Inflammatory Connective Tissue Research Articles

Combination of denosumab and biologic DMARDs in inflammatory muscle-skeletal diseases and connective tissue diseases.

Osteoporosis (OP) can complicate the course of rheumatic musculoskeletal diseases (RMDs) and connective tissue diseases (CTDs). Denosumab, a monoclonal antibody against RANK-L, showed beneficial effect in rheumatoid arthritis in inhibiting radiographic progression and erosive burden. We tested the efficacy, safety, and persistence on the treatment of the combination of biologic disease-modifying antirheumatic drugs (bDMARDs)/denosumab versus bDMARD in patients with RMD and CTD. This is a retrospective evaluation of a single center, including patients with RMD/CTD (including rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, systemic sclerosis, and overlap syndromes) treatment with bDMARD/denosumab, compared to age, gender, disease, bDMARD, and conventional synthetic disease-modifying antirheumatic drugs-matched controls. Twenty-eight bDMARD/denosumab patients and 49 bDMARD patients were eligible. Despite a statistically significant difference during the first-year efficacy (due to the different baseline timepoint), there was no difference in the efficacy profile in the second year of treatment and in the safety profile (including local, systemic, and serious adverse events). Moreover, no statistically significant difference in the persistence of bDMARD treatment over 2 years of evaluation was found. The combination of bDMARD and denosumab was not an independent predictor of disease flare or bDMARD treatment withdrawal. The combination of bDMARD and denosumab does not alter the efficacy and the safety profile of the bDMARD in patients with RMD/CTD. Future studies verifying the radiological disease inhibition could support denosumab use in RMD/CTD other than rheumatoid arthritis, when complicated by OP.

P13 Finding an answer for an adolescent with back pain

Case report - IntroductionThis is the case of an adolescent referred to rheumatology following 5 years of back pain. After years of trying a number of treatments without much success, the cause was found to be a previously undiagnosed urological pathology. The case highlights awareness of non-rheumatological causes and incidental findings which can redirect a patient towards more appropriate treatment and reduce the potential for long-term adverse health issues and anxiety.Case report - Case descriptionB was referred age 16 to rheumatology with a 5-year history of lower back pain. She had previously seen paediatricians with symptoms initially attributed to constipation due to intermittent straining and hard stool. However, constipation remedies had not relieved the pain which progressed gradually to a more persistent dull ache with impact on daily activities. Various analgesics (including paracetamol and non-steroidal anti-inflammatories), exercises and acupuncture had not helped. There was no history of recurrent urinary tract infections or symptom correlation with fluid intake, menstruation or bowel habit. No inflammatory features or connective tissue disease symptoms were noted and family history was unremarkable Clinical examination was normal apart from mild tenderness in the lumbar region.Rheumatoid factor was borderline positive (15 iu/mL) with the rest of blood tests normal including renal function, inflammatory markers (CRP, ESR), anti CCP and ANA. She had minimal microscopic haematuria without proteinuria. MRI spine in 2015 was normal. In view of her young age and symptoms affecting daily activities, STIR sequence spinal MRI was requested. This excluded any new or old inflammatory changes but incidentally identified a dilated left pelvi-calyceal system.Renal ultrasound confirmed a grossly hydronephrotic left kidney with hydroureter and minimal renal tissue suggesting longstanding obstruction. No calculi were seen. The patient was referred to urologists. Further investigations (including MRI abdomen) confirmed similar findings and a distal ureteric stricture. A MAG 3 renogram showed a normal right kidney but only 12% functioning of the left kidney. Urologists have advised surgery (removal of left kidney and ureter) which may relieve symptoms or a conservative non-surgical approach (continue analgesia, physiotherapy and monitoring). The patient and her family are relieved to have a possible cause identified and are considering the surgical option due to ongoing flank discomfort. Case report - DiscussionThis was an interesting finding of hydroureter and hydronephrosis causing longstanding back pain presenting to rheumatologists. Until completion of the spondyloarthropathy protocol MRI (STIR images), aetiology had been unclear. Hydronephrosis and hydroureter has no specific age or racial predilection. Signs and symptoms may depend on whether obstruction is acute/chronic. Chronic cases may be asymptomatic or present as a dull discomfort (like this case). Some cases may only present in adulthood with pain precipitated by fluid intake. Blood tests may show impaired kidney function. Post-mortem studies suggest 50% of people have at least one renal abnormality (e.g., renal cysts, duplex ureters) with autopsy series incidence of hydronephrosis reported as 3.1%. Causes include anatomical abnormalities such as vesico-ureteric reflux, urethral strictures (usually present in childhood), calculi, benign prostatic hyperplasia, or intrapelvic neoplasms, pregnancy and infections (e.g., TB). Sudden onset unilateral renomegaly was reported in one case of primary Sjogren’s with lymphocytic interstitial nephritis and positive Sjogren’s autoantibodies. Our patient has no clinical or serological evidence of connective tissue disease.Minor pelvi-calyceal distension can occur as a normal finding in well-hydrated patients and pregnancy. However, significant hydronephrosis requires assessment to determine cause as it may affect long term renal function. Imaging via computed tomography, ultrasound and urograms can help guide further management.In this case the preceding cause and duration of pathology is unknown. Sterile, giant hydronephrosis treatment options include observation and ureteric stent or nephrostomy in patients unfit for surgery. Nephrectomy is advised for pain and recurrent infection in a non-functioning kidney. Complications may include bowel perforation, vascular injury and urine leakage. Both open and minimally invasive procedures have good reported outcomes. The COVID-19 pandemic and exams have affected timing of any elective procedures and the patient understands surgery may or may not offer complete symptom resolution.Case report - Key learning pointsNon-inflammatory causes of back pain should always be considered in cases of persistent back pain, particularly in young people to ascertain if there is a treatable causeHydronephrosis cases can be asymptomatic or present with vague, intermittent, non-specific abdominal symptoms with normal physical examination with or without haematuria. This can cause diagnostic uncertainty and delay referral to urology and appropriate renal investigations Assessment of renal function (including MAG 3 renogram) is important to guide further managementSurgical interventions (pyeloplasty/nephrectomy) may ease symptoms long term but there is no guarantee of a successful outcome and operative risks need to be considered tooLeft undiagnosed, potentially this patient could have had further disruption to daily activities and both physical and mental well being

O12 A rare mimic of inflammatory arthritis

Case report - IntroductionMelorheostosis is a very rare benign bone disorder involving sclerosing hyperostosis. The name derives from the Greek terms Melos ‘limb’, rheos ‘flow’ and osteon ‘bone’. The incidence of melorheostosis is 0.9 cases per million population, and in the majority of cases is diagnosed before the age of 20 years. It presents with pain, deformities, limitations of a range of motion, contractures, muscle atrophy, and limb swelling. We present a case of a 33-year-old lady who was referred with a history of pain and swelling of the right knee.Case report - Case descriptionThis 33-year-old lady of Nigerian origin was referred to the rheumatology department with a 7-year history of fluctuating pain and swelling in the right knee with the possibility of inflammatory arthritis. Prior to this, she had been seen by the local orthopaedic team with subsequent input sought from the regional specialist orthopaedic bone unit in Birmingham. The synovial biopsies did not show any evidence of inflammation or pigmented villo-nodular synovitis (PVNS). Prior to moving to the UK, she had been assessed in Germany and Dubai due to knee pain and swelling with a diagnosis of the unclear bone-related condition and fibromyalgia. Clinically the right knee had a chronic cool swelling with reduced range of movement but no synovitis and no signs of inflammatory arthritis in other joints. There were no features of seronegative inflammatory arthritis or connective tissue diseases. Investigations showed weak positive ANA with normal CRP, bone profile, FBC, urea and electrolytes, with negative rheumatoid factor and anti-CCP antibody. X-ray knee arranged, showed a flowing periosteal thickening medial cortices of the femur and tibia consistent with ‘melorheostosis’. MRI right knee also confirmed the same diagnosis. Imaging of the upper limbs, spine and pelvis showed no involvement. Input from the metabolic bone health team was arranged who did not deem bisphosphonates useful in her case. Physiotherapy input was arranged to improve her leg posture and movements along with appropriate patient education and analgesia titration.Case report - DiscussionWe present a rare mimic of inflammatory arthritis. Initially referred by GP to orthopaedic team who considered PVNS which was ruled out by biopsies, then next question was about inflammatory arthritis due to recurrent history of knee pain and swelling which is valid differential for monoarthritis. Rheumatology assessment noted a puffy knee but no effusion to aspirate, x-ray imaging was diagnostic for melorheostosis due to the typical presence of ‘dripping wax appearance’. As rheumatologists while assessing joints, genetic and metabolic causes need to be considered besides inflammatory and infective causes. A thorough history remains essential along with interaction with radiology colleagues which is the main learning point. Case report - Key learning pointsNon-inflammatory conditions like melorheostosis can mimic inflammatory arthritisSimple imaging like X-rays and discussion with radiology colleagues are often underrated.

Acquired Esophageal Strictures in Children: Morphometric and Immunohistochemical Analyses.

Esophageal strictures (ES) in children are not well characterized pathologically. We report unique histopathologic analyses of resected acquired ES and control esophagi (CE). Muscle layer thicknesses were measured in intact well-oriented areas; inflammatory cells were counted in the most inflamed high power field (hpf). Sections were stained with relevant antibodies. Results were expressed as median, lower and upper quartiles. Wilcoxon Rank Sums non-parametric test was used to compare groups; P ≤ 0.05 was considered significant. All ES (N = 10) showed focal replacement of lamina propria, muscularis mucosa and submucosa by actin+ fibers emanating from muscularis propria. Compared to CE (N = 8), ES displayed significantly thickened muscularis mucosa and propria, and increased mast cells (tryptase- and chymase-positive), and eosinophils in muscle layers (all P ≤ 0.01). Matrix proteins periostin and fibronectin were identified in the muscle layers of CE, and in the extracellular matrix in areas of disrupted architecture in ES. Compared to CE, acquired ES in children show significant structural alterations, including obliterative muscularization, inflammatory cell mural infiltrates, and extracellular matrix protein deposits. Therapies targeting connective tissue expansion, mast cells, eosinophils and inflammation may be beneficial to treat ES.

Cardiac involvement in primary Sjӧgren's syndrome.

Primary Sjӧgren's syndrome (pSS) is an autoimmune-mediated, inflammatory, and systemic connective tissue disease (CTD), especially in middle-aged women, which often involves multiple systems and organs of the body. In fact, the heart is an important target organ in patients with pSS. In recent years, it has been confirmed that the morbidity of cardiac involvement has increased in patients with pSS, and cardiovascular disease (CVD) is one of the main causes of death. The increased risk of CVD in pSS patients is associated with a great variety of risk factors, such as age, gender, hypertension, diabetes mellitus, dyslipidemia, disease duration, extra-glandular manifestations, therapeutic drugs of pSS, and so on. Early recognition and effective treatment of CVD may play a crucial role in improving adverse cardiovascular prognosis. Whereas cardiac involvement is closely related to patient prognosis and survival, the cardiac involvement of patients with pSS remains poorly studied. Therefore, this article reviews the cardiovascular risk factors, clinical manifestations of cardiac involvement, cardiovascular biomarkers, and therapeutic strategies of pSS patients.

Serological Evidence of Borrelia burgdorferi in Patients with Morphea from West-Central Poland: An Original Paper and Review of Literature.

Morphea (localized scleroderma) is an inflammatory connective tissue disease. Borrelia burgdorferi, as a causative factor, has been discussed controversially. The aim of this original study was to evaluate the frequency of IgM and IgG classes of anti-Borrelia antibodies in groups of morphea and psoriasis patients using the traditional ELISA method. Blood samples of 82 patients with morphea and 112 patients with psoriasis vulgaris were examined for the presence of IgM and IgG classes of anti-Borrelia antibodies (ELISA). IgM and IgG classes of anti-Borrelia antibodies were detected in 4% of blood samples taken from morphea patients, while 4.5% of blood samples from patients with psoriasis vulgaris. There is one major limitation in this study that could be addressed in future research. First, the study focused on the determination of IgM and IgG classes of anti-Borrelia antibodies as a risk factor for morphea, but other infectious agents also require further testing, such as Hepatitis B, Hepatitis C, and other viral or bacterial infections. The results of this study showed no significant relationship between Borrelia infection and morphea. Detection of IgM and IgG classes of anti-Borrelia antibodies is not recommended for routine diagnostics of patients with morphea at this time.

Residual periodontal pocket treatment with Er:YAG laser-assisted comprehensive periodontal pocket therapy: a retrospective study

Recently, the application of erbium-doped yttrium aluminum garnet (Er:YAG) laser has been increasing in periodontal therapy. In this retrospective study, we evaluated the safety and effectiveness of a novel pocket therapy using Er:YAG laser in combination with conventional mechanical scaling and root planing treatment (Er:YAG laser-assisted comprehensive periodontal pocket therapy). Forty sites in 29 elderly patients having residual periodontal pockets of ≥ 5mm depth were treated by curette and Er:YAG laser from 2006 to 2009. After root debridement by curette, laser irradiation was performed on the root surfaces. Then, inflamed connective tissue on the inner gingival surface and on the bone surface/within extant bone defects was thoroughly debrided by curette and laser. Furthermore, in most cases, removal of the outer epithelium and coagulation of the blood clot in the pocket entrance were additionally performed with laser. Clinical parameters were evaluated before and 3, 6, and 12months after treatment. With Er:YAG laser-assisted pocket therapy, debridement of pockets was thoroughly and safely performed, and favorable clinical improvements were observed in most cases, without any adverse side effects and complications. After 1year, probing pocket depth significantly decreased from 6.4 ± 1.4 to 3.5 ± 1.3mm (p < 0.001, 3.0mm reduction), and clinical attachment level significantly decreased from 7.5 ± 1.6 to 5.2 ± 1.9mm (p < 0.001, 2.3mm gain). The results of this study indicate that Er:YAG laser-assisted therapy is useful for the treatment of residual pockets as a minimally invasive flapless surgery. Er:YAG laser-assisted comprehensive pocket therapy reduces the necessity of more conventional surgical therapies.

Correlation of p53 Immunoexpression with Depth of Tumor in Microinvasive Oral Squamous Cell Carcinoma

Introduction: “Oral squamous cell carcinoma (OSCC)” is a major health issue in India, the incidence of OSCC is 3-7 times more in developing countries than developed countries. OSCC is the ‘3rd most common cancer’ in India followed by “cervical and breast cancer”. One side of OSCC that has not much explore is the ‘microinvasive squamous cell carcinoma’ which is an early stage neoplasm without infiltration in the deeper tissues. There is no particular definition of “microinvasive oral squamous cell carcinoma (MIOSCC)” There are no specific guideline are present to categories the “microinvasive squamous cell carcinoma (MIOSCC)”. Most of the time the infiltrating neoplastic cells are masked under the background of the inflammatory cell infiltrate present connective tissue stroma. So this study is humble attempt to recognized and measured depth of invasion of infiltrative neoplastic cells to categories MIOSCC and to find better management protocol for it&#x0D; Aim: This study aims to: Measure p53 immunoexpression in “microinvasive oral squamous cell carcinoma, evaluate the depth of invasion in MIOSCC in H &amp; E stained section, and correlate the p53 immunoexpression with the depth of tumor in it.&#x0D; Methodology: The 25 cases of “microinvasive oral squamous cell carcinoma” will be selected and 10 cases of “normal oral mucosa (NOM)” will be obtained from “gingiva and vestibular mucosa” as controls after extraction of impacted teeth. “The depth of tumor” will be measured from the “basement membrane or in areas of basement membrane loss, from an imaginary line reconstructing the basement membrane from the adjacent epithelium to the deepest point of invasion in connective tissue” by Leica DMLB2 research microscope with Leica Q-win standard software (Switzerland).&#x0D; Results: The results show that the depth of invasion in MIOSCC, will be categorized the lesion and give the better guidelines for histological grading and treatment protocol for MIOSCC&#x0D; Conclusion: There are no definite guidelines for histological grading and final treatment protocol for MIOSCC. The assessments of depth of tumor through p53 immunoexpression may be one of the criteria for grading in MIOSCC. Thus the correlation of p53 immunoexpression with the depth of tumor in MIOSCC helps to determine the treatment modalities of MIOSCC.

Autoimmune inflammatory rheumatic diseases and COVID-19 outcomes in South Korea: a nationwide cohort study.

BackgroundReal-world evidence on the association between autoimmune inflammatory rheumatic diseases, therapies related to these diseases, and COVID-19 outcomes are inconsistent. We aimed to investigate the potential association between autoimmune inflammatory rheumatic diseases and COVID-19 early in the COVID-19 pandemic.MethodsWe did an exposure-driven, propensity score-matched study using a South Korean nationwide cohort linked to general health examination records. We analysed all South Korean patients aged older than 20 years who underwent SARS-CoV-2 RT-PCR testing between Jan 1 and May 30, 2020, and received general health examination results from the Korean National Health Insurance Service. We defined autoimmune inflammatory rheumatic diseases (inflammatory arthritis and connective tissue diseases) based on the relevant ICD-10 codes, with at least two claims (outpatient or inpatient) within 1 year. The outcomes were positive SARS-CoV-2 RT-PCR test, severe COVID-19 (requirement of oxygen therapy, intensive care unit admission, application of invasive ventilation, or death), and COVID-19-related death. Adjusted odds ratios (ORs) with 95% CIs were estimated after adjusting for the potential confounders.FindingsBetween Jan 1 and May 30, 2020, 133 609 patients (70 050 [52·4%] female and 63 559 [47·6%] male) completed the general health examination and were tested for SARS-CoV-2; 4365 (3·3%) were positive for SARS-CoV-2, and 8297 (6·2%) were diagnosed with autoimmune inflammatory rheumatic diseases. After matching, patients with an autoimmune inflammatory rheumatic disease showed an increased likelihood of testing positive for SARS-CoV-2 (adjusted OR 1·19, 95% CI 1·03–1·40; p=0·026), severe COVID-19 outcomes (1·26, 1·02–1·59; p=0·041), and COVID-19-related death (1·69, 1·01–2·84; p=0·046). Similar results were observed in patients with connective tissue disease and inflammatory arthritis. Treatment with any dose of systemic corticosteroids or disease-modifying antirheumatic drugs (DMARDs) were not associated with COVID-19-related outcomes, but those receiving high dose (≥10 mg per day) of systemic corticosteroids had an increased likelihood of a positive SARS-CoV-2 test (adjusted OR 1·47, 95% CI 1·05–2·03; p=0·022), severe COVID-19 outcomes (1·76, 1·06–2·96; p=0·031), and COVID-19-related death (3·34, 1·23–8·90; p=0·017).InterpretationEarly in the COVID-19 pandemic, autoimmune inflammatory rheumatic diseases were associated with an increased likelihood of a positive SARS-CoV-2 PCR test, worse clinical outcomes of COVID-19, and COVID-19-related deaths in South Korea. A high dose of systemic corticosteroid, but not DMARDs, showed an adverse effect on SARS-CoV-2 infection and COVID-19-related clinical outcomes.FundingNational Research Foundation of Korea.

Interstitial Lung Disease in Connective Tissue Disease: A Common Lesion With Heterogeneous Mechanisms and Treatment Considerations.

Connective tissue disease (CTD) related interstitial lung disease (CTD-ILD) is one of the leading causes of morbidity and mortality of CTD. Clinically, CTD-ILD is highly heterogenous and involves rheumatic immunity and multiple manifestations of respiratory complications affecting the airways, vessels, lung parenchyma, pleura, and respiratory muscles. The major pathological features of CTD are chronic inflammation of blood vessels and connective tissues, which can affect any organ leading to multi-system damage. The human lung is particularly vulnerable to such damage because anatomically it is abundant with collagen and blood vessels. The complex etiology of CTD-ILD includes genetic risks, epigenetic changes, and dysregulated immunity, which interact leading to disease under various ill-defined environmental triggers. CTD-ILD exhibits a broad spectra of clinical manifestations: from asymptomatic to severe dyspnea; from single-organ respiratory system involvement to multi-organ involvement. The disease course is also featured by remissions and relapses. It can range from stability or slow progression over several years to rapid deterioration. It can also present clinically as highly progressive from the initial onset of disease. Currently, the diagnosis of CTD-ILD is primarily based on distinct pathology subtype(s), imaging, as well as related CTD and autoantibodies profiles. Meticulous comprehensive clinical and laboratory assessment to improve the diagnostic process and management strategies are much needed. In this review, we focus on examining the pathogenesis of CTD-ILD with respect to genetics, environmental factors, and immunological factors. We also discuss the current state of knowledge and elaborate on the clinical characteristics of CTD-ILD, distinct pathohistological subtypes, imaging features, and related autoantibodies. Furthermore, we comment on the identification of high-risk patients and address how to stratify patients for precision medicine management approaches.

AB0903-HPR DURATION OF TELEPHONE CONSULTATIONS AMONGST RHEUMATOLOGY PRACTITIONERS IN A DISTRICT GENERAL HOSPITAL - ADAPTING TO REMOTE CONSULTATION IN A COVID-19 PANDEMIC

Background:The Covid-19 pandemic has resulted in a rapid adoption of remote consultations in order to limit face to face clinical contact wherever appropriate, as recommended by the British Society for Rheumatology. The same clinic templates which existed for face-to-face encounters have been retrospectively adapted, without consideration of any potential difference in duration of consultations. Rheumatology practitioners from a variety of clinical backgrounds work alongside the rheumatology consultants, providing clinical care to patients with both inflammatory arthritis and connective tissue disease.Objectives:To record the duration of all scheduled telephone consultations carried out by advances rheumatology practitioners in a 4-week period.Methods:All scheduled telephone clinic encounters over a 4-week period were timed and the duration recorded in a spreadsheet. Data was collected in real time by all 8 rheumatology advanced practitioners working within the rheumatology department of a district general hospital, following each clinic episode.Results:Data was recorded from a total of 337 clinic appointments. Of these, 317 (94%) were booked as routine, 3 (0.9%) as urgent, 4 (1.2%) were expedited following an advice line contact, and 13 (3.9%) no data was recorded. 28 (8%) of the patients did not answer when contacted. 80 (24%) clinic appointments lasted 15 minutes or less, 186 (55%) lasted 16 - 30 minutes, 37 (11%) lasted 31 - 45 minutes, and 6 (2%) lasted 46 - 60 minutes. The average duration was 22 minutes.Conclusion:Within this department, remote consultations appear to have a similar duration when compared against the traditional clinic template for a fully face-to-face clinic, with some encounters lasting significantly longer than the planned duration. This would appear to differ to telephone consultations used in other settings, such as general practice where the duration is reportedly shorter1. This may be representative of the additional complexity and co-morbidity of a typical rheumatology patient, or due to the multi-faceted nature of a rheumatology follow-up appointment2. Although remote consultations are effective in limiting risk of exposure to Covid-19, they may not offer a quicker or more efficient service compared with the face-to-face model. Further study in this field is required to evaluate this widely adopted new pattern of working.

POS0326 ROLE OF THE IL-25 / IL-17RB AXIS IN TH9 POLARIZATION IN PATIENTS WITH PROGRESSIVE SYSTEMIC SCLEROSIS

Background:Systemic sclerosis (SSc) is an inflammatory connective tissue disease leading to chronic and progressive fibrosis, typically affecting the skin and internal organs. The alteration of both innate and adaptive immune responses plays a pivotal role in SSc pathophysiology, although it has not yet been fully elucidated [1].Recent findings have demonstrated interleukin (IL)-9 overexpression and significant group 2 innate lymphoid cells (ILC2) expansion in patients with SSc. Th9-ILC2-mast cells axis seems to be involved in SSc tissue damage and in the induction of fibrosis [2]. Activation and production of IL-9 by Th9 cells are promoted by transforming growth factor (TGF)-β, thymic stromal lymphopoietin (TSLP), IL-25 and IL-33. Thus, the IL-25 / IL-17RB pathway would act as a key player in SSc.Objectives:The purpose of this study was to evaluate the role of the IL-25 / IL-17RB axis as a driver in Th9 polarization and ILC2 expansion and polarization in SSc patients.Methods:26 patients were enrolled in this study. Peripheral blood and skin biopsy specimens were obtained from SSc patients. PBMCs were isolated and incubated with and without recombinant (r)IL-25 for 24-48-72 hours and the frequencies of Th9 cells, Th17 cells and ILC2 were assessed by flow cytometry analysis. Moreover, the ex vivo expression of IL-17RB in ILC2 was also assessed. Immunofluorescence analysis was performed on biopsy skin samples to evaluate IL-17RB expression in ILC2.Results:In SSc samples, Th9 cells frequency progressively increased after stimulation with rIL-25, compared to healthy controls in which IL-9 frequency decreased over time regardless of rIL-25.Simultaneously, we evaluated the role of the IL-25 / IL-17RB axis in Th17 cells.In the SSc pool, the initially low rate of IL-17 increased at 72 hours after stimulation with rIL-25. In unstimulated SSc samples, the initially higher IL-17 rate decreased at 72 hours; conversely, it was consistently low in healthy controls, at both baseline and stimulated conditions.Our results confirmed the presence of IL-25-dependent clonal ILC2 expansion, suggesting a greater and progressive expansion over time in patients with SSc, compared to controls.Interestingly, increased IL-17RB expression was found in circulating ILC2 from SSc patients supporting the characterization of ILC2 inflammatory phenotype.Consistently, immunofluorescence on the skin of SSc patients showed a marked infiltrate of CD3-GATA3+ IL-17RB+ cells, confirming the presence of the activated inflammatory phenotype ILC2, absent in skin biopsies of healthy controls (Figure 1).Conclusion:These preliminary data suggest an active role of the IL-25/IL-17RB axis in SSc. It results in Th9 polarization and Th17 clonal expansion, inducing the production of IL-9 and, to a lesser extent, IL-17. Moreover, in addition to promoting Th9-mediated ILC2 differentiation, IL-25 directs the polarization of ILC2 towards the inflammatory phenotype.

Alloplastic Temporomandibular Joint Replacement in Patients With Systemic Inflammatory Arthritis and Connective Tissue Disorders

We present a retrospective study to report the outcomes of total temporomandibular joint (TMJ TJR) replacement with alloplastic devices in patients suffering from systemic inflammatory arthropathies. A total of 39 patients with a diagnosis of rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PA), juvenile idiopathic rheumatoid arthritis (JIA), or systemic lupus, underwent alloplastic total joint replacement(s) (TJR) from 1999 to 2019. Maximal interincisal opening (in mm) was recorded before surgery (T0), at 1-year post-surgery (T1) and at last follow-up (T2). A visual analog scale (from 0 to 10) was used for subjective examination of pain before surgery (T0) and at last follow-up (T2). Comparisons were conducted with statistical significance set at P < .05. Seventy-four joints were replaced in 39 patients. Thirty-two were female. The mean age was 36 years old (range 18-61) and the mean follow-up was 45.9 months (SD 49.4). The most common diagnosis was RA (n = 21), followed by JIA (n = 5) and AS (n = 5), PA (n = 4), lupus (n = 3), and mixed connective tissue disorder (n = 1). The mean pain score had fallen from 6.8 (SD 3.2) at T0 to 1.3 (SD 2.4) (P < .001) at T2. The maximal interincisal opening had improved from a mean of 22.1 mm (SD 13.3) at T0 to 34.3 mm (SD 8.5) (P < .001) at T2. One patient got persistent dysesthesia in the V3 distribution. There were no serious late complications. Patients suffering from systemic inflammatory arthropathies involving the TMJs can be successfully treated by TJR with alloplastic devices. The long-term reduction of TMJ symptoms and functional improvement in this initial study suggest good predictability for this treatment.

Genome-wide DNA methylation of the liver reveals delayed effects of early-life exposure to 17-α-ethinylestradiol in the self-fertilizing mangrove rivulus

ABSTRACT Organisms exposed to endocrine disruptors in early life can show altered phenotype later in adulthood. Although the mechanisms underlying these long-term effects remain poorly understood, an increasing body of evidence points towards the potential role of epigenetic processes. In the present study, we exposed hatchlings of an isogenic lineage of the self-fertilizing fish mangrove rivulus for 28 days to 4 and 120 ng/L of 17-α-ethinylestradiol. After a recovery period of 140 days, reduced representation bisulphite sequencing (RRBS) was performed on the liver in order to assess the hepatic genome-wide methylation landscape. Across all treatment comparisons, a total of 146 differentially methylated fragments (DMFs) were reported, mostly for the group exposed to 4 ng/L, suggesting a non-monotonic effect of EE2 exposure. Gene ontology analysis revealed networks involved in lipid metabolism, cellular processes, connective tissue function, molecular transport and inflammation. The highest effect was reported for nipped-B-like protein B (NIPBL) promoter region after exposure to 4 ng/L EE2 (+ 21.9%), suggesting that NIPBL could be an important regulator for long-term effects of EE2. Our results also suggest a significant role of DNA methylation in intergenic regions and potentially in transposable elements. These results support the ability of early exposure to endocrine disruptors of inducing epigenetic alterations during adulthood, providing plausible mechanistic explanations for long-term phenotypic alteration. Additionally, this work demonstrates the usefulness of isogenic lineages of the self-fertilizing mangrove rivulus to better understand the biological significance of long-term alterations of DNA methylation by diminishing the confounding factor of genetic variability.

Патоморфологические аспекты стриктур уретры различной этиологии

Introduction The study of the structure of strictures of various etiologies is an open and uncertain issue of modern urology. Aim To evaluate the morphological and immunohistochemical structure of strictures of various etiologies. Materials and methods The study involved postoperative tissue of a pathologically altered urethra of 110 patients aged 23 to 74 years who underwent treatment at the University Clinic of Urology, Russian National Research Medical University. N.I. Pirogova (2014-2018) with Ds: urethral stricture. Morphological study: Van-Gieson staining; hemotoxylin - eosin. Immunohistochemical study: mouse monoclonal antibodies to muscle and connective tissue markers (Smooth Muscle Actin, Vimentin, Calponin) and inflammation markers (CD45R, CD58, CD138, CD20, CD3) were used as primary antibodies in all reactions. Results According to the revealed morphological changes, the material was divided into three groups: group I (n=27) - active inflammation; group II (n=33) - the predominant development of connective tissue with low activity of inflammation; group III (n=50) - mixed (chronic mild inflammation, an even amount of connective tissue). In a morphological study of idiopathic urethral strictures, it was noted that the multicolumnar epithelium was replaced by a multi-layer flat epithelium with a weakly pronounced keratinization. Inflammatory changes were mild, including the submucosal connective tissue and the spongy body. Spongiofibrosis is accompanied by a significant reduction in the vascular bed of both venous sinuses and arteries. The same changes were observed in the inflammatory genesis of urethral strictures. In the study of strictures with traumatic etiology, a restructuring of the cylindrical epithelium was observed. In cases with severe inflammation in the mucosa, the changes were atrophic-hyperplastic in nature with reactive cell atypia. Conclusion urethral Strictures in men have a specific etiological factor, but the pathogenesis of urethral lesions can be divided into: post-traumatic and post-inflammatory.

The Relationship Among Intra-Amniotic Inflammatory Response, The Progression of Inflammation in Chorionic Plate and Early-Onset Neonatal Sepsis.

Background: The chorionic plate (CP) has been denigrated by the well-known route of the extraplacental membranes from the decidua parietalis through the chorion to the amnion in the progression of ascending intrauterine infection among preterm births (PTBs). However, considering previous studies reporting the relationship among intra-amniotic inflammatory response (IAIR), the progression of inflammation in extraplacental membranes and early-onset neonatal sepsis (EONS), and the anatomic connection between extraplacental membranes and CP, there is a good chance that IAIR would be more likely and severe according to the progression of inflammation in CP, and this progression of inflammation in CP would be associated with a significant increase in EONS in neonates delivered due to either PTL or preterm-PROM. Unfortunately, there is no information about the relationship among IAIR, the progression of inflammation in CP, and EONS among spontaneous PTBs. The objective of the current study is to examine this issue.Method: The study population included 309 singleton pregnant women-delivered preterm neonates with the following conditions: (1) gestational age (GA) at delivery: 20.0~36.9 weeks; (2) spontaneous PTBs: PTL (151 cases) or preterm-PROM (158 cases); (3) available results of placental histologic examination; (4) without congenital anomaly; and (5) delivery within 60 h of amniocentesis. We examined IAIR, and the frequency of intra-amniotic inflammation (IAI) and EONS according to the progression of inflammation in CP [i.e., stage-0, inflammation-free CP; stage-1, inflammation restricted to subchorionic fibrin (SCF); stage-2, inflammation in connective tissue (CT) of CP but without chorionic vasculitis; and stage-3, chorionic vasculitis]. IAIR was determined by amniotic fluid (AF) matrix metalloproteinase-8 (MMP-8) concentration (ng/ml), and IAI was defined as an elevated AF MMP-8 concentration (≥23 ng/ml). EONS included either suspected or proven EONS.Results: (1) Each stage (stage-0 to stage-3) was present in 69.3% (214/309), 15.9% (49/309), 11.0% (34/309), and 3.9% (12/309) of the study population. (2) AF MMP-8 concentrations continuously elevated according to the progression of inflammation in CP [stage-0 vs. stage-1 vs. stage-2 vs. stage-3; median (ng/ml), range (ng/ml); 6.0 (0.3–4202.7) vs. 153.9 (0.3–6142.6) vs. 464.9 (5.8–3929.0) vs. 1,780.4 (35.1–5019.5); Kruskal–Wallis test, P < 0.001 and Spearman's rank-correlation test, P < 0.000001, r = 0.553]. (3) Moreover, the frequency of IAI and EONS gradually increased with the progression of inflammation in CP [stage-0 vs. stage-1 vs. stage-2 vs. stage-3; IAI, 30.5% (64/210) vs. 70.2% (33/47) vs. 96.7% (29/30) vs. 100% (12/12); EONS, 3.5% (7/200) vs. 25.5% (12/47) vs. 32.3% (10/31) vs. 40.0% (4/10); each for Pearson's chi-square test, P < 0.000001 and linear-by-linear association, P < 0.000001]. (4) Of note, multiple logistic regression analysis demonstrated that a more advanced stage in the progression of inflammation within CP was associated with a higher odds ratio (OR) for EONS [stage-1 vs. stage-2 vs. stage-3; OR, 7.215, 95% confidence-interval (CI) (2.177–23.908) vs. OR, 10.705, 95% CI (2.613–43.849) vs. OR, 27.189, 95% CI (2.557–289.124)] compared with stage-0 even after the adjustment for potential confounding variables.Conclusion: IAIR is more likely and severe according to the progression of inflammation in CP, and this progression of inflammation in CP is an independent risk factor for EONS in spontaneous PTBs. This finding suggests that CP may be another playground for the progression of ascending intrauterine infection in addition to extraplacental membranes, and the progression of inflammation in CP may be used for the prediction of EONS in spontaneous PTBs.

Invasive Aortic Valve Endocarditis: Clinical and Tissue Findings From a Prospective Investigation

BackgroundAdvanced aortic valve infective endocarditis (IE) with progression and destruction beyond the valve cusps—invasive IE—is incompletely characterized. This study aimed to characterize further the invasive disease extent, location, and stage and correlate macroscopic operative findings with microscopic disease patterns and progression. MethodsA total of 43 patients with invasive aortic valve IE were prospectively enrolled from August 2017 to July 2018. Of these patients, 23 (53%) had prosthetic valve IE, 2 (5%) had allograft IE, and 18 (42%) had native aortic valve IE. Surgical findings and intraoperative photography were analyzed for invasion location, extent, and stage. Surgical samples were formalin fixed and analyzed histologically. The time course of disease and management were evaluated. ResultsPathogens included Staphylococcus aureus in 17 patients (40%). Invasion predominantly affected the non–left coronary commissure (76%) and was circumferential in 15 patients (35%) (14 had prosthetic valves). Extraaortic cellulitis was present in 29 patients (67%), abscess in 13 (30%), abscess cavity in 29 (67%), and pseudoaneurysm in 8 (19%); 7 (16%) had fistulas. Histopathologic examination revealed acute inflammation, abscess formation, and lysis of connective tissue but not of myocardium or elastic tissue. Median time from onset of symptoms to antibiotics was 5 days, invasion confirmation 15 days, and surgery 37 days. Patients with S aureus had a 21-day shorter time course than patients non–S aureus. New or worsening heart block developed in 8 patients. ConclusionsAdvanced invasive aortic valve IE demonstrates consistent gross patterns and stages correlating with histopathologic findings. Invasion results from a confluence of factors, including pathogen, time, and host immune response, and primarily affects the fibrous skeleton of the heart and expands to low-pressure regions.

Mechanisms That Underly T Cell Immunity in Graves' Orbitopathy.

Graves’ orbitopathy (GO), also known as thyroid-associated ophthalmopathy, is the most common ocular abnormality of Graves’ disease. It is a disfiguring, invalidating, and potentially blinding orbital disease mediated by an interlocking and complicated immune network. Self-reactive T cells directly against thyroid-stimulating hormone receptor-bearing orbital fibroblasts contribute to autoimmune inflammation and tissue remodeling in GO orbital connective tissues. To date, T helper (Th) 1 (cytotoxic leaning) and Th2 (antibody leaning) cell subsets and an emerging role of Th17 (fibrotic leaning) cells have been implicated in GO pathogenesis. The potential feedback loops between orbital native residential CD34- fibroblasts, CD34+ infiltrating fibrocytes, and effector T cells may affect the T cell subset bias and the skewed pattern of cytokine production in the orbit, thereby determining the outcomes of GO autoimmune reactions. Characterization of the T cell subsets that drive GO and the cytokines they express may significantly advance our understanding of orbital autoimmunity and the development of promising therapeutic strategies against pathological T cells.

Identification and functional analysis of a novel phospholipase D2 gene mutation associated with familial systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a kind of autoimmune inflammatory connective tissue disease which seriously endangers human health. Genetic factors play a key role in the pathogenesis of SLE. This study aims to investigate a novel phospholipase D2 (PLD2) mutation associated with familial SLE, and further explore the underlying mechanism of the mutation in SLE. The blood samples from a SLE patient, the patient's parents, and 147 normal controls were collected and DNA was extracted. Whole genome high-throughput sequencing was performed in the patient and her parents and the results were further analyzed by various bioinformatics methods. The wild type (wt), mutant type (mu), and negative control PLD2 plasmids were further constructed and transfected into 293 cells. The expression level of HRAS protein in 293 cells was detected by Western blotting. In this SLE family, the female SLE patient and her mother, 1 in generation II and 1 in generation III had typical clinical manifestations of SLE, and all of them had lupus nephritis at early stage. The genetic characteristics are consistent with autosomal dominant inheritance. A novel PLD2 heterozygous mutation (c.2722C>T) was found in the patient and her mother, but not in her father and other normal controls. Compared with wtPLD2 plasmid and negative control PLD2 plasmid, the expression of HRAS in 293 cells transfected with muPLD2 plasmid was significantly up-regulated (both P<0.05). PLD2 c.2722C>T mutation may be one of the pathogeny of SLE in this family.

Maternal autoimmune disease is not associated with cancer in the offspring.

Autoimmune disease and its medication are associated with increased cancer risk in adults, but it is unknown whether maternal autoimmune disease and/or medication use in pregnancy are associated with increased cancer risk in offspring. In this case-control study, we identified all patients under 20years of age with their first cancer diagnosis in 1996-2014 from the Finnish Cancer Registry (n=2029) and 1:5 population-based controls (n=10,103) from the Medical Birth Register. We obtained information on maternal autoimmune disease and its medication from the relevant Finnish registries and used conditional logistic regression to analyse the risk of offspring cancer after maternal autoimmune disease exposure. The odds ratio (OR) for cancer in offspring following maternal autoimmune exposure was 0.76 (95% confidence interval [CI] 0.47-1.23). Individual ORs for inflammatory bowel and connective tissue diseases were 1.08 (95% CI 0.56-2.01) and 0.50 (95% CI 0.23-1.08), respectively. The OR for maternal autoimmune medication was 0.95 (95% CI 0.80-1.14) overall and similar by drug subtype. There was an increased risk with medication in late pregnancy but the ORs were unstable owing to small numbers. Our study does not support an increased cancer risk among offspring of women with autoimmune disease or its medication during pregnancy.