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Raynaud's disease and phenomenon [keywords]
- Postural tachycardia syndrome (POTS) and other autonomic disorders in antiphospholipid (Hughes) syndrome (APS). [JOURNAL ARTICLE]
- Lupus 2014 Feb 25.
BackgroundAntiphospholipid syndrome (APS) is an autoimmune hypercoagulable disorder that has been shown to cause a large number of cardiac and neurological manifestations. Two recent studies have demonstrated abnormalities in cardiovascular autonomic function testing in APS patients without other cardiovascular or autoimmune disease. However, an association between autonomic disorders such as postural tachycardia syndrome and APS has not previously been described.Methods and resultsData were obtained by retrospective chart review. We identified 15 patients who have been diagnosed with APS and an autonomic disorder. The median age of the patients at the time of data analysis was 39 years. The autonomic disorders seen in these patients included postural tachycardia syndrome, neurocardiogenic syncope and orthostatic hypotension. The majority of patients (14/15) were female and the majority (14/15) had non-thrombotic neurological manifestations of APS, most commonly migraine, memory loss and balance disorder. Many also had livedo reticularis (11/15) and Raynaud's phenomenon (nine of 15). In some patients, the autonomic manifestations improved with anticoagulation and/or anti-platelet therapy; in others they did not. Two patients with postural tachycardia syndrome who failed to improve with the usual treatment of APS have been treated with intravenous immunoglobulin with significant improvement in their autonomic symptoms.ConclusionWe believe that autonomic disorders in APS may represent an important clinical association with significant implications for treatment.
- The association of antiphospholipid antibodies with cardiopulmonary manifestations of systemic sclerosis. [JOURNAL ARTICLE]
- Clin Exp Rheumatol 2014 Feb 24.
To determine the prevalence and correlates of antiphospholipid antibodies (APLA) in systemic sclerosis (SSc).Nine hundred and forty SSc patients were tested for APLA using an ELISA assay at recruitment. Clinical manifestations were defined as present, if ever present from SSc diagnosis. Logistic regression analysis was used to determine the associations of APLA.One or more types of APLA were present in 226 (24.0%) patients. Anticardiolipin (ACA) IgG (ACA-IgG) antibodies were associated with right heart catheter-diagnosed pulmonary arterial hypertension (PAH), with higher titres corresponding with a higher likelihood of PAH (moderate titre (20-39 U/ml) ACA-IgG odds ratio [OR] 1.70, 95% CI: 1.01-2.93, p=0.047; high titre (>40 U/ml) ACA-IgG OR 4.60, 95% CI:1.02-20.8, p=0.047). Both ACA-IgM (OR 2.04, 95% CI: 1.4-3.0, p<0.0001) and ACA-IgG (OR 1.84, 95% CI: 1.2-2.8, p=0.005) were associated with interstitial lung disease (ILD). Increasing ACA-IgM and IgG titres were associated with increased likelihood of ILD. ACA-IgG was a marker of coexistent pulmonary hypertension and ILD (ILD-PH) (OR 2.10, 95% CI: 1.1-4.2, p=0.036). We also found an association between ACA-IgG and digital ulcers (OR 1.76, 95% CI: 1.16-2.67, p=0.008) and ACA-IgM and Raynaud's phenomenon (OR 2.39, 95% CI: 1.08-5.27, p=0.031). There was no association between APLA and SSc disease subtype, peak skin score, presence of other autoantibodies, mortality or other disease manifestations.The association of APLA with PAH, ILD, ILD-PH, Raynaud's phenomenon and digital ulcers suggests that endothelial abnormalities and small vessel thrombosis may be important in the pathogenesis of these disease features.
- Rare autoantibodies to cellular antigens in systemic lupus erythematosus. [JOURNAL ARTICLE]
- Lupus 2014 Feb 20.
ObjectiveA high number of antinuclear antibody specificities can be detected in systemic lupus erythematosus (SLE). Some of them are related to a distinct clinical subset of disease, independently of their frequency. The aim of our study was to investigate, in a cohort of SLE patients, the prevalence and the clinical relevance of autoantibodies to cellular antigens less frequently found in SLE.MethodsAntinuclear antibodies were detected by indirect immunofluorescence on HEp-2 cells while counterimmunoelectrophoresis was used to detect anti-ENA antibodies in 540 patients with SLE, classified according to ACR and SLICC criteria. Clinical and serological features were collected from clinical charts.ResultsA total of 319 (58.9%) out of 540 sera were positive for anti-ENA antibodies. Anti-Ro/SSA was found in 235 sera, 50 of which also contained anti-La/SSB. Anti-U1RNP were detected in 67, anti-Sm in 46 and anti-ribosomal P protein in 13 sera. In a multivariate analysis anti-Sm was associated with discoid lupus (p = 0.045) and photosensitivity (p = 0.037), anti-U1RNP with malar rash and Raynaud's phenomenon (p = 0.01 and p = 0.0004, respectively) and anti-Ro/SSA with malar rash, oral ulcers, xerostomia, xerophthalmia and rheumatoid factor (p = 0.029, p = 0.01, p = 0.031, p = 0.002 and p = 0.028, respectively). Other anti-ENA antibodies were found in 50 positive sera (15.6%). Anti-Ki antibodies were detected in 31, anti-Ku in 8, anti-centromere in 5, isolated anti-La/SSB, anti-PCNA and anti-Topo I in 3 each and anti-Jo-1 in 2 sera. About half of these antibodies (27 out of 50) were detected as the single anti-ENA specificity in serum. At multivariate analysis anti-Ki was significantly associated with male gender while anti-Ku with African ethnicity (p = 0.017 and p < 0.0001, respectively). No sign of muscular or pulmonary involvement was found in anti-Jo-1-positive patients whilst features of systemic sclerosis were detectable in two out of three anti-Topo I.ConclusionsOur study shows that antibodies to cellular antigens more rarely found in SLE are detectable in more than 15% of patients with anti-ENA antibodies. Most of them are found as single anti-ENA specificity. Anti-Ki and anti-Ku are found in a subset of disease, characterized by male gender and African origin, respectively. Clinical features of scleroderma were found only in patients with anti-Topo I.
- Anti-Jo-1 myositis and the antiphospholipid syndrome showing right ventricular thrombus: a novel overlap syndrome with atypical presentation. [JOURNAL ARTICLE]
- Mod Rheumatol 2014 Feb 11.
Abstract It has long been recognized that patients with myositis and positive anti-Jo1 antibody tend to be associated with interstitial lung disease. Recent studies revealed that such patients may also have fever, Raynaud's phenomenon, mechanic's hand, polyarthralgia, or usually mild, self-limiting, non-erosive or erosive polyarthritis known as antisynthetase syndrome. The hallmark of this disorder is the presence of the autoantibodies that recognize the aminoacyl-tRNA synthetases, which play a critical role in protein synthesis. The most well recognized of the autoantibodies is anti-histidyl (Jo-1). Antisynthetase syndrome cases associated with other autoimmune diseases are rarely reported. We here present a case of antisynthetase syndrome presented with right ventricle thrombus and deep vein thrombosis in the lower limbs. Secondary antiphospholipid syndrome was then diagnosed after a series of examinations. The patient was successfully treated with anticoagulant alone without surgical thrombectomy. Our case revealed that clinical physicians should watch for thrombotic complications when facing patients with antisynthetase syndrome. Medical therapy with anticoagulants alone may be an alternative treatment option in patients with right ventricle thrombus who cannot tolerate surgical thrombectomy.
- Associations of nailfold capillary abnormalities and immunological markers in early Raynaud's phenomenon. [JOURNAL ARTICLE]
- Scand J Rheumatol 2014 Feb 12.
Objectives: Nailfold capillaroscopy (NC) and laboratory tests for antinuclear antibodies (ANA) are routinely used in parallel for detection of emerging connective tissue disease (CTD) in patients with Raynaud's phenomenon (RP). The aim of this study was to assess the associations between distinct nailfold capillary abnormalities and concomitant autoantibodies in patients with incipient RP without previously known CTD. Method: Patients with incipient RP without previously known CTD were included in this retrospective analysis. We analysed the association of particular capillary abnormalities (reduced density, avascular fields, dilations, giant capillaries, haemorrhages, tortuosity, ramifications, oedema) with ANA and ANA subsets (anti-Scl-70, anti-CENP-B, anti-U1-RNP, anti-dsDNA, anti-SSA(Ro), anti-SSB(La), anti-Sm, and anti-Jo-1 antibodies). We also developed a score that allows the estimation of each patient's individual probability for the presence of an ANA titre ≥ 1:160. Results: The final analysis comprised 2971 patients. Avascular fields, giant capillaries, reduced capillary density, and capillary oedema were closely related to an ANA titre ≥ 1:160. Both giant capillaries and avascular fields were associated with anti-Scl-70 and anti-CENP-B antibodies. Only a weak association was found between giant capillaries and anti-U1-RNP antibodies. Each patient's individual probability for the presence of an ANA titre ≥ 1:160 can be represented by a sum score comprising giant capillaries, reduced density, avascular fields, ramifications, and oedema as well as patients' sex and age. Conclusion: In patients with incipient RP, anti-Scl-70 and anti-CENP-B antibodies are related most specifically to distinct capillary alterations. Although a sum score can represent the patient's probability for elevated ANA titres, NC cannot substitute for immunological tests in patients with incipient RP.
- Early systemic sclerosis: Analysis of the disease course in patients with marker autoantibody or capillaroscopic positivity or both. [JOURNAL ARTICLE]
- Arthritis Care Res (Hoboken) 2014 Feb 10.
Objective: To investigate whether patients affected by one of the 3 subsets of early systemic sclerosis (SSc): subset I, Raynaud's phenomenon with SSc marker autoantibodies and typical capillaroscopic findings; subset II, autoantibody positive only; subset III, capillaroscopy positive only and not satisfying the 2013 ACR/EULAR classification criteria for SSc at admission differ from each other in the time to satisfy the criteria. Methods: Early SSc patients subdivided into the 3 above-indicated subsets consecutively admitted to a Rheumatology/ Angiology center were monitored for 12-102 months (median 36). Patients were re-evaluated twice yearly to assess whether and when each patient satisfied the new ACR/EULAR SSc classification criteria. Patients with undifferentiated connective tissue disease (UCTD) served as comparator group. Results: During follow-up, 11/21 subset I (52.3%), 10/15 subset II (66.6%), 0/24 subset III and 0/44 UCTD patients satisfied the criteria (p=0.0001). The difference was significant between early SSc and UCTD patients (p=0.0001) and, within the group of early SSc patients, between each of the 2 autoantibody-positive subsets (subsets I and II) and the capillaroscopic positive-autoantibody-negative subset (subset I versus III: p=0.0001; subset II versus III: p=0.0009). There was no difference between the 2 autoantibody-positive subsets (p=0.454). In addition to marker autoantibody positivity, preclinical lung or heart involvement was associated with an increased risk to satisfy the criteria during follow-up. Conclusion: Our data demonstrate faster progression of SSc in autoantibody-positive patients, particularly in those with preclinical internal organ involvement at baseline, than in autoantibody-negative patients. © 2014 American College of Rheumatology.
- [Cardiac involvement at rest in patients with systemic sclerosis: differences between the limited and the diffuse form of the disease]. [English Abstract, Journal Article]
- G Ital Cardiol (Rome) 2014 Jan; 15(1):44-50.
Heart involvement confers a poor prognosis in patients affected by systemic sclerosis (SSc). Nevertheless, the prevalence of heart involvement in these patients is not fully known. In this study we analyzed the most frequent manifestations of heart involvement at rest in a cohort of patients with SSc, comparing their prevalence in patients with the limited form (lcSSc) and in patients with the diffuse form (dcSSc) of the disease, taking also into account the duration of the disease.We thoroughly evaluated with electrocardiographic and echocardiographic examinations 174 patients affected by SSc who were followed at our hospital between 2001 and 2011. They were divided according to the disease subtype (dcSSc vs lcSSc) and information about the disease duration was available for 121 of them (calculated from the onset of the Raynaud's phenomenon).Patients with dcSSc had a greater prevalence of heart involvement at rest when evaluated within 5 and 10 years after the onset of the Raynaud's phenomenon (p=0.0051 within 5 years and p=0.035 within 10 years). Indeed, patients with dcSSc had a greater prevalence of atrioventricular conduction abnormalities within 20 years after the onset of the Raynaud's phenomenon (p=0.03 within 10 years and p=0.04 within 20 years) and a greater prevalence of valvular abnormalities within 5 years (p=0.04). In dcSSc there was a greater prevalence of rhythm disturbances in patients with a disease duration ≤20 or >20 years (p=0.04 within 20 years and p=0.04 after 20 years), but not in those with a disease duration ≤5 and ≤10 years. Left ventricular hypertrophy had a greater prevalence in dcSSc after 20 years of disease duration (p=0.02).Cardiac manifestation occurs earlier and more frequently in patients affected by dcSSc than in patients with lcSSc.
- A3.21 MicroRNA-34a and microRNA-155 in Systemic Sclerosis: possible epigenetic biomarkers of endothelial dysfunction in VEDOSS and long-standing disease. [Journal Article]
- Ann Rheum Dis 2014 Mar 1.:A50.
MicroRNAs (miRs) are a novel class of post-transcriptional regulators that have been implicated in the pathogenesis of Systemic sclerosis (SSc). MiR-34a and miR-155 were found to be related to endothelial senescence and inflammation. The aim of this study was to investigate the expression of miR-34a and miR-155 in peripheral blood mononuclear cells (PBMCs) in SSc.Twenty-seven consecutive patients with Raynaud phenomenon (RP) were enrolled in this exploratory study. Particularly, patients were divided into 3 different study cohorts: patients with primary RP with normal capillaroscopic findings and without any autoantibodies (n = 8), SSc patients fulfilling the Very Early Diagnosis Of Systemic Sclerosis (VEDOSS) criteria (n = 9) and SSc patients fulfilling the 1987 ACR criteria (n = 10) respectively. Gender and age matched healthy individuals (n = 7) were enrolled as controls. Expression of miR-34a and miR-155 was evaluated by qPCR on PBMCs isolated by gradient hystopaque technique from peripheral blood (PB) of all patients. To identify miR-34a HumanTargetScan cross-referenced was employed. Identified targets were experimentally verified by qPCR. VEGF, VEGF-RII, IL-6 and IL-6R plasma levels were determined through ELISA.MiR-155 is overexpressed either in VEDOSS (p = 0.0002) and SSc (p = 0.04) patients compared to healthy controls. MiR-34a expression is increased only in SSc compared to healthy controls (p = 0.01). Patients with primary RP did not differ according to miR-155 and miR-34a expression from healthy controls (p>0.05) Dividing SSc and VEDOSS patients according to the autoimmune profile, anti-Scl70 + have higher expression of miR-34a compared to anti-centromere + patients (p = 0.04). Furthermore, stratifying SSc patients according to the clinical vascular manifestations, SSc patients with active and/or previous digital ulcers have significantly higher miR-34a expression compared to patients without ulcers history (p = 0.01). Finally the expression of miR-34a directly correlated with the skin score value (R = 0.52, p = 0.032) in both SSc and VEDOSS patients and with IL-6 plasma levels (R = 0.42, p = 0.01). Using HumanTargetScan cross-referenced methodology, IL-6 receptor (IL6-R) was selected as target of miR-34a. IL6-R gene expression was found to be significantly higher in VEDOSS compared to SSc patients (p = 0.02). VEGF plasma levels were significantly higher in SSc patients compared to healthy controls (p = 0.01) as well as IL-6 plasma levels (p = 0.02), whereas no significant differences were found in VEGF-RII and IL-6R plasma levels comparing the different patients' cohorts.Epigenetic factors, as miR-34a and miR-155 are deregulated in SSc and VEDOSS. Their expression analysis could help to differentiate different disease phases and between primary and SSc associated RP.
- A3.9 IGG subclasses of autoantibodies directed against the angiotensin receptor type 1 and the endothelin receptor type a and their clinical relevance. [Journal Article]
- Ann Rheum Dis 2014 Mar 1.:A45.
IgG4-related diseases are often characterised by a generalised inflammatory fibrosis which is also present in patients suffering from systemic sclerosis (SSc). Recent findings indicate the importance of autoantibodies (Aabs) against the angiotensin II type-1 receptor (AT1R) and the endothelin type-A receptor (ETAR) in the pathogenesis of SSc. Therefore, we analysed the levels of anti-AT1R/ETAR IgG sublasses in patients with SSc to determine a possible role of IgG subclasses as markers for disease manifestations in SSc.Sera from 91 SSc patients, 59 patients suffering from systemic lupus erythematosus (SLE), and from 199 healthy donors were analysed for the levels of anti-AT1R and anti-ETAR Aabs as well as for the different anti-AT1R and anti-ETAR IgG subclasses by ELISA. The results were associated with clinical manifestations using Mann-Whitney test and correlated with the time since onset of disease manifestations by Spearman correlation test.IgG3 followed by IgG1 was found to show highest anti-AT1R/ETAR Aab levels in all analysed groups, in which SSc patients as well as SLE patients had higher IgG1 and IgG3 anti-AT1R/ETAR Aab levels as compared to healthy donors. Comparing SLE and SSc patients IgG1 and IgG3 showed slightly higher anti-AT1R/ETAR Aab levels in SLE. Within the SSc group patients with diffuse SSc had higher anti-AT1R/ETAR IgG3 levels as compared to those with limited disease or overlap forms. Correlation analysis with SSc-related clinical manifestations revealed that levels of anti- AT1R/ETAR IgG3 negatively correlated with time since onset of Raynaud's phenomenon, and with time since first detection of PAH. Of note, there were negative correlations between levels of anti-AT1R/ETAR IgG3 levels and diffusion capacity for carbon monoxide (DLCO) as well as between anti-AT1R/ETAR-IgG3 levels and forced vital capacity (FVC) values (p = 0.02/0.07 and p = 0.01/0.03, respectively).Interestingly, not IgG4 but IgG3 showed highest anti-AT1R/ETAR Aab levels when compared to other IgG subclasses. However, in SSc patients, anti-AT1R/ETAR IgG3 levels are strongly correlated to certain disease manifestations, whereby high anti-AT1R/ETAR IgG3 levels are associated with low DLCO and FVC indicating deterioration of lung function. According to these findings high anti-AT1R/ETAR IgG3 levels could predict for lung function deterioration and represent a new marker for SSc complications.