Undifferentiated Connective Tissue Disease Research Articles

Altered gut fungi in systemic lupus erythematosus - A pilot study.

Gut fungi, as symbiosis with the human gastrointestinal tract, may regulate physiology via multiple interactions with host cells. The plausible role of fungi in systemic lupus erythematosus (SLE) is far from clear and need to be explored. A total of 64 subjects were recruited, including SLE, rheumatoid arthritis (RA), undifferentiated connective tissue diseases (UCTDs) patients and healthy controls (HCs). Fecal samples of subjects were collected. Gut fungi and bacteria were detected by ITS sequencing and 16S rRNA gene sequencing, respectively. Alpha and beta diversities of microbiota were analyzed. Linear discriminant analysis effect size analysis was performed to identify abundance of microbiota in different groups. The correlation network between bacterial and fungal microbiota was analyzed based on Spearman correlation. Gut fungal diversity and community composition exhibited significant shifts in SLE compared with UCTDs, RA and HCs. Compared with HCs, the alpha and beta diversities of fungal microbiota decreased in SLE patients. According to principal coordinates analysis results, the constitution of fungal microbiota from SLE, RA, UCTDs patients and HCs exhibited distinct differences with a clear separation between fungal microbiota. There was dysbiosis in the compositions of fungal and bacterial microbiota in the SLE patients, compared to HCs. Pezizales, Cantharellales and Pseudaleuria were enriched in SLE compared with HCs, RA and UCTDs. There was a complex relationship network between bacterial and fungal microbiota, especially Candida which was related to a variety of bacteria. This study presents a pilot analysis of fungal microbiota with diversity and composition in SLE, and identifies several gut fungi with different abundance patterns taxa among SLE, RA, UCTDs and HCs. Furthermore, the gut bacterial-fungal association network in SLE patients was altered compared with HCs.

Reactive perforating collagenosis and systemic lupus erythematosus: A rare case report

Transepidermal clearance of altered collagen and excessive excretion of keratin are characteristics of a rare cutaneous disorder known as reactive perforating collagenosis (RPC). There are different forms of RPC; however, the acquired form is the most prevalent and inherited. Reactive perforating collagenosis is rarely described in autoimmune rheumatic diseases; instead, it is typically linked to systemic conditions such as renal failure or hepatic disease. A 31-year-old Saudi female patient who was initially diagnosed with undifferentiated connective tissue disease. She developed RPC with a severe diffuse itchy skin rash with numerous papules and nodules with central hyperkeratotic plugs over the lower limb, upper limb, and face. The patient tested positive for antinuclear antibody; however, a year later, patient developed Raynaud's phenomenon, oral and nasal ulcers, malar rash, fatigue, and lupus rash around her eyes, and systemic lupus erythematosus was diagnosed clinically. The patient was treated for reactive perforating collagenosis with systemic antihistamines (diphenhydramine 50 mg orally twice daily), topical steroid cream (betamethasone dipropionate cream), and oral isotretinoin (20 mg daily). The patient was advised to undergo phototherapy. A year later, she presented with symptoms of systemic lupus erythematosus and started taking oral hydroxychloroquine 200 mg twice daily for systemic lupus erythematosus. The patient is listed on follow-up. Variable skin rash can mimic systemic lupus erythematosus and vasculitis. Therefore, reactive perforating collagenosis is a skin condition that requires high clinical suspension for diagnosis, and it might be challenging to determine whether it is an association or a complication. Furthermore, the timing of the skin biopsy may be crucial for the diagnosis of reactive perforating collagenosis.

Safety of Gam-COVID-Vac (Sputnik V) Combined Vector Vaccine in Patients With Immunoinflammatory Rheumatic Diseases: Preliminary Data

Background . Patients with autoimmune and inflammatory rheumatic diseases (AIRDs) are at high risk of developing COVID-19. Vaccination is an effective method of preventing this disease, which may be unsafe for patients with AIRDs. The aim of the study is to assess the safety of Gam-COVID-Vac in patients with IVRD in real clinical practice. Material and methods . A cross-sectional study was carried out. The main group consisted of patients with AIRDs, the control group consisted of individuals without AIRDs. All participants were interviewed by the research physician using a unified questionnaire, additional information was obtained from medical records. Results . The study included 222 patients with AIRDs (119 with rheumatoid arthritis, 36 with ankylosing spondylitis, 17 with psoriatic arthritis, 17 with Sjögren's disease, 10 with undifferentiated spondyloarthritis, 8 with systemic lupus erythematosus, 4 with metabolic arthritis, 3 with systemic scleroderma, 3 with systemic vasculitis, 2 with polymyalgia rheumatica, 2 with undifferentiated systemic connective tissue disease, 1 with adult Still's disease) and 111 patients without AIRDs. The number of patients with AIRDs who had a combination of local and systemic adverse events (AE) on the introduction of the first component of the vaccine was significantly less than in the control group (22.1 and 44.1%, respectively, P<0.001). Similar differences were also noted after the introduction of the second component (14.0 and 29.7%, respectively, P<0.001). AEs such as pain at the injection site without restriction of movement, weakness, fever, arthralgia/myalgia, headache, and chills were significantly more common in the control group after the introduction of the first component of the vaccine. After complete immunization, AEs were absent in 35.6% of patients with AIRDs and in 21.6% of control group patients (P=0.01). Exacerbations of AIRDs and new autoimmune phenomena were not registered in any cases. Conclusions . According to preliminary data, immunization of patients with AIRDs with the Gam-COVID-Vac combined vector vaccine appears to be quite safe.

Impact of pregnancy on progression of preclinical autoimmune disorders: a prospective cohort study.

The objective of this study was to evaluate the role of pregnancies in the progression from the preclinical phase of autoimmune disorder to a definite rheumatic disease. A cohort study of women with symptoms and laboratory findings suggestive for autoimmune disorder were enrolled during the first trimester of pregnancy and followed-up for 5 years with clinical and laboratory assessment. Multinomial logistic regression was used to compute the risk of progression to definite autoimmune disease correcting for confounders. At the end of follow-up, out of 208 subjects, 81 (38.9%) were considered negative, 53 (25.5%) had symptoms and abnormalities of autoantibody profile compatible with a non-criteria rheumatic status and 74 (35.6%) had a definite rheumatic disease (43 undifferentiated connective tissue disease, 5 systemic lupus erythematosus, 3 SS, 10 antiphospholipid syndrome, and 12 miscellaneous autoimmune disorders). The median time from enrolment to definite diagnosis was 28 months (interquartile range = 18-42). The rate of progression towards a definite autoimmune disease was 47.1% (48/102) among subjects with one or more subsequent viable pregnancies compared with 24.5% (26/106) of those with no subsequent pregnancies (adjusted odds ratio = 4.9, 95% CI: 2.4, 10). The occurrence of preeclampsia during the index pregnancy or subsequent pregnancy was an additional and independent risk factor for progression to a definite autoimmune disease (adjusted odds ratio = 4.3, 95% CI: 1.2, 14.8). Among women with suspected autoimmune disease during pregnancy, additional viable pregnancies and diagnosis of preeclampsia were independently associated with an increased rate of progression to definite rheumatic disorder. Hormonal modifications associated with pregnancy could worsen preclinical rheumatic disorders favouring their progression to a defined autoimmune disease.

ODP592 Delay in Diagnosis of Adult with Familial Hypophosphatasia

Abstract Background Familial Hypophosphatasia (HPP) is a rare genetic disorder characterized by defecitve bone and/or teeth mineralization in the presence of low alkaline phosphatase activity due to loss-of-function mutations in the Alkaline Phosphatase, Biomineralization Associated (ALPL) gene. HPP typically presents in middle age with a mild phenotype. Case Presentation A 43-year-old woman with PMH undifferentiated connective tissue disease and GERD referred to endocrinology clinic. She was previously diagnosed with schleroderma and was treated with prednisone and hydroxychloroquine without symptom improvement. Symptoms included: progressing bone, joint, and muslce pain; unsteady gait; proximal muscle weakness; fatigue; early loss of deciduous teeth; loss of teeth mineralization; history of finger and toe fractures from repetitive stress. Family History: Mother: ongoing joint/muscle pain as well as tooth loss. Daughter: failure to thrive, kyphosis, orthopedic problems, required leg casting for 1 year. Physical Exam: unrevealing (limited due to video visits). Significant Laboratory/Imaging Findings: Serum alkaline phosphatase (ALP): 16 U/L (ref. 35-140 U/L)Vitamin B6: 235.3 nmol/L (ref. 20-125 nmol/UL)Calcium: 9.3 mg/dL (ref. 8.5-10.6 mg/dL).Dual energy X-ray absorptiometry (DXA): normal bone mass for age.Genetic testing: one heterozygous pathogenic variant in ALPL, c.318G>C (p.CIn106His). Treatment Course: Genetic testing consistent with a diagnosis of familial HPP, specifically juvenile onset. Initiated on Asfotase-alfa, an alkaline phosphatase enzyme replacement therapy. Screening prior to treatment: Renal ultrasonography without ectopic calcificationOpthalmology exam without calficiations identified Discussion HPP should be suspected in patients with defective mineralization of bone and/or teeth in the setting of an unexplained low serum ALP activity and elevated Vitamin B6 level. Non-specific symptoms such as bone, joint, and muscle pain are common presenting symptoms in adults with HPP. Treatment with asfotase-alfa may be considered for adults with symptom onset in childhood, including early loss of deciduous teeth. Early diagnosis and treatment may improve overall quality of life. At this time, there are no guidelines for selecting adult patients for treatment with alfoterase-alfa. Further studies are needed to evaluate the benefits of enzyme replacement therapy among adults with HPP. Presentation: No date and time listed

Diastolic dysfunction in late postmenopausal patients with undifferentiated connective tissue disease and hypertension

Aim. To assess myocardial diastolic function (DF) in late postmenopausal women with undifferentiated connective tissue disease (UCTD) and hypertension (HTN).Material and methods. This cross-sectional study included 135 postmenopausal women, the median age of which was 68 years (65÷70,5 years). The anamnesis was collected using a standardized questionnaire. Verification of UCTD was carried out according to clinical guidelines. All patients underwent standard transthoracic echocardiography. The assessment of left ventricular (LV) DF was carried out according to the transmitral flow. LV diastolic dysfunction (DD) was classified into three types: rigid, pseudonormal, and restrictive. Statistical processing was carried out in the STATISTICA 13.0 environment. The measure of data averaging is the median, the measure of dispersion is 25%÷75%. The significance of differences was assessed using the Mann-Whitney test. Differences were considered significant at p˂0,05.Results. Group 1 — 20 (14,8%) patients with verified UCTD and HTN, group 2 — 88 (65,2%) patients with HTN without UCTD, control group — 23 (30%) patients without HTN and UCTD. There were no differences in age, duration of postmenopause and body mass index between the groups. In the first group, a significant decrease in the ratio of peak early to late diastolic LV filling velocity was revealed (p˂0,01). A significant increase in left ventricular end-systolic wall stress revealed in group 1. In 108 (100%) patients, LVDD was detected; among the patients of the control group, DD was not detected. In 8 (40%) patients in group 1, a pseudo-normal type of DD was detected, while in 12 out of 20 patients (60%) — rigid type of DD. When assessing DF in patients of group 2, a significant decrease was found in the ratio of peak early to late diastolic LV filling velocity, a significant increase in LV end-diastolic wall stress and end-diastolic pressure. In 2 out of 3 (57,80%) patients of group 2, DD of the rigid type was detected, while pseudonormal type — in 32,2% of patients in this group. Group 2 patients had a significant decrease in the early diastolic mitral annular velocity (p˂0,01).Conclusion. The analysis of myocardial echocardiographic characteristics indicates a significant contribution of HTN-associated UCTD to the development of LVDD in postmenopausal women.

Standardized diagnosis and treatment of undifferentiated connective tissue disease and mixed connective tissue disease

Undifferentiated connective tissue disease (CTD) usually refers to patients who are presented with certain symptoms and signs related to CTD, and positive serological evidence of autoimmune diseases but don't fulfill any of the classification criteria for a certain CTD. Mixed CTD refers to patients who are presented with one or more clinical manifestations such as hand swelling, synovitis, myositis, Raynaud's phenomenon, and acrosclerosis. Patients with mixed CTD always have high-titer anti-nuclear antibodies (ANA) of speckled pattern and high-titer anti-U1 ribonuclear protein (RNP) antibody in serum, while with negative anti-Sm antibody. The update of diagnosis and treatment of undifferentiated CTD and mixed CTD lags behind other established CTD. There is a lack of evidence from randomized controlled trials or guidelines/recommendations on the treatment of undifferentiated CTD or mixed CTD. At present, the conventional therapy is mainly adopted according to the specific clinical manifestations of the disease. The standardized diagnosis and treatment of undifferentiated CTD and mixed CTD were drafted by the Chinese Rheumatology Association based on the previous guidelines and the progress of available evidence, so as to improve the management of these patients in China.

Frequency of ANA/DFS70 autoantibodies in Colombian patients with undifferentiated connective tissue disease.

The objective was to describe the clinical characteristics and the frequency of the ANA/DFS70 autoantibodies in patients affected by undifferentiated connective tissue disease (UCTD) in a tertiary hospital in Colombia. This descriptive cross-sectional study enrolled patients who fulfilled the classification criteria for UCTD. ANAHEp- 2 test and the modified assay for ANA/DFS70 autoantibodies were performed through the indirect immunofluorescence technique. Erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, and the antibodies to anti-extractable nuclear antigens, DNA, phospholipids (IgG, IgM, IgA), and cyclic citrullinated peptide were also evaluated. Fifty-three patients were studied; 42/53 (79%) tested positive for ANA and 5/42 (11.9%) for ANA/DFS70 antibodies with a dense fine speckled fluorescent pattern (AC-2) in ANA HEp-2 test that was confirmed by a modified HEp-2-DFS70 assay. Patients had arthralgia (87%, n=47), non-erosive arthritis (66%, n=34), xerostomia (64%, n=34), xerophthalmia (42%, n=22), and Raynaud's phenomenon (17%, n=9). Arthralgia, xerophthalmia, xeroderma, and absence of disease evolution to a specific disease over five years were more frequent in patients with a positive result for the anti-DFS70 antibodies. The ANA/DFS70 autoantibodies were more frequent in patients with UCTD compared to other rheumatic diseases for which they were initially evaluated. More studies are required to support the predictive role of this antibody to the absence of progression to a well-defined connective tissue disease.

Analysis of Ana/Dfs70 Pattern in a Large Cohort of Autoimmune/Autoinflammatory Diseases Compared with First Degree Relatives and Healthy Controls Evaluated from Colombia.

Background: The presence of Antinuclear antibodies/Dense Fine Speckled 70 (ANA/DFS70) has been proposed as a negative biomarker in the process of exclusion of systemic autoimmune/autoinflammatory rheumatic diseases (SARD). The purpose was to evaluate and characterize ANA/DFS70 patients in a large Colombian population with SARD; rheumatoid arthritis (RA), Psoriasis (PsO), Undifferentiated connective tissue disease (UCTD), first-degree relatives of (FDR), and healthy controls (HC). Methods: ANA determination was performed using indirect immunofluorescence. Samples with positive dense fine granular staining in the nucleoplasm of the interphase cell (AC2) fluorescence were confirmed with CytoBead/ANA and ANA/modified (Knocked out for the PSPI1 gen). Results: 530 mestizo Colombian participants were included. ANA/DFS70 antibody positivity in the whole group was 2.3%, and 0.8% in SARD; no RA patients were positive. ANA/DFS70 positives in UCTD were three women; the average time of evolution of the disease was 9.4 years. The most frequent clinical findings were arthralgias, non-erosive arthritis, and Raynaud’s phenomenon. The PsO positive was a woman with C-reactive protein (CRP) positivity and a negative erythrocyte sedimentation rate (ESR) without any other positive autoantibody or extracutaneous manifestation. FDR and HC positives were 7/8 women. All were negative for other autoantibodies. Conclusions: ANA/DFS70 autoantibodies were present in Colombian patients with SARD at a shallow frequency, they were more prevalent in healthy individuals.

Insights into molecular and clinical characteristics of very early systemic sclerosis.

The early heterogenous presentation of systemic sclerosis (SSc), in particular without skin involvement, has been a confounding factor delaying early diagnosis. In fact, early signs of SSc as Raynaud's phenomenon and puffy fingers, are also typical of other connective tissue diseases (CTDs) such as mixed CTD and undifferentiated CTD. In the last decade, a significant effort has been dedicated in defining molecular characteristics that could be used as early SSc biomarkers. In this narrative review, we address the present situation where several clinical scenarios are in search of a correct positioning into the prescleroderma (pre-SSc) phase as well as in the very early phase of SSc. Literature data showed that a part of patients classified as sine scleroderma SSc (ssSSc), mixed CTD and undifferentiated CTD may already belong to the very early phase of SSc, thus having a different pattern of progression to SSc. Recently, the very early diagnosis of systemic sclerosis (VEDOSS) criteria has been validated. while the area of pre-SSc still remains fuzzy, the VEDOSS study has shown that a 'window of opportunity' does exist also for SSc. In the very next future, this may allow to start the treatment to prevent the disease progression to a more advanced fibrotic stage.

Machine Learning for the Identification of a Common Signature for Anti-SSA/Ro 60 Antibody Expression Across Autoimmune Diseases.

Anti-Ro autoantibodies are among the most frequently detected extractable nuclear antigen autoantibodies, mainly associated with primary Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), and undifferentiated connective tissue disease (UCTD). This study was undertaken to determine if there is a common signature for all patients expressing anti-Ro 60 autoantibodies regardless of their disease phenotype. Using high-throughput multiomics data collected from the cross-sectional cohort in the PRECISE Systemic Autoimmune Diseases (PRECISESADS) study Innovative Medicines Initiative (IMI) project (genetic, epigenomic, and transcriptomic data, combined with flow cytometry data, multiplexed cytokines, classic serology, and clinical data), we used machine learning to assess the integrated molecular profiling of 520 anti-Ro 60+ patients compared to 511 anti-Ro 60- patients with primary SS, patients with SLE, and patients with UCTD, and 279 healthy controls. The selected clinical features for RNA-Seq, DNA methylation, and genome-wide association study data allowed for a clear distinction between anti-Ro 60+ and anti-Ro 60- patients. The different features selected using machine learning from the anti-Ro 60+ patients constituted specific signatures when compared to anti-Ro 60- patients and healthy controls. Remarkably, the transcript Z score of 3 genes (ATP10A, MX1, and PARP14), presenting with overexpression associated with hypomethylation and genetic variation and independently identified using the Boruta algorithm, was clearly higher in anti-Ro 60+ patients compared to anti-Ro 60- patients regardless of disease type. Our findings demonstrated that these signatures, enriched in interferon-stimulated genes, were also found in anti-Ro 60+ patients with rheumatoid arthritis and those with systemic sclerosis and remained stable over time and were not affected by treatment. Anti-Ro 60+ patients present with a specific inflammatory signature regardless of their disease type, suggesting that a dual therapeutic approach targeting both Ro-associated RNAs and anti-Ro 60 autoantibodies should be considered.

Development of Systemic Autoimmune Diseases in Healthy Subjects Persistently Positive for Antiphospholipid Antibodies: Long-Term Follow-Up Study

We longitudinally followed a single-center cohort of anti-phospholipid (aPL) positive healthy subjects to evaluate the evolution to systemic autoimmune diseases (sAD) and to describe clinical and serological associated features. Since 2010, we have consecutively screened healthy subjects who were positive, in at least two consecutive determinations, for one or more aPL [anti-Cardiolipin (aCL) IgM/IgG, anti-Beta2Glycoprotein I (aB2GPI) IgM/IgG, Lupus Anticoagulant (LA)]. All subjects were evaluated every six months, or in accordance with the patient’s clinical course, in order to record the development of clinical and laboratory features suggestive for sAD. Ninety-five subjects [M/F 20/75, median age at first determination 46 years, Interquartile Range (IQR) 19] were enrolled. Thirty-three subjects (34.7%) were positive for only one aPL [15 (15.8%) for aCL, 15 (15.8%) for LA, and 5 (5.3%) for aB2GPI]; 37 (38.9%) had double positivity [32 (33.6%) for aCL and aB2GPI; 5 (5.3%) for aCL and LA], 23 (24.2%) had triple positivity. We prospectively followed up our cohort for a median period of 72 months (IQR 84). During a total follow-up of 7692 person-months, we found an absolute risk for sAD development equal to 1.8%. Specifically, 14 (14.7%) patients developed a sAD: in four patients (4.2%), after developing a thrombotic event, an antiphospholipid syndrome was diagnosed, 7 (7.4%) patients developed an Undifferentiated Connective Tissue Disease after a median period of 76 months (IQR 75.5), and lastly, three (3.1%) patients could be classified as affected by Systemic Lupus Erythematosus according to the ACR/EULAR 2019 criteria. The presence of triple positivity status resulted in being significantly associated with the progression to sAD (p-value = 0.03). In conclusion, we observed the development of sAD in almost 15% of aPL positive subjects. Triple positivity was significantly associated with this progression, suggesting a possible role as biomarker for this condition. Thus, our results could suggest the need for periodic follow-up for such patients to assess early diagnosis and treatment.

The enigma of mixed connective tissue disease—challenges in routine care

ObjectivesAs a rare and heterogeneous disease, mixed connective tissue disease (MCTD) represents a challenge. Herein, we aimed to unravel potential pitfalls including correct referral diagnosis, distinction from other connective tissue diseases (CTD) and treatment modalities.MethodsWe characterised the MCTD cohort at our tertiary referral centre. All patients were evaluated for fulfilment of classification criteria of various CTDs. SLEDAI-2 K and EUSTAR-AI were used in accordance with previous research to evaluate disease activity and treatment response.ResultsOut of 85 patients initially referred as MCTD, only one-third (33/85, 39%) fulfilled the diagnostic MCTD criteria and the other patients had undifferentiated CTD (16/85, 19%), non-MCTD overlap syndromes (11/85, 13%) and other rheumatic diseases. In our final cohort of 33 MCTD patients, 16 (48%) also met the diagnostic criteria of systemic sclerosis, 13 (39%) these of systemic lupus erythematosus, 6 (18%) these of rheumatoid arthritis and 3 (9%) these of primary myositis. Management of MCTD required immunomodulating combination therapy in most cases (15/28, 54%), whereas monotherapy was less frequent (10/28, 36%), and only a few (3/28, 11%) remained without immune modulators until the end of the follow-up period. Treatment led to a significant decline in disease activity.ConclusionsOur study showed a high risk for misdiagnosis for patients with MCTD. As a multi-organ disease, MCTD required prolonged immunomodulating therapy to achieve remission. The establishment of an international registry with longitudinal data from observational multi-centre cohorts might represent a first step to address the many unmet needs of MCTD.Key Points• This cohort study aimed to identify challenges in the highly complex management of MCTD.• Clinical presentation of MCTD significantly overlaps with that of other CTDs, leading to a high risk of misdiagnosis.• Manifestations of MCTD are highly variable and potentially life-threatening, requiring continued immunomodulating treatment in most cases.• A composite score based on SLEDAI-2 K and EUSTAR-AI measures could represent an easy applicable tool to monitor disease activity and treatment response.

Systemic Autoimmune Diseases in Patients Hospitalized with COVID-19 in Spain: A Nation-Wide Registry Study.

We aimed to evaluate the clinical outcome of Systemic Autoimmune Diseases (SADs) patients hospitalized with COVID-19 in Spain, before the introduction of SARS-CoV-2 vaccines. A nationwide, retrospective and observational analysis of the patients admitted during 2020, based on the ICD10 codes in the National Registry of Hospital Discharges, was performed. Among 117,694 patients, only 892 (0.8%) presented any type of SAD before COVID-19-related admission: Sjogren’s Syndrome constituted 25%, Systemic Vasculitides 21%, Systemic Lupus Erythematosus 19%, Sarcoidosis 17%, Systemic Sclerosis 11%, Mixed and Undifferentiated Connective Tissue Disease 4%, Behçet’s Disease 4% and Inflammatory Myopathies 2%. The in-hospital mortality rate was higher in SAD individuals (20% vs. 16%, p < 0.001). After adjustment by baseline conditions, SADs were not associated with a higher mortality risk (OR = 0.93, 95% CI 0.78–1.11). Mortality in the SADs patients was determined by age (OR = 1.05, 95% CI 1.04–1.07), heart failure (OR = 1.67, 95% CI 1.10–2.49), chronic kidney disease (OR = 1.29, 95% CI 1.05–1.59) and liver disease (OR = 1.97, 95% CI 1.13–3.44). In conclusion, the higher COVID-19 mortality rate seen in SADs patients hospitalized in Spain in 2020 was related to the higher burden of comorbidities, secondary to direct organ damage and sequelae of their condition. Whilst further studies should evaluate the impact of baseline immunosuppression on COVID-19 outcomes in this population, efforts should be focused on the optimal management of SAD to minimize the impact of the organ damage that has been shown to determine COVID-19 prognosis.

Surgical Specifics of Lower Limb Superficial Thrombophlebitis Combined with Undifferentiated Connective Tissue Disease

Background. Superficial thrombophlebitis of lower extremities is among the most frequent acute vascular pathologies. Concomitant undifferentiated connective tissue dysplasia exerts specific changes in its clinical course.Aim: A study of the specific dynamics of acute lower limb superficial thrombophlebitis (ST) and its surgical treatment in patients with undifferentiated connective tissue dysplasia (UCTD).Materials and methods. The case histories, surgery reports and follow-up examinations of patients treated at the Vascular Surgery Unit during 2012–2020 were analysed. A total of 86 patients had signs of UCTD and underwent classical crossectomy of the great saphenous vein (Troyanov operation).Results and discussion. Duplex ultrasound of lower limb veins in 34 (39.53 %) patients revealed a discrepancy between the upper localisation of thrombotic masses in the great saphenous lumen and the external boundary registered for clinical manifestations, hyperaemia and tissue thickening. In 69 (80.23 %) patients, four or more phenotypic UCTD markers were exposed. In 74 (86.05 %) cases, a classical Babcock phlebectomy was performed as a next stage within one year after an acute thrombophlebitis attack had subsided. Of 12 (13.95 %) patients not having had a second-stage phlebectomy within one year: 4 people had UCTD signs — they refused surgery due to absent significant complaints or marked saphenous reflux; 3 had a deep vein thrombosis episode; 5 had no saphenous reflux of lower extremities in ultrasound examination.Conclusion. The registration of phenotypic signs of undifferentiated connective tissue dysplasia is recommended in choosing a surgical tactic to treat acute ascending thrombophlebitis of lower limb saphenous veins.

Pregnancy Outcomes in Undifferentiated Connective Tissue Disease Compared to Systemic Lupus Erythematosus: A Single Academic Center's Experience.

Systemic lupus erythematosus (SLE) patients have more pregnancy complications than healthy patients. Data regarding pregnancy outcomes in women with undifferentiated connective tissue disease (UCTD) are more limited, and existing studies are concentrated in Italy and predominantly in patients with a new diagnosis. Our objective was to compare pregnancy outcomes for UCTD and SLE patients with established disease. Between 2008 and 2017, patients with UCTD and SLE at an academic medical center were recruited to a prospective pregnancy registry. UCTD was defined as a positive autoantibody plus connective tissue disease symptoms not meeting criteria for another rheumatic diagnosis. SLE was defined by American College of Rheumatology or Systemic Lupus International Collaborating Clinics classification criteria or by physician diagnosis. Data were collected throughout pregnancy and postpartum. Comparator groups included UCTD, low-activity SLE, and high-activity SLE. A total of 150 SLE and 51 UCTD pregnancies were analyzed. Disease activity was low in most patients, although more patients with SLE had severe activity during pregnancy (12% versus 2%; P = 0.05). The frequencies of prematurity and preeclampsia were significantly lower in UCTD than in high-activity SLE patients (preterm 17% versus 45% [P = 0.004] and preeclampsia 6% versus 34% [P = 0.0008]), although similar to low-activity SLE patients. More infants who were small for gestational age were born to SLE than UCTD patients (33% versus 7% [P = 0.0005]), regardless of disease activity level. Pregnancies in women with UCTD managed by a rheumatologist have a high rate of pregnancy success and fewer risks than those in women with active SLE.

Capillaroscopic analysis of the microvascular status in mixed versus undifferentiated connective tissue disease.

Raynaud phenomenon (RP), typically, precede the clinical onset of systemic manifestations in several connective tissue diseases (CTDs). These autoimmune disorders usually share a microvascular damage whose alterations can be detected by nailfold videocapillaroscopy (NVC). The aim of the study was to compare the NVC microvascular status in Mixed Connective Tissue Disease (MCTD) versus the Undifferentiated Connective Tissue Disease (UCTD), and to search correlations between NVC findings and specific autoantibodies in UCTD patients. Clinical data and NCV patterns were retrospectively obtained from the files of 46 MCTD patients, 47 stable UCTD patients and 51 individuals with primary RP (PRP) as controls collected in a central database (VideoCap®, DS Medica, Milan, Italy). ANA and ENA Abs were tested respectively by indirect immunofluorescence and enzyme-linked immunosorbent assay. "Scleroderma-like" (SSc-like) NVC pattern was significantly more frequent in MCTD than in UCTD patients (48% vs 11%, p<0.001). Giant capillaries, abnormal shapes (i.e. neoangiogenesis) and lower capillary density were predominantly detected among MCTD versus UCTD patients (48% vs 11%, 49% vs 13%, 52% vs 9%, respectively, p<0.001). The absolute number of capillaries was significantly lower in MCTD versus UCTD patients (mean 7±1.7 SD vs mean 9.2±1.3 SD, respectively, p<0.001). Fully normal NVC pattern and non-specific NVC alterations were respectively observed in 6% and 46% of MCTD and in 6% and 83% of UCTD. Moreover, PRP patients showed normal NVC pattern and non-specific capillary abnormalities in 23% and in 77%, respectively. No statistically significant correlations were observed between NVC patterns and ANA patterns/specific ENA-Abs among the UCTD patients. The significant presence of the SSc-like NVC pattern and reduced number of capillaries seem the most typical NVC findings in MCTD in comparison to UCTD patients, suggesting a reflection of more complex and severe disease in MCTD ones.

Long-term exposure to fine particulate matter and ozone and the onset of systemic autoimmune rheumatic diseases: an open cohort study in Quebec, Canada

ObjectivesTo estimate associations between fine particulate matter (PM2.5) and ozone and the onset of systemic autoimmune rheumatic diseases (SARDs).MethodsAn open cohort of over 6 million adults was constructed from provincial physician billing and hospitalization records between 2000 and 2013. We defined incident SARD cases (SLE, Sjogren’s syndrome, scleroderma, polymyositis, dermatomyositis, polyarteritis nodosa and related conditions, polymyalgia rheumatic, other necrotizing vasculopathies, and undifferentiated connective tissue disease) based on at least two relevant billing diagnostic codes (within 2 years, with at least 1 billing from a rheumatologist), or at least one relevant hospitalization diagnostic code. Estimated PM2.5 and ozone concentrations (derived from remote sensing and/or chemical transport models) were assigned to subjects based on residential postal codes, updated throughout follow-up. Cox proportional hazards models with annual exposure levels were used to calculate hazard ratios (HRs) for SARDs incidence, adjusting for sex, age, urban-versus-rural residence, and socioeconomic status.ResultsThe adjusted HR for SARDS related to one interquartile range increase in PM2.5 (3.97 µg/m3) was 1.12 (95% confidence interval 1.08–1.15), but there was no clear association with ozone. Indirectly controlling for smoking did not alter the findings.ConclusionsWe found associations between SARDs incidence and PM2.5, but no relationships with ozone. Additional studies are needed to better understand interplays between the many constituents of air pollution and rheumatic diseases.

POS0863 ANTI-NOR90 ANTIBODIES IN THE SETTING OF CONNECTIVE TISSUE DISEASE: CLINICAL SIGNIFICANCE AND COMPARISON WITH A COHORT OF PATIENTS WITH SYSTEMIC SCLEROSIS

BackgroundAnti-NOR90 antibodies are directed against a 90-kD nucleolar protein located in the nucleolus organizing regions (NORs), mainly described in systemic sclerosis (SSc) [1, 2, 3] but reported also in other rheumatologic and oncologic diseases [4, 5, 6]. The clinical correlates of anti-NOR90 antibodies are still to be defined because the cohorts described thus far include a low number of patients.ObjectivesTo describe the characteristics of a large cohort of anti-NOR90 antibodies positive patients and compare them with a matched cohort of SSc patients negative for anti-NOR90 antibodies.MethodsA retrospective analysis was performed on patients positive for anti-NOR90 antibodies referring to participating centres. The concomitant positivity for anti-RNA polymerase III, Th/To, PM-Scl, Ku, and PDGFR antibodies was an exclusion criterion. In all cases the diagnoses, the different organ involvement and related clinical, instrumental and laboratory characteristics were evaluated. The EUROLINE SystemicSclerosisProfile kit from Euroimmun (Lübeck, Germany) was used to detect anti-NOR90 antibodies.ResultsWe included 101 patients positive for anti-NOR90 (M/F=13/88, mean age 52.5 years). They were mainly classified as SSc (n=38), undifferentiated connective tissue disease (UCTD) (n=21), interstitial pneumonia with autoimmune features (IPAF) (n=11) (graph 1). The most frequent clinical manifestations were arthralgias (n=72), Raynaud’s phenomenon (RP) (n=58), sicca syndrome (n=49), ILD (n=40), puffy fingers (n=32), arthritis (n=30), and limited skin sclerosis (n=24). Anti-NOR90 antibodies were associated with anti-Ro52 antibodies in the 16% of cases, with anticentromere antibodies in the 7% of cases, and with anti-Scl70 in the 5% of cases. After excluding these patients, and considering the isolated anti-NOR90 positivity, 12 patients had SSc, 35 UCTD, and 11 IPAF. The most frequent clinical manifestations were arthralgias (n=40), RP (n=37), and sicca syndrome (n=21). Compared to 242 matched SSc without anti-NOR90 antibodies, patients with anti-NOR90 had more frequently joint manifestations and sicca syndrome and less frequently all vasculopathic manifestations (RP, telangiectasias, pitting scars, acral ulcers), dysphagia and fibromyalgia.ConclusionOur study shows that anti-NOR90 antibodies are more commonly observed in females, and clinically associated with the occurrence of arthritis/arthralgias, sicca syndrome and RP. In more than the 50% of cases they may be found with other autoantibodies, such as the anti-Ro52, the anticentromere, and the anti-Scl70 antibodies. Anti-NOR90 seems to play an accompanying role in the context of CTDs, without strong influence on the clinical phenotype expression of the underlying CTD.

Role of genetic research in the prevention of life-threatening rhythm and cardiac conduction disorders in young people

According to epidemiological studies, in Russia there is a tendency towards an increase in sudden cardiac death (SCD), including among young workingage people. The leading mechanism for SCD in young patients, including those with undifferentiated connective tissue disease, is recognized as rhythm and conduction disorders. At the same time, the most tragic cases are the first and only manifestation of SCD in children and young people without structural heart disease. The article presents a brief analysis of the genetic causes of life-threatening rhythm and conduction disorders in young people, as well as a generalization of the modern possibilities of a personalized diagnostic approach from the standpoint of early cardiovascular prevention. Timely genetic diagnosis of SCD risk makes it possible to identify a predisposition to the development of a fatal event long before its occurrence, which contributes to the timely implementation of preventive measures within a high cardiovascular risk strategy and secondary prevention, maintaining working capacity, creative and social activity of young patients, and improving the quality of life.