Basophils and IgE contribute to mixed connective tissue disease development.

BACKGROUND: Mixed connective tissue disease (MCTD) is a rare and complex autoimmune disease that presents mixed features with other connective tissue diseases, such as systemic lupus erythematosus, systemic sclerosis, and myositis. It is characterized by high levels of anti-U1 small nuclear ribonucleoprotein 70k autoantibodies and a high incidence of life-threatening pulmonary involvement. The pathophysiology of MCTD is not well understood, and no specific treatment is yet available for the patients. Basophils and IgE play a role in the development of systemic lupus erythematosus and thus represent new therapeutic targets for systemic lupus erythematosus and other diseases involving basophils and IgE in their pathogenesis. OBJECTIVE: We sought to investigate the role of basophils and IgE in the pathophysiology of MCTD. METHODS: Basophil activation status and the presence of autoreactive IgE were assessed in peripheral blood of a cohort of patients with MCTD and in an MCTD-like mouse model. Basophil depletion and IgE-deficient animals were used to investigate the contribution of basophils and IgE in the lung pathology development of this mouse model. RESULTS: Patients with MCTD have a peripheral basopenia and activated blood basophils overexpressing C-C chemokine receptor 3. Autoreactive IgE raised against the main MCTD autoantigen U1 small nuclear ribonucleoprotein 70k were found in nearly 80% of the patients from the cohort. Basophil activation and IgE anti-U1 small nuclear ribonucleoprotein 70k were also observed in the MCTD-like mouse model along with basophil accumulation in lymph nodes and lungs. Basophil depletion dampened lung pathology, and IgE deficiency prevented its development. CONCLUSIONS: Basophils and IgE contribute to MCTD pathophysiology and represent new candidate therapeutic targets for patients with MCTD.

Spectrum of interstitial lung disease from a tertiary care hospital in Karachi.

OBJECTIVE: To determine the clinical features and patterns of interstitial lung disease. METHODS: This retrospective study was conducted at the Aga Khan University Hospital, Karachi, and comprised record of patients diagnosed with interstitial lung disease from January 2005 to December 2015. All patients aged 16 years and above diagnosed with interstitial lung disease on the basis of clinical features, radiological features on high-resolution computed tomography of the chest, and lung biopsies were included. SPSS 19 was used for data analysis. RESULTS: Of the 537 patients, 324(60.3%) of the participants were females. The overall mean age was 60.5±14.9 years. The most common co-morbid condition was diabetes mellitus in 72(13.4%) patients, followed by hypertension in 48(8.9%) and ischaemic heart disease in 21(3.9%). The most common interstitial lung disease was idiopathic pulmonary fibrosis in 217(40.4%) patients, followed by non-specific interstitial pneumonia in 106(19.7%), sarcoidosis in 82(15.3%) and connective tissue disease-related interstitial lung disease in 56(10.4%) patients. CONCLUSIONS: Idiopathic pulmonary fibrosis was found to be the most common interstitial lung disease subtype followed by non-specific interstitial pneumonia, sarcoidosis and connective tissue disease-related-interstitial lung disease.

Concurrent presentation of cutaneous lesions of deep linear morphoea and discoid lupus erythematosus.

Patients with autoimmune disorders are predisposed to develop a second immunologic disease, frequently with systemic involvement. We present a patient who developed lesions of discoid lupus erythematosus (DLE) limited to the face, and, concurrently, a linear morphoea involving her right axilla. No criteria for systemic lupus erythematosus or systemic scleroderma were present in the patient. To our knowledge, no patients with concomitant DLE and linear morphoea, without systemic involvement, have been previously reported in the literature.

A case of mixed connective tissue disease with pseudo-pseudo Meigs' syndrome (PPMS)-like features.

Pseudo-pseudo Meigs' syndrome (PPMS) has been reported to be a rare presentation of patients with systemic lupus erythematosus (SLE). However, such a presentation is not common in other forms of connective tissue disease. We presented a case of gross ascites, pleural effusion, and marked elevation of CA-125 level (PPMS-like features) that led to a diagnosis of MCTD. The patient responded to systemic steroid therapy.

A case of idiopathic portal hypertension associated with nodular regenerative hyperplasia-like nodule of the liver and mixed connective tissue disease.

A 51-year-old woman was diagnosed with mixed connective tissue disease (MCTD) in 2011. She underwent treatment with prednisolone. Her hepatobiliary enzyme level increased, and multiple nodules were found in both liver lobes in abdominal imaging studies. Ultrasonography revealed large and small hyperechoic lesions with indistinct or well-defined borders. No findings of classic hepatocellular carcinoma or liver cirrhosis were observed on contrast-enhanced computed tomography, but some nodules showed an enhanced effect of the central lesion that was characteristic of focal nodular hyperplasia (FNH) in an arterial phase. On gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging, slightly high-intensity nodules, 10-40mm in size, were observed on T1- and T2-weighted images. The nodules showed highest intensities in the hepatocyte phase and were enhanced with the uptake of Gd-EOB-DTPA as compared with the background liver. FNH was suspected based on the imaging findings, but we performed a liver tumor biopsy for differential diagnosis of the malignant lesion. Based on the immunohistopathological examination results, the final diagnosis was idiopathic portal hypertension associated with nodular regenerative hyperplasia (NRH)-like nodule of the liver. Benign nodular hepatocellular lesions are caused by abnormal hepatic circulation and were previously known as anomalous portal tract syndrome. Our case of atypical NRH with large nodules may be included in this disease entity. Here, we report a rare case of MCTD with NRH-like nodules and idiopathic portal hypertension with a review of literature.

A case of catastrophic antiphospholipid syndrome, which presented an acute interstitial pneumonia-like image on chest CT scan.

We report the case of catastrophic antiphospholipid syndrome (CAPS) complicated with mixed connective tissue disease (MCTD). A female patient was diagnosed with acute interstitial pneumonia (AIP) with MCTD by chest CT scan. Corticosteroid therapy was refractory for lung involvement, and she died due to acute respiratory failure. The autopsy revealed that AIP was compatible with lung involvement of CAPS. We therefore suggest that chest CT might reveal AIP-like findings in CAPS patients whose condition is complicated with pulmonary manifestations.

Elevated double negative T cells in pediatric autoimmunity.

PURPOSE: Autoimmune diseases are thought to be caused by a loss of self-tolerance of the immune system. One candidate marker of immune dysregulation in autoimmune disease is the presence of increased double negative T cells (DNTs) in the periphery. DNTs are characteristically elevated in autoimmune lymphoproliferative syndrome, a systemic autoimmune disease caused by defective lymphocyte apoptosis due to Fas pathway defects. DNTs have also been found in the peripheral blood of adult patients with systemic lupus erythematosus (SLE), where they may be pathogenic. DNTs in children with autoimmune disease have not been investigated. METHODS: We evaluated DNTs in pediatric patients with SLE, mixed connective tissue disease (MCTD), juvenile idiopathic arthritis (JIA), or elevated antinuclear antibody (ANA) but no systemic disease. DNTs (CD3(+)CD56(-)TCRαß(+)CD4(-)CD8(-)) from peripheral blood mononuclear cells were analyzed by flow cytometry from 54 pediatric patients including: 23 SLE, 15 JIA, 11 ANA and 5 MCTD compared to 28 healthy controls. RESULTS: Sixteen cases (29.6 %) had elevated DNTs (≥2.5 % of CD3(+)CD56(-)TCRαß(+) cells) compared to 1 (3.6 %) control. Medication usage including cytotoxic drugs and absolute lymphocyte count were not associated with DNT levels, and percentages of DNTs were stable over time. Analysis of multiple phenotypic and activation markers showed increased CD45RA expression on DNTs from patients with autoimmune disease compared to controls. CONCLUSION: DNTs are elevated in a subset of pediatric patients with autoimmune disease and additional investigations are required to determine their precise role in autoimmunity.

The diagnosis and classification of undifferentiated connective tissue diseases.

The term undifferentiated connective tissue disease (UCTD) refers to unclassifiable systemic autoimmune diseases which share clinical and serological manifestations with definite connective tissue diseases (CTDs) but not fulfilling any of the existing classification criteria. In this review we will go through the more recent evidence on UCTD and we will discuss in what extent the availability of new criteria for the CTDs could interfere with the "UCTD concept". The development of criteria able to identify early phases of defined CTD, may help in the differentiation of stable UCTD form their early stages and may offer a valuable guide to the treating physician to set up appropriate follow up schedules as well as therapeutic protocols. This simplified subset of CTD could offer a model to study clinic pathological correlations as well as the role of possible environmental factors in the development of autoimmunity.

Naifold capillaroscopy in mixed connective tissue disease patients.

INTRODUCTION: Mixed connective tissue disease (MCTD) is a rare systemic disease characterized by overlapping features of systemic lupus erythematosus (SLE), systemic sclerosis (SSc), dermato-/polymyositis (DM/PM), and rheumatoid arthritis (RA). Naifold capillaroscopy (NFC) is a non-invasive test for evaluating the capillaries of the nail shaft used in the diagnosis of rheumatic diseases. OBJECTIVES: To determine whether there are characteristic abnormalities in NFC in MCTD patients, and whether the type of NFC lesions correlates with organ involvement in these patients. METHODS: Clinical picture and NFC patterns were analyzed in 43 patients with MCTD. Capillaroscopic images were divided into scleroderma-like pattern (SD-like pattern) according to the Cutolo classification, non-specific lesions, and normal images. Relationships between the clinical aspects considered in the MCTD classification criteria and the changes in the capillaroscopic images were evaluated. RESULTS: SD-like pattern was present in 20 MCTD patients (46.51%) with a predominance of the "early" pattern. Giant, branched, dilated capillaries and reduced capillary density were found more frequently in MCTD patients compared to the control group (p-values 0.0005, 0.005, 0.02, < 0.0001 respectively). There were associations found between the presence of a reduced number of vessels, avascular areas, and SD-like pattern with the presence of sclerodactyly in MCTD patients (p = 0.002, p = 0.006, p = 0.02, respectively), alongside an association between the presence of branched vessels and the subpapillary plexus with pulmonary arterial hypertension (PAH) (p = 0.04 and p = 0.005, respectively). CONCLUSIONS: MCTD patients are significantly more likely to have abnormalities upon NFC. It is worthwhile to perform capillaroscopic examination in MCTD patients. Key Points • Scleroderma-like pattern was found in more than half of the MCTD patients. • Reduced capillary density was found to be a significant predictor of the diagnosis of MCTD. • There were relationships between the presence of reduced capillary density, avascular areas, and SD-like with the presence of sclerodactyly in the MCTD patients. • There was an association between the presence of branched vessels and the visibility of the subpapillary plexus and pulmonary arterial hypertension (PAH).

Assessment of T regulatory cells and expanded profiling of autoantibodies may offer novel biomarkers for the clinical management of systemic sclerosis and undifferentiated connective tissue disease.

In order to identify disease biomarkers for the clinical and therapeutic management of autoimmune diseases such as systemic sclerosis (SSc) and undifferentiated connective tissue disease (UCTD), we have explored the setting of peripheral T regulatory (T reg) cells and assessed an expanded profile of autoantibodies in patients with SSc, including either limited (lcSSc) or diffuse (dcSSc) disease, and in patients presenting with clinical signs and symptoms of UCTD. A large panel of serum antibodies directed towards nuclear, nucleolar, and cytoplasmic antigens, including well-recognized molecules as well as less frequently tested antigens, was assessed in order to determine whether different antibody profiles might be associated with distinct clinical settings. Beside the well-recognized association between lcSSc and anti-centromeric or dcSSC and anti-topoisomerase-I antibodies, we found a significative association between dcSSc and anti-SRP or anti-PL-7/12 antibodies. In addition, two distinct groups emerged on the basis of anti-RNP or anti-PM-Scl 75/100 antibody production among UCTD patients. The levels of T reg cells were significantly lower in patients with SSc as compared to patients with UCTD or to healthy controls; in patients with lcSSc, T reg cells were inversely correlated to disease duration, suggesting that their levels may represent a marker of disease progression.

Tumoral calcinosis in the nose in a patient with scleroderma: an unusual site for a rare tumor.

Tumoral calcinosis is a rare calcifying disorder with deposition of calcium phosphate and calcium hydroxyapatite within the soft tissue at periarticular sites. There have been series of sporadic cases of tumoral calcinosis in the trunk and the extremities due to renal failure. However, we describe a 35-year-old woman without renal problems or trauma history who had tumoral calcinosis in the nose. This is the first report on facial occurrence.

ANCA-associated vasculitis with dual ANCA positivity in coexistence with mixed connective tissue disease.

We here report a rare case of dual antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in a 38-year-old Japanese woman previously diagnosed with mixed connective tissue disease. The patient was found to be positive for myeloperoxidase- and proteinase 3-ANCA, and was diagnosed with AAV following admission to hospital with fervescence, polyarthralgia, purpura, and asymmetric numbness of the extremities. Examination of her genetic background revealed that she carried HLA-DR9, which confers risk of both diseases in Japanese populations.

Prevalence and severity of interstitial lung disease in mixed connective tissue disease: a nationwide, cross-sectional study.

BACKGROUND: Mixed connective tissue disease (MCTD) is an immune-mediated, systemic disorder of unknown cause. OBJECTIVE: To assess the prevalence, pattern and severity of interstitial lung disease (ILD) in a cross-sectional study of the nationwide, Norwegian MCTD cohort. METHODS: 126 patients with MCTD were systematically examined for ILD by high-resolution CT (HRCT), pulmonary function tests (PFT), 6 min walk test (6MWT) and by the New York Heart Association (NYHA) functional classification of dyspnoea. The extent and type of HRCT lung abnormalities were scored according to the CT criteria of ILD recommended by the Fleischner Society. RESULTS: All 126 patients were Caucasian, 75% women. At the time of the cross-sectional ILD study, the patients had a mean disease duration of 9.0 years. 52% of the patients had abnormal HRCT findings, most commonly reticular patterns consistent with lung fibrosis (35%). Lung fibrosis was quantified as minor in 7%, moderate in 9% and severe in 19% of the patients. Fibrosis was uniformly concentrated in the lower parts of the lungs and was not associated with smoking. Patients with severe lung fibrosis had lower PFT values, shorter 6MWT and a higher mean NYHA functional class. After a mean 4.2 years' follow-up, overall mortality was 7.9%. Mortality in patients with normal HRCT was 3.3%, as compared with 20.8% in patients with severe lung fibrosis (p<0.01). CONCLUSIONS: Severe lung fibrosis is common in MCTD, has an impact on pulmonary function and overall physical capacity and is associated with increased mortality.

Collapsing glomerulopathy in a patient with mixed connective tissue disease.

Collapsing glomerulopathy (CG) is a distinct clinicopathological entity characterized by glomerular capillary collapse, podocyte proliferation, diffuse mesangial sclerosis, and podocyte maturation arrest. Initially noted primarily in HIV infected patients, a number of other diseases have now been associated with CG. Mixed connective tissue disease (MCTD) is a disease with overlapping features of systemic lupus erythematosus, progressive systemic sclerosis, and polymyositis. It was originally thought that renal involvement was a rare complication of MCTD. However, over the years, it has become clearer that renal involvement, although not always clinically apparent, is frequent. In this report we present a patient with MCTD who developed CG.

Mixed connective tissue disorder and Castleman's disease.

We present a 16-year-old girl who presented with polyarthritis in association with Raynaud's phenomenon, malar rash, oral ulcers, photosensitivity and alopecia of 6 months duration. On evaluation, it emerged that she had a mixed connective tissue disorder with a mesangio-proliferative glomerulonephritis. Her Chest radiograph revealed a well defined left mid and lower zone opacity with evidence of a hilar mass on CT Thorax. Histopathological examination following CT guided biopsy of the mass revealed a hyaline vascular type of Castleman's disease. Mixed Connective Tissue Disorder with Castleman's Disease is a rare association; the patient presenting with varied and interesting manifestations. It is important to understand this association in view of management. The exact etio-pathogenesis of the autoimmune manifestations in patients with Castleman's disease is not clear. Treatment with immunosuppression can suppress both immune manifestations and result in tumour regression as well.