Red flags for clinical suspicion of eosinophilic granulomatosis with polyangiitis (EGPA).

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA), is a rare ANCA-associated systemic vasculitis. Its overlapping features with other vasculitic or eosinophilic diseases, and the wide and heterogeneous range of clinical manifestations, often result in a delay to diagnosis. OBJECTIVE: To identify red flags that raise a suspicion of EGPA to prompt diagnostic testing and to present an evidence-based clinical checklist tool for use in routine clinical practice. METHODS: Systematic literature review and expert consensus to identify a list of red flags based on clinical judgement. GRADE applied to generate a strength of recommendation for each red flag and to develop a checklist tool. RESULTS: 86 studies were included. 40 red flags were identified as relevant to raise a suspicion of EGPA and assessed by the experts as being clinically significant. Experts agreed that a diagnosis of EGPA should be considered in a patient aged ≥6 years with a blood eosinophil level >1000 cells/µL if untreated and >500 cells/µL if previously treated with any medication likely to have altered the blood eosinophil count. The presence of asthma and/or nasal polyposis should reinforce a suspicion of EGPA. Red flags of asthma, lung infiltrates, pericarditis, cardiomyopathy, polyneuropathy, biopsy with inflammatory eosinophilic infiltrates, palpable purpura, digital ischaemia and ANCA positivity, usually anti-myeloperoxidase, among others, were identified. CONCLUSION: The identification of a comprehensive set of red flags could be used to raise a suspicion of EGPA in patients with eosinophilia, providing clinicians with an evidence-based checklist tool that can be integrated into their practice.

Sequence analysis of TMEM173 exon 5 in patients with systemic autoimmune diseases.

BACKGROUND: Overactivation of the interferon pathways has been demonstrated in patients suffering from different systemic autoimmune diseases (SADs). Genetic associations have been described for many genes involved in these pathways. Gain-of-function mutations in the TMEM173 gene have recently been reported in patients with autoinflammatory diseases that share some clinical features with SADs. METHODS: We aimed at detecting the reported three mutations of transmembrane protein 173 (TMEM173) exon 5 in 100 patients suffering from: systemic lupus erythematosus (SLE) (n = 22), primary antiphospholipid syndrome (PAPS) (n = 20), systemic sclerosis (SSc) (n = 20), dermatomyositis (DM) (n = 20), and vasculitis (n = 18). Samples from 19 healthy controls were also included. Sequence analyses were performed from the derived TMEM173 exon 5 PCR fragment amplified from DNA obtained from whole blood. RESULTS: Neither mutations nor single nucleotide polymorphisms (SNPs) in the exon 5 of the TMEM173 gene were detected. Just the rs7380272 SNP, located in the intronic region upstream exon 5, was detected in some patients and controls. The allele frequency of this SNP, though, was not statistically different between the patients groups and the control group. CONCLUSIONS: Our study demonstrates the lack of association between the presence of SADs and mutations in exon 5 of the TMEM173 gene. SADs are complex multifactorial diseases in which not just one but probably many different genetic alterations may coexist. Although we cannot rule out the possibility that other variations may exist in other regions of this gene, we think that studies must be directed towards the analysis of other genes which, as TMEM173, also code for nucleic acid sensors that activate the nucleic-acid induced type I IFN pathway.

Prevalence of HHV-8 in systemic autoimmune diseases.

BACKGROUND: Epidemiological data suggest that some viruses may be linked to the development of autoimmunity. OBJECTIVES: The objective of this work was to determine the presence of HHV-8 viral DNA in whole blood from patients suffering from different systemic autoimmune diseases (SAD). We also aimed at testing the prevalence of patients showing antibodies against an HHV-8 orfK8.1 peptide. STUDY DESIGN: Two hundred and eighty SAD patients and 50 healthy blood donor controls were included. Molecular analyses were performed by nested PCR from DNA obtained from whole blood and an enzyme immunoassay was developed in order to test for the presence of antibodies directed against a synthetic peptide derived from the HHV-8 orfK8.1 protein. RESULTS: Only 2 out of the 280 samples analyzed yielded the specific HHV-8 PCR product. Antibodies against orfK8.1 were detected in 2 SLE patients, 1 patient suffering from Sjögren's syndrome and 2 patients with vasculitis. CONCLUSIONS: We conclude that HHV-8 is usually not present in blood neither from autoimmune patients nor from healthy controls. Furthermore, HHV-8 antibodies against the HHV-8 orfK8.1 peptide were rarely detected. It leads us to infer that HHV-8 is not involved on the development of these disorders. It does not rule out the possibility that other environmental and microbiological triggers may account for their etiopathogenesis.

Aortic involvement in giant cell arteritis.

Giant cell arteritis (GCA) is a primary large-vessel vasculitis predominantly seen in the elderly that preferentially involves the external carotid artery and its branches. However, inflammation of the aorta and its branches occurs in a subset of patients although symptoms of aortic involvement may appear years after the initial diagnosis of GCA. Therefore, aortic involvement has probably been underestimated and its incidence may be more frequent than suspected. Systematic evaluation of patients with imaging techniques such as magnetic resonance imaging angiography (MRA) and positron emission tomography (PET) may reveal that the clinical impact of extracranial involvement by GCA may be more relevant than previously thought. Regarding the histopathology, there are some similarities between chronic periaortitis (including idiopathic retroperitoneal fibrosis, inflammatory abdominal aortic aneurysms and perianeurysmal retroperitoneal fibrosis), idiopathic aortitis, and GCA, suggesting that all these illnesses probably share common pathological mechanisms. Inflammatory aortitis can arise in different clinical settings been idiopathic aortitis more frequent than expected in surgical specimens of aortic aneurysm surgeries in the general population. In the setting of GCA an early diagnosis of aortic involvement is mandatory in order to perform a treatment capable of avoiding the chronic and acute complications associated with an elevated mortality [1, 2].

Colour-duplex ultrasonography of the temporal and ophthalmic arteries in the diagnosis and follow-up of giant cell arteritis.

OBJECTIVE: To evaluate the diagnostic value of colour-duplex ultrasonography (CDU) of the temporal and ophthalmic arteries in the diagnosis of giant cell arteritis (GCA) and its usefulness in the follow-up of the disease. Furthermore, to examine the relationship between CDU abnormalities in ophthalmic arteries and blindness. METHODS: This is a prospective study of all patients with clinical suspicion of GCA or polymyalgia rheumatica (PMR) seen consecutively at the Internal Medicine Department at Vall d'Hebron University Hospital, Spain, between March 2003 and July 2006. Patients were evaluated with regard to the sensitivity and specificity of the dark halo sign in the temporal artery for the diagnosis of GCA, as well as the sensitivity and specificity of the presence of stenosis in temporal and/or ophthalmic arteries. Additionally, the usefulness of the dark halo sign in the follow-up of GCA was addressed. RESULTS: Forty-seven patients (30 with GCA, 17 with PMR) and 13 controls were included in the study. The sensitivity and specificity for the diagnosis of biopsy-proven GCA were higher for the temporal halo (72% in both cases) than for temporal artery stenosis (41% and 89%, respectively), or for ophthalmic artery stenosis (58% and 89%, respectively). Disappearance of the halo was observed in 50% of patients six months after diagnosis, although all patients were in clinical remission, and laboratory parameters were within normal values. CONCLUSION: CDU of the temporal arteries may be a valid tool in the diagnosis of GCA. However, its role in the follow up of the disease deserves re-evaluation. CDU of the ophthalmic arteries is less useful for CGA diagnosis and no relationship with blindness is suspected.

Clinical features and therapeutic management of subglottic stenosis in patients with Wegener's granulomatosis.

The objective of the study was to evaluate the clinical features, response to treatment, and long-term outcome of subglottic stenosis (SGS) in a series of patients diagnosed as having Wegener's granulomatosis (WG) at a single institution. Subglottic stenosis developed in 6 out of 51 (11.7%) patients, in four of them in the absence of other features of active disease, and was the symptom that leads to WG diagnosis in three cases. In two cases, SGS began while the patients were receiving systemic immunosuppressive therapy for disease activity involving other sites. PR3-ANCAs were positive in four cases. An urgent tracheostomy was needed in two patients. Four patients achieved SGS clinical remission on standard treatment with glucocorticoids and cyclophosphamide, but three of them experienced repeated local relapses and required additional immunosuppressive therapy and mechanical dilations. In one case, a local relapse was successfully managed with endotracheal dilation of the stenotic segment and intralesional injection of a long-acting corticosteroid plus mechanical dilation of the stenotic segment (ILCD) without adding supplemental immunosuppressant drugs. Two patients with isolated SGS were also successfully managed with ILCD alone and did not require the institution of systemic immunosuppressive therapy. One patient underwent open surgical repair when the disease was under control. Our data suggest that Subglottic stenosis often occurs or progresses independently of other features of active WG, and that ILCD may be a safe alternative to conventional immunosuppressive therapy in patients who develop SGS in the absence of other features of active disease, allowing reducing the treatment-related toxicity.

Intravenous cyclophosphamide pulse therapy in the treatment of systemic sclerosis-related interstitial lung disease: a long term study.

OBJECTIVE: Interstitial lung disease (ILD) frequently complicates systemic sclerosis (SSc). Cyclophosphamide (CYC) is a promising immunosuppressive therapy for SSc-related ILD. Our objective was to investigate the effectiveness of an intravenous CYC (iv CYC) pulse regime in SSc-related ILD during treatment and thereafter. METHODS: In a prospective observational study ten consecutive patients with SSc-related ILD were treated with iv CYC in a pulse regime lasting from 6 to 24 months. Clinical status, pulmonary functional testing (PFT) and high resolution computed tomography (HRCT) of the chest were evaluated at enrolment and 6, 12 and 24 months thereafter. After treatment withdrawal, patients were followed up every 6 months with PFT and chest HRCT to monitor lung disease. RESULTS: Clinical improvement was apparent in 8 out of 10 patients. The median values of forced vital capacity (FVC), forced expiratory volume in the first second (FEV1) and diffusion lung capacity for carbon monoxide (DLCO) as well as ground-glass pattern on HRCT did not change significantly after 6, 12 and 24 months of therapy. The follow-up continued in 8 out of 10 patients after treatment withdrawal for a median of 26.5 months (range: 12-48 months). The final median FVC was 54.5% of predicted value (interquartile range, IQR= 31.6%-94%). Only one patient suffered a FVC deterioration greater than 10%, even though less than 160 ml. The final median DLCO was 68% of predicted value (IQR=38.3-83.6%). Only 2 patients who developed pulmonary arterial hypertension deteriorated their DLCO values of more than 15%. CONCLUSIONS: An iv CYC pulse regimen over 24 months may stabilize pulmonary activity in patients with SSc-related ILD during the course of treatment and for a median of 26.5 months thereafter.

Polymyositis/dermatomyositis-associated lung disease: analysis of a series of 81 patients.

The objective of this study was to assess the prevalence, clinical, histological and immunological characteristics, and the long-term outcome of polymyositis- (PM) and dermatomyositis- (DM) associated lung disease, and to define subgroups of lung-associated inflammatory myopathies. This retrospective study included 81 consecutive patients diagnosed with PM/DM. Pulmonary involvement was systematically investigated in relation to clinical symptoms by chest radiography, high resolution computed tomography and pulmonary function testing. Anti-synthetase autoantibodies (ASA) were analysed by ELISA and confirmed by protein and RNA immunoprecipitation methods. Statistical analyses were done with the Student t-test and Fisher exact test. Cumulative survival probabilities were estimated by the Kaplan-Meier method and Cox regression analysis. Fifty patients (61%) presented pulmonary involvement. Thirty-two (39%) had interstitial lung disease and five of them had devastating acute interstitial pneumonia with pneumomediastinum and an unfavorable prognosis. Histology showed diffuse alveolar damage in this subgroup and ASA were negative. Eighteen patients (22%) presented restrictive myopathic lung disease; in three of them respiratory muscles could not maintain ventilation. ASA were positive in 17 of the 50 patients (34%) and were significantly associated with interstitial lung disease (OR: 4.5 [95% CI: 1.3-15.3]), arthritis (OR: 6.0 [95% CI: 1.3-29.2]) and 'mechanic hands' (OR: 8.5 [95% CI: 1.7-41.4]); the presence of these autoantibodies did not imply worse survival prognosis. We concluded that clinical and immunological characteristics allowed the grouping of patients into different types of PM/DM lung-associated disease. Presence of ASA did not affect survival. ASA-negative patients with acute interstitial pneumonitis and pneumomediastinum had an unfavorable prognosis.

Clinical significance of antinuclear antibodies in malignant diseases: association with rheumatic and connective tissue paraneoplastic syndromes.

Our objective was to determine the prevalence of antinuclear antibodies (ANAs) in patients with malignancies and to investigate if their presence might be related with development of musculoskeletal symptoms or paraneoplastic rheumatic syndromes. Antinuclear antibodies were determined by indirect immunofluorescence on Hep-2 cells in 274 neoplastic patients and in a control group of 140 age-adjusted healthy subjects. Antinuclear antibody specificities (anti-DNA and anti-ENA) were investigated in patients with rheumatological symptoms and positive ANA. Antinuclear antibodies were detected in 76 of 274 (27.7%) patients with malignancies and in nine of 140 (6.4%) healthy subjects. Twenty patients reported paraneoplastic rheumatic symptoms or syndromes. Two of them developed clinical symptoms mimicking rheumatoid arthritis (rheumatoid-like arthropathy), one systemic lupus erythematosus (lupus-like syndrome), one dermatomyositis and four cutaneous vasculitides. Musculoskeletal symptoms and paraneoplastic rheumatic symptoms and syndromes were both more frequently observed in patients with positive ANA. Antinuclear antibody specificities were found in only two cases. We can conclude that there is an increased incidence of antinuclear antibodies in malignant conditions. Musculoskeletal symptoms and rheumatic paraneoplastic symptoms and syndromes seem to be more frequent in patients with cancer-related positive ANAs. The failure to find ANA specificities (anti-ENA, anti-DNA) in patients with malignancies and positive ANAs in our study may simply reflect molecular differences between the autoantigens involved in cancer and those characteristically involved in the systemic autoimmune diseases.

Lack of evidence of foetal microchimerism in female Spanish patients with systemic sclerosis.

Our objective was to study the presence of microchimerism in a series of 47 female Spanish patients with scleroderma (SSc) and to compare with a control group. Polymerase chain reaction was used to identify Y-chromosome sequences in DNA extracted from peripheral blood cells. Y-chromosome sequences were found in DNA from peripheral blood cells in four out of 47 (8.5%) patients with scleroderma (two limited and two diffuse) and in two out of 40 (5%) healthy women (no statistical differences were found). When we compared SSc patients and healthy controls who had had at least one male child, four out of 29 (13.7%) and two out of 26 (7.6%) had microchimerism respectively (no statistically significant differences were found). Patients with both scleroderma and persistent microchimerism had had a male offspring. Foetal microchimerism does not seem to play a major role in most cases of female Spanish patients with SSc.

[Primary Sjögren's syndrome: clinical and immunological characteristics of 114 patients]. / Síndrome de Sjögren primario: características clínicas e inmunológicas de 114 pacientes.

BACKGROUND: To analyze the clinical and immunological characteristics of a series of 114 patients with primary Sjögren's syndrome (PSS), and to evaluate the different diagnostic criteria and the association to lymphoproliferative disorders. PATIENTS AND METHOD: We included 114 patients (108 female and 6 male) with a diagnosis of PSS. All patients fulfilled the 1993 European Community criteria for the diagnosis of PSS and 76 patients fulfilled the San Diego Criteria. RESULTS: Mean age was 51 years with a mean follow-up of 7.3 years. The commonest clinical manifestation at onset (70%) was xerostomia/xerophtalmia (sicca syndrome). Extra glandular involvement was articular in 42% of cases, neurologic (35%), respiratory (21%) and hepatic (13%). Eleven patients (9%) developed vasculitis, and three (2%) developed a lympho-proliferative disorder. No statistically significant differences regarding symptoms at onset, frequency of glandular or extra glandular manifestations and severity of disease were observed between the two diagnostic criteria groups. HCV infection was associated with vasculitis (p < 0.001; OR: 20.6; CI 95%, 3.2-129) and lymphoproliferative disorders (p < 0.001). CONCLUSIONS: The clinical evolution of PSS does not vary when using different diagnostic criteria (San Diego and European Community criteria). A subset of patients with vasculitis and lymphoproliferative diseases is found to have an associated HCV infection.