Autoimmune Connective Tissue Disease Research Articles

Calcinosis Prevalence in Autoimmune Connective Tissue Diseases-A Retrospective Study.

Background/Objectives: Calcinosis cutis is the deposition of insoluble calcium salts, which may cause inflammation, ulceration, pain, and restricted joint mobility. It rarely develops in damaged tissues (dystrophic subtype), most frequently in autoimmune connective tissue diseases (CTDs), but there is very limited data on the prevalence. Also, therapy remains an unsolved issue. In this study, we aimed to collect data on the prevalence of calcinosis in CTD patients to highlight that it is a considerable problem. Methods: A retrospective study was conducted in our department to assess the epidemiology of dystrophic calcinosis in CTDs between January 2003 and January 2024. Results: A total of 839 CTD patients were identified, of whom 56 had calcinosis (6.67%). The mean age of the calcinosis patients at diagnosis of underlying CTD was 41.16 ± 19.47 years. The mean time interval from the onset of calcinosis was 5.96 ± 8.62 years. Systemic sclerosis was the most common CTD complicated by calcinosis (n = 22). Conclusions: Our results are comparable to those reported previously in the literature. Although calcinosis is rare in the overall population, it is a present and unsolved problem in CTD patients. Therefore, further studies are needed on the factors involved in the development and progression of calcinosis as well as its treatment.

Growth arrest-specific protein 6 as a marker of nephritis in systemic sclerosis and juvenile systemic lupus erythematosus patients.

Background: Renal impairments commonly occur as a complication of autoimmune connective tissue diseases (CTDs). Therefore, early nephritis prediction is vital for patient outcomes. Growth Arrest-Specific Protein 6 (GAS6) was found to be upregulated in many types of inflammatory renal disease, including diabetic nephropathy.Aim: To evaluate GAS6 as a predictor of renal impairment in adults with systemic sclerosis (SSc) and children with systemic lupus Erythematosus (SLE).Methods: The study included 60 patients with SSc and 40 children with SLE. The serum level of GAS6 was measured using the ELISA technique. In adults with SSc, total proteins in 24-h urine concentration of >300mg/24 h indicated renal inflammation, while in children with SLE, nephritis was diagnosed by abnormal renal pathology.Results: In SSc patients, GAS6 significantly increased in patients with proteinuria. GAS6 is an independent predictor of nephritis with an odds ratio (OR) of 1.06 and a 95% confidence interval (CI) of 1.0-1.1. at cutoff 12.2ng/mL GAS6 predicted proteinuria with sensitivity 86.7% (95% CI: 59.5% to 98.3%), specificity 57.8% (95% CI: 42.1% to 72.3%), positive predictive value 40.6% (95% CI: 31.5% to 50.4%), negative predictive value 92.9% (95% CI: 77.7% to 97.73%), and accuracy 65.0% (95% CI: 51.6% to 76.9%). In SLE patients, Serum GAS6 did not differ significantly between children with and without lupus nephritis.Conclusion: GAS6 is an independent predictor of nephritis in patients with SSc. However, there is no association between GAS6 and nephritis in juvenile patients with SLE.

#1532 Correlation between TNF-alpha, IL-4 and IL-6 levels and vitamin D in patients with SLE lupus nephritis

Abstract Background and Aims Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease characterized by multisystem organ damage and high titers of autoantibodies to a number of nuclear and cytoplasmic antigens. Numerous abnormalities of the cytokine network have been observed in patients suffering from SLE. However, the relationship between cytokines and vitamin D in damage to the kidneys and various organs has not been studied enough. Aim To determine whether interleukin-6.4 (IL-6.4) and tumor necrosis factor (TNF-alpha) levels correlate with vitamin D deficiency in patients with SLE/FN. Method We determined the levels of TNF-alpha, IL-6, IL-4 and vitamin D in the blood of patients with SLE/FN in 108 people. Results Levels of TNF-alpha, IL-4 and IL-6 were higher in SLE/FN patients with vitamin D deficiency. Further analysis showed that this association was dependent on an inverse correlation (P = 0.017, r = ‒0, 49) for IL-6, (P = 0.023, r = ‒0.42) for IL-4, and (P = 0.76, r = ‒0.243) for TNF-alpha. The average level of TNF-alpha was (3.2+/-6.92 pg/ml), IL-4 and IL-6 showed results (2.13+/-8.72 pg/ml) and 5.02+ /-7.22 pg/ml) respectively for patients with vitamin D deficiency, while it was for IL-6, for IL-4 (3.5+/-6.43 pg/ml) and TNF- alpha (4.33+/-8.61 pg/ml) for patients with normal concentrations of vitamin D in the blood and IL-6, (1.02+/-5.1 pg/ml), IL-4 (2.13+/- 6.4 pg/ml), TNF-alpha (1.45+/-5.28 pg/ml), for the healthy control group, respectively. The difference was statistically significant (P = 0.002). We found a significant positive correlation between TNF-alpha, IL-4 and IL-6 and low vitamin D levels, respectively, and with the SLE Disease Activity Index (SLEDAI). (r = +0.743 and +0.772, respectively). Conclusion Increased levels of IL-4, IL-6 and TNF-alpha may influence the development and progression of nephritis in patients with SLE, in addition, the production of large amounts of IL-4, IL-6 and TNF-alpha correlates with low levels of vitamin D in the blood.

Anti-Th/To Antibodies in Scleroderma: Good Prognosis or Serious Concern?

Systemic sclerosis (SSc) represents a rare and intricate autoimmune connective tissue disease, the pathophysiology of which has not been fully understood. Its key features include progressive fibrosis of the skin and internal organs, vasculopathy and aberrant immune activation. While various anti-nuclear antibodies can serve as biomarkers for the classification and prognosis of SSc, their direct role in organ dysfunction remains unclear. Anti-Th/To antibodies are present in approximately 5% of SSc patients, and are particularly prevalent among those with the limited subtype of the disease. Although the presence of these autoantibodies is associated with a mild course of the disease, there is a strong connection between them and severe clinical manifestations of SSc, including interstitial lung disease, pulmonary arterial hypertension and gastrointestinal involvement. Also, the additional clinical correlations, particularly with malignancies, need further research. Moreover, the disease's course seems to be influenced by antibodies, specific serum cytokines and TLR signaling pathways. Understanding the relationships between presence of anti-Th/To, its molecular aspects and response to treatment options is crucial for the development of novel, personalized therapeutic techniques and should undergo profound analysis in future studies.

Using Antinuclear Antibody Testing in Pediatric Rheumatology.

The antinuclear antibody (ANA) test is frequently used for the identification of patients who are at a high risk of developing autoimmune rheumatological diseases. The aim of this study is to evaluate the final diagnoses of patients applied to the pediatric rheumatology outpatient clinic with a positive ANA test result. In this study, the medical records of 283 children who had ANA positivity between January 2010 and January 2022 were evaluated retrospectively. All patients were younger than 18 years of age at diagnosis and were followed up in the pediatric rheumatology department for at least 6 months. The majority of the patients were females (69%), and the mean age was 9.9 ± 4.7 years. 94% of the ANA tests were requested in pediatric rheumatology outpatient clinics, and 6% in general pediatrics and other outpatient clinics. Arthritis was the most common reason for ANA testing (41.7%). Of the patients who had ANA positivity, 37% were diagnosed with juvenile idiopathic arthritis (JIA), 15% with connective tissue diseases, 10% with autoinflammatory disease, and 7% with vasculitides. Positivity at 1/320 and 1/640 titers were more common in the patients diagnosed with autoimmune connective tissue diseases or JIA compared to the patients without these diagnoses (P = .009 and P = .013, respectively). The ANA test should be judiciously requested by pediatric rheumatologists, especially in suspected cases of autoimmune rheumatic disorders and JIA patients to aid in classification. Indiscriminate use of the ANA test for screening may potentially misguide clinicians.

Ocular Manifestation in Systemic Sclerosis-A Literature Review.

Systemic sclerosis (SSc) is a chronic autoimmune connective tissue disease that affects more than 2 million people worldwide. It manifests through vasculopathy, an abnormal immunological response, and fibrosis leading to dysfunction of the multiple organs. The disease is categorized into two subtypes: limited cutaneous SSc and diffuse cutaneous SSc. Scleroderma can affect vital organs with respiratory, cardiac, renal, ocular, and dermatological complications. The ocular manifestations of the disease can occur in the anterior and posterior segments of the eye. Changes in the anterior segment related to the disease include eyelid skin remodeling, dry eye syndrome, and conjunctival abnormalities. The disease's impact on the posterior segment of the eye mostly causes pathologies in the retinal microcirculatory system and abnormalities in the optic nerve. This review provides detailed insights into ocular complications associated with scleroderma.

Intestinal pseudo-obstruction as systemic lupus erythematosus complication: is it time to reconsider the role of surgery?: A case report of a tailored multidisciplinary managed 44-year-old male patient

Rationale: Intestinal pseudo-obstruction (IPO) represents an unclarified dysmotility disorder characterized by clinic-radiological signs of intestinal obstruction not associated with organic conditions. IPO may occur as a rare complication of autoimmune connective tissue diseases, including Systemic Lupus Erythematosus (SLE). Surgery is recognized as having a marginal management position for IPO patients: this case investigates its role, in the context of a multidisciplinary approach, in the diagnosis and treatment of acute complications of IPO. Patient concerns: An SLE-affected 44-year-old man with a history of recurring nonspecific abdominal sub-obstructive episodes was admitted to our department for constipation, vomiting, and unintentional weight loss. Clinical examination revealed a family history of eosinophilic gastroenteritis (EG). Laboratory tests, including Systemic Sclerosis screening, presented no significant alterations. Abdominal X-ray highlighted multiple air-fluid levels; contrast-enhanced CT showed fluid surrounding dilated loops, and fluid-filled ileal loops, without evidence of organic intrinsic/ab-extrinsic obstruction, perforation, or extraluminal gas. Considering these findings, stenosing-pattern Crohn disease and strictures-complicated EG were mainly suspected. However, ileum-colonoscopy with the histological analysis resulted in inconclusive for Crohn disease and EG. Diagnosis: The histological examination, by showing an SLE fibro-inflammatory pattern, not sparing the enteric plexus, infiltrating the intestinal wall of the surgical samples collected during the right hemicolectomy intervention, allowed the diagnosis of IPO. Interventions and outcomes: The patient, indeed, was initially managed conservatively with nasogastric decompression, immunosuppressive therapy, and parenteral nutrition by a multidisciplinary team including gastroenterologists, rheumatologists, and nutritionists. Unfortunately, 2 weeks later, the worsening symptoms required a lifesaving right hemicolectomy followed by ileostomy. Lessons: IPO should be suspected in SLE patients presenting treated-unresponsive GI symptoms. Its early recognition finalized to start a tailored multidisciplinary approach appears prognostically crucial. Surgery could represent a paramount diagnostic moment and therapeutic life-saving approach.

Pattern of Autoimmune Connective Tissue Diseases Among Patients Attending Al-Thawra Teaching General Hospital, Sana'a-Yemen

Background: Connective tissue is also called connectivum. Many autoimmune diseases affect the connective tissue and blood vessels, are often referred to as connective tissue disorders. Autoimmune diseases currently are estimated to affect 2-5% of the population in the developed countries. Aim: The aim of this study was to determine the pattern of autoimmune inflammatory connective tissue diseases among patients attending Al-Thawra teaching general hospital, Sana'a-Yemen. Method: This study is observational prospective study conducted at Al-Thawra hospital, Sana'a-Yemen, department of internal medicine, duration of the study was 12 months. Sample size was 137. Results: The results showed that systemic lupus erythematosus, antiphospholipid syndrome and rheumatoid arthritis have the highest prevalence. The main clinical presentations are arthritis, leg swelling and dyspnea. The main drugs used are corticosteroids, low molecular weight heparin, and rituximab. The proportion of females to males is 3.55 to 1. The age range 20 – 30 years is the highest representing 47% of the total patients. Patients from Sana'a, Taiz, and Ibb being the most common. Illiterates represent 63%, housewives represent 72% of the total patients. Conclusion: We conclude that autoimmune connective tissue diseases affect 8% of the total patients admitted to the internal medicine department. SLE is the most common autoimmune connective tissue disease encountered and represents 43% of total cases. Arthritis and leg swelling are the most common clinical presentations encountered; both represents 48% of the total presentations. Corticosteroids are the most common prescribed drugs, 45%. The aetiology of autoimmune connective tissue diseases is still not fully known. Immuno-modulators are needed to regulate the immune system. Physiotherapy is recommended beside medical therapy.

ВЛИЯНИЕ РЕВМАТОИДНОГО АРТРИТА НА ТЕЧЕНИЕ ЗАБОЛЕВАНИЙ ПАРОДОНТА

The most common chronic systemic autoimmune disease of connective tissue is rheumatoid arthritis, the incidence of which is up to 50% (in Russia). The etiology of rheumatoid arthritis is still not known for certain. Scientists pay special attention to searching and studying the factors influencing the occurrence of this disease. Researchers are interested in periodontitis as a likely factor in the development of rheumatoid arthritis. The literature presents limited data on the study of the characteristics of the course of dental diseases in patients with rheumatoid arthritis, which indicates the need for further study of this issue and clarification of the relationships between the intensity of caries, the condition of periodontal tissues and the temporomandibular joint in this category of patients. The study of these issues is of scientific and practical interest, as it allows us to improve the methods of diagnosis and monitoring of patients with rheumatoid arthritis by a dentist. The purpose of this study is to determine the effect of rheumatoid arthritis on the course of periodontal diseases. Materials and methods. The methodology of the scientific research is based on the analysis of domestic and foreign literature in the eLIBRARY databases; basic and additional methods of examining the patient were carried out. During the clinical examination, we assessed the general condition of the patient with rheumatoid arthritis, his dental and periodontal status. Results and discussion. A clinical examination of a patient with somatic pathology was carried out. Microorganisms of periodontal pockets were determined, the data obtained were compared with a patient who does not have a systemic disease. Conclusions. Patients with rheumatoid arthritis generally have a thin gingival biotype. Immunological parameters of oral fluid (IgA) in rheumatoid arthritis decrease, which indicates a lack of local and general immunity and leads to damage to periodontal tissue. In the future, this scientific research will help us develop optimal methods for diagnosing and treating patients with autoimmune disease.

De novo autoimmune connective tissue disease and mortality in patients treated with anti-PD-1 and anti-PD-L1 therapy: a population-level cohort study.

Using a population-level cohort analysis, our study demonstrates that, although rare, de novo autoimmune cutaneous connective tissue diseases (AiCTDs) in the setting of immune checkpoint inhibitors (ICIs) are not associated with a greater risk of mortality and overall approach a statistically significant decrease in mortality when compared with patients treated with ICIs who do not experience cutaneous immune-related adverse events. These findings are significant and highly relevant to dermatologists and oncologists caring for ICI recipients as it adds to the limited information on development of cutaneous AiCTD following ICI administration, for which enhanced understanding is critical to improving the care for this challenging patient population.

E001 Pre-screen chest X-ray before starting methotrexate in autoimmune disease

Abstract Background/Aims This audit seeks to assess adherence to BSR guidelines and NICE recommendations concerning chest X-ray screening before initiating methotrexate. We also aim to evaluate the time elapsed from X-ray to radiologist reporting and the frequency of methotrexate initiations for various diagnoses. Methods We identified 127 cases from the rheumatology department (2017-2021) involving patients aged 18 or older with diagnoses of rheumatoid arthritis, psoriatic arthritis, lupus, or autoimmune connective tissue disease. We checked patient records for evidence of pre-treatment chest X-rays Results Rheumatoid arthritis was the most common diagnosis for methotrexate initiation. Out of the 127 patients, 102 underwent chest X-rays (80%), while 23 did not. For 2 patients, the status of chest X-ray performance remained unknown. The breakdown of percentages by hospital was as follows: QEQM (87%), WHH (70%), KCH (77%). The distribution of report times across the three hospitals was as follows: 1-7 days (52%), 8-14 days (4%), 15-31 days (12%), 32-62 days (11%), 63-100 days (15%), 101+ days (6%). Conclusion Urgent reporting of chest X-rays is imperative. Proposed solutions include flagging X-rays as urgent by incorporating a 'Patient starting Methotrexate?’ query. If selected 'yes’ this would flag the report as urgent on the Soliton system. This allows for prompt reporting of these X-rays with timely starting of the DMARDs treatment in various autoimmune conditions. This was done as beforehand, X-rays were not reported in a prompt manner even if they were stated as urgent in the requests. A smaller post-audit analysis involving 15 patients achieved 100% compliance of reporting within one week by implementing these changes. Disclosure M.A. Khan: None. A. Khan: None. A. Vijayan: None. A. Hajilou: None. M. Win: None.

P147 M2 macrophage associated fibrosis in early stage systemic sclerosis: an update on plasma biomarkers

Abstract Background/Aims Systemic sclerosis is an autoimmune connective tissue disease characterised by vasculopathy and fibrosis. The CCN family of matricellular proteins have a regulatory role in inflammation and fibrosis. CD206, an M2 macrophage surface marker, is cleaved by metalloproteases to release soluble form of CD206; this acts as an active disease marker in systemic sclerosis. We investigated the profile of CCN2 and CCN3 in the presence of soluble CD206 (sCD206) in patients with early and late stage diffuse systemic sclerosis (dcSSc). Methods Patients with a diagnosis of dcSSc at the UCL Centre for Rheumatology and Connective Tissue Diseases were recruited. Informed consent was obtained from patients and healthy controls (HC). Blood samples were taken from which plasma was isolated and stored at -80 °C prior to assay. Expression of CCN2, CCN3, and sCD206 was measured in these plasma samples by ELISA. Study participants were categorised into healthy controls (n = 20), early stage dcSSc (n = 20) and late dcSSc (n = 20), with early stage defined as the blood sample taken within two years since diagnosis, and late stage defined as over five years since diagnosis. Results Plasma CCN2, CCN3 and sCD206 levels were significantly higher in early dcSSc patients, when compared to HC. CCN2 was raised in early dcSSc patients (early dcSSc mean 20,221pg/ml, SD 16,503, p < 0.05) with concentration in late disease matching that of HC (late dcSSc 12,893pg/ml, HC 11,289pg/ml). CCN3 was significantly higher in early and late disease when compared to HC (early mean 16,526pg/ml, late 12,838pg/ml, HC 4,201pg/ml, p < 0.05). sCD206 levels were higher in early dcSSc (mean 5356pg/ml, SD 3154, p < 0.05), with there being no significance between levels in late dcSSc (mean 4184pg/ml, SD 3900, p > 0.05) and HC (mean 3319pg/ml, SD 1925). CCN2 expression was higher compared to that of CCN3 in early disease, with CCN2:CCN3 ratio elevated in early dcSSc (mean 3.17, SD 8.26) compared to late dcSSc (mean 1.26, SD 0.99) and HC. Conclusion This investigation demonstrates that upregulation of CCN2 and CCN3 expression has a regulatory role in fibrosis in early stage dcSSc. These biomarkers of M2 macrophage associated fibrosis are to be correlated with their clinical phenotype and have potential for a role in targeted treatment of systemic sclerosis. Disclosure L.A. Leeves: None. Z. Kannan: None. Y. Ali: None. L. Pan: None. T. Malley: None. D. Abraham: None. A. Leask: None. B. Riser: None. B. Ahmed Abdi: None. R.J. Stratton: None.

Pathologic Features of Anti-Ku Myositis.

Characteristics of myositis with anti-Ku antibodies are poorly understood. The purpose of this study was to elucidate the pathologic features of myositis associated with anti-Ku antibodies, compared with immune-mediated necrotizing myopathy (IMNM) with anti-signal recognition particle (SRP) and anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies, in muscle biopsy-oriented registration cohorts in Japan and Germany. We performed a retrospective pathology review of patients with anti-Ku myositis samples diagnosed in the Japanese and German cohorts. We evaluated histologic features and performed HLA phenotyping. Fifty biopsied muscle samples in the Japanese cohort and 10 in the German cohort were obtained. After exclusion of myositis-specific autoantibodies or other autoimmune connective tissue diseases, 26 samples (43%) of anti-Ku antibody-positive myositis were analyzed. All the samples shared some common features with IMNM, whereas they showed expression of MHC class II and clusters of perivascular inflammatory cells more frequently than the anti-SRP/HMGCR IMNM samples (71% vs 7%/16%; p < 0.005/<0.005; 64% vs 0%/0%; p < 0.005/<0.005). Anti-Ku myositis biopsies could be divided into 2 subgroups based on the extent of necrosis and regeneration. The group with more abundant necrosis and regeneration showed a higher frequency of MHC class II expression and perivascular inflammatory cell clusters. HLA phenotyping in the 44 available patients showed possible associations of HLA-DRB1*03:01, HLA-DRB1*11:01, and HLA-DQB1*03:01 (p = 0.0045, 0.019, and 0.027; odds ratio [OR] 50.2, 4.6, and 2.8; 95% CI 2.6-2942.1, 1.1-14.5, and 1.0-7.0) in the group with less conspicuous necrosis and regeneration. On the contrary, in the group of more abundant necrosis and regeneration, the allele frequencies of HLA-A*24:02, HLA-B*52:01, HLA-C*12:02, and HLA-DRB1*15:02 were lower than those of healthy controls (p = 0.0036, 0.027, 0.016, and 0.026; OR = 0.27, 0, 0, and 0; 95% CI 0.1-0.7, 0-0.8, 0-0.8, and 0-0.8). However, these HLA associations did not remain significant after statistical correction for multiple testing. While anti-Ku myositis shows necrotizing myopathy features, they can be distinguished from anti-SRP/HMGCR IMNM by their MHC class II expression and clusters of perivascular inflammatory cells. The HLA analyses suggest that anti-Ku myositis may have different subsets associated with myopathologic subgroups.

Antinuclear antibody (ANA) positivity pattern by line immunoassay in a hospital from eastern India: Update from a laboratory perspective.

The existence of more than one antibody in systemic autoimmune rheumatic diseases (SARDs) or connective tissue disease (CTD) along with features of more than one autoimmune disease (AD) in an individual is suggestive of overlap syndrome (OS). Line immunoassay (LIA) can target many autoantibodies in a single approach, thus making the identification of OS feasible. This study aimed to identify the pattern of distribution of antinuclear antibodies by LIA prevalent in a hospital population in eastern India and identify common forms of SARD in this belt based on laboratory findings. A total of 1660 samples received for ANA profile testing by LIA were analysed. Factor analysis was performed with factor loading scores used in the k-means algorithm to identify clustering of various autoantibodies. U1-snRNP positivity was the highest at 16.69%, and the least frequent autoantibody noted was anti-Jo-1 at 0.71% positivity. Based on the outcome of factor analysis, three clusters were determined. Cluster 1 showed a predominance of anti-PM/Scl antibodies, cluster 2 showed a predominance of anti-dsDNA, anti-histone, anti-SmD1, anti-nucleosomes, anti-PCNA, anti-Po, anti-SSA/Ro52, anti-SSA-Ro60, anti-SSB/La, anti-Scl-70, anti-Mi-2, anti-Ku and anti-AMA-M2, and cluster 3 showed a predominance of anti-U1-snRNP. Mixed connective tissue disease (MCTD) and overlap syndrome (OS) are prevalent more than pure form of an AD in our study population. OS may be missed out by monospecific immunoassays and hence adds to diagnostic challenges. LIA may be more useful in identifying specific autoantibodies by a single approach rather than monospecific immunoassays in populations after a positive screen by indirect immunofluorescence (IIF).

Distinctive profile of monomeric and polymeric anti-SSA/Ro52 immunoglobulin A1 isoforms in saliva of patients with primary Sjögren’s syndrome and Sicca

ObjectivePrimary Sjögren’s syndrome (pSS) is the second most common chronic autoimmune connective tissue disease. Autoantibodies, immunoglobulin (IgG) anti-SSA/Ro, in serum is a key diagnostic feature of pSS. Since pSS is...

Nintedanib downregulates the profibrotic M2 phenotype in cultured monocyte-derived macrophages obtained from systemic sclerosis patients affected by interstitial lung disease

BackgroundSystemic sclerosis (SSc) is an autoimmune connective tissue disease characterized by vasculopathy and progressive fibrosis of skin and several internal organs, including lungs. Macrophages are the main cells involved in the immune-inflammatory damage of skin and lungs, and alternatively activated (M2) macrophages seem to have a profibrotic role through the release of profibrotic cytokines (IL10) and growth factors (TGFβ1). Nintedanib is a tyrosine kinase inhibitor targeting several fibrotic mediators and it is approved for the treatment of SSc-related interstitial lung disease (ILD). The study aimed to evaluate the effect of nintedanib in downregulating the profibrotic M2 phenotype in cultured monocyte-derived macrophages (MDMs) obtained from SSc-ILD patients.MethodsFourteen SSc patients, fulfilling the 2013 ACR/EULAR criteria for SSc, 10 SSc patients affected by ILD (SSc-ILD pts), 4 SSc patients non affected by ILD (SSc pts no-ILD), and 5 voluntary healthy subjects (HSs), were recruited at the Division of Clinical Rheumatology-University of Genova, after obtaining Ethical Committee approval and patients’ informed consent. Monocytes were isolated from peripheral blood, differentiated into MDMs, and then maintained in growth medium without any treatment (untreated cells), or treated with nintedanib (0.1 and 1µM) for 3, 16, and 24 h. Gene expression of macrophage scavenger receptors (CD204, CD163), mannose receptor-1 (CD206), Mer tyrosine kinase (MerTK), identifying M2 macrophages, together with TGFβ1 and IL10, were evaluated by quantitative real-time polymerase chain reaction. Protein synthesis was investigated by Western blotting and the level of active TGFβ1 was evaluated by ELISA. Statistical analysis was carried out using non-parametric Wilcoxon test.ResultsCultured untreated SSc-ILD MDMs showed a significant increased protein synthesis of CD206 (p < 0.05), CD204, and MerTK (p < 0.01), together with a significant upregulation of the gene expression of MerTK and TGFβ1 (p < 0.05; p < 0.01) compared to HS-MDMs. Moreover, the protein synthesis of CD206 and MerTK and the gene expression of TGFβ1 were significantly higher in cultured untreated MDMs from SSc-ILD pts compared to MDMs without ILD (p < 0.05; p < 0.01). In cultured SSc-ILD MDMs, nintedanib 0.1 and 1µM significantly downregulated the gene expression and protein synthesis of CD204, CD206, CD163 (p < 0.05), and MerTK (p < 0.01) compared to untreated cells after 24 h of treatment. Limited to MerTK and IL10, both nintedanib concentrations significantly downregulated their gene expression already after 16 h of treatment (p < 0.05). In cultured SSc-ILD MDMs, nintedanib 0.1 and 1µM significantly reduced the release of active TGFβ1 after 24 h of treatment (p < 0.05 vs. untreated cells).ConclusionsIn cultured MDMs from SSc-ILD pts, nintedanib seems to downregulate the profibrotic M2 phenotype through the significant reduction of gene expression and protein synthesis of M2 cell surface markers, together with the significant reduction of TGFβ1 release, and notably MerTK, a tyrosine kinase receptor involved in lung fibrosis.

Emerging therapeutic targets in systemic sclerosis.

Systemic sclerosis is an autoimmune connective tissue disease which is characterised by vascular perturbations, inflammation, and fibrosis. Although huge progress recently into the underlying molecular pathways that are perturbed in the disease, currently no therapy exists that targets the fibrosis element of the disease and consequently there is a huge unmet medical need. Emerging studies reveal new dimensions of complexity, and multiple aberrant pathways have been uncovered that have shed light on disturbed signalling in the disease, primarily in inflammatory pathways that can be targeted with repurposed drugs. Pre-clinical animal models using these inhibitors have yielded proof of concept for targeting these signalling systems and progressing to clinical trials. This review will examine the recent evidence of new perturbed pathways in SSc and how these can be targeted with new or repurposed drugs to target a currently intractable disease.

Relationship between ultrasound imaging of dorsalis pedis artery and foot health symptoms in people with rheumatoid arthritis

BackgroundRheumatoid arthritis (RA) is an autoimmune connective tissue disease which affects joint function and multiple body systems. Poor foot health for people with RA has a negative impact on mobility, functional capacity, and quality of life. Additional to joint pain, people with RA may develop vascular disease e.g., vasculitis, which can have increasingly detrimental effects on foot health, quality of life and longevity. If identified early, adverse effects may be prevented. However, the link between foot health symptoms and ultrasound identified precursory changes for vasculitis is yet to be established. ObjectivesThis study aimed to examine the association between foot health symptoms and the integrity of the dorsalis pedis artery (DPA). MethodsWe recruited 47 participants with RA and 47 characteristic-matched controls. All participants completed an online survey which included demographic questions and Foot Health Status Questionnaire (FHSQ). Ultrasound imaging measured participants’ proximal DPA in terms of degree of wall inflammation, lumen diameter, artery diameter, lumen-to-artery diameter ratio and peak systolic velocity. ResultsSignificant differences (p < 0.001) were noted between groups for degree of wall inflammation, artery diameter and lumen to artery diameter ratio, while lumen diameter and peak systolic velocity demonstrated no statistical difference. Degree of wall inflammation demonstrated stronger association with FHSQ score (r = −0.454, p < 0.001) than artery diameter (r = −0.361, p < 0.001) and lumen-to-artery diameter ratio (r = 0.404, p < 0.001), while FHSQ score did not relate to lumen diameter (p = 0.798) nor peak systolic velocity (p = 0.258). ConclusionWe identified specific vascular ultrasound parameters were associated with foot symptoms among people with RA. This non-invasive imaging technique may be a viable method to monitor foot health and disease management.

Nutritional interventions as modulators of the disease activity for idiopathic inflammatory myopathies: a scoping review.

Idiopathic inflammatory myopathies (IIMs) are chronic, autoimmune connective tissue diseases associated with significant morbidity and disability. Nutrients can activate the immune system and contribute to chronic low-grade inflammation (LGI). Chronic muscle inflammation leads to imbalanced pro-inflammatory and anti-inflammatory cytokines, causing inadequate nutrition, weight loss and muscle weakness during a negative cycle. Owing to its potential to modulate LGI in various diseases, the Mediterranean diet (Med Diet) has been extensively studied. This scoping review explores the nutritional implications and recommendations of the Med Diet as a treatment for immune-mediated diseases, focusing on the gaps in IIM nutritional interventions. A comprehensive literature search of the MEDLINE and EBSCO databases between September 2018 and December 2022 was performed. We identified that the Med Diet and its specific components, such as omega-3 (nω3) fatty acids, vitamin D and antioxidants, play a role in the dietary treatment of connective tissue-related autoimmune diseases. Nutritional interventions have demonstrated potential for modulating disease activity and warrant further exploration of IIMs through experimental studies. This review introduces a dietary therapeutic approach using the Med Diet and related compounds to regulate chronic inflammatory processes in IIMs. However, further clinical studies are required to evaluate the efficacy of the Med Diet in patients with IIMs. Emphasising a clinical-nutritional approach, this study encourages future research on the anti-inflammatory effects of the Med Diet on IIMs. This review highlights potential insights for managing and treating these conditions using a holistic approach.

Therapeutic management of fibrosis in systemic sclerosis patients - an analysis from the Swiss EUSTAR cohort.

Systemic sclerosis is a chronic autoimmune connective tissue disease leading to microvascular and fibrotic manifestations in multiple organs. Several treatment options and recommendations from different European countries are available. In this study, for which the ambit is Switzerland specifically, we aim to describe the treatment patterns of systemic sclerosis patients with fibrotic manifestations. Systemic sclerosis patients were selected from six Swiss tertiary centres recorded in the multicentre, prospective European Scleroderma Trials and Research (EUSTAR) registry. Patients fulfilling the 2013 ACR/EULAR systemic sclerosis classification criteria at baseline were included. To determine the differences in treatment of varying degrees of fibrosis, four groups were identified: (1) patients with a modified Rodnan skin score (mRSS) >0; (2) those with mRSS ≥7; (3) those with interstitial lung disease (SSc-ILD), diagnosed by either chest X-Ray or high-resolution computed tomography; and (4) patients fulfilling one of the additional criteria for extensive interstitial lung disease, defined as interstitial lung disease involvement of >20% in high-resolution computed tomography, dyspnea NYHA-stage 3/4, or a predicted forced vital capacity (FVC) of <70%. A total of 590 patients with systemic sclerosis fulfilled the inclusion criteria. In this cohort, 421 (71.4%) had mRSS >0, of whom 195 (33.1%) had mRSS ≥7; interstitial lung disease was diagnosed in 198 of 456 (43.4%), of whom 106 (18.0 %) showed extensive interstitial lung disease. Regarding non-biologic disease-modifying medications (DMARDs), the most frequently prescribed was methotrexate, followed by hydroxychloroquine and mycophenolate mofetil. Rituximab and tocilizumab were most frequently used among the biologic DMARDs. Specifically, 148/372 (39.8%) of treated patients with skin fibrosis received methotrexate, mycophenolate mofetil or rituximab, and 80/177 (45.2%) with interstitial lung disease received cyclophosphamide, mycophenolate mofetil, tocilizumab or rituximab. Most patients received a proton-pump inhibitor, and few patients underwent hematopoietic stem cell transplantation. Overall, in Switzerland, a wide range of medications is prescribed for systemic sclerosis patients. This includes modern, targeted treatments for which randomised controlled clinical trial have been recently reported.