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Mixed connective tissue disease (MCTD) predominantly affects women in their reproductive age (30-40 years). This study is aimed to analyze a case series of MCTD-complicated pregnancies. The study design utilized a combined case-series and case-control approach. Pregnant women with MCTD were included and categorized into two groups: the live-birth and non-live birth (encompassing miscarriages at <12 weeks and stillbirths at ≥12 weeks) groups. Primary outcomes included delivery outcomes and factors associated with live births. A total of 57 pregnancies from 34 mothers (median age: 33.0 years) were included. Regarding delivery outcomes, the rates for live birth, miscarriage, and stillbirth were 64.9, 29.8, and 5.3%, respectively. Additionally, the respective rates of preterm delivery, fetal growth restriction (FGR), and small-for-gestational-age (SGA) were 18.9, 18.9, and 27.0%. Higher steroid usage (62.2 vs. 30.0%, p = 0.02) and lower prednisolone dosage in the live birth group (median dose: 7 vs. 10 mg, p = 0.03) were found to be significant factors contributing to live births. MCTD during pregnancy was associated with increased risks of miscarriage, stillbirth, preterm delivery, FGR, and SGA. Notably, low-dose steroid therapy was identified as a contributing factor to successful live births., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Yoshida et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: 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., Objectives: 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., Conclusion: 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., (© 2024 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Introduction: Overlap autoimmune syndromes (OAS) and mixed connective tissue disease (MCTD) are rare in children. We performed a retrospective, longitudinal and descriptive study of Afro-Caribbean patients from the French West Indies followed for MCTD and OAS to describe their characteristics and outcomes during childhood., Methods: Retrospective study from January 2000 to 2023. Listings of patients were obtained from multiple sources: computerized hospital archives and national hospital-based surveillance system, registry of pediatricians and adult specialists in internal medicine and the national registry for rare diseases. MCTD was defined according to Kasukawa's criteria. OAS was defined as overlapping features of systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and dermatomyositis/autoimmune myositis (DM/AM)., Results: Sixteen patients were included over a 23-year period (10 MCTD and 6 OAS). The incidence was 0.23 per 100,000 children-years. The mean age at diagnosis was 11.9 years old (2.4-17) with median follow up of 7.9 years (2.1-19.6). SLE phenotype was present in the highest, followed by SSc and DM/AM. Patients had an average of three flares during childhood (1-7). A quarter (25%) had symptomatic pulmonary arterial hypertension (PAH). Ninety-four percent received steroids during follow-up and 88% required a corticosteroid-sparing therapy. Three patients (19%) developed SLE after more than 10y of follow-up. There were no death and no chronic organ failure., Conclusion: This is the largest pediatric cohort of MCTD and OAS in Afro-descendant patients treated in a country with a high standard of care. The clinical evolution did not differ between MCTD and OAS. The main complication was PAH, more frequent in our cohort., (© 2024. The Author(s).)

Objectives: The prevalence and outcome of mixed connective tissue disease-associated pulmonary arterial hypertension (MCTD-PAH) has not been well understood. Our aim was to review the current knowledge on the prevalence, severity, and mortality of MCTD-PAH. We also aimed to examine the prevalence trend of MCTD-PAH over the years., Methods: PubMed/Medline, Embase, Scopus and Web of Science electronic databases were searched for the published randomised controlled clinical trials (RCTs) and observational/original studies on PAH in patients with MCTD from January 1972 to December 2020., Results: The results were pooled using random-effects meta-analysis based on DerSimonian and Laird method. A total of 983 patients from eight studies were included in the meta-analysis (K=8, n=983). Pooled prevalence of PAH in MCTD patients was 12.53% [95% CI 8.30-18.48%] with significant level statistical heterogeneity (tau2=0.30, tau=0.55, i2 83.3%, H=2.13 Q(df,7)=31.90, p=0.001). There was no association between PAH and female gender or age. The percentage of deaths in MCTD patients due to PAH varied and reached up to 81.8%., Conclusions: This is the first systematic review and meta-analysis investigating the prevalence of PAH in patients with MCTD and it revealed an overall prevalence of PAH in patients with MCTD of 12.53%. Our results showed trends of reduced prevalence of MCTD-PAH over last four decade, reconfirmed the lower prevalence rate in recent studies, but revealed an increased mortality rate. We also determined the low impact of the age, gender, and interstitial lung disease on MCTD-PAH.

Pulmonary hypertension (PH) is a clinical condition characterized by increased pulmonary arterial pressure arising from a heterogeneous range of diseases that has a deteriorating effect on the quality of life and may cause early mortality if left untreated. Connective tissue disorders (CTD)-associated PH is the second most common cause of pulmonary arterial hypertension (PAH), after the idiopathic form, categorized as group I. Systemic scleroderma (SSc) accounts for 75% of CTD-associated PH cases. Although SSc ranks first place for CTD-associated PH, SSc is followed by systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD), having a lesser frequency of PH occurrence, while it occurs as a rare complication in cases with rheumatoid arthritis (RA) and inflammatory myositis. PH may also occur during non-SSc CTDs and even other rheumatic diseases, including Behcet's disease and adult-onset Still's disease, albeit to a lesser extent. The prognosis of CTD-associated PH is worse than the other forms of PH. Although, as in idiopathic pulmonary arterial hypertension (IPAH), the mechanism of CTD-related PH is associated with an increase in vasoconstrictors like endothelin-1 and a decrease in vasodilators like prostacyclin and nitric oxide production, inflammation, and autoimmune mechanisms also play a role in the development and progression of PH. This may lead to the involvement of more than one mechanism in CTD-associated PH. Knowing which mechanism is dominant is very important in determining the treatment option. This review will primarily focus on the epidemiology, risk factors, and prognosis of PH that develops during rheumatic diseases; the pathogenesis and treatment will be briefly mentioned in light of the newly published guidelines. Key Points • Pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD) in Western countries is the second most common type of PAH after idiopathic PAH (IPAH). • CTD-PH can be seen most often in systemic scleroderma (SSc), less in systemic lupus erythematosus (SLE), mixed CTD (MCTD), and rarely in other CTDs. • While current guidelines recommend annual transthoracic echocardiography as a screening test for asymptomatic SSc patients, screening for PH is not advised in the absence of symptoms suggestive of PH in other CTDs. • CTD-PH treatment can be divided into specific vasodilator PH treatments and immunosuppressive therapy. Current treatment guidelines recommend the same treatment algorithm for patients with CTD-associated PH as for patients with IPAH. Several case series have shown the beneficial effect of immunosuppressive agents in patients with SLE-PH and MCTD-PH., (© 2022. International League of Associations for Rheumatology (ILAR).)

Objective: Epidemiological data for MCTD are limited. Leveraging data from the Manhattan Lupus Surveillance Program (MLSP), a racially/ethnically diverse population-based registry of cases with SLE and related diseases including MCTD, we provide estimates of the prevalence and incidence of MCTD., Methods: MLSP cases were identified from rheumatologists, hospitals and population databases using a variety of International Classification of Diseases, Ninth Revision codes. MCTD was defined as one of the following: fulfilment of our modified Alarcon-Segovia and Kahn criteria, which required a positive RNP antibody and the presence of synovitis, myositis and RP; a diagnosis of MCTD and no other diagnosis of another CTD; and a diagnosis of MCTD regardless of another CTD diagnosis., Results: Overall, 258 (7.7%) cases met a definition of MCTD. Using our modified Alarcon-Segovia and Kahn criteria for MCTD, the age-adjusted prevalence was 1.28 (95% CI 0.72, 2.09) per 100 000. Using our definition of a diagnosis of MCTD and no other diagnosis of another CTD yielded an age-adjusted prevalence and incidence of MCTD of 2.98 (95% CI 2.10, 4.11) per 100 000 and 0.39 (95% CI 0.22, 0.64) per 100 000, respectively. The age-adjusted prevalence and incidence were highest using a diagnosis of MCTD regardless of other CTD diagnoses and were 16.22 (95% CI 14.00, 18.43) per 100 000 and 1.90 (95% CI 1.49, 2.39) per 100 000, respectively., Conclusions: The MLSP provided estimates for the prevalence and incidence of MCTD in a diverse population. The variation in estimates using different case definitions is reflective of the challenge of defining MCTD in epidemiologic studies., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To describe patients with autoimmune inflammatory rheumatic diseases (AIRD) who had COVID-19 disease; to compare patients who required hospital admission with those who did not and assess risk factors for hospital admission related to COVID-19., Methods: An observational longitudinal study was conducted during the pandemic peak of severe acute respiratory syndrome coronavirus 2 (1 March 2020 to 24 April). All patients attended at the rheumatology outpatient clinic of a tertiary hospital in Madrid, Spain with a medical diagnosis of AIRD and with symptomatic COVID-19 were included. The main outcome was hospital admission related to COVID-19. The covariates were sociodemographic, clinical and treatments. We ran a multivariable logistic regression model to assess risk factors for the hospital admission., Results: The study population included 123 patients with AIRD and COVID-19. Of these, 54 patients required hospital admission related to COVID-19. The mean age on admission was 69.7 (15.7) years, and the median time from onset of symptoms to hospital admission was 5 (3-10) days. The median length of stay was 9 (6-14) days. A total of 12 patients died (22%) during admission. Compared with outpatients, the factors independently associated with hospital admission were older age (OR: 1.08; p=0.00) and autoimmune systemic condition (vs chronic inflammatory arthritis) (OR: 3.55; p=0.01). No statistically significant findings for exposure to disease-modifying antirheumatic drugs were found in the final model., Conclusion: Our results suggest that age and having a systemic autoimmune condition increased the risk of hospital admission, whereas disease-modifying antirheumatic drugs were not associated with hospital admission., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Paediatric rheumatic disorders are common in children and result in significant impairment in quality of life, morbidity and mortality. There is limited information on the burden of these disorders in lower income countries especially in sub-Saharan Africa. Few case reports have documented presence of paediatric rheumatic disorders in Tanzania. This study was conducted to determine the spectrum of rheumatic disorders among children at Muhimbili National Hospital (MNH)., Methods: This was a retrospective study conducted among children who were attended at MNH between January 2012 and August 2019. Paediatric patients seen in the out-patient clinics and those admitted in the wards were eligible. All patients with diagnosis of rheumatic disorders were identified from admission books and outpatient clinic logbooks, and later data were collected from their case notes and were recorded in clinical research forms. Collected information included age, sex, clinical features and laboratory tests results., Results: A total of 52 children with mean age of 9.5 ± 4.3 years, 12 (40.4%) participants were aged above 10 years and 32 (61.5%) were females. Frequently reported clinical presentations were joint pain 44 (84.6%), joint swelling 34 (65.4%), fever 24 (46.2%) and skin rashes 21(40.4%). Juvenile idiopathic arthritis (JIA) was the predominant diagnosis reported in 28 (53.8%) participants followed by juvenile systemic lupus erythematosus 8 (15.4%), mixed connective tissue diseases 4 (7.7%) and juvenile dermatomyositis 4 (7.7%). Antinuclear antibody test was performed in 16 participants it was positive in 9 (56.2%). Nine participants were tested for anti-double stranded DNA test and 5 (55.6%) were positive for this test. C-reactive protein was tested in 46 participants out of which 32 (69.6%) had elevated levels. HIV was tested in 24 (46.2%) participants and results were negative. Thirty-five out of 52 (67.3%) participants had anaemia. Predominant drugs used for treatment of JIA include prednisolone and methotrexate., Conclusions: Paediatric rheumatic disorders are not uncommon in Tanzania-and were noted to affect more female children in this study. Predominant conditions included juvenile idiopathic arthritis (JIA), juvenile systemic lupus erythematosus (JSLE) and juvenile dermatomyositis (JDM).

Raynaud's phenomenon (RP) is frequent in autoimmune connective tissue diseases (AICTD) and its approach includes nailfold capillaroscopy (NFC), as it is a non-invasive technique that permits direct visualization of the microcirculation. The aim of this study is to analyze and establish clinical correlations between NFC findings and particular aspects of autoimmune disorders. This is a retrospective study. Clinical data from patients attending our NFC clinic were reviewed. Inclusion criteria included AICTD previous diagnosis, which included systemic sclerosis (SSc), mixed connective tissue disease (MCTD), systemic lupus erythematosus (SLE), Sjögren syndrome, inflammatory idiopathic myopathies (IIM), rheumatoid arthritis, undifferentiated connective tissue disease and antiphospholipid syndrome (APS). Videocap ® version 3.0 biomicroscope was used. NFC score was determined. For statistics, SPSS software was utilized. 384 patients were included; most of them were women, with mean age of 47 years. RP was present in 91% of the patients, with greater prevalence in SSc and MCTD. Scleroderma pattern was the most prevalent NFC pattern, mainly in SSc, MCTD and IIM. Mean capillary density was reduced in IIM, SSc and MCTD. NFC score was worse in SSc, IIM and MCTD. In patients with AICTD, RP is related to microvascular damage and worse NFC score. NFC scleroderma pattern correlates with SSc classification criteria score. In MCTD, scleroderma pattern relates to myositis. SLE and APS reveal significant hemorrhages, but not related to APS antibodies. This study highlights the possible role of NFC as biomarker of AICTD, particularly in SSc and IIM.

Background: The phenotypic stability of mixed connective tissue disease (MCTD) is not clear, and knowledge about disease activity and remission is scarce. We aimed to establish the occurrence of evolution from MCTD to another defined rheumatic condition, and the prevalence and durability of remission after long-term observation., Methods: In this large population-based prospective observational MCTD cohort study (N = 118), disease conversion was defined by the development of new auto-antibodies and clinical features compliant with another well-defined rheumatic condition. Remission was defined by a combination of systemic lupus erythematosus disease activity index 2000 (SLEDAI-2 K) of 0 and European League Against Rheumatism scleroderma trials and research (EUSTAR) activity index <2.5. Predictors of phenotypic stability and disease remission were assessed by logistic regression., Results: Among 118 patients, 14 (12%) developed another well-defined rheumatic condition other than MCTD after mean disease duration of 17 (SD 9) years. Puffy hands predicted a stable MCTD phenotype in univariable regression analysis (OR 7, CI 2-27, P = .010). Disease activity defined by SLEDAI-2 K, decreased gradually across the observation period and > 90% of patients had EUSTAR activity index <2.5. There were 13% patients in remission throughout the whole mean observation period of 7 (SD 2) years. The strongest predictor of remission was percentage of predicted higher forced vital capacity., Conclusions: Our results strengthen the view of MCTD as a relatively stable disease entity. Long-term remission in MCTD is not frequent; however, the low SLEDAI-2 K and EUSTAR scores during the observation period suggests that the disease runs a milder course than systemic lupus erythematosus and systemic sclerosis.

Objective: Fibromyalgia (FM) is a confounding factor for diagnosing and assessing rheumatic disease activity. This study sought to assess the extent of this syndrome in rheumatism patients at a French rheumatology department., Method: This monocentric epidemiological study enrolled all patients consulting due to rheumatoid arthritis (RA), spondyloarthritis (SpA), or connective tissue disease (CTD). FM diagnosis was confirmed or excluded according to the rheumatologist opinion and the 1990 American College of Rheumatology (ACR) criteria., Results: We enrolled 691 patients, including 451 women (65.3%), with a mean age of 55.8 years (18-93). Of the enrolled patients, 325 presented with RA, 298 SpA [59 psoriatic arthritis (PsA), 137 ankylosing spondylitis (AS), 64 non-radiographic SpA (nr-SpA), and 38 peripheral SpA], and 71 CTD. The rheumatologist established FM diagnosis in 97 patients (14%), while 55 (8%) fulfilled the 1990 ACR criteria. The frequency of FM was lower in RA patients (4.9% by 1990 ACR criteria; 7.7% by expert opinion) compared to SpA (11.1% by 1990 ACR, p < 0.05; 17.5% by expert opinion, p < 0.003) and CTD (11.3% by 1990 ACR, non-significant; 28.2% by expert opinion, p < 0.001). In the SpA subgroups, FM was more common in the nr-SpA than in PsA or AS (23.9%, 9.6%, and 6.4%, by 1990 ACR, p = 0.001; 37.3%, 13.5%, and 7.2%, by expert opinion, p < 0.001)., Conclusion: FM-like symptoms are commonly associated with rheumatic diseases. The frequency of FM is particularly high in non-radiographic axial SpA, thus raising questions about the specificity of the Assessment of SpondyloArthritis International Society (ASAS) classification criteria., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The literature reports that mixed connective tissue disease seems more frequent in the black population and among Asians. This study aims to determine the prevalence of mixed connective tissue disease (MCTD) among connective tissue disorders and all rheumatologic pathologies in a hospital population in Gabon as well as to describe the clinical features of this disease. We conducted a retrospective study by reviewing the medical records of patients treated for mixed connective tissue disease (Kasukawa criteria) and other entities of connective tissue disorders (ACR criteria) in the Division of Rheumatology at the University Hospital in Libreville between January 2010 and December 2015. For each case of MCTD the parameters studied were articular and extra-articular manifestations, anti-U1RNP antibodies levels, patient's evolution. Over a period of 6 years, data were collected by medical records of 7 patients out of 6050 patients and 67 cases of connective tissue disorders, reflecting a prevalence of 0.11% and 10.44% respectively. the 7 patients were women (100%), with an average age of 39.5 years. Articular manifestations included: polyarthritis, myalgias, chubby fingers and Raynaud's phenomenon in 87.5%, 87.5%, 28.6% and 14% respectively. The 7 patients had high anti-U1RNP antibodies levels, ranging between 5 and 35N (N≤ 7 IU). A case of death due to pulmonary arterial hypertension (PAH) was certified. This is the largest case series of MCTD reported in Black Africa. The disease seems to be rare among the black Africans; the reason could be genetic. The demographic and clinical aspects appear similar to those in Caucasians, Asians and Blacks except for a low frequency of Raynaud?s phenomenon among Blacks.

Objectives: Mixed connective tissue disease (MCTD) is characterized by the presence of anti-U1-snRNP autoantibodies and a variable set of associated clinical features. Some MCTD patients test positive over time to autoantibodies against Sm, proteins spatially related with U1-snRNP. This situation has been attributed to expanding of the autoimmune response by a phenomenon known as epitope spreading. Our aim was to study the frequency of this phenomenon in MCTD patients and the specific clinical features of those with epitope spreading., Methods: All anti-U1-RNP-positive patients (2010-2015) were retrospectively reviewed, and those meeting the MCTD criteria were included in the study. Patients showing epitope spreading were compared with the remainder of the MCTD cohort. In addition, the clinical features of patients with epitope spreading were compared before and after the phenomenon occurred., Results: Among 72 anti-U1-RNP-positive patients, 40 (37 women) were diagnosed with MCTD. Thirteen MCTD patients (43%) presented epitope spreading, mainly during the first 2 years after the diagnosis of the disease (median, 1.4 years). Patients with epitope spreading had a significantly lower prevalence of skin sclerosis (0% vs. 44%, P = 0.004) and a greater prevalence of interstitial lung disease (46% vs. 15%, P = 0.05) than those without. Arthritis (92% vs. 25%, P = 0.02) and muscle involvement (67% vs. 17%, P = 0.02) were less frequent after epitope spreading had occurred., Conclusion: Epitope spreading is common in MCTD, occurring early after the diagnosis. The clinical manifestations in patients with this phenomenon differ from those without, and their clinical features change after the immunological phenomenon has occurred.

Objective The objective of this paper is to develop novel classification criteria to distinguish between unclear systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD) cases. Methods A total of 205 variables from 111 SLE and 55 MCTD patients were evaluated to uncover unique molecular and clinical markers for each disease. Binomial logistic regressions (BLRs) were performed on currently used SLE and MCTD classification criteria sets to obtain six reduced models with power to discriminate between unclear SLE and MCTD patients that were confirmed by receiving operating characteristic (ROC) curve. Decision trees were employed to delineate novel classification rules to discriminate between unclear SLE and MCTD patients. Results SLE and MCTD patients exhibited contrasting molecular markers and clinical manifestations. Furthermore, reduced models highlighted SLE patients exhibiting prevalence of skin rashes and renal disease while MCTD cases show dominance of myositis and muscle weakness. Additionally decision tree analyses revealed a novel classification rule tailored to differentiate unclear SLE and MCTD patients (Lu-vs-M) with an overall accuracy of 88%. Conclusions Validation of our novel proposed classification rule (Lu-vs-M) includes novel contrasting characteristics (calcinosis, CPK elevated and anti-IgM reactivity for U1-70K, U1A and U1C) between SLE and MCTD patients and showed a 33% improvement in distinguishing these disorders when compared to currently used classification criteria sets. Pending additional validation, our novel classification rule is a promising method to distinguish between patients with unclear SLE and MCTD diagnosis.

Objectives: To describe the characteristics, outcome and predictive factors of juvenile mixed connective tissue disease (JMCTD) in a nationwide cohort of patients., Methods: We examined 55 patients with JMCTD after a mean disease duration of 16.2 years (SD 10.0). Patients were registered according to Kasukawa's criteria. Remission criteria were defined according to those for juvenile idiopathic arthritis, plus absence of cytopenia, myositis, progressive sclerodactyly, lung and oesophageal manifestations. Organ damage was assessed with the Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index and the Juvenile Arthritis Damage Index (JADI). Medical records were reviewed for early predictors for outcome, which were assessed by multivariate logistic regression analyses., Results: Three patients developed systemic lupus erythematosus (SLE). Fifty-two patients had continuous JMCTD; the most common manifestations were: Raynaud (100%), arthritis (94%), puffy hands (77%) and pulmonary manifestations (58%). SLE-like, systemic sclerosis (SSc)-like and polymyositis (PM)-like findings were found in 98%, 77% and 48%, respectively. Over time, SLE-like and PM-like manifestations decreased, and SSc-like findings increased. At follow-up, 35 patients (67%) had active disease and 17 (33%) were in remission. In 34 patients (65%), SLICC or JADI≥1 assessments indicated organ damage. Active disease was associated with higher anti-ribonucleoprotein antibody titres at follow-up and positive rheumatoid factor (RF) at diagnosis and follow-up., Conclusions: Most patients with JMCTD had active disease and organ damage after a mean follow-up of 16.2 years. Active disease was associated with higher anti-ribonucleoprotein antibody levels and positive RF. The presence of RF at diagnosis predicted persistent disease activity., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Objective: To characterize the epidemiology of mixed connective tissue disease (MCTD) from 1983 to 2014., Methods: An inception cohort of patients with incident MCTD in 1985-2014 in Olmsted County, Minnesota was identified based on comprehensive individual medical record review. Diagnosis of MCTD required fulfillment of at least 1 of the 4 widely accepted diagnostic criteria without fulfillment of classification criteria for other connective tissue diseases. Data were collected on demographic characteristics, clinical presentation, laboratory investigations, and mortality., Results: A total of 50 incident cases of MCTD were identified (mean age 48.1 years and 84% were female). The annual incidence of MCTD was 1.9 per 100,000 population. Raynaud's phenomenon was the most common initial symptoms (50%), followed by arthralgia (30%) and swollen hands (16%). The diagnosis was frequently delayed with the median time from first symptom to fulfillment of criteria of 3.6 years. At fulfillment of criteria, arthralgia was the most prevalent manifestation (86%), followed by Raynaud's phenomenon (80%), swollen hands (64%), leukopenia/lymphopenia (44%), and heartburn (38%). Evolution to other connective tissue occurred infrequently with a 10-year rate of evolution of 8.5% and 6.3% for systemic lupus erythematosus and systemic sclerosis, respectively. The overall mortality was not different from the general population with a standardized mortality ratio of 1.1 (95% confidence interval 0.4-2.6)., Conclusion: This study was the first population-based study of MCTD to provide a complete picture of epidemiology and clinical characteristics of MCTD. MCTD occurred in about 2 persons per 100,000 per year. Evolution to other connective diseases occurred infrequently and the mortality was not affected., (© 2016, American College of Rheumatology.)

We report here the case of a 50-years-old man treated for mixed connective tissue disease (MCTD) positive for anti-U1 ribonucleoprotein (U1RNP) antibodies who secondarily developed a granulomatosis with polyangiitis (GPA) associated with anti-proteinase 3 anti-neutrophil cytoplasmic antibodies (PR3-ANCA). We then evaluated the frequency of the association between anti-U1RNP and anti-PR3-ANCA antibodies by a systematic retrospective study in ten European hospitals. Overall, out of 11,921 samples analyzed for both auto-antibodies, 18 cases of anti-U1RNP and anti-PR3-ANCA double positivity were found and only one patient presented with both MCTD and GPA symptoms. Our retrospective analysis indicates that anti-U1RNP and anti-PR3-ANCA antibodies double positivity is infrequent and very rarely associated with both MTCD and GPA. Our observation describes for the first time the coexistence of MTCD and severe GPA in a Caucasian patient. Association of anti-U1RNP and ANCA antibodies was rarely reported in the literature. Eleven cases of MCTD and ANCA vasculitis have been reported to date, with only two cases with anti-PR3-ANCA association, and only one vasculitis. The seven other cases reported in the literature presented with an association of MCTD and microscopic polyangiitis which appears to be a more frequent presentation than MTCD associated with GPA.

Objective: The Norwegian nationwide MCTD cohort was established to obtain unbiased data on key disease issues, and thereby reappraise the concept of MCTD. In the current study, the aims were to obtain detailed HLA profile data on the large Norwegian MCTD cohort and compare these with the HLA profiles of ethnically matched healthy controls and related CTD controls., Methods: HLA profiles, determined by sequence-based typing of HLA-B* and DRB1*, were compared between four control groups of Norwegian ancestry, SLE (n = 96), SSc (n = 95), PM/DM (n = 84), healthy individuals (n = 282), the complete MCTD cohort (n = 155) and MCTD subsets defined by key clinical parameters., Results: HLA-B*08 [odds ratio (OR) 2.05, P = 1.31 × 10(-4)) and DRB1*04:01 (OR 2.82, P = 3.64 × 10(-8)) were identified as risk alleles for MCTD, while DRB1*04:04, DRB1*13:01 and DRB1*13:02 were protective. Risk alleles for SLE and PM/DM were B*08 and DRB1*03:01. SSc risk was associated with DRB1*08:01. Analyses of MCTD subsets identified B*18 [OR 3.32 (95% CI 1.38, 8.01)] and DRB1*03:01 [OR 1.83 (95% CI 1.03, 3.25)] as independent risk factors for lung fibrosis., Conclusion: Novel HLA alleles associated with MCTD and disease subsets were identified and DRB1*04:01 was confirmed as a major risk allele. Altogether, the data reinforce the notion of MCTD as a disease entity distinct from SLE, SSc and PM/DM., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: To report the clinical characteristic of cardiac disease in patients with mixed connective tissue disease (MCTD)., Method: We identified published case series that reported cardiac manifestations of patients with MCTD by searching the PubMed database using the search terms "mixed connective tissue disease". We identified 11 case series that met our eligibility criteria., Result: 616 patients were included. Prevalence of cardiac involvement varied from 13% to 65% depending on patient selection and method used for detection. Pericarditis was the most common cardiac diagnosis with a prevalence of 30% and 43% in two prospective studies. Non-invasive cardiac tests, including electrocardiogram and echocardiogram, detected subclinical cardiac abnormalities in 6%-38% of patients. These abnormalities included conduction abnormalities, pericardial effusion and mitral valve prolapse. Diastolic dysfunction and accelerated atherosclerosis were well-documented in a case-control study. Three prospective studies revealed an overall mortality of 10.4% over the period of follow-up of 13-15 years. 20% of the mortality was directly attributable to cardiac cause., Conclusion: Cardiac involvement was common among patients with MCTD though the involvement was often clinically inapparent. Non-invasive cardiac tests might have a role for subclinical disease screening for early diagnosis and timely treatment as cardiac involvement was one of the leading causes of mortality., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

The term "mixed connective tissue disease" (MCTD) concerns a systemic autoimmune disease typified by overlapping features between two or more systemic autoimmune diseases and the presence of antibodies against the U1 small nuclear ribonucleoprotein autoantigen (U1snRNP). Since the first description of this condition in 1972, the understanding of clinical manifestations and long-term outcome of MCTD have significantly advanced. Polyarthritis, Raynaud's phenomenon, puffy fingers, lung involvement and esophageal dysmotility are the most frequently reported symptoms among the different cohorts during the course of the disease. Moreover, in recent years a growing interest has been focused on severe organ involvement such as pulmonary arterial hypertension and interstitial lung disease which can accrue during the long-term follow-up and can still significantly influence disease prognosis. Over the last years, significant advances have been made also in disease pathogenesis understanding and a central pathogenetic role of anti-U1RNP autoantibodies has clearly emerged. Although controversies on disease definition and classification still persist, MCTD identifies a group of patients in whom increased surveillance for specific manifestations and prognostic stratification became mandatory to improve patient's outcomes., (Copyright © 2014. Published by Elsevier Ltd.)

Objectives: The aim of this study was to assess the overall prevalence of pulmonary hypertension (PH) in an unselected MCTD cohort and review the current knowledge with a systematic database search., Methods: A nationwide multicentre cohort of 147 adult MCTD patients were initially screened for PH by echocardiography, high-resolution computed tomography (HRCT), pulmonary function tests and N-terminal pro-brain natriuretic peptide (NT-proBNP) and then followed up for a mean of 5.6 years. Right-sided heart catheterization was performed when estimated pulmonary artery systolic pressure was >40 mmHg on echocardiography. PH was diagnosed according to the 2009 European Society of Cardiology and European Respiratory Society guidelines., Results: At inclusion, 2.0% (3/147) had established PH. Two additional PH patients were identified during follow-up, giving a total PH frequency in the cohort of 3.4% (5/147). All five had elevated serum NT-proBNP. Two had isolated pulmonary arterial hypertension (PAH) and three PH associated with interstitial lung disease (PH-ILD). Three PH patients died during follow-up. Nine other patients in the cohort also died, but none of them had echocardiographic signs of PH prior to death., Conclusion: The data from the current unselected MCTD cohort suggest that the prevalence of PH is much lower than expected from previous studies but confirm the seriousness of the disease complication.

The aim of the present study was to assess the autoantibody profile, dominant clinical symptoms and cluster characteristics of different mixed connective tissue disease (MCTD phenotypes. Two-hundred-and-one patients with MCTD were followed-up longitudinally. Five clinical parameters, Raynaud's phenomenon, pulmonary artery hypertension (PAH), myositis, interstitial lung disease (ILD), erosive arthritis and five auto-antibodies besides anti-U1RNP, antiendothelial cell antibodies (AECA), anti-CCP, anti-cardiolipin (anti-CL), anti-SSA/SSB and IgM rheumatoid factor (RF) were selected for cluster analysis. The mean age of patients was 52.9 ± 12.4 years and the mean follow-up of the disease was 12.5 ± 7.2 years. Patients were classified into three cluster groups. Cluster 1 with 77 patients, cluster 2 with 79 patients and cluster 3 with 45 patients. In cluster 1 the prevalence of PAH (55.8%; p < 0.001), Raynaud's phenomenon (92.2%; p < 0.001) and livedo reticularis (24.6%, p < 0.001) was significantly greater than in cluster 2 and 3. In cluster 2, the incidence of ILD (98.7%; p < 0.001), myositis (77.2%; p < 0.001), and esophageal dysmotility (89.8%; p < 0.001) was significantly greater than that in cluster 1 and 3. In cluster 3, anti-CCP antibodies were present in 31 of 45 patients (68.8%) with erosions. Anti-CCP antibodies were present in 37 of 42 patients (88.0%) with erosions. PAH, angina, venous thrombosis was observed in cluster 1 and pulmonary fibrosis in cluster 2, musculosceletal damage, gastrointestinal symptoms and osteoporotic fractures were most frequent in cluster 3. Cumulative survival assessment indicated cluster 1 patients having the worst prognosis. Cluster analysis is valuable to differentiate among various subsets of MCTD and useful prognostic factor regarding the disease course.

Objectives: The REgistry of Pulmonary Hypertension Associated with Rheumatic Disease (REOPARD) was established in Korea. The baseline data are described from the second year of the registry's operation., Methods: Patients with a connective tissue disease (CTD) who met the modified definition of the WHO group I pulmonary arterial hypertension (PAH) were enrolled. PAH was defined as a systolic pulmonary arterial pressure> 40 mmHg by echocardiography or mean pulmonary arterial pressure> 25 mmHg by right heart catheterization. Hemodynamic parameters and clinical data such as demographics, functional class, underlying disease, organ involvement, laboratory tests and current treatment were recorded., Results: A total of 321 patients were enrolled during the 2-year study period from 2008 to 2010. The mean age of the patients at registration was 51.9 years and 87.5% were female. Most patients were diagnosed by echocardiography and only 24 patients (7.5%) underwent cardiac catheterization. Exertional dyspnea was present in 63.6% of patients and 31.8% were New York Heart Association class III or IV. Among the patients, systemic lupus erythematosus accounted for 35.3%, systemic sclerosis 28.3%, rheumatoid arthritis 7.8%, overlap syndrome 9.0%, and mixed connective tissue disease 5.9%. There were no significant differences in hemodynamics, functional class, diffusing capacity and N-terminal pro-brain natriuretic peptide levels between the disease subgroups. Treatments consisted of calcium antagonists (57.0%), endothelin antagonists (32.7%), prostanoids (27.1%), phosphodiesterase-5 inhibitors (14.3%) and combinations (37.4%)., Conclusion: Compared with previous studies, the results showed some differences: underlying diseases, functional status and treatments. This may be due to differences in ethnic background and diagnostic methods of our study., (© 2012 The Authors International Journal of Rheumatic Diseases © 2012 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.)

Systemic sclerosis (SSc) is a chronic autoimmune connective tissue disease. Of the numerous organ manifestations, involvement of the upper and lower gastrointestinal tract (GIT) appears to be the most frequent with regard to the clinical symptoms. However, as the frequency and clinical relevance of GI involvement in patients with SSc are not known in detail, the German network of the systemic sclerosis (DNSS) has developed a detailed questionnaire to evaluate the extent and profile of gastrointestinal involvement in SSc patients. The multi-symptom questionnaire was used at baseline and after 1 year in registered patients of the DNSS. In addition, the results were compared with gastrointestinal disorders in patients with SSc and other rheumatic diseases, as well as with the medical history of the patients. In total, 90 patients were included in the study. The results of the study show that in reality, a much higher (nearly all) percentage of (98,9%) patients than expected suffer from GI-symptoms, regardless of the stage of their disease. Of these, meteorism (87,8%) was the most common followed by coughing/sore voice (77,8%), heartburn (daytime 68,9%, nighttime 53,3%), diarrhea (67,8%), stomach ache (68,9%) and nausea (61,1%). Although SSc patients were treated according to the respective recommendations, only limited improvements with regard to GI-symptoms could be achieved after 1 year of follow-up. In addition, the study revealed that the multi-symptom questionnaire is a useful tool to contribute to identify the gastrointestinal sequelae in systemic sclerosis.

Objective: The underlying mechanism(s) by which antiphospholipid antibodies (aPL) result in thrombosis remains poorly understood. A significant body of evidence has evolved to support the hypothesis that antibody-mediated disruption of an annexin A5 anticoagulant shield may play a role in the pathogenesis; this proposed mechanism has not been previously studied in children., Methods: We investigated the association between aPL and resistance to annexin A5 anticoagulant activity in 90 children with a variety of rheumatic diseases using a novel mechanistic assay, the annexin A5 resistance assay (A5R)., Results: Patients with a diagnosis of primary aPL syndrome, systemic lupus erythematosus, and mixed connective tissue disease demonstrated lower mean A5R levels (p = 0.030), higher prevalence of positive aPL (p < 0.001), and more thrombotic events (p = 0.014) compared to those with other diagnoses. Patients with persistently positive aPL had significantly lower mean A5R compared to patients with no aPL (mean A5R = 203% ± 44% vs 247% ± 35%; p < 0.001), whereas patients with transient aPL did not. Patients with thrombosis had lower A5R levels compared to those without thrombosis (mean A5R = 207% ± 36% vs 237% ± 46%; p = 0.048)., Conclusion: Children and adolescents with rheumatic diseases and persistent aPL have reduced annexin A5 anticoagulant activity, whereas transient, nonpathogenic aPL have less effect on annexin A5 activity.

Background and Aims: Chronic intestinal pseudo-obstruction (CIPO) is an intractable disease in which clinical symptoms of intestinal obstruction appear without mechanical cause. No clear diagnostic criteria have been established; therefore, we proposed diagnostic criteria to facilitate the diagnosis of this rare disease and aim to evaluate their usefulness and validity., Materials and Methods: A questionnaire was sent to 378 institutions belonging to the Japanese Society of Gastroenterology between December 2009 and February 2010. We summarized the returned data and performed a statistical analysis., Results: A total of 160 cases were included, and 141 cases (88.1%) fulfilled the criterion of disease duration of >6 months, 157 cases (98.1%) the criterion of the clinical symptoms of abdominal pain and/or bloating and 154 cases (96.2%) fulfilled the criterion of imaging findings. Eventually, 138 cases (86.3%) fulfilled all criteria., Conclusions: The proposed diagnostic criteria were useful, with a high sensitivity of 86.3% for Japanese patients. Improved recognition of CIPO and practical use of the criteria are desired. The criteria should be appropriately modified by additional researchers to make them more practical and internationally applicable., (Copyright © 2012 S. Karger AG, Basel.)

Objectives: Mixed connective tissue disease (MCTD) is an immune-mediated, systemic disorder of unknown aetiology. As the epidemiology of the disease is largely unknown, the authors performed a nationwide cross-sectional retrospective study to assess the prevalence and incidence of MCTD in Norway., Methods: Every adult patient (≥ 18 years) with MCTD seen at one of the departments of rheumatology was reviewed for inclusion. Only patients who satisfied the following four criteria were included: clinical diagnosis of MCTD verified by a rheumatologist; positive serum anti-ribonucleoprotein antibody test; fulfilment of at least one of three of following criteria sets: the modified Sharp's criteria, the criteria of Alarcón-Segovia and Villareal and those of Kasukawa; and exclusion of other connective tissue diseases., Results: The four inclusion criteria were fulfilled by 147 adult Caucasian patients. The female to male ratio was 3.3 and the mean age at diagnosis of adult-onset MCTD was 37.9 years (95% CI 35.3 to 40.4 years). At the end of 2008, the point prevalence of living adult MCTD patients in Norway was 3.8 (95% CI 3.2 to 4.4) per 100,000 adults. The incidence of adult-onset MCTD in Norway during the period from 1996 to 2005 was 2.1 (95% CI 1.7 to 2.5) per million per year., Conclusions: MCTD has a female predominance and the incidence and prevalence of MCTD is low, and lower than reported figures for polymyositis, dermatomyositis, systemic sclerosis and systemic lupus erythematosus. The prevalence estimates were similar across the three criteria sets of MCTD.

Background: Overlap syndrome is an entity that satisfies the criteria of at least two connective tissue diseases (CTD). These conditions include systemic sclerosis (SSc), dermatomyositis or polymyositis, Sjogren's syndrome, rheumatoid arthritis and systemic lupus erythematosus. A combined pathology has impact on the clinical features, diagnosis and treatment., Objectives: To analyze the features of SSc patients with overlap syndrome registered in the European (EUSTAR) database at our center and to review the literature focusing on clinical and diagnostic issues and new treatments., Methods: We studied the medical records of 165 consecutive SSc patients and reviewed cases with scleroderma overlap syndrome. A PubMed search for the period 1977 to 2009 was conducted using the key words "overlap syndrome", "systemic sclerosis", "connective tissue disease" and "biological agents.", Results: Forty patients satisfied the criteria for scleroderma overlap syndrome. The incidence of additional connective tissue diseases in the whole group and in the overlap syndrome group respectively was: dermatomyositis or polymyositis 11.5% and 47.5%, Sjogren's syndrome 10.3% and 42.5%, rheumatoid arthritis 3.6% and 15.4%, and systemic lupus erythematosus 1.2% and 5.0%. Coexistence of SSc and another CTD aggravated the clinical course, especially lung, kidney, digestive, vascular and articular involvement. Coexisting non-rheumatic complications mimicked SSc complications. An additional rheumatic or non-rheumatic disease affected treatment choice., Conclusions: The definition of scleroderma overlap syndrome is important, especially in patients who need high-dose corticosteroids for complications of a CTD. The use of novel biological therapies may be advocated in these patients to avoid the hazardous influences of high-dose steroids, especially renal crisis. In some overlap syndrome cases, biological agents serve both conditions; in others one of the conditions may limit their use. In the absence of formal clinical trials in these patients a cautious approach is preferred.

Background: REVEAL (the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management) is the largest US cohort of patients with pulmonary arterial hypertension (PAH) confirmed by right-sided heart catheterization (RHC), providing a more comprehensive subgroup characterization than previously possible. We used REVEAL to analyze the clinical features of patients with connective tissue disease-associated PAH (CTD-APAH)., Methods: All newly and previously diagnosed patients with World Health Organization (WHO) group 1 PAH meeting RHC criteria at 54 US centers were consecutively enrolled. Cross-sectional and 1-year mortality and hospitalization analyses from time of enrollment compared CTD-APAH to idiopathic disease and systemic sclerosis (SSc) to systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), and rheumatoid arthritis (RA)., Results: Compared with patients with idiopathic disease (n = 1,251), patients with CTD-APAH (n = 641) had better hemodynamics and favorable right ventricular echocardiographic findings but a higher prevalence of pericardial effusions, lower 6-min walk distance (300.5 ± 118.0 vs 329.4 ± 134.7 m, P = .01), higher B-type natriuretic peptide (BNP) levels (432.8 ± 789.1 vs 245.6 ± 427.2 pg/mL, P < .0001), and lower diffusing capacity of carbon monoxide (Dlco) (44.9% ± 18.0% vs 63.6% ± 22.1% predicted, P < .0001). One-year survival and freedom from hospitalization were lower in the CTD-APAH group (86% vs 93%, P < .0001; 67% vs 73%, P = .03). Compared with patients with SSc-APAH (n = 399), those with other CTDs (SLE, n = 110; MCTD, n = 52; RA, n = 28) had similar hemodynamics; however, patients with SSc-APAH had the highest BNP levels (552.2 ± 977.8 pg/mL), lowest Dlco (41.2% ± 16.3% predicted), and poorest 1-year survival (82% vs 94% in SLE-APAH, 88% in MCTD-APAH, and 96% in RA-APAH)., Conclusions: Patients with SSc-APAH demonstrate a unique phenotype with the highest BNP levels, lowest Dlco, and poorest survival of all CTD-APAH subgroups., Trial Registry: ClinicalTrials.gov; No.: NCT00370214; URL: clinicaltrials.gov.

Background: This study aims to study the clinical and histopathological characteristics of hypocomplementemic and normocomplementemic urticarial vasculitis (HUVS and NUV) among dermatology clinic attendees in a tertiary care hospital in South India., Patients and Methods: A prospective study was conducted in the dermatology department from February 2003 to May 2004. Seventy-five patients met the inclusion criteria for UV. Sixty-eight patients in whom complement levels were available were classified into either NUV or HUVS groups. Clinical features, laboratory parameters and histological features were compared, and the significance of differences was established using Pearson's Chi-squared test., Results: There was a female preponderance among patients with HUVS. Wheals > 24 h were seen in 90% of patients, and in 54.4% of patients, the wheals were partially blanching or non-blanching. Angioedema was more prevalent in patients with NUV than HUVS (44.4% vs. 21.4%). Systemic involvement was seen in 64.3% of patients with HUVS and 44.4% of patients with NUV. Fever, ANA positivity and systemic lupus erythematosus (SLE) were significantly associated with HUVS. In most cases of UV, a provoking factor could not be identified. Neutrophilic small vessel vasculitis was seen in 42.9% of patients with HUVS and 16.6% patients with NUV. Direct immunofluorescence test showing immunoreactants at the dermo-epidermal junction were present in 60% of patients with HUVS and 33.3% patients with NUV., Conclusion: The clinical features of Indian patients with UV were similar to those reported from the West. Fever, ANA positivity and SLE were significantly associated with HUVS.

Mixed connective tissue disease (MCTD) has been rarely reported from India. Thus, we did a retrospective analysis of cases of MCTD seen at our hospital during the last 13 years. We found 16 cases among 441 patients with connective tissue disease. All the 16 patients (15 females) of MCTD fulfilled classification criteria by Kasukawa and at least one of the other two (Sharp's and Alarcon-Sergovia). Raynaud's phenomenon, sclerodactyly, puffy fingers, esophageal hypomotility, and pulmonary disease were the most common manifestations. At a median follow-up of 12 months (1-172), 12 patients developed features of limited scleroderma and three patients had pulmonary hypertension.

Aim: To study prevalence of colon diverticula (CD) and phenotypical features of patients with this anomaly., Material and Methods: At the first stage of the study we analysed colon x-ray evidence for 3 years to assess prevalence of CD. At the second stage we examined 59 patients with CD. Sixty patients with idiopathic constipation and 48 patients with irritable colon syndrome served control., Results: We discovered the following independent factors associated with a high CD risk: history of CD in the relatives of the patients (OR 24.6; 95% CI 5.23-116.23; p = 0.0001) and age of the patient (OR 2.5; 95% CI 1.03-1.13; p = 0.0010). Age-dependent CD occurrence, similar anomalies in the relatives, other structural gastrointestinal anomalies in them, hyperaminociduria suggest that CD represent a metabolic involutionary process with hereditary predisposition. CD manifested clinically with abdominal pain and problems with colon passage. Abdominal pain related to defecation occurred with low pain threshold to extension. Abdominal pain risk in CD patients is significantly associated with intestinal infections (OR 4.56; 95% CI 1.09-18.97; chi-square = 4.34; p = 0.0372) and connective tissue dysplasia syndrome (OR 2.21; 95% CI 1.23-3.95; chi-square = 7.08; p = 0.0078). Independent risk factors of constipation in CD are non-morning defecation (OR 8.68; 95% CI 1.55-48.51; chi-square = 6.06; p = 0.0138), connective tissue dysplasia syndrome (OR 1.77; 95% CI 1.0-3.20; chisquare = 3.65; p = 0.0501), sedentary life style (OR 7.42; 94% CI 1.24 - 44.57; chi-square = 4.81; p = 0.0284)., Conclusion: Incomplete CD reflect colon involution. Abdominal pain associated with defecation has much in common with irritable colon syndrome.

Pulmonary arterial hypertension (PAH) is a severe vasculopathy, which is characterised by progressive narrowing and obliteration of the pulmonary arterioles and increased endothelin-1 levels. The increase of vascular resistance in the lung vessels leads to chronic pressure overload and to right heart failure, if untreated. PAH often occurs in association with rheumatic-inflammatory diseases (e.g., in 15% of patients with systemic sclerosis (SSc), especially in the limited form or in CREST patients) and determines their prognosis: in advanced stages, untreated patients die within a short period. Therefore all SSc patients, particularly the newly diagnosed ones, should be screened for PAH with echocardiography. If PAH is suspected, a right heart catheter should be performed, and if PAH is confirmed, adequate treatment should be initiated. While few years ago lung transplantation was the only option for patients with severe PAH, in recent years enormous progress was seen in drug treatment. Today prostanoids (Ventavis) and the endothelin receptor antagonist bosentan (Tracleer) are available for patients with PAH in WHO/NYHA stage III: they have substantially improved the prognosis of PAH in the last years. Since few months, also the phosphodiesterase inhibitor sildenafil (Revatio) is available. The combination of drugs with different mode of action will likely further improve the prognosis of PAH patients.

Systemic sclerosis (SSc) and mixed connective tissue disease (MCTD) are rare autoimmune diseases which share the common feature of non-inflammatory vasculopathy. Studies evaluating pregnancy outcomes in these patients have yielded conflicting results. We sought to describe the outcomes of pregnancies associated with SSc and MCTD followed at our center utilizing a retrospective review of all pregnant women with SSc and MCTD followed at Stanford University from 1993 to 2003. We identified 20 pregnancies occurring in 13 women with SSc or MCTD. Twelve pregnancies occurred in seven women with SSc and eight pregnancies occurred in six women with MCTD. The overall preterm delivery rate was 39% and small for gestational age infants occurred in 50% and 63% of pregnancies associated with SSc and MCTD, respectively. Fetal loss complicated two pregnancies in women with severe diffuse SSc and the antiphospholipid antibody syndrome. There were no cases of congenital heartblock among infants, and only one case of pre-eclampsia was observed. Maternal flares of disease during pregnancy were generally mild. Most pregnancies in women with SSc and MCTD in this cohort were uncomplicated. The high rates of prematurity and small for gestational age infants underscore the risk for growth restriction consistent with the vasculopathy associated with these diseases.

This article discusses the literature on pediatric-onset mixed connective tissue disease (MCTD) and adds 34 new cases. Although not benign, pediatric-onset MCTD carries less mortality than adult-onset disease.

Objective: Most of the data about the prevalence of pulmonary arterial hypertension (PAH) are from tertiary centers that are biased toward seeing more severe cases; therefore, the true prevalence of PAH among patients with connective tissue disease is unknown. We sought to determine the point prevalence of undiagnosed PAH in community-based rheumatology practices., Methods: The study design was a multicenter, prospective and retrospective survey and analysis of clinical cases in 50 community rheumatology practices. We evaluated a total of 909 patients with either scleroderma (systemic sclerosis [SSc]) or mixed connective tissue disease (MCTD). If a subject had not been diagnosed as having PAH, then a new Doppler echocardiogram was obtained to measure cardiac parameters, including estimated right ventricular systolic pressure (ERVSP), and a full review of medical records was done., Results: Of 909 screened patients, 791 were evaluable and completed the study; 669 had not previously been studied for PAH. Of these 669 patients, 89 (13.3%) were found by Doppler echocardiography to have an ERVSP of > or = 40 mm Hg. Of these 89 patients, 82 (92.1%) had SSc and 7 (7.9%) had MCTD. The total prevalence of PAH in the survey was 26.7% (211 of 791 patients, including 122 with known PAH and 89 newly diagnosed as having PAH). Doppler echocardiographic data showed 20 of 89 patients (22.5%) with ERVSP of > or = 50 mm Hg, 20 of 89 patients (22.5%) with increased RV dimension, and 25 of 89 patients (28.1%) with right atrial enlargement. Patients with ERVSP > or = 40 mm Hg had decreased exercise tolerance compared with those with ERVSP <40 mm Hg (27% compared with 9.5%, respectively, were severely symptomatic)., Conclusion: A significant number of patients with SSc or MCTD (13.3%) followed up in a community rheumatology practice setting have undiagnosed elevated ERVSP consistent with PAH.

Mixed connective tissue disease is a disease entity characterized by overlapping symptoms of lupus erythematosus (LE), systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM) and rheumatoid arthritis (RA). Diagnostic criteria include high titers of antibodies against U1RNP as well as the presence of at least 3 of 5 of the following clinical features: edema of hands, synovitis, myositis, Raynaud phenomenon and acroscierosis. In terms of the pathogenesis, genetic as well as infectious (viral) factors appear to play a role. The acceptance of MCTD as a distinct disease entity is controversial. Terms such as "undifferentiated connective tissue disease" or "overlapping syndromes" are not helpful. One-quarter of MCTD patients transform into LE, while one-third progress to SSc. Therapeutic recommendations are glucocorticoids in combination with immunosuppressive agents and endothelin receptor antagonists. Double blind studies are not available. The prognosis is relatively good. Causes of death include pulmonary hypertension, infections and both pulmonary and cardiac failure.

The existence of osteoporosis in 58 postmenopausal women with mixed connective tissue disease (MCTD) was investigated. The mean bone mineral density assessed by dual energy X-ray absorptiometry in the lumbar spine was decreased in 25.8% of the patients, reflecting osteoporosis (T score < -2.5). In the femoral neck there was no significant difference between the BMD of MCTD patients and that of age-matched, healthy postmenopausal women. Low bone mineral density was found among patients on, as well as off, corticosteroids. The extent of bone loss was associated with disease duration, as well as corticosteroid therapy. Serum osteocalcin levels were lower in MCTD patients than in controls. Lower serum oestradiol, testosterone and dehydroepiandrosterone sulphate levels were detected in MCTD patients than in controls. Thus, MCTD may be associated with increased bone loss. Pathogenic factors may include the disease itself, corticosteroid therapy, impaired osteoblast function, and low serum sex hormone levels.

Systemic autoimmune diseases form a diverse group which includes: systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), scleroderma, dermato-polymyositis, Wegener's granulomatosis, Sjögren syndrome. Although multisystem involvement is the hallmark of these diseases, the heart seems to be less affected than other organ systems. The aim of the study was to study possible cardiac abnormalities in patients with documented systemic autoimmune diseases and to assess whether there was any relation between antiphospholipid, anti-dsDNA antibodies and myocardial dysfunction findings. 76 patients (53 with SLE, 9 with MCTD, 8 with scleroderma, 6 with Wegener's granulomatosis) were subjected to our study, 69% of these patients manifested cardiac involvement, based on two-dimentional echocardiografic examination (36%--post-inflammatory valvular thickening, 20%--pericardial effusions, 15%--valvular regurgitation, 7%--left atrial enlargement, 5%--left ventricular hypertrophy, 4%--left ventricular dysfunction). None of the patients showed characteristic, acute Libman-Sacks endocarditis, which probably can be explained by chronic corticosteroid-treatment. Clinical evidence of cardiac abnormalities has been observed, in as many as 58% of cases with positive echocardiographic findings. The frequency and extend of cardiac pathology positively correlated with the detection of antiphospholipid antibodies. No such relationship was observed in patients with the presence of very high titers of antinuclear antibodies (anti-dsDNA). In conclusion, our results indicate that echocardiography is a useful method for assessment and monitoring cardiac involvement in the systemic autoimmune diseases.

We studied the prevalence and clinical significance of anti-U1 RNA antibodies in patients with systemic sclerosis. The presence of anti-U1 RNA antibodies was determined using immunoprecipitation in systemic sclerosis patients with anti-U1 RNP antibodies (n=36), antitopoisomerase I antibodies (n=20), or anticentromere antibodies (n=20), mixed connective tissue disease patients (n=23), systemic lupus erythematosus patients with anti-U1 RNP antibodies (n=26), and normal controls (n=20). Moreover, antigen specificities for anti-U1 RNP antibodies were examined in patients with systemic sclerosis by immunoblotting and enzyme-linked immunosorbent assay. Anti-U1 RNA antibodies was detected in 22 of 36 systemic sclerosis patients (61%) with anti-U1 RNP antibodies, 14 of 23 patients (61%) with mixed connective tissue disease, and eight of 26 systemic lupus erythematosus patients (31%) with anti-U1 RNP antibodies. Anti-U1 RNA antibodies were not detected in other groups. As for systemic sclerosis patients, the frequencies of pulmonary fibrosis and reduced percentage diffusion capacity for carbon monoxide were significantly greater in patients with anti-U1 RNA antibodies than in those without (76%vs 18%, p<0.005; 82%vs 27%, p<0.005, respectively). Moreover, patients with anti-U1 RNA antibodies had significantly lower percentage diffusion capacity for carbon monoxide and percentage vital capacity values than those without (51.9+/-16.8 vs 79.4+/-16.4, p<0.01; 83.8+/-21.4 vs 101.4+/-12.9, p<0.05, respectively). Regarding the antigen specificities of anti-U1 RNP antibodies in systemic sclerosis patients, the frequency of anti-70 kDa antibodies determined by immunoblotting was significantly higher in patients with anti-U1 RNA antibodies than in those without (77%vs 43%, p<0.05). This finding was also confirmed by enzyme-linked immunosorbent assay for anti-70 kDa antibodies (86%vs 43%, p<0.05). These results indicate that anti-U1 RNA antibodies may be a serologic indicator for pulmonary fibrosis in systemic sclerosis patients with anti-U1 RNP antibodies.

In order to investigate major histocompatibility complex (MHC) class I chain-related gene A (MICA), tumor necrosis factor (TNFa), -308TNFA, and human leukocyte antigen (HLA-DR/DQ) polymorphisms in mixed connective tissue disease (MCTD), we analyzed 24 patients and 229 healthy controls from Sweden. MICA and TNFa typing was performed by polymerase chain reaction (PCR) and genotyping. HLA-DR and -DQ were genotyped using PCR-sequence specific primers (PCR-SSP) and PCR-sequence-specific oligonucleotide probe (PCR-SSOP), respectively. For analysis of -308TNFA polymorphisms we performed PCR with restriction endonuclease enzymes. We found that the MICA5.1-5.1 genotype was positively associated with MCTD. Shared epitope genes (DRB1*01 and DRB1*04) were also significantly positively associated with MCTD. Polymorphism of -308TNFA was not differently distributed in MCTD patients compared with controls. Furthermore, we demonstrated that frequencies of three estimated haplotypes were increased in MCTD patients compared with controls. Interestingly, the haplotype with MICA allele 4 together with DRB1*04 and TNF1 alleles gives the most specific pattern for MCTD patients compared with controls. Our study demonstrates a clear contribution of HLA loci in susceptibility to MCTD in the Swedish population. Susceptibility to MCTD may be linked to the MICA4/HLA-DRB1*04/TNF1 haplotype and MICA 5.1-5.1 genotype. Mixed connective tissue disease was also associated with shared epitope genes, which in RA has been associated with a more severe disease. Whether these genotypes affect the clinical phenotype of MCTD needs to be determined.

Objective: To examine a large well characterized cohort of patients with mixed connective tissue disease (MCTD) and determine longitudinally the prevalence of clinical and serologic features of Sjogren's syndrome in these patients., Methods: Patients were followed longitudinally up to 30 years with systematic clinical and serologic analysis. Sera were analyzed for reactivity with SSA/Ro, SSB/La, and snRNP polypeptide U1-70kD and for anticardiolipin antibodies., Results: Among a well characterized patient population with MCTD, 18/55 (32.7%) had antibodies to SSA/Ro, while 2/55 (3.6%) had antibodies to SSB/La, either initially or during the course of followup. All patients had antibodies to U1-70kD small nuclear ribonucleoprotein antigen. Sicca symptoms were common, occurring in 23/55 (41.8%) patients. Patients with MCTD who were anti-SSA/Ro positive had increased incidence of malar rash (p < 0.03) and photosensitivity (p < 0.001) compared to anti-SSA/Ro negative patients., Conclusion: Sicca symptoms are frequent in patients with MCTD, occurring in up to one-third of the patients studied. The presence of anti-SSA/Ro antibodies identifies a group of MCTD patients with a very high incidence of malar rash and photosensitivity.

Aim of the Study: To study the clinical and immunological profile of mixed connective tissue disease (MCTD) in rheumatic disease population., Methods: We retrospectively analyzed 6400 cases of rheumatic disease population who took treatment in the Department of Rheumatology, Madras Medical College, Chennai during the period of 1996 to 1999, in which eight cases fulfilled the preliminary diagnostic criteria of mixed connective tissue disease devised by Kasukawa et al. All eight cases were studied in detail., Results: All cases were females between 23 to 50 years of age. Polyarthritis, Raynaud's phenomenon and sclerodactyly were present in all eight patients. Oesophageal abnormalities, pulmonary changes and myositis were present in six patients. Facial erythema was observed in five patients. Alopecia and oral ulcers were seen in four patients. Two patients had pulmonary hypertension and migraine like headache. One patient had diffuse proliferative glomerulonephritis as an interesting feature by renal biopsy. Pleuritis, pericarditis and trigeminal neuropathy with lower cranial nerve palsies were present in one case each. Immunological tests showed presence of antinuclear antibodies and anti U1 ribonucleoprotein (anti U1RNP) antibodies in all eight patients., Conclusions: Mixed connective tissue disease should be considered as an important syndrome in any patient who presents with heterogeneous clinical presentation and who do not fit into any definite criteria of systemic connective tissue disorders.

Objective: To study the frequency and disease specificity of antinucleosome antibody reactivity in diverse connective tissue diseases (CTD), and to determine factors, such as antibody subclass, that may influence the pathogenicity of these antibodies in relation to disease activity., Methods: IgG and IgM antinucleosome activities on nucleosome core particles from 496 patients with 13 different CTD and 100 patients with hepatitis C were measured by enzyme-linked immunosorbent assay (ELISA). Of the patients with CTD, 120 had systemic lupus erythematosus (SLE), 37 had scleroderma (systemic sclerosis; SSc), 20 had mixed connective tissue disease (MCTD), and 319 had other CTD, including Sjögren's syndrome, inflammatory myopathy, rheumatoid arthritis, primary antiphospholipid syndrome, Wegener's granulomatosis, Takayasu arteritis, giant cell arteritis, relapsing polychondritis, Behçet's syndrome, and sarcoidosis. Antinucleosome-positive sera were further analyzed, by isotype-specific ELISA, for antinucleosome and anti-double-stranded DNA (anti-dsDNA) IgG subclasses., Results: SLE, SSc, and MCTD were the only 3 CTD in which antinucleosome IgG were detected (71.7%, 45.9%, and 45.0% of patients, respectively). Antinucleosomes of the IgG3 subclass were present at high levels in patients with active SLE and were virtually absent in those with SSc, MCTD, or inactive SLE, and their levels showed a positive correlation with SLE disease activity. Of note, an increase in levels of antinucleosome of the IgG3 isotype was observed during SLE flares, and this increase was found to be closely associated with active nephritis. Levels of antinucleosome of the IgG1 subclass showed a trend toward an inverse correlation with SLE disease activity. No significant fluctuation in the anti-dsDNA isotype profile was observed in relation to SLE severity or clinical signs., Conclusion: Our data suggest that IgG antinucleosome is a new marker that may help in the differential diagnosis of CTD; antinucleosome of the IgG3 isotype might constitute a selective biologic marker of active SLE, in particular, of lupus nephritis.