6i (n=79)]; JAnus Kinase Inhibitors [JAKi (n=58)], Tumour Necrosis Factor inhibitor [TNFi (n=68)] and Interleukin12/23/17 inhibitors [IL12/23/17i (n=42)]. Percentage of patients with positive antibody response after two doses was significantly lower in rituximab (33,8%) and abatacept (40,9%) (p<0,001) but not in IL12/23/17i, TNFi or JAKi groups compared to controls (80,3%). Higher age, rituximab treatment and shorter time between last rituximab course and vaccination predicted impaired antibody response. Antibody levels collected 21-40weeks after second dose decreased significantly (IL6i: p=0,02; other groups: p<0,001) compared to levels at 2-12week but most participants remained seropositive. Proportion of patients with positive antibody response increased after third dose but was still significantly lower in rituximab (p<0,001). Older individuals and patients on maintenance rituximab have an impaired response after two doses of COVID-19 vaccine which improves if the time between last rituximab course and vaccination extends and also after an additional vaccine dose. Rituximab patients should be prioritized for booster vaccine doses. TNFi, JAKi and IL12/23/17i does not diminished humoral response to primary and an additional vaccination.