Treatment strategies and survival of patients with connective tissue disease and pulmonary arterial hypertension: a COMPERA analysis.

OBJECTIVES: Pulmonary arterial hypertension (PAH) occurs in various connective tissue diseases (CTDs). We sought to assess contemporary treatment patterns and survival of patients with various forms of CTD-PAH. METHODS: We analysed data from COMPERA, a European pulmonary hypertension registry, to describe treatment strategies and survival in patients with newly diagnosed PAH associated with SSc, SLE, MCTD, UCTD and other types of CTD. All-cause mortality was analysed according to the underlying CTD. For patients with SSc-PAH, we also assessed survival according to initial therapy with endothelin receptor antagonists (ERAs), phosphodiesterase type 5 inhibitors (PDE5is) or a combination of these two drug classes. RESULTS: This analysis included 607 patients with CTD-PAH. Survival estimates at 1, 3 and 5 years for SSc-PAH (n = 390) were 85%, 59% and 42%; for SLE-PAH (n = 34) they were 97%, 77% and 61%; for MCTD-PAH (n = 33) they were 97%, 70% and 59%; for UCTD-PAH (n = 60) they were 88%, 67% and 52%; and for other CTD-PAH (n = 90) they were 92%, 69% and 55%, respectively. After multivariable adjustment, the survival of patients with SSc-PAH was significantly worse compared with the other conditions (P = 0.001). In these patients, the survival estimates were significantly better with initial ERA-PDE5i combination therapy than with initial ERA or PDE5i monotherapy (P = 0.016 and P = 0.012, respectively). CONCLUSIONS: Mortality remains high in patients with CTD-PAH, especially for patients with SSc-PAH. However, for patients with SSc-PAH, our results suggest that long-term survival may be improved with initial ERA-PDE5i combination therapy compared with initial monotherapy.

The phenotype of mixed connective tissue disease patients having associated interstitial lung disease.

OBJECTIVE: We aimed to compare two matched populations of patients with MTCD with and without associated ILD and to identify predictive factors for ILD progression and severity. METHODS: This international multicenter retrospective study (14 tertiary hospitals), included MCTD patients who fulfilled at least one historical MCTD classification criteria. ILD was defined by the presence of typical chest high-resolution computed tomography (HRCT) abnormalities. Factors associated with ILD were assessed at baseline. Long-term progressive ILD was assessed in MCTD-ILD patients with multiple forced vital capacity (FVC) measurements. RESULTS: 300 patients with MCTD were included. Mean age at diagnosis was 39.7 ± 15.4 years and 191 (63.7%) were women. Mean follow-up was 7.8 ± 5.5 years. At baseline, we identified several factors associated with ILD presence: older age (p = 0.01), skin thickening (p = 0.03), upper gastro-intestinal (GI) symptoms (p<0.001), FVC <80% (p<0.0001), diffusing capacity for carbon monoxide <80% (p<0.0001), anti-topoisomerase antibodies (p = 0.01), SSA/Ro antibodies (p = 0.02), cryoglobulinemia (p = 0.04) and elevated C-reactive protein (p<0.001). Patients with MTCD-ILD were more likely to be treated with synthetic immunosuppressant agents (p<0.001) in particular mycophenolate mofetil (p = 0.03). Digital ulcers (DU) were identified as a risk factor for FVC decline >10%. During follow-up mortality was higher in the MTCD-ILD group (p<0.001). CONCLUSION: In this large international cohort of patients with MTCD, we identified different factors associated with ILD. Our findings also provide evidence that MCTD-ILD patients have increased mortality and that DU are associated with progressive lung disease.

An unusual cardiac involvement in mixed connective tissue disease / Una afección cardíaca poco común en la enfermedad mixta del tejido conjuntivo

Mixed connective tissue disease is an autoimmune disorder with overlapping features of systemic lupus erythematosus, systemic sclerosis and polymyositis. Cardiac involvement is common, being pericarditis the most frequent manifestation, as also pulmonary hypertension. The authors present a case of a woman with one year of symptoms of polyarthritis and myalgia with gradual muscle weakness and weight loss, with severe impaired mobility in the last months. The initial evaluation showed an inflammatory systemic condition with an infiltrative pattern in echocardiogram, with pulmonary hypertension, that was confirmed by cardiac magnetic resonance. After an extensive study, where infiltrative cardiomyopathies were a differential diagnosis, the patient meet criteria to mixed connective disease with signs of pulmonary hypertension and an atypical cardiac involvement. Immunosuppressive treatment and rehabilitation were initiated and one year after the patient remains asymptomatic without any limitations. (AU)

La enfermedad mixta del tejido conectivo es un trastorno autoinmune con características superpuestas de lupus eritematoso sistémico, esclerosis sistémica y polimiositis. La afectación cardiaca es común, siendo la pericarditis la manifestación más frecuente, al igual que la hipertensión pulmonar. Los autores presentan el caso de una mujer con un año de síntomas de poliartritis y mialgia con debilidad muscular gradual y pérdida de peso, con grave deterioro de la movilidad en los últimos meses. La evaluación inicial mostró un cuadro inflamatorio sistémico con patrón infiltrativo en ecocardiograma, con hipertensión pulmonar, que se confirmó por resonancia magnética cardiaca. Tras un amplio estudio, en el que las miocardiopatías infiltrativas constituyeron un diagnóstico diferencial, la paciente cumplía criterios de conectivopatía mixta con signos de hipertensión pulmonar y una afectación cardiaca atípica. Se inició tratamiento inmunosupresor y rehabilitación y un año después la paciente permanece asintomática sin limitaciones. (AU)

Collapsing glomerulopathy in a patient with mixed connective tissue disease.

Collapsing glomerulopathy (CG) is a form of podocytopathy that is challenging to manage. CG can be idiopathic or associated with other conditions including autoimmune connective tissue diseases. In the setting of autoimmune connective tissue diseases, there are no current guidelines to guide therapy. Here we report a unique and challenging case of CG with mixed connective tissue disease (MCTD) that responded to steroids followed by mycophenolate. In PubMed, we identified three previously reported cases of CG with MCTD in addition to other forms of autoimmune diseases, including Sjogren syndrome, adult-onset still's disease, and vasculitis, etc. We are providing a literature review of collapsing glomerulopathy cases in the setting of autoimmune connective tissue diseases and with MCTD. CG in the setting of autoimmune connective tissue diseases is more common in females and black patients. Response to therapy was inconsistent. Many patients progressed to dialysis despite use of various treatment modalities.

Efficacy of intravenous immunoglobulin in shrinking lung syndrome associated with mixed connective tissue disease: a case report.

Shrinking lung syndrome is a rare manifestation of connective tissue diseases, namely systemic lupus erythematosus. It is characterised by reduced lung volumes and extra-pulmonary restrictive ventilatory pattern with good response to high-dose glucocorticoids alone or in combination with a second immunosuppressive agent. Here, we describe a case associated with mixed connective tissue disease and effectively treated with intravenous immunoglobulin.

Protracted severe COVID-19 pneumonia following rituximab treatment: caution needed.

The outcomes of COVID-19 in patients treated with biologic agents are a subject of intense investigation. Recent data indicated that patients under rituximab (RTX) may carry an increased risk of serious disease. We performed an electronic search in Medline and Scopus using the keywords rituximab and COVID-19. We present a rare case of severe, protracted COVID-19 pneumonia in a patient with mixed connective tissue disease (MCTD) who was infected a few days following RTX treatment. In a relevant literature search, we identified 18 cases of patients with rheumatic diseases (6 RA, 8 ANCA vasculitis, 3 systemic sclerosis and 1 polymyositis) treated with RTX who experienced an atypical and/or prolonged course of COVID-19 pneumonia with no evidence of cytokine storm. Our case indicates that RTX may unfavorably affect outcomes following SARS-CoV-2 infection. B cell depletion may dampen the humoral response against the virus; we may hypothesize that B cell-depleted patients may be protected from cytokine storm but on the other hand may have difficulties in virus clearance leading to a protracted course. Taking into account that COVID-19 vaccines are available we may consider delaying RTX infusions at least in patients without life threatening disease, until vaccination is completed.

Macula pigment optical densitometry changes in hydroxychloroquine use.

PURPOSE: To investigate the association between hydroxychloroquine (HCQ) use and macular pigment optic densitometry (MPOD) abnormalities. MATERIALS AND METHODS: Fifty patients that have been receiving HCQ treatment and forty-eight control subjects were randomly selected from patients with no visual impairment with similar age and gender. All participants underwent detailed ophthalmologic examination including fundus photography, fundus autofluorescence, optic coherence tomography, and visual field analysis. Macular pigment optical density (MPOD) was measured by fundus reflectometry using one-wavelength reflection method. Patients with ongoing HCQ treatment formed the HCQ group and healthy subjects formed the control group. RESULTS: Mean age was 50.9 ± 7.9 and 47.9 ± 9.4 years in the HCQ and controls groups respectively (p = 0.098) Between the groups, there is no significant difference in central foveal thickness and mean deviation and pattern standard deviation in the visual field analysis. Parafoveal hyper fluorescence lesions were detected in 5 (%10) patients. Choroidal thickness was significantly decreased in the HCQ group (p = 0.001). Maximum and mean MPOD outcomes were significantly lower in the HCQ group (p = 0.005, p = 0.003, respectively). Between the groups, there was no difference in mean MPOD volume and MPOD area. CONCLUSIONS: Patients with HCQ use have reduced MPOD. Further studies are required investigating the sensitivity and specificity of MPOD in detecting initial retinal changes in patients with HCQ use.

Posterior reversible encephalopathy syndrome as the first manifestation of mixed connective tissue disorder: a case report.

BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is a neurological syndrome characterised by a range of neurological symptoms and signs, and distinctive neuroimaging findings reflecting vasogenic oedema. Posterior reversible encephalopathy syndrome has been described in association with many autoimmune diseases, but its association with mixed connective tissue disorder (MCTD) is very rare. After an extensive review of the literature, we found only three cases of posterior reversible encephalopathy syndrome in association with mixed connective tissue disorder. But unlike other cases, in our patient, PRES is the presenting manifestation of mixed connective tissue disorder which is first of its kind. CASE PRESENTATION: We present a 30-year-old female from Southern India who had initially reported with complaints of fever, multiple episodes of vomiting and cough with expectoration. She had accelerated hypertension and moderate thrombocytopenia. Two days later, she developed sudden onset of visual disturbances and had a drop in sensorium. Neuroimaging done was suggestive of atypical posterior reversible encephalopathy syndrome, and autoimmune workup was positive for mixed connective tissue disorder. With prompt blood pressure control and anti-seizure medications, she recovered completely. CONCLUSION: Early diagnosis and prompt control of blood pressure, along with anti-seizure measures, play a crucial role in management. Awareness about this rare association is essential for early diagnosis and treatment, and therefore reducing the risk of permanent neurologic deficits. This case is being reported because of its rarity.

Clinical Features of Systemic Sclerosis-Mixed Connective Tissue Disease and Systemic Sclerosis Overlap Syndromes.

OBJECTIVE: To describe the clinical characteristics and outcomes of systemic sclerosis-mixed connective tissue disease (SSc-MCTD) and SSc overlap syndrome. METHODS: We included patients from the Australian Scleroderma Cohort Study who met American College of Rheumatology/European Alliance of Associations for Rheumatology criteria for SSc. Three mutually exclusive groups were created: SSc-MCTD, SSc overlap, and SSc only. Univariate comparison of clinical features was performed by analysis of variance or chi-square test. Survival analysis was performed using Kaplan-Meier (KM) curves and Cox proportional hazards regression models. RESULTS: Of 1,728 patients, 97 (5.6%) had SSc-MCTD, and 126 (7.3%) had SSc overlap. Those with MCTD-SSc were more commonly Asian (18.3% versus 10.1% in SSc overlap, and 3.6% in SSc only; P < 0.0001) and younger at disease onset (38.4 years versus 46.5 or 46.8 years, P < 0.0001). Those with SSc-MCTD or SSc overlap were more likely to have limited cutaneous SSc. All 3 groups had similar frequency of interstitial lung disease (ILD), although pulmonary arterial hypertension (PAH) was less common in SSc overlap. Synovitis and myositis were more common in SSc overlap and SSc-MCTD than in SSc only. KM curves showed better survival in SSc-MCTD than SSc overlap or SSc only (P = 0.011), but this was not significant after adjustment for sex and age at disease onset. SSc-specific antibodies were survival prognostic markers, with antinuclear antibody centromere or anti-RNP conferring better survival than anti-Scl-70 or anti-RNA polymerase III (P = 0.005). Patients with SSc-MCTD and SSc overlap had lower mortality following diagnosis of ILD and PAH than patients with SSc only. CONCLUSION: This study provides insights into the clinical characteristics of patients with SSc-MCTD, SSc overlap, and SSc only and shows that anti-RNP antibodies are associated with better survival than anti-Scl-70 and anti-RNA polymerase III antibodies.

[SARS-CoV-2 infection in a patient treated by hydroxychloroquine and anti TNF α for Inflammatory Rheumatic Disease]. / Une infection par le SARS-CoV-2 chez un patient sous hydroxychloroquine et anti TNF α pour rhumatisme inflammatoire chronique.

Hydroxychloroquine is an agent used as a treatment but also considered as a prophylaxis for SARS-CoV-2 infection. We report the case of a patient who developed COVID-19 while on hydroxychloroquine for mixed connectivitis associated with spondyloarthritis. Although more work is needed before any conclusions can be drawn, this raises questions about the protective role of this drug against infection. Are they really protected against COVID-19 or will they develop pauci-symptomatic forms?

Risk factors for hospital admissions related to COVID-19 in patients with autoimmune inflammatory rheumatic diseases.

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.

Belimumab Concentrations in Maternal Serum and Breast Milk During Breastfeeding and the Safety Assessment of the Infant: A Case Study.

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

"Mixed connective tissue disease": a condition in search of an identity.

Mixed connective tissue disease was first described as a new autoimmune rheumatic disease in 1972 based on the claim of a distinct clinical picture associated with anti-RNP antibody positivity. Subsequently, this new entity has divided opinions in the rheumatology community. We have reviewed recent cohort studies with more than 100 patients, comparing the clinical and immunological features, treatment, prognosis and evolution to well-defined autoimmune rheumatic diseases. We also reviewed clinical features of undifferentiated autoimmune rheumatic diseases based on the most recent studies. After gathering and reviewing these data, we discuss whether the designation "mixed connective tissue disease" should be maintained.

Pulmonary infection due to Acrophialophora fusispora in a patient with underlying mixed connective tissue disease and chronic pulmonary aspergillosis: A case report and review of literature.

Acrophialophora fusispora is a soil-borne fungus rarely implicated in human infections. Here, we report a case of pulmonary infection due to A. fusispora in a 59-year-old male who presented with productive cough and gradually progressive dyspnoea for 20 days. He had a past history of pulmonary tuberculosis and was a known case of chronic obstructive pulmonary disease for past five years. He was diagnosed with mixed connective tissue disease and had been receiving oral azathioprine and prednisolone for three months. CECT thorax revealed an aspergilloma and serum Aspergillus fumigatus-specific IgG levels were raised, suggestive of chronic pulmonary aspergillosis. He was also tested positive for influenza A (H1N1) and received treatment with oral oseltamivir without any clinical benefit. Culture of sputum and bronchoalveolar lavage fluid showed growth of a fungus which was identified as Acrophialophora fusispora based on characteristic microscopic morphology and internal transcribed spacer sequencing of the ribosomal DNA. Antifungal susceptibility testing for six antifungal drugs showed itraconazole to have the most potent in vitro activity (MIC=0.25µg/mL) against A. fusispora in comparison to the other drugs tested. Treatment with itraconazole capsule 200mg twice daily was initiated and favourable clinical response was observed after 10 days of therapy. Follow-up visit after three months showed marked clinical and radiological improvement. A. fusispora is an emerging opportunistic fungus capable of causing invasive infections in immunocompromised hosts. Lack of knowledge about this fungus and confusion with morphologically similar opportunistic fungi have led to its misidentification and hence its prevalence remains largely underestimated. Accurate identification is crucial as it can help initiate early effective antifungal therapy and improve patient outcomes. To our knowledge, this is the first case of pulmonary infection due to A. fusispora reported from India.

Increased Endothelial Activation in Patients with Mixed Connective Tissue Disease.

OBJECTIVE: Juvenile-onset mixed connective tissue disease (JMCTD) is a chronic inflammatory disease. We have previously demonstrated preclinical atherosclerosis in these patients, now exploring this further by assessing markers of endothelial dysfunction. METHODS: Thirty-three patients with JMCTD and 33 age-and sex-matched controls were included. Soluble intercellular adhesion molecule-1 (sICAM-1), Il-6 and, von Willenbrand factor (vWF) were assayed from blood taken at the time of carotid ultrasound. RESULTS: Our major findings were: (1) Levels of sICAM-1 (P < .001), IL-6 (P = .004), and vWF (P = .001) were higher, whereas (2) high density lipoprotein cholesterol (<.01) and apolipoprotein A1 (P < .01) were lower in the patient group compared to controls. CONCLUSIONS: Patients with JMCTD had significantly increased levels of markers of endothelial dysfunction.

Drop Head Syndrome as a Rare Complication in Mixed Connective Tissue Disease.

A 54-year-old woman developed drop head syndrome (DHS), Raynaud's phenomenon and creatine kinase (CK) elevation. She did not meet the international classification criteria of dermatomyositis/polymyositis, as we observed no muscle weakness, grasping pain or electromyography abnormality in her limbs, and anti-aminoacyl tRNA synthetase (ARS) antibody was negative. Cervical magnetic resonance imaging and a muscle biopsy of the trapezius muscle revealed myositis findings as the only clinical observations in muscle. These findings, along with her anti-U1-ribonucleoprotein (RNP) antibody positivity and leukopenia, resulted in a diagnosis of mixed connective tissue disease (MCTD). Prednisolone treatment significantly improved her myositis. To our knowledge, this is the first report of DHS as the only muscle complication of MCTD.

Effect on Cardiac Function of Longstanding Juvenile-onset Mixed Connective Tissue Disease: A Controlled Study.

OBJECTIVE: To assess cardiac function in patients with juvenile mixed connective tissue disease (JMCTD) compared to matched controls, and to investigate possible associations between cardiac impairment and disease variables and cardiovascular risk factors. METHODS: Fifty JMCTD patients (86% female) examined median 14.9 (6.6-23.0) years after disease onset were compared with 50 age- and sex-matched controls. Electrocardiogram and echocardiography [including e' as a marker for diastolic dysfunction and long-axis strain (LAS) and left ventricular (LV) ejection fraction (EF) as markers of systolic function] were performed. LV dysfunction (LVD) was defined as low EF, low LAS, or low e'. Right ventricular function was assessed with tricuspid annular plane systolic excursion (TAPSE). Cardiovascular risk factors and disease variables were assessed. RESULTS: LVD was found in 16% of patients and 4% of controls (p = 0.035). EF and LAS were lower in patients compared to controls (6% lower, p < 0.001, and 4% lower, p = 0.044, respectively). TAPSE was 8% lower in patients versus controls (p = 0.008). No patients had signs of pulmonary hypertension. Patients had longer corrected QT time than controls (p = 0.012). LVD was associated with higher levels of apolipoprotein B, higher disease activity measured by physician's global assessment, longer prednisolone treatment, and more organ damage assessed with the Myositis Damage Index. CONCLUSION: Patients with JMCTD had impaired left and right ventricular function compared to matched controls after median 15 years disease duration. High disease activity and longer treatment with prednisolone were factors associated with LVD.

Autoimmunity and immunodeficiency at the crossroad: autoimmune disorders as the presenting feature of selective IgM deficiency.

Selective immunoglobulin M deficiency (sIgMD) is an immunodeficiency with undefined pathogenesis and commonly presenting with recurrent infections. 1 The European Society for Immunodeficiencies Registry defines sIgMD as a serum IgM level repeatedly below 2 SD of normal with normal levels of serum IgA, IgG and IgG subclasses, normal vaccination responses, absence of T-cell defects and absence of causative external factors. Rarely it can also be associated with autoimmune diseases. 2-7 Here we describe a patient with primary sIgMD; who presented with multiple autoimmune diseases without a history of recurrent infections and we provide a short literature review on sIgMD and autoimmune diseases.