Miquel Vilardell-Tarrés

Usefulness of anti‐p155 autoantibody for diagnosing cancer‐associated dermatomyositis: A systematic review and meta‐analysis

OBJECTIVE Anti-p155 autoantibody, which was recently described in adult patients with dermatomyositis (DM), seems to be associated with cancer in this population. We performed a systematic review and meta-analysis to ascertain the accuracy of anti-p155 testing for the diagnosis of cancer-associated myositis. METHODS We searched relevant databases, with no restrictions on study design or language, for original studies that included adult patients with probable/definite DM or amyopathic DM who were evaluated for neoplasm and anti-p155 status. Pooled sensitivity and specificity were calculated using a bivariate model. We computed the diagnostic odds ratio (OR), likelihood ratios (LRs) for positive and negative test results, positive and negative predictive values, and the summary receiver operating characteristic (SROC) curve. Statistical heterogeneity between studies was assessed using the I(2) statistic, and 95% confidence intervals (95% CIs) were computed for the parameters studied. RESULTS Six studies including a total of 312 adult patients with DM were selected. The pooled sensitivity of anti-p155 for diagnosing cancer-associated DM was 78% (95% CI 45-94%), and specificity was 89% (95% CI 82-93%). The diagnostic OR was 27.26 (95% CI 6.59-112.82), and LRs for positive and negative test results were 6.79 (95% CI 4.11-11.23) and 0.25 (95% CI 0.08-0.76), respectively. Heterogeneity was substantial except with regard to the LR for a positive test result. The area under the SROC curve was 0.91 (95% CI 0.88-0.93). Taking the pooled prevalence of 17% as pretest probability, anti-p155 had a positive predictive value of 58% and a negative predictive value of 95%. CONCLUSION Our findings indicate that anti-p155 autoantibody determination is useful for diagnosing cancer-associated myositis and guiding disease management.

Libman-Sacks endocarditis in the antiphospholipid syndrome: immunopathologic findings in deformed heart valves:

Objective. To examine the potential immunologic mechanism and involvement of antiphos pholipid antibodies in the pathogenesis of heart valve lesions in patients with the antiphos pholipid syndrome (APS). Methods. Immunoperoxidase and immunofluorescence staining methods were used to evaluate 13 heart valve specimens derived from eight patients with the APS, either primary or secondary to systemic lupus erythematosus. Primary antibodies to human immuno globulins, complement components, serum albumin and a monoclonal anti-idiotypic anti body to human anticardiolipin antibodies (aCL) were employed. Various tissue specimens from a patient with the APS as well as deformed and normal valves from subjects without the APS were used as controls. Results. Linear subendothelial deposition consisting of immunoglobulins with complement components but not of a non-specific serum protein was found in deformed valves from patients with the APS. None of the control valves or tissues disclosed similar deposition. The same pattern and location of staining was obtained by the anti-idiotypic antibody to aCL. A significant amount of IgG immunoglobulins that bound to cardiolipin was eluted from a valve of a patient with secondary APS. Conclusion. Deposits of immunoglobulins including aCL, and of complement components, are common in affected valves of patients with primary and secondary APS. Such deposits may be involved in the pathogenesis of valvular lesions.

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 ELISAandconfirmedbyproteinandRNA 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.

DNA methylation and systemic lupus erythematosus.

Abstract:  Several studies have indicated the importance of DNA hypomethylation in the etiology of systemic lupus erythematosus (SLE). Different enzymes linked to the DNA methylation process have been described. The identification of all these enzymes means that cells have the capacity to modify their methylation patterns. Therefore, to obtain a deeper understanding of the role this epigenetic mechanism may have on SLE, the enzymes involved in the DNA methylation mechanism must be thoughtfully analyzed. In fact, studies of enzymes (other than DNMT1) in this autoimmune disease are still lacking. We have recently investigated the simultaneous gene expression of DNMT1, DNMT3A, DNMT3B, MBD2, and MBD4 in SLE patients. Here we review some of the studies that focus on the relationship between DNA methylation and SLE as well as we report our recent findings in this field. We suggest some alternative hypothesis that could help to understand the causes of the global DNA hypomethylation observed in the CD4+ T cells of these patients.

Molecular mechanisms mediated by human endogenous retroviruses (HERVs) in autoimmunity.

Eight per cent of the human genome is derived from the integration of retroviral sequences that were incorporated in our DNA more than 25 million years ago. Although some of these elements show mutations and deletions, some HERVs are transcriptionally active and produce functional proteins. Different mechanisms have been described which link HERVs to some chronic diseases such as several cancers, nervous system diseases and autoimmune rheumatic and connective tissue diseases. They could cause disease because of their capacity for being moved and inserted next to certain genes whose expression would be consequentially altered. Another way in which disease could potentially arise is when HERV‐encoded proteins are expressed. These proteins would be considered as [foreign] and they could trigger B‐cells to produce antibodies against them, which, in turn, might cross‐react with other proteins of our bodies. This mechanism could give rise to autoimmune diseases such as rheumatoid arthritis (RA), lupus erythematosus, Sjögrens syndrome (SJS), mixed connective tissue diseases and inflammatory neurological disease. Furthermore, it should be pointed out that HERV‐proteins may act as superantigens. Interestingly, some environmental agents seem to induce the expression of HERVs. Thus, ultraviolet light and several chemical agents could reactivate such sequences by altering their structure without modifying their nucleotide composition when the methylation pattern is changed. Therefore, the epigenetic changes observed in pathological conditions such as systemic lupus erythematosus (SLE) or cancer could be translated into an effect on the activation of some of the retroelements present in our genome which ultimately could have a direct or indirect role on the initiation and clinical evolution of certain chronic diseases. Copyright

Metalloproteinase-2 and -9 in Giant Cell Arteritis Involvement in Vascular Remodeling

Background—Both matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9) have been postulated to play roles in the pathophysiology of giant cell arteritis (GCA) because of their ability to degrade elastin. Understanding the specific mediators of arterial damage in GCA could lead to new therapeutic targets in this disease. Methods and Results—Temporal artery biopsy specimens were obtained from 147 consecutive patients suspected of GCA. Clinical and histopathological data were collected according to protocol. Using immunohistochemistry, we compared the expression of MMP-2 and MMP-9 in the temporal artery biopsies of both GCA cases (n=50) and controls (n=97). MMP-9 was found more frequently in positive than in negative temporal artery biopsies (adjusted odds ratio [OR], 3.20; P=0.01). In contrast, the frequency of MMP-2 was not significantly different between positive and negative biopsies (adjusted OR, 2.18; P=0.22). Both MMP-2 and MMP-9 were found in macrophages and giant cells near the internal elastic lamina and in smooth muscle cells and myofibroblasts of the media and intima. MMP-9 was also found in the vasa vasorum. MMP-9 but not MMP-2 was associated with internal elastic lamina degeneration, intimal hyperplasia, and luminal narrowing, even after adjustment for possible confounding variables. Conclusions—MMP-9 appears more likely than MMP-2 to be involved in the pathophysiology of GCA. MMP-9 not only participates in the degradation of elastic tissue but also is associated with intimal hyperplasia, subsequent luminal narrowing, and neoangiogenesis. The expression of MMP by smooth muscle cells implicates these cells as potential secretory cells in GCA.

DNase 1 and systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown aetiology with a complex genetic basis that includes many susceptibility genes on multiple chromosomes. As many complex human diseases, SLE involves multiple, interacting genetic and environmental determinants, and identifying genes and enzymes for complex traits is challenging and has had limited success so far. DNase1 has been implicated in the pathophysiology of SLE since the 1950s. The importance of DNase1 has grown up since the description that apoptotic cells can be the source of self-antigens in SLE. Many articles have focused in disturbed apoptosis and in the defects of the apoptotic cell debris as the origin of nucleosomes against which the immune response can be induced. The enzyme DNase1 plays a role in the clearance of apoptotic debris, and is therefore of capital interest in this process. In this review we highlight the current findings in the pathophysiology, genetics, and therapeutical role of DNase1 in SLE.

Transcript overexpression of the MBD2 and MBD4 genes in CD4+ T cells from systemic lupus erythematosus patients

Global DNA hypomethylation in CD4+ T cells has been detected in systemic lupus erythematosus (SLE), and it seems to be linked to its pathogenesis. We investigated the relationship between overall DNA methylation and the expression of two methyl CpG‐binding domain (MBD) proteins. DNA deoxymethylcytosine (dmC) content of purified CD4+ T cells from 29 SLE patients and 30 healthy controls was measured by means of an ELISA. Transcript levels of two methyl CpG‐binding proteins (MBD2 and MBD4) were quantified by real‐time RT‐PCR. Association studies were also carried out with several laboratory parameters, as well as with the patients’ clinical manifestations. SLE patients had significantly less CD4+ T cell DNA dmC content than controls (0.802±0.134 vs. 0.901±0.133; P=0.007). MBD2 and MBD4 mRNA levels were considerably higher in the patients’ group: 0.975 ± 0683 versus 0.604 ± 0.614 (P=0.004) and 0.359 ± 0.330 versus 0.092 ± 0.169, respectively (P<0.0005). It is interesting that SLE patients showed a negative correlation between methylation indices and MBD2 (r=–0.609, P<0.0005) and MBD4 (r=–0.395, P=0.034) transcript levels. MBD2 and MBD4 transcript overexpression and inverse correlations with DNA methylation indices indicate that both enzymes may really have a direct and active role on the genome‐wide DNA hypomethylation observed in CD4+ T cells from SLE patients.

Predictors of poor renal outcome in patients with lupus nephritis treated with combined pulses of cyclophosphamide and methylprednisolone

Lupus nephritis remains a major cause of morbidity and mortality in patients with systemic lupus erythematosus. Although the renal prognosis has improved, the optimal therapeutic regime has not been definitively established, and significant challenges remain in the management of disease progression and recurrent renal relapse. We performed a prospective study to evaluate the outcome of 38 patients with severe lupus nephritis treated with standard cyclophosphamide and methylprednisolone pulse therapy, and to determine the variables associated with poor outcome. Five patients developed end-stage renal disease (ESRD) (13%), 10 (26%) developed persistent proteinuria (>1 g=24 h) and 15 (39%) suffered at least one relapse after 8 years of follow-up. A high chronicity index, interstitial fibrosis (P = 0.04), persistent hypertension (P < 0.0001) and hypocomplementaemia(P = 0.002) after treatment were the major variables associated with ESRD. Tubular atrophy (P = 0.01), persistent hypertension (P = 0.0001) and hypocomplementaemia after treatment (P = 0.0281) were associated with persistent proteinuria. Persistence of anti-dsDNA antibodies and hypocomplementaemia after treatment (P = 0.0118) were associated with renal relapse. Our data suggest that the group of patients with persistence of hypocomplementaemiaand raised anti-dsDNA antibodies titres are at high risk of renal relapse and may be candidatesfor continuation of immunosuppressive treatment. Patients with persistent proteinuria alone or a high chronicity index are less likely to respond to immunosuppression, and strict control of the hypertension may be the best approach.

Transcript levels of DNA methyltransferases DNMT1, DNMT3A and DNMT3B in CD4+ T cells from patients with systemic lupus erythematosus.

Global DNA hypomethylation in CD4+ T cells has been detected in systemic lupus erythematosus (SLE) and it seems to be linked to its pathogenesis. We investigated the relationship between overall DNA methylation and the expression of three DNA (cytosine‐5) methyltransferases involved in the DNA methylation process. The DNA deoxymethylcytosine (dmC) content of purified CD4+ T cells from 29 SLE patients and 30 healthy controls was measured by means of an enzyme‐linked immunosorbent assay (ELISA). The transcript levels of DNA cytosine‐5‐methyltransferase 1 (DNMT1), DNA cytosine‐5‐methyltransferase 3A (DNMT3A) and DNA cytosine‐5‐methyltransferase 3B (DNMT3B) were quantified by real‐time reverse transcription–polymerase chain reaction (RT‐PCR). Association studies were also carried out with several laboratory parameters, as well as with the patients’ clinical manifestations. SLE patients had a significantly lower CD4+ T‐cell DNA dmC content than controls (0·802 ± 0·134 versus 0·901 ± 0·133) (P = 0·007). No differences in transcript levels were observed for DNMT1, DNMT3A and DNMT3B between patients and controls. The simultaneous association of low complement counts with lymphopenia, high titres of anti‐double‐stranded DNA (anti‐dsDNA), or an SLE disease activity index (SLEDAI) of > 5, resulted in the increase of at least one of the three DNA methyltransferases. It is possible that patients were reacting indirectly to an underlying DNA hypomethylation status by increasing the mRNA levels of DNA methyltransferases when the disease was being definitely active.