The interplay between rheumatic diseases and pulmonary health.

Patients with rheumatic diseases (RDs) are prone to a number of comorbidities, particularly those affecting the respiratory system due to inflammatory and autoimmune mechanisms. Rheumatoid arthritis (RA), systemic sclerosis (SSc), and inflammatory idiopathic myopathies (IIMs) often present with progressive interstitial lung disease (ILD). The prevalence of ILD varies among patients with RDs, with 11% in RA, 47% in SSc, and 41% in IIMs. Some diagnostic markers, including KL-6, cytokines TNF-α and IL-6, and autoantibodies (anti-CCP), play a crucial role in assessing and predicting the course of pulmonary involvement in RDs. Lung fibrosis is a progressive disorder in SSc and RA, limiting the effiency of therapeutic interventions. Re-evaluating treatment approaches with disease-modifying anti-rheumatic drugs (DMARDs) is crucial for understanding their impact on the risk of lung affections. Despite initial concerns surrounding methotrexate, recent evidence points to its benefits in RA-associated interstitial lung disease (RA-ILD). Recognizing the intricate relationship between autoimmune RDs and lung affections is crucial for formulating effective treatment strategies. Emphasis is placed on collaborative efforts of rheumatologists and pulmonologists for early diagnosis, comprehensive care, and optimal patient outcomes in RA-ILD.

Systemic sclerosis associated respiratory involvement: Scopus-based analysis of articles in 2013-2022.

BACKGROUND: Systemic sclerosis (SSc), a complex autoimmune disorder, manifests as a convergence of rheumatologic, dermatologic, and pulmonary challenges. Among the severe complications contributing to morbidity and mortality are SSc Associated Interstitial Lung Disease (SSc-ILD) and pulmonary hypertension. Over the past decade, research on pulmonary involvement in SSc has intensified, leading to a heightened understanding of its pathogenesis, diagnostic methods, and therapeutic strategies. AIM: This study aims to provide a data-driven overview of the current state of systemic sclerosis research, identifying emerging trends and fostering informed decisions regarding resource allocation and research priorities. METHODS: A literature search was conducted in the Scopus database, using MESH keywords such as "systemic sclerosis" AND "lungs" OR "pulmonary hypertension" OR "interstitial lung disease". After applying exclusion criteria, a thorough analysis was performed, considering factors such as document category, authorship, journal source, citation frequency, country of publication, language, and keywords. The bibliometric analysis utilized Scopus as the preferred database, leveraging its extensive coverage, user-friendly interface, and commitment to data accuracy. Visual networks were constructed using VOSviewer software to map the relationships between keywords, countries, and authors. Altmetric Attention Scores (AAS) were employed to assess the social impact of articles. RESULTS: The analysis revealed a total of 2538 scholarly items, with 55.7% identified as open access. The USA (n = 532), Italy (n = 458), France (n = 304), Japan (n = 271), and the UK (n = 236) emerged as primary contributors, with English being the predominant language. A notable upward tendency in annual publication and citation scores indicated sustained interest and relevance in SSc-ILD research. The top journals, including Rheumatology United Kingdom, Clinical and Experimental Rheumatology, Clinical Rheumatology, Arthritis and Rheumatology, and Journal of Rheumatology, played a pivotal role in scholarly output. Original Articles (n = 1795; 70.7%) constituted the majority of publications, followed by Reviews, Letters, Notes, and Editorials. The analysis of publication impact within different scholarly formats revealed varying citation patterns, with Original Articles and Reviews leading in influence. The identification of influential research hubs and key contributors provided insights into collaborative efforts and geographic distribution. A strong correlation (rho = 0.612, p < 0.001) was observed between the quantity of Mendeley readers and the citations received by scholarly articles. CONCLUSION: This bibliometric analysis offers a comprehensive overview of SSc-ILD research, highlighting its dynamic and interdisciplinary nature. The surge in publications, citation scores, and the identification of key contributors underscore the continued relevance and impact of this field. The nuanced relationships between social attention and scientific recognition, as revealed by Mendeley readership and AAS, contribute to a deeper understanding of the multifaceted nature of scholarly impact.

COVID-19 from a rheumatology perspective: bibliometric and altmetric analysis.

The Coronavirus disease 2019 (COVID-19) outbreak turned out the greatest pandemic for decades. It challenged enormously the global health system, forcing it to adjust to the new realities. We aimed to analyze articles covering COVID-19 papers in the rheumatological field and outline emerging topics raising within this frame. We applied the bibliometric database Scopus for our literature search and conducted it on the 5th of June using the following keywords: "rheumatic" OR "rheumatology" OR "rheumatoid arthritis" OR "systemic lupus erythematosus" OR "myositis" OR "systemic sclerosis" OR "vasculitis" OR "arthritis" OR "ankylosing spondylitis" AND "COVID-19". We analyzed all selected articles according to various aspects: type of document, authorship, journal, citations score, rheumatology field, country of origin, language, and keywords. With the help of the software tool VOSviewer version 1.6.15, we have built the visualizing network of authors and keywords co-occurrence. The measurement of the social impact of articles was made using Altmetric data. This study included 1430 retrieved articles with open access mostly. The top five journals in this field were Annals of the Rheumatic Diseases (n = 65), Rheumatology International (n = 51), Clinical Rheumatology (n = 50), Lancet Rheumatology (n = 50), and Frontiers In Immunology (n = 33). Most studies originate from countries with a high incidence of COVID-19 among the general population (the USA-387; Italy-268; UK-184; France-114; Germany-110; India-98 and Spain-96, China-94, Canada-73 Turkey-66). Original Articles (42.1%) were the most common articles' type, following by Letters (24.4%), Reviews (21.7%), Notes (6%), Editorials (4.8%), Erratum (1%). According to the citations scores, articles dedicated to the clinical course of COVID-19 in patients with rheumatic diseases were of the highest importance for the scientific rheumatologic community. Rheumatoid arthritis (n = 527), systemic lupus erythematosus (n = 393), vasculitis (n = 267), myositis (n = 71), systemic sclerosis (n = 68), and psoriatic arthritis (n = 68) were the most widely discussed rheumatic diseases in the view of COVID-19. The analysis of Altmetric and citations scores revealed a moderate correlation between them. This article provides a comprehensive bibliometric and altmetric analysis of COVID-19 related articles in the rheumatology field and summarizes data about features of rheumatology service in the time of the pandemic.

Challenges in diagnosis of limited granulomatosis with polyangiitis.

Granulomatosis with polyangiitis (GPA) is an orphan disease with multifaceted clinical presentations and delayed diagnosis. Given the risks of delayed diagnosis and treatment, improving clinicians' awareness of atypical course of this disease is critically important. The aim of this report is to analyze a case of delayed diagnosis of GPA in view of similar publications. We analyzed articles retrieved from Scopus and MEDLINE/PubMed. The following keywords were used: "granulomatosis with polyangiitis", "Wegener granulomatosis", and "diagnostic errors". All case studies that fulfilled the Chapel Hill Consensus Conference and the American College of Rheumatology GPA criteria were retrieved. We report a 71-year-old female patient with a facial defect in the nasal region, nasal congestion, and serosanguineous discharge. Her final diagnosis of GPA was reached after a series of incorrect diagnoses in the past 40 years. A deforming facial lesion developed during this period of uncertainty and absence of appropriate treatment. This patient presented with atypical features of laboratory and instrumental examinations. Anti-neutrophil cytoplasmic antibodies (ANCA) were negative, while rheumatoid factor (RF; 46.3 IU/mL) and anti-citrullinated protein antibody (ACPA; 25.6 IU/mL) were elevated. The histological analysis of the nasal mucous membrane specimen did not indicate definite signs of vasculitis. However, it revealed a granuloma with aggregation of macrophages and massive infiltration of lymphocytes, ruling out previous diagnosis of carcinoma. We analyzed delayed diagnosis of GPA in our patient in the context of 12 previously reported similar cases of limited form of GPA. We emphasize the importance of histological examination for differential diagnosis of GPA.

Efficacy, pharmacokinetics and safety of subcutaneous versus intravenous CT-P13 in rheumatoid arthritis: a randomized phase I/III trial.

OBJECTIVE: To assess non-inferiority of s.c. to i.v. CT-P13 in RA. METHODS: Patients with active RA and inadequate response to MTX participated in this phase I/III double-blind study at 76 sites. Patients received CT-P13 i.v. 3 mg/kg [week (W) 0 and W2] before randomization (1:1) at W6 to CT-P13 s.c. via pre-filled syringe (PFS) 120 mg biweekly until W28, or CT-P13 i.v. 3 mg/kg every 8 weeks until W22. Randomization was stratified by country, W2 serum CRP and W6 body weight. From W30, all patients received CT-P13 s.c. In a usability sub-study, patients received CT-P13 s.c. via auto-injector (W46-54) then PFS (W56-64). The primary endpoint was change (decrease) from baseline in disease activity score in 28 joints (DAS28)-CRP at W22 (non-inferiority margin: -0.6). RESULTS: Of 357 patients enrolled, 343 were randomized to CT-P13 s.c. (n = 167) or CT-P13 i.v. (n = 176) at W6. The least-squares mean change (decrease) from baseline (standard error) in DAS28-CRP at W22 was 2.21 (0.22) for CT-P13 s.c. (n = 162) and 1.94 (0.21) for CT-P13 i.v. [n = 168; difference 0.27 (95% CI: 0.02, 0.52)], establishing non-inferiority. Efficacy findings were similar between arms at W54. Safety was similar between arms throughout: 92 (54.8%; CT-P13 s.c.) and 117 (66.9%; CT-P13 i.v.) patients experienced treatment-emergent adverse events (from W6). There were no treatment-related deaths or new safety findings. Usability was similar for CT-P13 s.c. via auto-injector or PFS. CONCLUSION: CT-P13 s.c. was non-inferior to CT-P13 i.v. in active RA. The convenience of s.c. administration could benefit patients. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT03147248.

Pulmonary involvement in systemic sclerosis: exploring cellular, genetic and epigenetic mechanisms.

Systemic sclerosis (SSc) is a chronic progressive autoimmune disease characterized by immune inflammation, vasculopathy, and fibrosis. There are still numerous uncertainties in the understanding of disease initiation and progression. Pulmonary involvement in SSc, and particularly pulmonary fibrosis, is critical for all organ systems affections in this disease. This review is aimed to describe and analyze new findings in the pathophysiology of SSc-associated pulmonary involvement and to explore perspective diagnostic and therapeutic strategies. A myriad of cellular interactions is explored in the dynamics of progressive interstitial lung disease (ILD) and pulmonary hypertension (PH) in SSc. The role of exosomes, microvesicles, and apoptotic bodies is examined and the impact of micro and long non-coding RNAs, DNA methylation, and histone modification in SSc is discussed.

Rheumatology in Ukraine.

Rheumatology in Ukraine is based on established research and clinical infrastructure that enable the integration with regional and global societies. This article overviews current state of Ukrainian rheumatology, important steps toward expanding clinical settings, and opportunities for strengthening cooperation of local rheumatologists and patients with rheumatic diseases with related international societies. The main achievements and some challenges encountered by the Association of Rheumatologists of Ukraine are outlined. The Association supports continuing medical education of local specialists and explores options for advancing research and publishing in rheumatology. One of the main challenges still remains the creation of registries of patients with rheumatic diseases and expansion of activities of public societies with interest in combating rheumatic diseases. The issue of inadequate access to immunobiological therapies is also highlighted.

Prostate involvement in granulomatosis with polyangiitis.

To present a case of prostate involvement (PI) in granulomatosis polyangiitis (GPA) and analyse related published reports. We employed the following keywords for retrieving reports indexed by MEDLINE/PubMed and/or Scopus: "granulomatosis with polyangiitis", "Wegener granulomatosis" and "prostate involvement". Additional searches were performed through Google Scholar and HINARI. All cases that fulfilled the American College of Rheumatology criteria for GPA, standards of Chapel Hill Consensus Conference, and did not match with exclusion criteria were analysed and summarised. A 35-year-old man presented with complaints of stuffy nose, difficulty breathing through the nose, swelling and pain in the left half of the nose, low-grade fever, and discomfort. The nasal mucosal biopsy did not reveal any specific changes. During the inpatient treatment, he developed eye redness, tearing, dysuria, and decreased urinary stream. Prostate-specific antigen (PSA) was elevated (2.81 µg/L; normal values ≤ 1.4 µg/L for males below 40 years). Prostate biopsy findings were consistent with diagnosis of GPA, which was confirmed by detecting elevated anti-PR3 antibodies (4.1 IU; normal values < 1.0 IU). We analysed our case in view of the clinical course of 45 published cases of PI in GPA. PI in GPA is a rare clinical manifestation of the vasculitis. Patients with atypical clinical symptoms of GPA are at risk of delayed diagnosis. The awareness of variable clinical presentations of GPA, particularly specific affection of the prostate gland, is crucial for timely diagnosis.

Safety, immunogenicity and efficacy after switching from reference infliximab to biosimilar SB2 compared with continuing reference infliximab and SB2 in patients with rheumatoid arthritis: results of a randomised, double-blind, phase III transition study.

OBJECTIVES: Efficacy, safety and immunogenicity results from the phase III study of SB2, a biosimilar of reference infliximab (INF), were previously reported through 54 weeks. This transition period compared results in patients with rheumatoid arthritis (RA) who switched from INF to SB2 with those in patients who maintained treatment with INF or SB2. METHODS: Patients with moderate to severe RA despite methotrexate treatment were randomised (1:1) to receive SB2 or INF at weeks 0, 2 and 6 and every 8 weeks thereafter until week 46. At week 54, patients previously receiving INF were rerandomised (1:1) to switch to SB2 (INF/SB2 (n=94)) or to continue on INF (INF/INF (n=101)) up to week 70. Patients previously receiving SB2 continued on SB2 (SB2/SB2 (n=201)) up to week 70. Efficacy, safety and immunogenicity were assessed up to week 78. RESULTS: Efficacy was sustained and comparable across treatment groups. American College of Rheumatology (ACR) 20 responses between weeks 54 and 78 ranged from 63.5% to 72.3% with INF/SB2, 66.3%%-69.4% with INF/INF and 65.6%-68.3% with SB2/SB2. Treatment-emergent adverse events during this time occurred in 36.2%, 35.6% and 40.3%, respectively, and infusion-related reactions in 3.2%, 2.0% and 3.5%. Among patients who were negative for antidrug antibodies (ADA) up to week 54, newly developed ADAs were reported in 14.6%, 14.9% and 14.1% of the INF/SB2, INF/INF and SB2/SB2 groups, respectively. CONCLUSIONS: The efficacy, safety and immunogenicity profiles remained comparable among the INF/SB2, INF/INF and SB2/SB2 groups up to week 78, with no treatment-emergent issues or clinically relevant immunogenicity after switching from INF to SB2. TRIAL REGISTRATION NUMBER: NCT01936181; EudraCT number: 2012-005733-37.

Comparing biosimilar SB2 with reference infliximab after 54 weeks of a double-blind trial: clinical, structural and safety results.

Objectives: SB2 is a biosimilar to the reference infliximab (INF). Similar efficacy, safety and immunogenicity between SB2 and INF up to 30 weeks were previously reported. This report investigates such clinical similarity up to 54 weeks, including structural joint damage. Methods: In this phase III, double-blind, parallel-group, multicentre study, patients with moderate to severe RA despite MTX were randomized (1:1) to receive 3 mg/kg of either SB2 or INF at 0, 2, 6 and every 8 weeks thereafter. Dose escalation by 1.5 mg/kg up to a maximum dose of 7.5 mg/kg was allowed after week 30. Efficacy, safety and immunogenicity were measured at each visit up to week 54. Radiographic damage evaluated by modified total Sharp score was measured at baseline and week 54. Results: A total of 584 patients were randomized to receive SB2 (n = 291) or INF (n = 293). The rate of radiographic progression was comparable between SB2 and INF (mean modified total Sharp score difference: SB2, 0.38; INF, 0.37) at 1 year. ACR responses, 28-joint DAS, Clinical Disease Activity Index and Simplified Disease Activity Index were comparable between SB2 and INF up to week 54. The incidence of treatment-emergent adverse events and anti-drug antibodies were comparable between treatment groups. Such comparable trends of efficacy, safety and immunogenicity were consistent from baseline up to 54 weeks. The pattern of dose increment was also comparable between SB2 and INF. Conclusion: SB2 maintained similar efficacy, safety and immunogenicity with INF up to 54 weeks in patients with moderate to severe RA. Radiographic progression was comparable at 1 year. Trial registration: ClinicalTrials.gov (http://clinicaltrials.gov; NCT01936181) and EudraCT (https://www.clinicaltrialsregister.eu; 2012-005733-37).

A randomised, double-blind, phase III study comparing SB2, an infliximab biosimilar, to the infliximab reference product Remicade in patients with moderate to severe rheumatoid arthritis despite methotrexate therapy.

OBJECTIVES: To compare the efficacy, safety, immunogenicity and pharmacokinetics (PK) of SB2 to the infliximab reference product (INF) in patients with moderate to severe rheumatoid arthritis (RA) despite methotrexate therapy. METHODS: This is a phase III, randomised, double-blind, multinational, multicentre parallel group study. Patients with moderate to severe RA despite methotrexate therapy were randomised in a 1:1 ratio to receive either SB2 or INF of 3 mg/kg. The primary end point was the American College of Rheumatology 20% (ACR20) response at week 30. Inclusion of the 95% CI of the ACR20 response difference within a ±15% margin was required for equivalence. RESULTS: 584 subjects were randomised into SB2 (N=291; 290 analysed) or INF (N=293). The ACR20 response at week 30 in the per-protocol set was 64.1% in SB2 versus 66.0% in INF. The adjusted rate difference was -1.88% (95% CI -10.26% to 6.51%), which was within the predefined equivalence margin. Other efficacy outcomes such as ACR50/70, disease activity score measured by 28 joints and European League against Rheumatism response were similar between SB2 and INF. The incidence of treatment-emergent adverse events was comparable (57.6% in SB2 vs 58.0% in INF) as well as the incidence of antidrug antibodies (ADA) to infliximab up to week 30 (55.1% in SB2 vs 49.7% in INF). The PK profile was similar between SB2 and INF. Efficacy, safety and PK by ADA subgroup were comparable between SB2 and INF. CONCLUSIONS: SB2 was equivalent to INF in terms of ACR20 response at week 30. SB2 was well tolerated with a comparable safety profile, immunogenicity and PK to INF. TRIAL REGISTRATION NUMBER: NCT01936181.

A phase III randomized study to evaluate the efficacy and safety of CT-P13 compared with reference infliximab in patients with active rheumatoid arthritis: 54-week results from the PLANETRA study.

BACKGROUND: CT-P13 (Remsima®, Inflectra®) is a biosimilar of the infliximab reference product (RP; Remicade®). The aim of this study was to compare the 54-week efficacy, immunogenicity, safety, pharmacokinetics (PK) and pharmacodynamics (PD) of CT-P13 and RP in patients with active rheumatoid arthritis (RA). METHODS: In this multinational phase III double-blind study, patients with active RA and an inadequate response to methotrexate (MTX) were randomized (1:1) to receive CT-P13 (3 mg/kg) or RP (3 mg/kg) at weeks 0, 2, 6 and then every 8 weeks to week 54 in combination with MTX (12.5-25 mg/week). Efficacy endpoints included American College of Rheumatology (ACR)20, ACR50 and ACR70 response rates, Disease Activity Score in 28 joints (DAS28), Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), European League Against Rheumatism (EULAR) response rates, patient-reported outcomes and joint damage progression. Immunogenicity, safety and PK/PD outcomes were also assessed. RESULTS: Of 606 randomized patients, 455 (CT-P13 233, RP 222) were treated up to week 54. At week 54, ACR20 response rate was highly similar between groups (CT-P13 74.7 %, RP 71.3 %). ACR50 and ACR70 response rates were also comparable between groups (CT-P13 43.6 % and 21.3 %, respectively; RP 43.1 % and 19.9 %, respectively). DAS28, SDAI and CDAI decreased from baseline to week 54 to a similar extent with CT-P13 and RP. Radiographic progression measured by Sharp scores as modified by van der Heijde was also comparable. With both treatments, patient assessments of pain, disease activity and physical ability, as well as mean scores on the Medical Outcomes Study Short Form Health Survey (SF-36), improved markedly at week 14 and remained stable thereafter up to week 54. The proportion of patients positive for antidrug antibodies at week 54 was similar between the two groups: 41.1 % and 36.0 % with CT-P13 and RP, respectively. CT-P13 was well tolerated and had a similar safety profile to RP. PK/PD results were also comparable between CT-P13 and RP. CONCLUSIONS: CT-P13 and RP were comparable in terms of efficacy (including radiographic progression), immunogenicity and PK/PD up to week 54. The safety profile of CT-P13 was also similar to that of RP. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01217086 . Registered 4 Oct 2010.