Search

INTRODUCTION: Data on real-world clinical practice and outcomes of patients with pulmonary arterial hypertension associated with connective tissue disease (CTD-PAH) are scarce. The OPUS/OrPHeUS studies enrolled patients newly initiating macitentan, including those with CTD-PAH. This analysis describes patient characteristics, treatment patterns, outcomes, and safety profiles of patients with CTD-PAH newly initiating macitentan in the US using the OPUS/OrPHeUS combined dataset. METHODS: OPUS was a prospective, US, multicenter, long-term, observational drug registry (April 2014-June 2020). OrPHeUS was a retrospective, US, multicenter medical chart review (October 2013-March 2017). The characteristics, treatment patterns, safety, and outcomes during macitentan treatment of patients with CTD-PAH and its subgroups systemic sclerosis (SSc-PAH), systemic lupus erythematosus (SLE-PAH), and mixed CTD (MCTD-PAH) were descriptively compared to patients with idiopathic/heritable PAH (I/HPAH). RESULTS: The combined OPUS/OrPHeUS population included 2498 patients with I/HPAH and 1192 patients with CTD-PAH (708 SSc-PAH; 159 SLE-PAH; 124 MCTD-PAH, and 201 other CTD-PAH etiologies). At macitentan initiation for patients with I/HPAH and CTD-PAH, respectively: 61.2 and 69.3% were in World Health Organization functional class (WHO FC) III/IV; median 6-min walk distance was 289 and 279 m; and 58.1 and 65.2% received macitentan as combination therapy. During follow-up, for patients with I/HPAH and CTD-PAH, respectively: median duration of macitentan exposure observed was 14.0 and 15.8 months; 79.0 and 83.0% experienced an adverse event; Kaplan-Meier estimates (95% confidence limits [CL]) of patients free from all-cause hospitalization at 1 year were 60.3% (58.1, 62.4) and 59.3% (56.1, 62.3); and Kaplan-Meier estimates (95% CL) of survival at 1 year were 90.5% (89.1, 91.7) and 90.6% (88.6, 92.3). CONCLUSIONS: Macitentan was used in clinical practice in patients with CTD-PAH and its subgroups, including as combination therapy. The safety and tolerability profile of macitentan in patients with CTD-PAH was comparable to that of patients with I/HPAH. TRIAL REGISTRATION: OPsumit® Users Registry (OPUS): NCT02126943; Opsumit® Historical Users cohort (OrPHeUS): NCT03197688; www. CLINICALTRIALS: gov Graphical abstract available for this article.

Background: Retinal artery occlusions are rare amongst young adults, and relevant risk factors and etiology remain unclear. In this report, we present a case of central retinal artery occlusion (CRAO) as the initial manifestation of mixed connective tissue disease (MCTD) in a young woman. Case presentation: A 22-year-old female presented to the emergency department with a sudden decrease in visual acuity in her right eye for 1 hour. She reported a similar episode in her left eye five years prior, which resolved spontaneously after 2 hours. Initially misdiagnosed with optic neuritis in the right eye at another hospital, she was referred to our institution the following day. Clinical examination revealed a CRAO in her right eye. A detailed medical history revealed that she had developed livedo reticularis (LR) on both lower limbs five years ago, which had been overlooked and untreated. Further rheumatologic history, hematologic tests, and an autoimmune work-up confirmed a diagnosis of mixed connective tissue disease (MCTD). Conclusion: In young patients presenting with CRAO, further examinations should be conducted to investigate systemic disease or an embolic source to prevent future sequelae. [ABSTRACT FROM AUTHOR]

Abstract Background Retinal artery occlusions are rare amongst young adults, and relevant risk factors and etiology remain unclear. In this report, we present a case of central retinal artery occlusion (CRAO) as the initial manifestation of mixed connective tissue disease (MCTD) in a young woman. Case presentation A 22-year-old female presented to the emergency department with a sudden decrease in visual acuity in her right eye for 1 hour. She reported a similar episode in her left eye five years prior, which resolved spontaneously after 2 hours. Initially misdiagnosed with optic neuritis in the right eye at another hospital, she was referred to our institution the following day. Clinical examination revealed a CRAO in her right eye. A detailed medical history revealed that she had developed livedo reticularis (LR) on both lower limbs five years ago, which had been overlooked and untreated. Further rheumatologic history, hematologic tests, and an autoimmune work-up confirmed a diagnosis of mixed connective tissue disease (MCTD). Conclusion In young patients presenting with CRAO, further examinations should be conducted to investigate systemic disease or an embolic source to prevent future sequelae.

Xueyan Shan,1,2 Yongpeng Ge3 1Department of Rheumatology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China; 2Postgraduate School, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 3Department of Rheumatology, The Key Laboratory of Myositis, China-Japan Friendship Hospital, Beijing, People’s Republic of ChinaCorrespondence: Yongpeng Ge, Department of Rheumatology, The Key Laboratory of Myositis, China-Japan Friendship Hospital, Yinghua East Road, Chaoyang District, Beijing, 100029, People’s Republic of China, Email gyp2016@163.comObjective: To investigate the clinical features, severity and prognosis of interstitial lung disease (ILD) in patients with mixed connective tissue disease (MCTD).Methods: 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.Results: 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%.Conclusion: 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.Keywords: mixed connective tissue disease, interstitial lung disease, gastroesophageal reflux

Objective To investigate the clinical characteristics and risk factors of mixed connective tissue disease associated with pulmonary arterial hypertension (MCTD-PAH). Methods Twelve MCTD-PAH patients diagnosed by right heart catheterization (RHC) at Tianjin Medical University General Hospital were retrospectively included, and 36 MCTD patients without pulmonary arterial hypertension (MCTD-non-PAH) were randomly selected from the same period of hospitalization based on gender and age. The clinical features and auxiliary examination of the two groups were compared, and the survival status of the two groups was compared. Results The proportion of dyspnea after activity, myositis and pericardial effusion were higher in the MCTD-PAH group than those of the control group. Serum sedimentation rate and immunoglobulin G (IgG) levels were higher in the MCTD-PAH group. Multivariate Logistic regression analysis showed that dyspnea after activity and high level of IgG were risk factors for predicting the occurrence of PAH in MCTD. Three patients (16.7%) died in the MCTD-PAH group, and no patients died in the control group. Conclusion Pulmonary arterial hypertension is one of the serious complications of MCTD. MCTD patients have shortness of breath after activity and high level of IgG should be wary of concomitant PAH. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to identify clinical and serological predictors of myositis in mixed connective tissue disease (MCTD). Methods: We performed a nationwide, retrospective, multicentre study including adult-onset MCTD patients fulfilling at least one of the following diagnostic criteria: Sharp’s, Kasukawa, Alarcón-Segovia, or Kahn’s. Univariable analysis was performed using Chi-square, Fisher exact, Student’s t or Mann-Whitney U tests, as appropriate. Multivariable analysis was performed using binary logistic regression. Results: Ninety-eight patients were included. Myositis was observed in 43.9% of patients, of whom 60.5% had myositis at disease onset. Proximal muscle weakness was described in 30 patients with muscle involvement (70%). Gastrointestinal involvement was identified in 28% and respiratory involvement in 29% of myositis patients. In the same subgroup of patients, 41.7% had a myopathic pattern on electromyography, and 47.1% had histological myositis features in the muscle biopsy. Fever (OR=6.96, p=0.022) was an independent predictor of myositis, regardless of sex, age at diagnosis, ancestry, and respiratory involvement. African ancestry (OR=8.39, p=0.019), leukopenia at the disease onset (OR 6.24, p=0.021), and younger age at diagnosis (OR=1.07/year, p=0.035) were identified as independent predictors of myositis at disease onset, regardless of sex and scleroderma pattern in capillaroscopy. Conclusions: Myositis is a common manifestation of MCTD, even at the disease onset. African ancestry, leukopenia at the disease onset, younger age at diagnosis, and fever should prompt a thorough evaluation for myositis. [ABSTRACT FROM AUTHOR]

Background: The positivity of anti-RNP autoantibodies as biological criteria for the diagnosis of mixed connective tissue disease (MCTD) has recently divided the rheumatology community. Autoantigenicity of the U1-snRNP complex tends to generate multiple autoantibodies against RNP-A, -C and -70 KDa or Sm proteins. The aim of this study is to identify the most informative autoantibodies in clinical practice, in particular, to contribute to differential diagnosis between MCTD and systemic lupus erythematosus (SLE). Methods: Sera from 74 patients positive for anti-RNP autoantibodies were selected over a period of one year of laboratory practice. Autoantibodies directed against extractable nuclear antigen, RNP proteins (A, C, 70 KDa) and 40 kDa fragments of RNP-70 KDa were investigated by using quantitative fluoroenzymatic assay and Western blot analysis. Results: Among the 74 patients, 40 patients were diagnosed with SLE, 20 with MCTD, six with another autoimmune disease, three with SARS-CoV-2 infection, three with cancer and two were healthy. No preferential clinical association of IgG or IgM autoantibodies directed against each of the RNP proteins was found between SLE and MCTD. In contrast, the proportion of autoantibodies directed against the RNP component within the U1-snRNP complex showed a significantly higher RNP index in patients with MCTD than in those with SLE (p = 0.011), with good performance (sensitivity: 69.2%, specificity: 88.9%). Conclusions: The analysis of the proportion of the different autoantibodies directed against the U1-snRNP complex is more informative than the analysis of each autoantibody separately. A follow-up of patients could be informative about the interest of the RNP index as a predictor of disease evolution. [ABSTRACT FROM AUTHOR]

Drug-induced immune thrombocytopenia is an adverse reaction marked by accelerated destruction of blood platelets. In cancer therapy, thrombocytopenia has many other causes including bone marrow suppression induced by chemotherapeutic agents, infection, and progression of cancer; drug-induced thrombocytopenia can easily be misdiagnosed or overlooked. Here, we present a case of an ovarian cancer patient with a history of mixed connective tissue disease who underwent surgery followed by treatment with paclitaxel, cisplatin, and bevacizumab. The patient developed acute isolated thrombocytopenia after the sixth cycle. Serum antiplatelet antibody testing revealed antibodies against glycoprotein IIb. After we analyzed the whole therapeutic process of this patient, drug-induced immune thrombocytopenia was assumed, and bevacizumab was conjectured as the most probable drug. Thrombocytopenia was ultimately successfully managed using recombinant human thrombopoietin, prednisone, and recombinant human interleukin-11. We provide a summary of existing literature on immune thrombocytopenia induced by bevacizumab and discuss related mechanisms and triggers for drug-induced immune thrombocytopenia. The present case underscores the potential of bevacizumab to induce immunemediated thrombocytopenia, emphasizing the need for heightened vigilance towards autoimmune diseases or an autoimmune-activated state as plausible triggers for rare drug-induced immune thrombocytopenia in cancer therapy. [ABSTRACT FROM AUTHOR]

Mixed connective tissue disease (MCTD) is an autoimmune disorder characterized by a combination of clinical features from systemic lupus erythematosus, systemic sclerosis, and inflammatory muscle disease, along with the presence of positive anti-U1-ribonucleoprotein (U1-RNP) antibodies. The exact etiology of the disease remains unclear, but it is believed to involve vascular damage within the context of heightened autoimmune responses. Consequently, Raynaud's phenomenon and pulmonary arterial hypertension are observed in patients with MCTD. While specific biomarkers for MCTD have not yet been identified, the recent study of the utility of anti-survival motor neuron complex (SMN) antibodies in MCTD suggests a promising avenue for further research and the accumulation of additional evidence. [ABSTRACT FROM AUTHOR]

AbstractMixed connective tissue disease (MCTD) is an autoimmune disorder characterized by a combination of clinical features from systemic lupus erythematosus, systemic sclerosis, and inflammatory muscle disease, along with the presence of positive anti-U1-ribonucleoprotein (U1-RNP) antibodies. The exact etiology of the disease remains unclear, but it is believed to involve vascular damage within the context of heightened autoimmune responses. Consequently, Raynaud’s phenomenon and pulmonary arterial hypertension are observed in patients with MCTD. While specific biomarkers for MCTD have not yet been identified, the recent study of the utility of anti-survival motor neuron complex (SMN) antibodies in MCTD suggests a promising avenue for further research and the accumulation of additional evidence.

Abstract Introduction Data on real-world clinical practice and outcomes of patients with pulmonary arterial hypertension associated with connective tissue disease (CTD-PAH) are scarce. The OPUS/OrPHeUS studies enrolled patients newly initiating macitentan, including those with CTD-PAH. This analysis describes patient characteristics, treatment patterns, outcomes, and safety profiles of patients with CTD-PAH newly initiating macitentan in the US using the OPUS/OrPHeUS combined dataset. Methods OPUS was a prospective, US, multicenter, long-term, observational drug registry (April 2014–June 2020). OrPHeUS was a retrospective, US, multicenter medical chart review (October 2013–March 2017). The characteristics, treatment patterns, safety, and outcomes during macitentan treatment of patients with CTD-PAH and its subgroups systemic sclerosis (SSc-PAH), systemic lupus erythematosus (SLE-PAH), and mixed CTD (MCTD-PAH) were descriptively compared to patients with idiopathic/heritable PAH (I/HPAH). Results The combined OPUS/OrPHeUS population included 2498 patients with I/HPAH and 1192 patients with CTD-PAH (708 SSc-PAH; 159 SLE-PAH; 124 MCTD-PAH, and 201 other CTD-PAH etiologies). At macitentan initiation for patients with I/HPAH and CTD-PAH, respectively: 61.2 and 69.3% were in World Health Organization functional class (WHO FC) III/IV; median 6-min walk distance was 289 and 279 m; and 58.1 and 65.2% received macitentan as combination therapy. During follow-up, for patients with I/HPAH and CTD-PAH, respectively: median duration of macitentan exposure observed was 14.0 and 15.8 months; 79.0 and 83.0% experienced an adverse event; Kaplan–Meier estimates (95% confidence limits [CL]) of patients free from all-cause hospitalization at 1 year were 60.3% (58.1, 62.4) and 59.3% (56.1, 62.3); and Kaplan–Meier estimates (95% CL) of survival at 1 year were 90.5% (89.1, 91.7) and 90.6% (88.6, 92.3). Conclusions Macitentan was used in clinical practice in patients with CTD-PAH and its subgroups, including as combination therapy. The safety and tolerability profile of macitentan in patients with CTD-PAH was comparable to that of patients with I/HPAH. Trial Registration OPsumit® Users Registry (OPUS): NCT02126943; Opsumit® Historical Users cohort (OrPHeUS): NCT03197688; www.clinicaltrials.gov Graphical abstract available for this article. Graphical Abstract

Mixed connective tissue disease (MCTD) is one of the very rare systemic autoimmune diseases; it accounts for 0.1–0.6% of cases in pediatric rheumatologists' practices. MCTD is characterized by a broad spectrum of clinical manifestations and a high frequency of extremely unspecific symptoms at the onset, with the overall picture of the disease forming slowly and gradually. The diagnosis is often delayed and confirmed only at an advanced stage of organ dysfunction with the development of irreversible changes.Objective: to identify a group of patients fulfilling the criteria for MCTD in an open, single-center, continuous retrospective study among anti-ribonucleoprotein (anti-RNP) antibody-positive patients and to analyze their demographic, clinical and laboratory characteristics and therapy.Material and methods. All anti-RNP-positive patients admitted to the pediatric department of V.A. Nasonova Research Institute of Rheumatology from 2019 to 2023 and meeting at least one of the variants of the MCTD criteria (Kasukawa, Alarcуn-Segovia, Kahn and Sharp criteria) were included in the study.Results and discussion. 18 (56.25%, 17 girls and 1 boy) of 32 anti-RNP-positive patients fulfilled criteria for MCTD. Patients most frequently fulfilled a combination of criteria – Sharp and Kahn (n=8) or Alarcуn-Segovia and Kahn (n=8). The median age of onset of MCTD was 12.2 [9.7; 13.9] years. The most common clinical manifestations were arthritis (100%), various skin lesions (94.4 %), Raynaud's phenomenon (88.9%), lymphadenopathy (72.2%) and general constitutional disorders (50%). Sjögren's syndrome (SS) was diagnosed in 17 (94.4%) patients. All patients had antinuclear factor (ANF) 1/1280, and the anti-RNP level was >200 U/ml. There were also antibodies against double-stranded DNA (n=5), Ro- (n=4) and Sm- (n=5) antigens. An IgM rheumatoid factor was detected in 6 patients and hypergammaglobulinemia in 10 patients. Capillaroscopic changes in the nailfold with predominant scleroderma type were found in 77.8% of patients. The most common combination was of Raynaud's phenomenon, arthritis, SS, lymphadenopathy and hypergammaglobulinemia (50%). All patients received glucocorticoids, 9 – hydroxychloroquine, 8 – methotrexate, 3 – mycophenolate mofetil, 1 – cyclophosphamide, 1 – azathioprine. Biologic DMARDs (bDMARDs) were prescribed to 12 (66.7%) patients: 3 – rituximab, 8 – abatacept, 1 – belimumab, with an acceptable safety profile and initial efficacy.Conclusion. Most patients in the study met the Kahn criteria. Only 2 patients met all variants of the criteria, which indicates the need to use a combination of criteria when a MCTD is suspected. A combination of Raynaud's phenomenon, arthritis, SS, lymphadenopathy and hypergammaglobulinemia was observed in half of patients with MCTD. The presence of Raynaud's phenomenon and high ANF titer in children with rheumatic diseases, especially with a polymorphic clinical picture, requires the inclusion of MCTD in differential diagnosis. Preliminary results indicate the safety of the use of biologic drugs in children with MCTD.

Mixed connective tissue disease (MCTD) is a rare autoimmune disorder. We present a case of a Chinese female who has been admitted to our hospital on eight separate occasions. Her initial symptoms involved internal organs including the lung and heart. Due to the presence of anti-U1RNP antibodies and other clinical features, a diagnosis of MCTD was considered. Throughout her first to seventh admissions, her serum creatinine levels remained normal. During her eighth hospitalization, her renal function deteriorated rapidly, culminating in renal crisis. Chest computed tomography (CT) confirmed pulmonary edema, necessitating hemodialysis. Her interleukin (IL)-6 level increased significantly during throughout hospitalizations. The patient responded well to treatment with an IL-6 receptor antagonist (IL-6RA). This case raises the question of whether IL-6 could serve as a potential biomarker for predicting renal crisis incidence in MCTD patients, a topic warranting further investigation in the future. [ABSTRACT FROM AUTHOR]

Objective The presence of anti-U1 RNP antibodies (Abs) is critical for diagnosing MCTD. The aim of this study is to evaluate the clinical relevance of anti-survival motor neuron (SMN) complex Abs, which often coexist with anti-U1 RNP Abs. Methods A total of 158 newly diagnosed consecutive cases of SLE, SSc or MCTD with anti-U1 RNP Abs were enrolled in this multicentre observational study between April 2014 and August 2022. Serum anti-SMN complex Abs were screened by immunoprecipitation of 35S-methionine-labelled cell extracts, and associations between anti-SMN complex Abs positivity and clinical characteristics were analysed. Results Anti-SMN complex Abs were detected in 36% of MCTD patients, which was significantly higher than that in SLE (8%) or SSc (12%). Among MCTD patients classified based on the combination of the clinical features of SLE, SSc and idiopathic inflammatory myopathies, anti-SMN complex Abs showed the highest prevalence in a subset with clinical features of all three components. Anti-SMN complex Abs–positive MCTD had a higher prevalence of pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD), which are related to poor prognosis, than negative patients. Moreover, all three cases of death within 1 year of the treatment were positive for anti-SMN complex Abs. Conclusions Anti-SMN complex Abs is the first biomarker of a typical subset of MCTD which bears organ damages such as PAH and ILD. [ABSTRACT FROM AUTHOR]

Objectives: The objective of this study is to better characterize the features and outcomes of a large population of patients with mixed connective tissue disease (MCTD). Methods: We performed an observational retrospective multicenter cohort study in France. Patients who fulfilled at least one diagnostic criterion set for MCTD and none of the criteria for other differentiated CTD (dCTD) were included. Results: Three hundred and thirty patients (88% females, median [interquartile range] age of 35 years [26–45]) were included. The diagnostic criteria of Sharp or Kasukawa were met by 97.3% and 93.3% of patients, respectively. None met other classification criteria without fulfilling Sharp or Kasukawa criteria. After a median follow‐up of 8 (3–14) years, 149 (45.2%) patients achieved remission, 92 (27.9%) had interstitial lung disease, 25 (7.6%) had pulmonary hypertension, and 18 (5.6%) died. Eighty‐five (25.8%) patients progressed to a dCTD, mainly systemic sclerosis (15.8%) or systemic lupus erythematosus (10.6%). Median duration between diagnosis and progression to a dCTD was 5 (2–11) years. The presence at MCTD diagnosis of an abnormal pattern on nailfold capillaroscopy (odds ratio [OR] = 2.44, 95% confidence interval [95%CI] [1.11–5.58]) and parotid swelling (OR = 3.86, 95%CI [1.31–11.4]) were statistically associated with progression to a dCTD. Patients who did not progress to a dCTD were more likely to achieve remission at the last follow‐up (51.8% vs. 25.9%). Conclusions: This study shows that MCTD is a distinct entity that can be classified using either Kasukawa or Sharp criteria, and that only 25.8% of patients progress to a dCTD during follow‐up. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Pulmonary arterial hypertension (PAH) represents an important vascular complication of mixed connective tissue disease (MCTD) and systemic sclerosis (SSc). Microvascular involvement in these diseases can be investigated by means of nailfold capillaroscopy (NFC). Microvascular involvement detected in the nailfold bed is the mirror of the microvascular damage occurring in the entire body, further indicating the involvement of the target organs. The aim of this study was to evaluate the microvascular involvement in MCTD patients with or without PAH, compared to that found in SSc patients with or without PAH. PATIENTS AND METHODS: This cross-sectional study was performed in the Department of Internal Medicine and Department of Rheumatology, Timișoara, Romania, during the time period between January 2017 and December 2022, on a group of 26 patients with MCTD and 26 SSc patients. Antinuclear antibodies, anti-U1-RNP, anti-Scl 70, anti-centromere, anti-cardiolipin antibodies (aCL) (IgM, IgG), anti-β2-glycoprotein I (aβ2GPI) (IgM, IgG) antibodies, and lupus anticoagulant (LAC) were determined in both the groups. PAH was evaluated through cardiac ultrasonography, determining the sPAP (systolic pulmonary artery pressure). Nailfold capillaroscopy was performed using a USB Digital Microscope and 2.0-megapixel digital camera recording capillaries density, giant capillaries, enlarged capillaries, capillaries hemorrhages, avascular areas, ramified/bushy capillaries scores. Data were recorded and presented as mean ± standard deviation. Statistical analyses were performed using the Student's t-test, ANOVA test, and Pearson's correlation. Differences were considered statistically significant if p-value < 0.05. RESULTS: Among the MCTD patients, PAH was identified in 12 patients (46.15%), while among the SSc patients PAH was identified in 14 patients (53.84%). Development of PAH in MCTD patients was associated with lower capillaries density (p-value < 0.00001), higher scores of giant capillaries, ramified/bushy capillaries, and capillary hemorrhages (p-value < 0.00001, for each of them). Anti-U1-RNP, aCL, aβ2GPI antibodies and LAC were also found to be involved in PAH-associated MCTD development. Unlike MCTD patients, SSc patients with PAH presented with lower capillaries density and ramified/ bushy capillaries scores (p-value < 0.05). CONCLUSIONS: The MCTD patients who presented significant NFC abnormalities (especially active and late scleroderma-like capillaroscopic pattern) are prone to PAH development. Capillary density reduction is the most important factor associated with the occurrence of PAH. Differences in NFC findings (especially capillary density and ramified/bushy capillaries) were detected among patients with MCTD and SSc having PAH. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) is a possible complication of connective tissue diseases (CTDs), especially systemic sclerosis (SSc), systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD). It is defined by an elevation of the mean pulmonary arterial pressure above 20 mmHg documented during a right heart catheterization (RHC). Due to their multiorgan involvement, CTDs can induce PH by several mechanisms, that are sometimes intricated: pulmonary vasculopathy (group 1) affecting arterioles (pulmonary arterial hypertension, PAH) and possibly venules (pulmonary veno-occlusive-like disease), left-heart disease (group 2), chronic lung disease (group 3) and/or chronic thromboembolic PH (group 4). PH suspicion is often raised by clinical manifestations (dyspnea, fatigue), echocardiographic data (increased peak tricuspid regurgitation velocity), isolated decrease in DLCO in pulmonary function tests, and/or unexplained elevation of BNP/NT-proBNP. Its formal diagnosis always requires a hemodynamic confirmation by RHC. Strategies for PH screening and RHC referral have been extensively investigated for SSc-PAH but data are lacking in other CTDs. Therapeutic management of PH depends of the underlying mechanism(s): PAH-approved therapies in group 1 PH (with possible use of immunosuppressants, especially in case of SLE or MCTD); management of an underlying left-heart disease in group 2 PH; management of an underlying chronic lung disease in group 3 PH; anticoagulation, pulmonary endartectomy, PAH-approved therapies and/or balloon pulmonary angioplasty in group 4 PH. Regular follow-up is mandatory in all CTD-PH patients. [ABSTRACT FROM AUTHOR]

Interstitial lung disease (ILD) frequently complicates mixed connective tissue disease (MCTD) and contributes to increased mortality. We aimed to identify predictors of ILD in MCTD patients. This is a nationwide, multicentre, retrospective study including patients with an adult-onset MCTD clinical diagnosis who met Sharp's, Kasukawa, Alarcón-Segovia, or Kahn's diagnostic criteria and had available chest high-resolution computed tomography (HRCT) data. Univariate and multivariate analyses were conducted. We included 57 MCTD patients, with 27 (47.4%) having ILD. Among ILD patients, 48.1% were asymptomatic, 80.0% exhibited a restrictive pattern on pulmonary function tests, and 81.5% had nonspecific interstitial pneumonia on chest HRCT. Gastroesophageal involvement (40.7% vs. 16.7%, p = 0.043) and lymphadenopathy at disease onset (22.2% vs. 3.3%, p = 0.045) were associated with ILD. Binary logistic regression identified lymphadenopathy at disease onset (OR 19.65, 95% CI: 1.91–201.75, p = 0.012) and older age at diagnosis (OR 1.06/year, 95% CI: 1.00–1.12, p = 0.046) as independent ILD predictors, regardless of gender and gastroesophageal involvement. This study is the first to assess a Portuguese MCTD cohort. As previously reported, it confirmed the link between gastroesophageal involvement and ILD in MCTD patients. Additionally, it established that lymphadenopathy at disease onset and older age at diagnosis independently predict ILD in MCTD patients. [ABSTRACT FROM AUTHOR]

SARS‐CoV2 primarily affects the respiratory system but a hyperinflammatory response leading to multisystem inflammatory syndrome – children (MIS‐C), immune dysfunction and various autoimmune manifestations has also been noted. Autoimmunity depends on various factors, including genetic predisposition, environmental factors, immune dysregulation and infections acting as triggers like Epstein‐Barr virus, cytomegalovirus, human immunodeficiency virus, hepatitis B. Molecular mimicry, bystander T‐cell activation and persistence of viral infection are the main mechanisms behind these manifestations. We present here 3 cases of newly diagnosed connective tissue disease with high titers of COVID19 immunoglobulin G antibody in children. A 9‐year‐old girl with fever, oliguria and malar rash (prior history of sore throat) and a 10‐year‐old girl with fever for 2 weeks and choreoathetoid movements were diagnosed as systemic lupus erythematosus (SLE) nephritis (stage 4) and neuropsychiatric SLE, respectively as per European League Against Rheumatism / American College of Rheumatology 2019 criteria. An 8‐year‐old girl with fever, joint pain and respiratory distress (a recent contact with a positive COVID19 patient) presented with altered sensorium, Raynaud's phenomenon noted, and eventually diagnosed as mixed connective tissue disease as per Kusukawa criteria. The immune‐mediated manifestations post‐COVID infection are a de‐novo phenomenon which necessitates further workup as not many studies exist in the pediatric population. [ABSTRACT FROM AUTHOR]

Background Interstitial lung disease frequently complicates systemic autoimmune disorders including scleroderma, idiopathic inflammatory myositis and mixed connective tissue disease, resulting in considerable morbidity and mortality. Based on the results of trials undertaken in scleroderma, cyclophosphamide is the standard of care for individuals with severe or progressive connective tissue disease-associated interstitial lung disease. Observational studies suggest that the anti-CD20 monoclonal antibody, rituximab is an effective rescue therapy in treatment of refractory connective tissue disease-associated interstitial lung disease, but it has not been studied as first-line therapy in clinical trials. Objectives To compare the safety and efficacy of rituximab against that of cyclophosphamide as treatment for individuals with severe, progressive interstitial lung disease associated with scleroderma, idiopathic inflammatory myositis or mixed connective tissue disease. Methods This was a Phase IIb, multicentre, randomised, double-blind, double-dummy study assessing the superiority of rituximab compared with cyclophosphamide, conducted in rheumatology or interstitial lung disease units at 11 UK centres. The study recruited individuals with extensive and/or progressive connective tissue disease-associated interstitial lung disease, excluding those with significant comorbidities, including airflow obstruction. Participants were randomised 1 : 1 to receive either rituximab 1 g given intravenously, twice at an interval of 2 weeks, or intravenous cyclophosphamide given monthly for 6 months at a dose of 600 mg/m2 body surface area. The primary end point for the study was the change in forced vital capacity at 24 weeks. Secondary end points included safety and tolerability, corticosteroid exposure, forced vital capacity change at 48 weeks and patient-reported quality of life. A cost-effectiveness analysis was undertaken to assess the impact of rituximab use in the United Kingdom National Health Service. Results One hundred and one subjects (70 females) with a mean age of 56.3 years were randomised; 51 to rituximab and 50 to cyclophosphamide. Ninety-seven were included in the modified intention-to-treat population for the primary and secondary efficacy analyses (49 in the rituximab group and 48 in the cyclophosphamide group). 38.6% had scleroderma, 44.6% idiopathic inflammatory myositis and 16.8% mixed connective tissue disease. Four subjects withdrew prior to the first dose of therapy (two in each arm). At 24 weeks, both rituximab and cyclophosphamide improved forced vital capacity from baseline [(mean ± standard deviation) 97 ± 234 and 99 ± 329 ml, respectively]. Using an adjusted mixed-effects model corrected for diagnosis and baseline forced vital capacity the difference in forced vital capacity at 24 weeks between rituximab and cyclophosphamide was −40 ml (95% CI −153 to 74 ml), p = 0.49. Other physiological and quality-of-life parameters improved in both arms following treatment but were not statistically significantly different between groups. Numerically fewer adverse events were reported by subjects receiving rituximab. Corticosteroid exposure over the 48 weeks of the trial was numerically less in the rituximab arm [13,291 (±14,657) mg of hydrocortisone equivalent per subject in the cyclophosphamide arm versus 11,469 (±10,041) mg per subject in the rituximab group; these differences did not reach statistical significance]. Limitations of the study include a disproportionate number of subjects being recruited from a single centre and insufficient subjects in each subgroup to determine whether there were treatment differences between individual connective tissue diseases. Based on the results of the trial, from a UK healthcare payer perspective, rituximab is more cost-effective than cyclophosphamide as a treatment for severe or progressive connective tissue disease-interstitial lung disease. Conclusions Rituximab improved forced vital capacity and patient-reported quality of life at 24 weeks but was not superior to cyclophosphamide. Rituximab should be considered as a therapeutic alternative to cyclophosphamide in individuals with connective tissue disease-associated interstitial lung disease requiring systemic therapy. Future work should explore the role of repeated dosing of rituximab and the use of rituximab earlier in the course of connective tissue disease-associated interstitial lung disease. Trial registration This trial is registered as ISRCTN16474148. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation Programme (NIHR award ref: 11/116/03) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 4. See the NIHR Funding and Awards website for further award information. Plain language summary Interstitial lung disease, a condition characterised by inflammation and scarring of the lungs, is the leading cause of death in systemic sclerosis (an autoimmune disease that typically causes thickening and scarring of the skin and which is associated with internal organ problems such as interstitial lung disease and kidney failure), and a major cause of morbidity (illness) in many other connective tissue diseases; a group of conditions that are caused by over activity of the immune system. When interstitial lung disease associated with connective tissue disease gets worse over time, treatment such as intravenous cyclophosphamide is required to slow down lung scarring. Occasionally, standard immunosuppressive drugs fail to control lung inflammation and scaring and this can result in death. Rituximab, a novel therapy, has been proven to be of benefit in suppressing inflammation associated with immune system over activity. Observational studies suggest that rituximab may be an effective treatment for pulmonary inflammation in connective tissue diseases. The study was designed to determine how well rituximab works compared to cyclophosphamide in treating patients with severe connective tissue disease-associated interstitial lung disease. We recruited 101 participants from 11 hospitals throughout the UK who were randomly allocated to one of two groups. Those in the first group were given rituximab on day 1 of the study and then on day 14. They were then given a placebo every 4 weeks for the next 18 weeks. Those in the second group were given cyclophosphamide every 4 weeks from day 1 of the study to week 20. On day 14, they were given a placebo. Lung function for all participants was assessed at 24 weeks. Our results suggest that rituximab improved lung function and quality of life but was not better than cyclophosphamide. Rituximab was associated with fewer unexpected medical events and a trend towards reduction in corticosteroid use and should be considered as a therapeutic alternative to cyclophosphamide. Scientific summary Background Interstitial lung disease (ILD) is characterised by inflammation and/or fibrosis within the parenchymal compartment bounded by the alveolar epithelium and capillary endothelium and frequently results in breathlessness progressing over time to respiratory failure. Autoimmune injury to the lung is a frequent cause of ILD. As such, the connective tissue diseases (CTDs), including systemic sclerosis (SSc), the inflammatory myopathies and mixed connective tissue disease (MCTD), are important causes of ILD. For individuals with CTD the development of ILD is an important cause of morbidity and mortality; for people with scleroderma, ILD is now the leading cause of death. Despite this there are few evidence-based treatments for CTD-associated ILD. At the time of planning this research there were no approved therapies available for CTD-ILD and all of the trial data which existed had been generated in the context of scleroderma-associated ILD. The Scleroderma Lung Study I assessed the efficacy of 52 weeks of treatment with oral cyclophosphamide (CP) compared to placebo in individuals with systemic sclerosis-associated ILD and evidence of an active inflammatory cell infiltrate on bronchoalveolar lavage. The trial demonstrated a positive effect of CP at 52 weeks but the drug was poorly tolerated and the benefit compared with placebo had disappeared by 2 years. A smaller 52-week study, also conducted in individuals with scleroderma-associated ILD, compared placebo to once-monthly intravenous CP given for 6 months followed by azathioprine and low dose prednisolone for the subsequent 6 months and showed a trend towards benefit in the active treatment arm. In the absence of treatment guidelines or evidence generated in other forms of CTD-ILD, most centres in the UK were routinely using intravenous CP as first-line therapy for individuals with clinically advanced or rapidly progressive ILD arising in the context of CTD. Rituximab, a chimeric (human/mouse) monoclonal antibody with a high affinity for the CD20 surface antigen expressed on B-lymphocytes, results in rapid depletion of B cells from the peripheral circulation for 6–9 months. Evidence for the efficacy of B cell depletion exists in a number of immune-mediated conditions, including rheumatoid arthritis, antineutrophil cytoplasmic antibody-associated vasculitis and immune thrombocytopenic purpura. Several case series suggest rituximab may also be effective in ILD occurring in the context of immunological over-activity, with favourable responses reported in antisynthetase-associated ILD and SSc-ILD. Our own clinical experience suggested that rituximab is an effective, potentially life-saving therapeutic intervention in the treatment of very severe, progressive CTD-ILD unresponsive to conventional immunosuppression. In head-to-head studies in the context of other autoimmune diseases rituximab has been shown to have a favourable safety and tolerability profile compared to CP. The absence of high-quality evidence to guide treatment of CTD-ILD provided an opportunity to assess the efficacy of rituximab compared to the accepted standard of care, CP. Objectives The primary objective of the study was to demonstrate that intravenous rituximab has superior efficacy compared to current best treatment (intravenous CP) for CTD-ILD as measured by assessment of change in forced vital capacity (FVC) at 24 weeks. Secondary objectives were: to compare the safety profile of rituximab to intravenous CP in individuals with CTD-ILD to assess the health economic benefits of rituximab compared to current standard of care for CTD-ILD – including measurements of healthcare utilisation, quality of life (QoL) and carer burden to evaluate a range of exploratory biomarkers for disease severity, prognosis and treatment response in CTD-ILD. Methods The study was a Phase IIb, UK multicentre, prospective, randomised, double-blind, double-dummy trial of intravenous rituximab compared with intravenous CP in patients with severe, progressive CTD-ILD. Patients were randomised 1 : 1 to two groups, both groups received placebo to match the different regimens. Patients were followed for 48 weeks after first treatment; after 24 weeks subjects were permitted additional immunotherapy as determined by their treating physician. Study settings The study was conducted in rheumatology or ILD units at 11 UK centres. Participant inclusion criteria A diagnosis of CTD, based on internationally accepted criteria, in one of the following categories: systemic sclerosis idiopathic interstitial myopathy (including polymyositis/dermatomyositis) MCTD. Severe and/or progressive ILD associated with the underlying CTD. Chest high-resolution computer tomography performed within 12 months of randomisation. Intention of the caring physician to treat the ILD with intravenous CP. Able to provide written informed consent. Participant exclusion criteria Previous treatment with rituximab and/or intravenous CP. Age 80 years. Known hypersensitivity to rituximab or CP or their components. Significant (in the opinion of the investigator) other organ comorbidity including cardiac, hepatic or renal impairment. Coexistent obstructive pulmonary disease (e.g. asthma, chronic obstructive pulmonary disease, emphysema) with pre-bronchodilator forced expiratory volume in 1 second (FEV1) and FVC ratio < 70%. Patients at significant risk for infectious complications following immunosuppression including those with human immunodeficiency virus positive or other immunodeficiency syndromes (including hypogammaglobulinemia). Suspected or proven untreated tuberculosis. Viral hepatitis. Infection requiring antibiotic treatment in the preceding 4 weeks. Unexplained neurological symptoms (which may be suggestive of progressive multifocal leucoencephalopathy). Neurological symptoms arising because of the underlying CTD do not necessitate exclusion. Other investigational therapy (participation in research trial) received within 8 weeks of randomisation. Immunosuppressive or CTD modifying therapy (other than corticosteroids) received within 2 weeks of the first intravenous treatment. Pregnant or breastfeeding women, or women of child-bearing potential, not using a reliable contraceptive method for up to 12 months following IMP. Unexplained haematuria, or previous bladder carcinoma. Computerised tomography scan > 12 months from randomisation. Unable to provide informed written consent. Interventions Patients were randomised to receive either: Rituximab 1000 mg for two doses at day 0 and day 14. Placebo was administered monthly from week 4 to week 20. CP given at a dose of 600 mg/m2 body surface area rounded to the nearest 100 mg every 4 weeks from day 0 to week 20. Placebo was given at day 14. Patients were pre-medicated on day 0 with hydrocortisone, paracetamol, chlorpheniramine and mesna, at day 14 with hydrocortisone, paracetamol and chlorpheniramine and at visits from week 4 to 20 with mesna. Measurements Wherever possible, even if treatment could not be given, spirometry was undertaken at the time of each planned visit and performed according to standards outlined in the American Thoracic Society/European Respiratory Society guidelines. Lung function tests (plethysmography and gas transfer) were measured at screening, baseline, week 12, week 24 and week 48. Assessment for adverse events (AEs) and clinical end points began from randomisation and continued for the individual patient until they completed their follow-up at 48 weeks. At each study visit the investigator or designee made an assessment of safety and reviewed the clinical history and investigation findings with regard to the occurrence of adverse or serious adverse events (SAEs). Peripheral blood was taken at the time of each planned visit. Collection of blood for laboratory analyses included full blood count, erythrocyte sedimentation rate, urea and electrolytes, glucose, hepatitis A, B and C serology (screening only) and liver function tests. Blood for lymphocyte subsets and biomarker analysis was taken at day 0, week 12, 24 and 48 only. Quality of life was assessed by self-administered validated questionnaires undertaken at baseline and repeated at the primary end point visit at 24 weeks and at the final follow-up visit at 48 weeks. The instruments used were: the Short Form 36 (SF36) questionnaire EuroQol-5 Dimensions (EQ-5D) St George’s Respiratory Questionnaire (SGRQ) King’s Brief Interstitial Lung Disease (K-BILD) Scleroderma Health Assessment (SHA) Questionnaire which was disease-specific. For individuals with scleroderma, assessment of skin thickening was undertaken using the modified Rodnan skin score at baseline, 24 and 48 weeks. Sample size The primary outcome was changed in FVC at 24 weeks. The trial was designed to have 90% power to detect a 5% difference in 24-week FVC between treatment groups with a significance level (alpha) of 0.05 (two-tailed). The target sample size was 116 with the anticipation that 52 patients would reach the end-of-study in each arm with an expected 10% drop out. Because of the COVID-19 pandemic and an anticipated prolonged interruption to recruitment, trial enrolment was halted in March 2020 after randomisation of 101 subjects. Statistical analysis No formal interim analysis was planned. A statistical analysis plan was produced and agreed prior to analysis. Analysis of the primary outcome was by modified intention to treat. In other words, data were included in respect of all subjects who met all the entry criteria for the trial and had been randomised and received at least one dose of study drug. Results The study recruitment period was from December 2014 until March 2020 from 11 sites. In total 145 subjects were assessed for eligibility and of these 104 participants were enrolled. Three of these failed screening and were excluded. One hundred and one subjects were therefore randomised and 97 subjects received at least one dose of study drug and were included in the modified intention-to-treat population for the primary and secondary efficacy analyses (49 in the rituximab group and 48 in the CP group). Overall, baseline characteristics between the rituximab and CP arms were well balanced albeit with slightly more male participants in the rituximab arm. For the total cohort the mean ± S.D. age was 56 ± 11.4 years. Seventy subjects (69.3%) were female, 70 (69.3%) were white, 16 (15.8%) Asian and 12 (11.9%) black. The most frequently encountered CTD was idiopathic inflammatory myopathy (44.6%), followed by scleroderma (38.6%) and then MCTD (16.8%). Primary outcome At week 24 the unadjusted mean [± standard deviation (SD)] change in FVC in the CP treatment arm was a gain of 99 ± 329 ml. In the rituximab arm the change was 97 ± 234 ml. The relative change from baseline for each arm was 4.35 ± 15.67% for CP and for rituximab 4.31 ± 11.80%. Using a mixed-effects model adjusted for baseline FVC and diagnosis the difference (and 95% confidence interval) at 24 weeks between rituximab and CP was −40 ml [95% confidence interval (CI) −153 to 74 ml], p = 0.49. Secondary outcomes The unadjusted change in FVC at 48 weeks was 138 ± 440 ml in the CP arm and 112 ± 249 ml in the rituximab group. In relative terms, over 48 weeks, the improvement in the CP group was 5.08 ± 19.96% and in the rituximab group 4.22 ± 10.31%. An adjusted mixed-effects model demonstrated a −58 (95% CI −178 to 62) ml difference at 48 weeks between the rituximab and CP arms (p = 0.251). At week 24 the mean relative change in diffusing capacity of the lung for carbon monoxide (DLco) in the CP arm was 1.43 ± 23.05% compared to 6.98 ± 17.19% in the rituximab arm. At 48 weeks the changes in DLco were 3.00 ± 31.35% and 7.43 ± 16.08% in the CP and rituximab arms, respectively. For 6-minute walk distance the 24-week change in the CP and rituximab arms was 10.4 ± 78.6 and 10.9 ± 74.2 m, respectively. At week 48 the changes were 15.1 ± 82.8 and −6.8 ± 69.8 m. Using an adjusted mixed-effects model the differences between the rituximab and CP arms were −0.72 (−24.76 to 23.32) m, p = 0.953 at 24 weeks and −22.46 (−48.43 to 3.51) m, p = 0.090 at 48 weeks. Quality of life was assessed using the K-BILD questionnaire. Change at 24 weeks was 9.4 ± 20.8 in the CP arm and 8.8 ± 17.0 in the rituximab arm. At 48 weeks the difference compared to baseline was 5.6 ± 25.6 and 6.4 ± 16.2 in the CP and rituximab arms, respectively. Analysis in an adjusted mixed-effects model showed the difference between rituximab and CP was 0.4 (−5.73 to 6.52) and 1.15 (−5.34 to 7.64) at weeks 24 and 48, respectively. Survival Over the 48-week course of the study there were five deaths. All were deemed to be due to complications of either CTD or ILD. Three occurred in subjects receiving rituximab and two in subjects receiving CP. There was no difference between groups in time to death as assessed by an adjusted Cox proportional hazards model [hazard ratio (HR) 1.72 (95% CI 0.311 to 9.56, p = 0.534)]. The rates of progression-free survival [HR 1.11 (95% CI 0.625 to 1.99, p = 0.715)], and time to treatment failure [HR 1.25 (95% CI 0.34 to 4.65, p = 0.742)] did not differ between treatment arms. Corticosteroids The mean per-subject total steroid exposure during the study (measured in hydrocortisone equivalents) was 13,291 (±14,657) mg in the CP and 11,469 (±10,041) mg in the rituximab group; a 12% reduction in corticosteroid exposure in the rituximab arm. The daily mean dose per patient was 42.89 mg hydrocortisone/day in the CP and 37.61 mg hydrocortisone/day in the rituximab group. Safety All subjects in both arms experienced at least one AE. There were more AEs reported in the CP arm (646) than in the rituximab arm (445). The imbalance was less marked for SAEs with 33 and 29 in the CP and rituximab arms, respectively. Gastrointestinal disorders (170 vs. 71), general disorders and administration site reactions (91 vs. 52) and nervous system disorders (72 vs. 35) were more common in the CP arm. The frequency of other AEs was balanced between groups including infections and infestations (50 vs. 46). One patient in each arm withdrew because of side effects. There were no reported cases of COVID-19 during the trial. Cost-effectiveness Over the 48-week trial period treatment with CP was associated with a cost of £94,338 compared with a cost of £93,227 for rituximab; a difference of £1110 in favour of rituximab. Rituximab was associated with a 0.022 gain in quality-adjusted life-years over that seen with CP. The incremental net monetary benefit was significantly higher in the rituximab group under a wide range of monetary values and quality-adjusted life-years. Conclusion This study demonstrated that both rituximab and CP improve FVC and QoL in patients with CTD-ILD. There were numerically fewer AEs and a trend towards reduction in corticosteroid exposure in the rituximab-treated subjects. Rituximab should therefore be considered as a treatment option in patients with severe or rapidly progressive CTD-associated ILD. Implications for health care Although this study failed to show superiority of rituximab over CP in improving FVC when used as first-line treatment for CTD-ILD, the consistent positive effects of rituximab on physiological end points, QoL, and corticosteroid requirements support the clinical use of this drug in what is a population of patients with high unmet need (especially in situations where CP is contraindicated or likely to cause deleterious effects such as gonad failure or bladder malignancy). Implications for research Further trials will be necessary to confirm whether repeated dosing with rituximab confers additional benefit as compared to a single baseline dose. Similarly, additional studies are necessary to confirm findings in individual CTDs and to assess the optimal longer-term therapeutic regimen following initial intravenous therapy. Trial registration This trial is registered as ISRCTN16474148. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation Programme (NIHR award ref: 11/116/03) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 4. See the NIHR Funding and Awards website for further award information.

Abstract Background Pulmonary arterial hypertension (PAH) is a severe complication of mixed connective tissue disease (MCTD) and contributes to increased morbidity and mortality. Still, the demographic characteristics and risk factors of PAH in MCTD remain poorly understood. This study explored risk factors for PAH development in MCTD. Methods Data from patients with MCTD and PAH hospitalized from May 2009 to December 2022 in a single center were collected and compared with patients with MCTD without PAH. The variables were analyzed by logistic regression to identify the factors associated with PAH in patients with MCTD. The receiver-operating characteristic (ROC) curve was used to assess the diagnostic value of the identified factors. Results Finally, 119 patients with MCTD were included; 46 had PAH. The mean age at PAH onset and diagnosis was 38.9 ± 13.4 and 39.9 ± 13.7 years, respectively. The median pulmonary arterial systolic pressure (PASP) was 67.0 mmHg. The median brain natriuretic peptide (BNP) level was 180.0 pg/ml at PAH diagnosis. Red cell distribution width (RDW) (OR: 2.128; 95% confidence interval: 1.497–3.026; P

IntroductionViral infections have been implicated in the initiation of the autoimmune diseases. Recent reports suggest that a proportion of patients with COVID-19 develop severe disease with multiple organ injuries. We evaluated the relationship between COVID-19 severity, prevalence and persistence of antinuclear and other systemic and organ specific autoantibodies as well as SARS-CoV-2 infection specific anti-nucleocapsid (N) IgG antibodies and protective neutralizing antibody (Nab) levels.MethodsSamples from 119 COVID-19 patients categorized based on their level of care and 284 healthy subjects were tested for the presence and persistence of antinuclear and other systemic and organ specific autoantibodies as well as SARS-CoV-2 and neutralizing antibody levels.ResultsThe data shows significantly increased levels of anti RNP-A, anti-nucleocapsid and neutralizing antibody among patients receiving ICU care compared to non-ICU care. Furthermore, subjects receiving ICU care demonstrated significantly higher nucleocapsid IgG levels among the RNP-A positive cohort compared to RNP-A negative cohort. Notably, the expression of anti RNP-A antibodies is transient that reverts to non-reactive status between 20 and 60 days post symptom onset.ConclusionsCOVID-19 patients in ICU care exhibit significantly higher levels of transient RNP-A autoantibodies, anti-nucleocapsid, and SARS-CoV-2 neutralizing antibodies compared to patients in non-ICU care.

Background: The positivity of anti-RNP autoantibodies as biological criteria for the diagnosis of mixed connective tissue disease (MCTD) has recently divided the rheumatology community. Autoantigenicity of the U1-snRNP complex tends to generate multiple autoantibodies against RNP-A, -C and -70 KDa or Sm proteins. The aim of this study is to identify the most informative autoantibodies in clinical practice, in particular, to contribute to differential diagnosis between MCTD and systemic lupus erythematosus (SLE). Methods: Sera from 74 patients positive for anti-RNP autoantibodies were selected over a period of one year of laboratory practice. Autoantibodies directed against extractable nuclear antigen, RNP proteins (A, C, 70 KDa) and 40 kDa fragments of RNP-70 KDa were investigated by using quantitative fluoroenzymatic assay and Western blot analysis. Results: Among the 74 patients, 40 patients were diagnosed with SLE, 20 with MCTD, six with another autoimmune disease, three with SARS-CoV-2 infection, three with cancer and two were healthy. No preferential clinical association of IgG or IgM autoantibodies directed against each of the RNP proteins was found between SLE and MCTD. In contrast, the proportion of autoantibodies directed against the RNP component within the U1-snRNP complex showed a significantly higher RNP index in patients with MCTD than in those with SLE (p = 0.011), with good performance (sensitivity: 69.2%, specificity: 88.9%). Conclusions: The analysis of the proportion of the different autoantibodies directed against the U1-snRNP complex is more informative than the analysis of each autoantibody separately. A follow-up of patients could be informative about the interest of the RNP index as a predictor of disease evolution.

Chiara Alfia Ferrara,1 Gaetano La Rocca,2 Giuseppe Ielo,1 Alessandro Libra,1 Gianluca Sambataro1 1Department of Clinical and Experimental Medicine, Regional Referral Centre for Rare Lung Diseases, A.O.U. “Policlinico-San Marco”, University of Catania, Catania, Italy; 2Department of Rheumatology, University of Pisa, Pisa, ItalyCorrespondence: Gianluca Sambataro, Regional Referral Center for Rare Lung Disease, University of Catania, via S. Sofia 68, Catania, 95123, Italy, Email dottorsambataro@gmail.comAbstract: Mixed Connective Tissue Disease (MCTD) is an autoimmune disease first described by Sharp et al in 1972, characterized by the presence of anti-Ribonucleoprotein antibodies directed against the U1 complex (anti-U1RNP). The condition shares clinical characteristics with Systemic Lupus Erythematosus, Rheumatoid Arthritis, and Systemic Sclerosis. Diagnosis is quite difficult due to its rarity, the lack of validated classification criteria, and its heterogeneous clinical presentation. While in the early stages its nuanced clinical features might lead to it being incorrectly classified as other Connective Tissue Diseases (CTDs) or even not recognized, in cases of longstanding disease its classification as a CTD is clear but challenging to discriminate from overlap syndromes. MCTD should be considered a distinct entity due to the presence of a specific genetic substrate and the presence of the high titer of a specific autoantibody, anti-U1RNP, present in all the commercial kits for Extractable Nuclear Antigens, and almost always associated with Antinuclear Antibody positivity with a coarse speckled pattern. Except for anti-U1RNP, no specific biomarkers are available to guide clinicians to a correct classification of MCTD, which is arrived at by the association of clinical, serological and instrumental evaluation. In the first stages, the disease is mainly characterized by Raynaud’s phenomenon, inflammatory arthritis, puffy fingers, myalgia and/or myositis, and rarely, trigeminal neuropathy. Longstanding disease is generally associated with the development of Pulmonary Hypertension and Interstitial Lung Disease, which are the two main causes of mortality in MCTD. The aim of this review is to summarize current knowledge on the early recognition of MCTD.Keywords: mixed connective tissue disease, diagnosis, Raynaud’s phenomenon, nailfold videocapillaroscopy, anti-RNP, inflammatory arthritis

Objectives. We present a very rare case of incomplete Graham-Little-Piccardi-Lassueur syndrome (GLPLS) overlap with Mixed Connective Tissue Disease (MCTD) versus Multiple Autoimmune Syndrome (MAS). Case Presentation. A 53- year-old female with a long history of more than two years of patchy hair loss on scalp like “footprints in the snow”, partial loss of eyebrows' hair, face erythema, scaly atrophied red/brown patches on face, grouped follicular papules 2-3 mm in diameter with a pointed or hair-like horny spine extending approximately 1-2 mm around the tip of the follicle on lumbar area. The histopathological results from biopsies of scalp and lumbar areas confirmed the clinical diagnosis of cicatricial alopecia induced by lichen plan pilaris (LPP) and also presence of lichen spinulosus (LS) on lumbar area. The description provided by pathologist is however borderline regarding so called interface dermatosis like chronic cutaneous lupus erythematous (CCLE) or Pseudopelade of Brocq (PPB) as the end stage of CCLE or LPP. Blood tests showed both Antinuclear antibodies and U1-nRNP in high titers and the absence of anti-Sm, anti SS-A, anti SS-B and anti-dsDNA antibodies, and also peculiar antibody patterns of MCTD. Outcome. After thorough investigation, MCTD was proven by antibodies results. After one year of treatment a lot of clinical features dramatically responded under therapy. Conclusions. Clinical manifestations in the pathology with strictly cutaneous or systemic localization in conjunction or overlap with other autoimmune diseases (grouped in the MAS) represent a rare diagnostic in daily practice.

Methods: In this observational study from October 2018 to August 2020, we included all the patients of MCTD and overlap syndromes. Alarcon–Segovia criteria was used as defining criteria for MCTD patients while the patients meeting diagnostic criteria for more than 1 of 6 classical autoimmune rheumatic diseases were selected in the overlap syndromes group. We compared their clinical features, laboratory parameters, and autoantibody profiles. MS Excel, STATA were used for statistical analysis, and comparison between the groups was done with t-test, Chi-square test, and Wilcoxon rank sum test. P < 0.05 was considered as statistically significant. Results: The study consisted of 60 consecutive patients (MCTD, n = 30 and overlap syndromes, n = 30) with higher female population in both groups (90% in MCTD and 84% in the overlap syndromes group) compared to males. The incidence of fever (83.3% vs. 46.6%), weight loss (60% vs. 26.6%), trigeminal neuralgia (76.6% vs. 13.3%), and myositis (63.3% vs. 20.0%) was significantly higher in MCTD than overlap syndromes whereas the incidence of cough (66.6% vs. 90.0%) and dry mouth (20.0% vs. 53.3%) was higher in overlap syndromes than MCTD (P < 0.05). Anti-U1 RNP antibodies were seen in all MCTD (100.0%) patients while anti-Scl 70 antibodies (60%) and anti-ribosomal-p-protein antibodies (13.3%) were seen in overlap syndromes. Conclusion: Fever and weight loss, trigeminal neuralgia, and myositis were more common in MCTD than overlap syndromes. Anti-U1 RNP antibodies seen in MCTD while Anti-Scl 70 antibodies and anti-ribosomal-P antibodies were commonly were seen in overlap syndromes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Pulmonary arterial hypertension (PAH) is a severe complication of mixed connective tissue disease (MCTD) and contributes to increased morbidity and mortality. Still, the demographic characteristics and risk factors of PAH in MCTD remain poorly understood. This study explored risk factors for PAH development in MCTD. Methods: Data from patients with MCTD and PAH hospitalized from May 2009 to December 2022 in a single center were collected and compared with patients with MCTD without PAH. The variables were analyzed by logistic regression to identify the factors associated with PAH in patients with MCTD. The receiver-operating characteristic (ROC) curve was used to assess the diagnostic value of the identified factors. Results: Finally, 119 patients with MCTD were included; 46 had PAH. The mean age at PAH onset and diagnosis was 38.9 ± 13.4 and 39.9 ± 13.7 years, respectively. The median pulmonary arterial systolic pressure (PASP) was 67.0 mmHg. The median brain natriuretic peptide (BNP) level was 180.0 pg/ml at PAH diagnosis. Red cell distribution width (RDW) (OR: 2.128; 95% confidence interval: 1.497–3.026; P < 0.001) was associated with PAH in patients with MCTD. There was a positive correlation between RDW and PASP (r = 0.716, P < 0.001). At a cutoff of 15.2%, RDW had the best sensitivity (80.4%) and specificity (82.2%) for PAH. Conclusion: RDW may serve as a sensitive index to predict PAH in patients with MCTD. [ABSTRACT FROM AUTHOR]

We report the case of a 62‐year‐old man who presented with shortness of breath, cough, bilateral lower limbs' swelling, and blackish discoloration of multiple fingertips over the past 2 months. Anti‐Ribonucleoprotein antibodies were found to be present, and gadolinium‐based cardiac MRI showed non‐vascular subendocardial enhancement with diffuse symmetrical thickening of the left ventricular wall. A diagnosis of Mixed connective tissue disease with secondary cardiac amyloidosis was thus made, and the patient was successfully managed with intravenous cyclophosphamide, corticosteroids, and other supportive measures. Although extremely rare, this case shows that secondary cardiac amyloidosis should be considered while managing patients with MCTD. [ABSTRACT FROM AUTHOR]

To report on a rare case of frosted branch angiitis in a patient presenting with subacute vision loss in the setting of a flare of her mixed connective tissue disease. The patient responded well to immunosuppressive therapy and had full visual recovery at 1-month follow-up. Purpose: To present a case of frosted branch angiitis associated with an exacerbation of mixed connective tissue disease (MCTD). Methods: Single case report. Results: A 31-year-old woman presented with a flare of her long-standing MCTD after a change in her immunosuppressive medications. She developed blurred vision and floaters first in the left eye but eventually in both eyes. Fundoscopy showed patchy perivascular sheathing of tertiary branch venules surrounded by retinal hemorrhages characterized as frosted branch angiitis. The patient's MCTD symptoms and retinal vasculitis improved with continued immunosuppressive therapy. At 1-month follow-up, her visual acuity had improved to 20/20 bilaterally with complete resolution on fundoscopy. Conclusion: To the authors' knowledge, this is the first report of frosted branch angiitis seen in association with MCTD. The improvement in the patient's visual acuity and fundoscopic findings in this case supports the role of immunosuppressive therapy to treat secondary frosted branch angiitis associated with an autoimmune condition such as MCTD. However, it is recommended that a comprehensive medical workup is performed to exclude an infective cause, particularly in immunocompromised patients. [ABSTRACT FROM AUTHOR]

Copyright of Galicia Clínica is the property of Sociedad Gallega de Medicina Interna and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The detection of antinuclear antibodies is central to the diagnosis and prognosis of systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS) and mixed connective tissue disease (MCTD). Anti-U1-RNP and anti-RNP70 antibodies were assayed in the sera of patients with SLE (n = 114), pSS (n = 54) and MCTD (n = 12). In the SLE group, 34/114 (30%) were anti-U1-RNP positive, and 21/114 (18%) were both anti-RNP70 positive and anti-U1-RNP positive. In the MCTD group, 10/12 (83%) were anti-U1-RNP positive, and 9/12 (75%) were anti-RNP70 positive. Only one individual with pSS was antibody positive (for both anti-U1-RNP and anti-RNP70). All anti-RNP70-positive samples were also anti-U1-RNP positive. Anti-U1-RNP-positive subjects with SLE were younger (p < 0.0001); showed lower concentrations of complement protein 3 (p = 0.03); had lower eosinophil (p = 0.0005), lymphocyte (p = 0.006) and monocyte (p = 0.03) counts; and had accrued less organ damage (p = 0.006) than the anti-U1-RNP-negative SLE patients. However, we observed no significant clinical or laboratory parameter differences between the anti-U1-RNP-positive individuals with/without anti-RNP70 in the SLE group. In conclusion, anti-RNP70 antibodies are not exclusive to MCTD but are rarely detected in pSS and healthy individuals. In SLE, anti-U1-RNP antibodies are associated with a clinical phenotype that resembles MCTD, with hematologic involvement and less damage accrual. Based on our results, the clinical value of subtyping anti-RNP70 in anti-U1-RNP-positive sera appears to be of limited value. [ABSTRACT FROM AUTHOR]

Anti‐MDA5 antibody dermatomyositis (DM) is a special type of myositis, which can potentially cause rapidly progressive interstitial lung disease (RP‐ILD). Mixed connective tissue disease (MCTD) is a complex disease with different characteristics of autoimmune connective tissue disease, associated with ILD. Both are rare diseases, and few patients with both diseases have been reported. A 71‐year‐old woman complained of palpitations, with a 2 months history of rash around her hands, extensor surface of right elbow, and the nape of her neck. Subsequently, the patient had acute exacerbation of dyspnea and tachypnea. Anti‐Ro52, U1 RNP and MDA5 antibodies were positive; the presenting evidence was suggestive of anti‐MDA5+DM‐RP‐ILD complicated with MCTD. Our patient deteriorated rapidly and had a fatal outcome, despite "triple therapy" for RP‐ILD. This case illustrates that patients with coexisting anti‐MDA5+DM and MCTD have the former's typical clinical manifestations, and may develop ILD quickly rather than slowly as in MCTD, especially with the coexistence of anti‐Ro52 antibodies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Methods: In this observational study from October 2018 to August 2020, we included all the patients of MCTD and overlap syndromes. Alarcon–Segovia criteria was used as defining criteria for MCTD patients while the patients meeting diagnostic criteria for more than 1 of 6 classical autoimmune rheumatic diseases were selected in the overlap syndromes group. We compared their clinical features, laboratory parameters, and autoantibody profiles. MS Excel, STATA were used for statistical analysis, and comparison between the groups was done with t-test, Chi-square test, and Wilcoxon rank sum test. P < 0.05 was considered as statistically significant. Results: The study consisted of 60 consecutive patients (MCTD, n = 30 and overlap syndromes, n = 30) with higher female population in both groups (90% in MCTD and 84% in the overlap syndromes group) compared to males. The incidence of fever (83.3% vs. 46.6%), weight loss (60% vs. 26.6%), trigeminal neuralgia (76.6% vs. 13.3%), and myositis (63.3% vs. 20.0%) was significantly higher in MCTD than overlap syndromes whereas the incidence of cough (66.6% vs. 90.0%) and dry mouth (20.0% vs. 53.3%) was higher in overlap syndromes than MCTD (P < 0.05). Anti-U1 RNP antibodies were seen in all MCTD (100.0%) patients while anti-Scl 70 antibodies (60%) and anti-ribosomal-p-protein antibodies (13.3%) were seen in overlap syndromes. Conclusion: Fever and weight loss, trigeminal neuralgia, and myositis were more common in MCTD than overlap syndromes. Anti-U1 RNP antibodies seen in MCTD while Anti-Scl 70 antibodies and anti-ribosomal-P antibodies were commonly were seen in overlap syndromes.