BACKGROUND: Mixed connective tissue disease (MCTD) is a rare entity in children. There is a paucity of studies on juvenile-onset MCTD (jMCTD) worldwide especially from Southeast Asia.
OBJECTIVE: To describe clinical and laboratory features of jMCTD diagnosed at pediatric rheumatology centers across India.
METHODS: A predesigned detailed case proforma in an excel format was prepared and was sent to all the Pediatric Rheumatology centers in India. Eleven centers provided the clinical and laboratory data of their jMCTD patients, which was then compiled and analyzed in detail.
RESULTS: Thirty-one jMCTD patients from 11 centers were included in the study. Our cohort had 27 females and four male patients over 12 months (August 2021 to July 2022). The median age at presentation was 12 years (range 5-18 years) and the median duration of symptoms was 24 months at diagnosis (range 2-96 months). The common features included arthritis (90%), malar rash (70.9%), and Raynaud\'s phenomenon (70.9%). At a mean follow-up of 43 months (range 1-168 months), 45% of them were in remission. There were two deaths reported, due to macrophage activation syndrome and sepsis respectively.
CONCLUSIONS: We present the largest multicenter experience on jMCTD from the Indian subcontinent. The study\'s findings serve as a crucial stepping stone toward unraveling the complexities of jMCTD and improving patient care and management strategies.

UNASSIGNED: To investigate the clinical features, severity and prognosis of interstitial lung disease (ILD) in patients with mixed connective tissue disease (MCTD).
UNASSIGNED: We performed a retrospective study on clinical data of MCTD patients admitted to China-Japan Friendship Hospital between October 2012 and October 2022. Data including long-term follow-up were retrieved from medical records. We compared MCTD patients with and without ILD in terms of clinical features, laboratory and imaging findings, severity and treatment response.
UNASSIGNED: A total of 59 patients were included, with a mean age of 46 years, among which 91.5% (n = 54) were females. Symptoms of pulmonary involvement were present in 44 patients (74.6%, 95% CI: 62.3-84.9%). Based on lung high-resolution computed tomography (HRCT), ILD was diagnosed in 39 (66.1%) patients, among which 31 (79.5%) showed nonspecific interstitial pneumonia (NSIP) as the radiological pattern, 21 (53.9%) showed a reticulation pattern, while 24 (61.5%) showed ground glass opacity (GGO). Eight (13.6%) patients had pulmonary arterial hypertension (PAH), and 7 (11.9%) had pleural effusions. Based on pulmonary function tests (PFTs), 27 patients were divided into the mild 13 (48.1%) and moderate 14 (51.9%) groups. Multivariate analysis showed that gastroesophageal reflux (GER; OR=5.28, p=0.010) and cough (OR=4.61, p=0.043) were the predictive factors for ILD. With a median follow-up of 50 months, the mortality rate was 2.38%.
UNASSIGNED: ILD is common in MCTD patients, with NSIP as the common imaging pattern. Patients with GER and cough are relevant factors in the development of ILD. The majority of MCTD patients with ILD are mild to moderate in severity.

We aimed to identify cardiac function in patients with established mixed connective tissue disease (MCTD). This was a cross-sectional case-control study of well-characterised MCTD patients who had previously been included in a nationwide cohort. Assessments comprised protocol transthoracic echocardiography, electrocardiogram and blood samples. In patients only, we evaluated the findings of high-resolution pulmonary computed tomography and disease activity. We assessed 77 MCTD patients (mean age 50.5 ± 12.3 years) with a mean disease duration of 16.4 years, and 59 age- and sex-matched healthy controls (49.9 ± 11.7 years). By echocardiography, measures of left ventricular function, i.e. fractional shortening (38.1 ± 6.4% vs. 42.3 ± 6.6%, p < 0.001), mitral annulus plane systolic excursion (MAPSE) (13.7 ± 2.1 mm vs. 15.3 ± 2.3 mm, p < 0.001) and early diastolic velocity of the mitral annulus (e\') (0.09 ± 0.02 m/s vs. 0.11 ± 0.03 m/s, p = 0.002) were subclinical and lower in patients than controls. Right ventricular dysfunction was found in patients assessed by tricuspid annular plane systolic excursion (TAPSE) (22.7 ± 4.0 mm vs. 25.5 ± 4.0 mm, p < 0.001). While cardiac dysfunction was not associated with pulmonary disease, e\' and TAPSE were found to correlate with disease activity at baseline. In this cohort of MCTD patients, echocardiographic examinations demonstrated a higher frequency of cardiac dysfunction than in matched controls. Cardiac dysfunction was associated with disease activity at baseline, but was independent of cardiovascular risk factors and pulmonary disease. Our study indicates that cardiac dysfunction is part of the multi-organ affliction seen in MCTD.

Pediatric mixed connective tissue disease (MCTD) is a subgroup of overlap syndromes. We aimed to compare the characteristics and outcomes in children with MCTD and other overlap syndromes. All MCTD patients met either Kasukawa or Alarcon-Segovia and Villareal criteria. The patients with other overlap syndromes had the features of ≥ 2 autoimmune rheumatic diseases but did not meet MCTD diagnostic criteria. Thirty MCTD (F/M = 28/2) and thirty (F/M = 29/1) overlap patients were included (disease onset < 18 years). The most prominent phenotype at disease onset and the last visit was systemic lupus erythematosus (SLE) in the MCTD group; juvenile idiopathic arthritis and dermatomyositis/polymyositis, respectively, in the overlap group. At the last visit, systemic sclerosis (SSc) phenotype was more frequent among MCTD than overlap patients (60% vs. 33.3%; p = 0.038). The frequency of the predominant SLE phenotype had decreased (60% to 36.7%), while predominant SSc phenotype had increased (13.3% to 33.3%) during follow-up in MCTD patients. Weight loss (36.7% vs. 13.3%), digital ulcers (20% vs. 0), swollen hands (60% vs. 20%), Raynaud phenomenon (86.7% vs. 46.7%), hematologic involvement (70% vs. 26.7%), and anti-Sm positivity (29% vs. 3.3%) were more common, while Gottron papules (16.7% vs. 40%) were less frequent among MCTD than overlap patients (p < 0.05). A higher percentage of overlap patients achieved complete remission than MCTD patients (51.7% vs. 24.1%; p = 0.047). The disease phenotype and outcome differ between pediatric MCTD and other overlap syndromes where MCTD may be regarded as a more severe disease. Analyzing these patients could pave the way for early and effective treatment.

Pulmonary arterial hypertension (PAH) is a leading cause of death in MCTD. We aimed to describe PAH in well-characterized MCTD patients.
MCTD patients enrolled in the French Pulmonary Hypertension Registry with a PAH diagnosis confirmed by right heart catheterization were included in the study and compared with matched controls: MCTD patients without PAH, SLE patients with PAH and SSc patients with PAH. Survival rates were estimated by the Kaplan-Meier method and risk factors for PAH in MCTD patients and risk factors for mortality in MCTD-PAH were sought using multivariate analyses.
Thirty-six patients with MCTD-PAH were included in the study. Comparison with MCTD patients without PAH and multivariate analysis revealed that pericarditis, polyarthritis, thrombocytopenia, interstitial lung disease (ILD) and anti-Sm antibodies were independent predictive factors of PAH/PH in MCTD. Estimated survival rates at 1, 5 and 10 years following PAH diagnosis were 83%, 67% and 56%, respectively. MCTD-PAH presentation and survival did not differ from SLE-PAH and SSc-PAH. Multivariate analysis revealed that tobacco exposure was an independent factor predictive of mortality in MCTD-PAH.
PAH is a rare and severe complication of MCTD associated with a 56% 10-year survival. We identified ILD, pericarditis, thrombocytopenia and anti-Sm antibodies as risk factors for PAH in MCTD and tobacco exposure as a predictor of mortality in MCTD-PAH.

The aim of this study was to develop a Croatian Delphi-based expert consensus for screening interstitial lung disease (ILD) associated with connective tissue disease (CTD). A systematic literature review was conducted on risk factors for the development of ILD, prevalence and incidence of ILD, diagnostic and screening methods for ILD, and prognosis of ILD in idiopathic inflammatory myopathy (IIM), mixed connective tissue disease (MCTD), primary Sjögren\'s syndrome (pSS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc) were performed. Based on the evidence found, experts developed questionnaires for screening and monitoring ILD in each CTD, which were provided via an online survey. Following the electronic survey, two screening algorithms were developed based on the consensus opinions. The detection strategy for ILD included high-resolution computed tomography (HRCT) in addition to pulmonary function testing for IIM, MCTD, and SSc. and pulmonary function testing for newly diagnosed pSS, RA and SLE. However, in patients with identified risk factors for ILD HRCT, these tests should also be performed. A screening strategy for early identification of patients with various CTD-ILD was first developed by a multidisciplinary team of rheumatologists, pulmonologists, and radiologists to identify early CTD patients at risk of ILD, a severe extra-articular manifestation of CTD.

To standardly assess and describe nailfold videocapillaroscopy (NVC) assessment in children and adolescents with juvenile rheumatic and musculoskeletal diseases (jRMD) vs healthy controls (HCs).
In consecutive jRMD children and matched HCs from 13 centres worldwide, 16 NVC images per patient were acquired locally and read centrally per international consensus standard evaluation of the EULAR Study Group on Microcirculation in Rheumatic Diseases. A total of 95 patients with JIA, 22 with JDM, 20 with childhood-onset SLE (cSLE), 13 with juvenile SSc (jSSc), 21 with localized scleroderma (lSc), 18 with MCTD and 20 with primary RP (PRP) were included. NVC differences between juvenile subgroups and HCs were calculated through multivariable regression analysis.
A total of 6474 images were assessed from 413 subjects (mean age 12.1 years, 70.9% female). The quantitative NVC characteristics were significantly lower or higher in the following subgroups compared with HCs: for density: lower in jSSc, JDM, MCTD, cSLE and lSc; for dilations: higher in jSSc, MCTD and JDM; for abnormal shapes: higher in JDM and MCTD; for haemorrhages: higher in jSSc, MCTD, JDM and cSLE. The qualitative NVC assessment of JIA, lSc and PRP did not differ from HCs, whereas the cSLE and jSSc, MCTD, JDM and cSLE subgroups showed more non-specific and scleroderma patterns, respectively.
This analysis resulted from a pioneering registry of NVC in jRMD. The NVC assessment in jRMD differed significantly from HCs. Future prospective follow-up will further elucidate the role of NVC in jRMD.

This study aimed to compare the sensitivity and specificity of the European League Against Rheumatism/American College of Rheumatology-2019 (EULAR/ACR-2019) classification criteria with prior classification schemes for patients with childhood-onset systemic lupus erythematosus (cSLE). This single-center retrospective study examined 53 patients with cSLE and 53 patients having antinuclear antibody (ANA) titers ≥ 1:80 but not cSLE as controls. Sensitivity and specificity were calculated for the EULAR/ACR-2019 criteria, original criteria reported earlier in 2019, the ACR-1997 criteria, and the Systemic Lupus International Collaborating Clinics-2012 (SLICC-2012) criteria. The frequency of positivity in the cSLE group for each item of the EULAR/ACR-2019, ACR-1997, and SLICC-2012 criteria was determined. Characteristics of the misclassified patients were also investigated. All patients with cSLE had ANA titers ≥ 1:80. The non-SLE diagnoses included juvenile idiopathic inflammatory myopathies, primary Sjögren\'s syndrome (pSS), juvenile idiopathic arthritis, systemic sclerosis, mixed connective tissue disease (MCTD), and others. Sensitivities of the EULAR/ACR-2019 criteria, the original criteria, the ACR-1997 criteria, and the SLICC-2012 criteria were 100%, 100%, 86.8%, and 100%, respectively; the specificities were 84.9%, 92.5%, 98.1%, and 88.7%, respectively. In the cSLE group, the items of the SLE-specific antibody (100%), complement (98.1%), hematological (94.3%), and renal (84.9%) domains were frequently observed in the EULAR/ACR-2019 criteria. The EULAR/ACR-2019 criteria misclassified patient controls more frequently, especially those with MCTD or pSS, as having SLE than the previous criteria. The EULAR/ACR-2019 criteria for cSLE had high sensitivity but low specificity; the weighted scoring of the original criteria reported earlier in 2019 may confer higher specificity and be more appropriate for the classification of SLE in a pediatric population. Key Points • The EULAR/ACR-2019 criteria for cSLE had high sensitivity but low specificity. • The EULAR/ACR-2019 criteria more frequently misclassified non-SLE patients who did not have SLE, especially those with MCTD or pSS, as having SLE than the previous criteria in patients with childhood onset. • The weighted scoring of the original criteria reported earlier in 2019 may confer higher specificity and be a more appropriate classification of SLE for a pediatric population.

Mixed connective tissue disease (MCTD) is a rare condition that is distinguished by the presence of specific U1-RNP antibodies. Information about its etiopathology and diagnostics is still unclear. miRNAs such as miR-146, miR-155, and miR-143 emerged as key regulators of the immune system, known to be involved in the development of autoimmune diseases and cancers. We performed an association study between immune-related miRNAs and MCTD severity and susceptibility.
A total of 169 MCTD patients and 575 healthy subjects were recruited to the case-control study. The miRNA polymorphisms were genotyped using TaqMan SNP genotyping assay. TNF-α, IL-6, and IFN-γ levels in serum were determined using ELISA. qRT-PCR of TRAF6, IRAK1, and microRNAs was performed using Taqman miRNA assays and TaqMan Gene Expression Assays.
miR-146a rs2910164 G allele and GG genotype as well as miR-143 rs713147 A allele were more frequent in healthy subjects than in MCTD patients. miR-146a rs2910164 CC genotype and miR-143 T-rs353299*T-rs353291*T-rs713147*G-rs353298 and C-rs353299*C-rs353291*T-rs713147*A-rs353298 haplotypes were associated with MCTD susceptibility. miR-146a rs2910164 C/T was associated with scleroderma and lymphadenopathy. miR-143 rs353299 C/T was associated with swollen fingers or hands, the presence of enlarged lymph nodes, and pericarditis/pleuritis. miR-143 rs353298 A/G was associated with the occurrence of pericarditis/pleuritis and scleroderma. miR-143 rs353291 T/C showed association with pericarditis/pleuritis. The serum TNF-α, IFN-γ, and IL-6 levels were significantly higher in MCTD patients compared to healthy subjects. miR-143 SNPs were associated with higher proinflammatory cytokine concentration in serum only in healthy controls. IRAK1 and TRAF6 expression were higher in the MCTD patients compared to controls.
The results of our case-control study indicate the possible significance of miR-146a and miR-143/145 in the susceptibility and clinical picture of MCTD.

Background: Belimumab is a recombinant human immunoglobulin G1 lambda monoclonal antibody that binds soluble B lymphocyte stimulator protein with high affinity and inhibits its biological activity. Belimumab is not recommended for breastfeeding women due to insufficient data about its excretion into breast milk. In this study, we measured belimumab concentrations in the breast milk of one nursing mother diagnosed with mixed connective tissue disease (MCTD) and evaluated the health of her breastfed infant. Materials and Methods: Maternal serum and breast milk belimumab concentrations were collected three times (2 weeks after the first dose, the day after the second dose, and 7 weeks after the second dose) after ethical approval and informed consent. An enzyme-linked immunosorbent assay was used to detect belimumab in serum and breast milk samples. Case Report: A 39-year-old para 4 female was diagnosed with MCTD. The serum concentrations at three times were 29.45, 76.82, and 33.95 mcg/mL. The concentrations in breast milk were 0.12, 0.17, and 0.12 mcg/mL. The milk-to-serum concentration ratios at each sampling point were 0.0041, 0.0022, and 0.0035, respectively. Her infant experienced no health problems. Routine vaccinations were administered without any adverse effects such as infection or immunoreaction. Discussion and Conclusions: Breast milk levels of belimumab ranged from 1/200 to 1/500 of those in serum, and no harmful effect occurred in her infant. This is the first study reporting belimumab concentrations in human breast milk. Further studies are needed to elucidate the impact of exposure on breastfeeding infants.