DUSP23 is over-expressed and linked to the expression of DNMTs in CD4+ T cells from systemic lupus erythematosus patients.

We evaluated the transcriptional expression of dual-specificity protein phosphatase 23 (DUSP23) in CD4+ T cells from 30 systemic lupus erythematosus (SLE) patients and 30 healthy controls. DUSP23 mRNA levels were considerably higher in the patient group: 1490 ± 1713 versus 294·1 ± 204·2. No association was found between DUSP23 mRNA expression and the presence of typical serological and clinical parameters associated with SLE. Meaningful statistical values were obtained in the patient group between the levels of DUSP23 and integrin subunit alpha L (ITGAL), perforin 1 (PRF1) and CD40L. Similarly, transcript levels of different DNA methylation-related enzymes [DNA methylation-related enzymes (DNMT1, DNMT3A, DNMT3B, MBD2, and MBD4)] were also correlated positively with the expression of DUSP23. In an attempt to counteract the hypomethylation status of the promoters of certain genes known to be over-expressed in SLE, it is possible that DUSP23 acts as a negative regulatory mechanism which ultimately silences the transcription of these epigenetically regulated genes by triggering an increase in the expression of different DNMTs.

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.

Registry of the Spanish Network for Systemic Sclerosis: Survival, Prognostic Factors, and Causes of Death.

Systemic sclerosis (SSc) is a rare, multisystem disease showing a large individual variability in disease progression and prognosis. In the present study, we assess survival, causes of death, and risk factors of mortality in a large series of Spanish SSc patients. Consecutive SSc patients fulfilling criteria of the classification by LeRoy were recruited in the survey. Kaplan-Meier and Cox proportional-hazards models were used to analyze survival and to identify predictors of mortality. Among 879 consecutive patients, 138 (15.7%) deaths were registered. Seventy-six out of 138 (55%) deceased patients were due to causes attributed to SSc, and pulmonary hypertension (PH) was the leading cause in 23 (16.6%) patients. Survival rates were 96%, 93%, 83%, and 73% at 5, 10, 20, and 30 years after the first symptom, respectively. Survival rates for diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc were 91%, 86%, 64%, and 39%; and 97%, 95%, 85%, and 81% at 5, 10, 20, and 30 years, respectively (log-rank: 67.63, P < 0.0001). The dcSSc subset, male sex, age at disease onset older than 65 years, digital ulcers, interstitial lung disease (ILD), PH, heart involvement, scleroderma renal crisis (SRC), presence of antitopoisomerase I and absence of anticentromere antibodies, and active capillaroscopic pattern showed reduced survival rate. In a multivariate analysis, older age at disease onset, dcSSc, ILD, PH, and SRC were independent risk factors for mortality. In the present study involving a large cohort of SSc patients, a high prevalence of disease-related causes of death was demonstrated. Older age at disease onset, dcSSc, ILD, PH, and SRC were identified as independent prognostic factors.

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.

Increased myo-inositol in parietal white and gray matter as a biomarker of poor prognosis in neuropsychiatric lupus: a case report.

Neuropsychiatric manifestations can be a serious complication of systemic lupus erythematosus, affecting nearly 56% of these patients. Frequently, acceptable clinical outcome is observed in neurolupus with immunosuppressive therapy. Different metabolites identified with MR spectroscopy may be associated with modifications in the natural history of this disease, specifically in the central nervous system. We report a case of neurolupus with progressive neurologic impairment despite aggressive immunosuppressive treatment. We describe clinical features, laboratory and MRI results, as well as characteristic findings on MR spectroscopy. Serial MRI identified atrophy of the left temporal lobe. MR spectroscopy showed an increase of myo-inositol/creatine ratio intensity, accompanied by a decrease of N-acetylaspartate/creatine ratio in both parietal white and gray matter. During follow-up, the patient developed progressive cognitive deficiency despite the intensification of therapy. Neurolupus manifestations are common and immunosuppressive treatment often avoids severe complications. Characteristic findings on MR spectroscopy may be useful for clinicians to determine poor prognosis and resistance to therapy.

Systemic sclerosis sine scleroderma and limited cutaneous systemic sclerosis: similarities and differences.

OBJECTIVES: To compare a cohort of patients with systemic sclerosis sine scleroderma (ssSSc) vs. patients with limited cutaneous systemic sclerosis (lcSSc). METHODS: Forty-five patients with ssSSc and 186 patients with lcSSc were investigated. Demographic, clinical and immunologic features and survival were compared. RESULTS: There were no significant differences between ssSSc and lcSSc in gender, age at onset and interval between onset and diagnosis. ssSSc patients fulfilled the ACR criteria for SSc less than lcSSc patients (13%/77%, p<0.0001). There were no significant differences in articular involvement, myopathy, tendon friction rubs and gastrointestinal, pulmonary, cardiac and renal involvements. There was a trend to higher prevalence of pulmonary arterial hypertension (PAH) in ssSSc patients (29%/19%) but not reach significant difference. The prevalence of antinuclear and anticentromere antibodies and slow capilaroscopic pattern was similar. Sicca syndrome (13%/30%; p=0.024), digital ulcers (16%/50%; p<0.0001), calcinosis (11%/26%; p=0.047) and acroosteolysis (0% /10%; p=0.028) were more frequently in lcSSc. Survival at 5, 10, and 15 yr was not different in ssSSc and lcSSc patients (100%/98%, 100%/98%, and 92%/89%, respectively). CONCLUSIONS: ssSSc and lcSSc patients share demographic, clinical and immunologic features. Survival is also similar in both groups. Differences are mainly due to peripheral vascular manifestations. However, despite great similarities, we believe that ssSSc patients should be considered as a different subset in order to avoid misdiagnosis. ssSSc patients should be truly differentiated from early SSc using sensitive and specific studies looking for any asymptomatic organ involvement.

Autoimmune/inflammatory syndrome (ASIA) induced by biomaterials injection other than silicone medical grade.

BACKGROUND: Systemic autoimmune/granulomatous adverse reactions related to biomaterials other than silicone have rarely been reported. AIM: The aim of this paper is to communicate the cases of autoimmune/inflammatory syndrome induced by adjuvants (ASIA) in a study of Spanish patients suffering from inflammatory disorders related to biomaterial injections other than silicone, principally hyaluronic acid, acrylamides or methacrylate compounds. METHODS: The authors performed a retrospective analysis of the clinical, laboratory, histopathology and follow-up of a cohort of 250 cases of patients suffering from inflammatory/autoimmune disorders related to bioimplant injections. RESULTS: Of these 250 cases, patients with adverse reactions related to silicone injections (n = 65) were excluded. Of the remaining 185, 15 cases (8%) had systemic or distant and multiple complaints that could be categorized as ASIA. In all but four patients, inflammatory features at the implantation site preceded distant or systemic manifestations. Abnormal blood tests were common. Eleven cases (73.3%) with inflammatory localized nodules and panniculitis evolved into a variety of disorders, namely, primary biliary cirrhosis, Sjögren's syndrome, sarcoidosis, human adjuvant disease and inflammatory polyradiculopathy. Four cases presented primarily with systemic autoimmune disorders. CONCLUSIONS: Infrequently, biomaterials other than silicone can provoke local inflammatory adverse reactions that may evolve into systemic autoimmune and/or granulomatous disorders. Whether or not these biomaterials act as an adjuvant, they could be included in the ASIA category.

Acquired haemophilia A. First line treatment with calcineurin inhibitors and steroid pulses: a 10-year follow-up study.

Acquired haemophilia A (AH) is defined as the presence of autoantibodies or inhibitors against factor VIII (FVIII) with a clinical bleeding onset that can be life-threatening. Immunosuppressant therapy must be initiated rapidly to eradicate the inhibitor. Current treatments based on steroids plus cyclophosphamide or rituximab are quite effective, but with significant side-effects. Based on previous described AH cases treated with cyclosporine, with a good side-effect profile, we aimed at assessing prospectively a first-line calcineurin inhibitor based immunosuppressive therapy. We included a total of 11 patients affected with AH. Once diagnosed, pulse steroids and calcineurin inhibitors were started. Time to achieve sustained response (SR), defined as testing negative for inhibitor and with stable FVIII level >50%, immunosuppressant side-effects, and relapse of AH were evaluated. Eight patients received cyclosporine and three patients received tacrolimus. SR was achieved in 10 of 11 patients (90.9%) in a median time of 3 weeks (range 2-8 weeks), and none of them relapsed during a median follow-up time of 14 months (range 4-120). One major side-effect appeared (posterior encephalopathy) that forced to discontinue cyclosporine. Overall 5-year survival rate was 54.5%, with a total of five patients dying during the follow-up (mortality rate of 45.5%). These five patients had achieved SR and died because of complications of basal morbidities and/or senescence, not related to AH (bleeding) or to immunosuppressant's (infection) side-effects. Combination therapy of calcineurin inhibitors and pulse steroids seems clinically effective as a first-line treatment of AH.

Thalidomide in the treatment of refractory cutaneous lupus erythematosus: prognostic factors of clinical outcome.

BACKGROUND: Although thalidomide has been shown to be effective in patients with refractory cutaneous lupus erythematosus (CLE), its use is still hampered by its potential severe side-effects and the current restricted availability. OBJECTIVES: To evaluate prospectively the clinical efficacy and safety of low-dose thalidomide in an observational study and to establish prognostic factors of clinical outcome. METHODS: Sixty consecutive patients with refractory CLE were treated with thalidomide (100 mg daily). Clinical response was assessed by the CLE Disease Area and Severity Index (CLASI). Clinical and immunological parameters were evaluated during treatment. RESULTS: Patients were followed for up to 8 years (range 2-18). One patient discontinued treatment because of side-effects. Of the 59 remaining patients, 58 (98%) achieved clinical response, already noticeable at 2 weeks following treatment. Complete response occurred in 50 patients (85%). Clinical relapse was frequent (70%) and usually occurred 5 months after withdrawal or reduction of thalidomide. Subacute CLE (SCLE) was the predicting factor of long-term remission after therapy discontinuation [odds ratio (OR) 30, 95% confidence interval (CI) 5·82-154·63], whereas discoid lupus erythematosus (DLE) was predictive of relapse (OR 5·71, 95% CI 1·36-24·06). Eleven patients (18%) reported paraesthesia; in five of the 11, nerve conduction studies confirmed a sensory polyneuropathy. Neurological symptoms resolved in 12 months (range 6-18) after thalidomide withdrawal. Two patients, heavy smokers and without antiphospholipid antibodies, had a cerebral ischaemic event. CONCLUSIONS: Low-dose thalidomide is an effective treatment for refractory CLE, but its benefits need to be balanced against the potential adverse effects. Whereas DLE forms tended to relapse and required a long-term maintenance dose of thalidomide, SCLE forms showed a sustained remission after withdrawal.

Beta2-glycoprotein I gene polymorphisms Val247Leu and Trp316Ser in Spanish patients with primary antiphospholipid syndrome.

The significance of beta2-glycoprotein I (ß2GPI) polymorphisms in the production of anti-ß2GPI and other antiphospholipid autoantibodies (aPL) and in the pathogenesis of primary antiphospholipid syndrome (PAPS) is not well understood. We performed a study comparing the distribution of polymorphisms at codons 247 (Val247Leu) and 316 (Trp316Ser) of the ß2GPI gene in a Caucasian Spanish population of PAPS patients and healthy controls, and then making correlations with the development of anti-ß2GPI antibodies and other aPL and associated clinical manifestations. A total of 57 PAPS patients and 100 control subjects were included. In the analysis of Val247Leu polymorphism, alleles (V and L) and genotypes (V/V, V/L, L/L) were similarly distributed in PAPS patients and controls (P = 0.66 and P = 0.22, respectively). Regarding Trp316Ser polymorphism, we found a higher percentage of patients with respect to controls expressing S allele (11.4 vs. 5%, P = 0.02) and T/S genotype (22.8 vs. 10%, P = 0.02). However, when we compared T/T and T/S genotypes in PAPS patients, we found no differences regarding generation of anti-ß2GPI, other aPL and clinical manifestations favoring any genotype. Our findings suggest that among Spanish Caucasians, polymorphisms at codon 247 (Val247Leu) do not seem to influence PAPS pathogenesis. On the contrary, polymorphisms at codon 316 (Trp316Ser), by means of an increased S allele and T/S genotype presence in Spanish Caucasian patients, might play a role in the pathogenic development of PAPS, although mechanism would not involve an increased production of anti-ß2GPI and other aPL.

The PTPN22*R620W polymorphism does not confer genetic susceptibility to antiphospholipid syndrome in the Spanish population.

In this work, we proposed to determine the association of the PTPN22*R620W SNP with primary antiphospholipid syndrome (PAPS) in a case-control association study of Spanish Caucasian individuals. A total of 81 PAPS patients were compared with 81 blood-donor healthy control subjects. PTPN22 SNP (R620W) genotyping was performed by using a polymerase chain reaction-restricted fragment length polymorphism assay. No statistically significant differences were found between control subjects and PAPS patients for the PTPN22*R620W genotypes (P = 0.214). No statistically significant differences were found according to either the presence or absence of antiphospholipid antibodies or the clinical manifestations associated to PAPS. Our results indicate that this functional PTPN22*R620W polymorphism is not associated to PAPS; it seems not to be a risk factor in our Spanish population. The effect of the PTPN22 SNP on clinical manifestations and presence of antiphospholipid antibodies in APS warrants further investigations.

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].

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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.