António Marinho

The Protective Role of HLA-DRB1∗13 in Autoimmune Diseases

Autoimmune diseases (AIDs) are characterized by a multifactorial aetiology and a complex genetic background, with the MHC region playing a major role. We genotyped for HLA-DRB1 locus 1228 patients with AIDs-213 with Systemic Lupus Erythematosus (SLE), 166 with Psoriasis or Psoriatic Arthritis (Ps + PsA), 153 with Rheumatoid Arthritis (RA), 67 with Systemic Sclerosis (SSc), 536 with Multiple Sclerosis (MS), and 93 with Myasthenia Gravis (MG) and 282 unrelated controls. We confirmed previously established associations of HLA-DRB1∗15 (OR = 2.17) and HLA-DRB1∗03 (OR = 1.81) alleles with MS, HLA-DRB1∗03 with SLE (OR = 2.49), HLA-DRB1∗01 (OR = 1.79) and HLA-DRB1∗04 (OR = 2.81) with RA, HLA-DRB1∗07 with Ps + PsA (OR = 1.79), HLA-DRB1∗01 (OR = 2.28) and HLA-DRB1∗08 (OR = 3.01) with SSc, and HLA-DRB1∗03 with MG (OR = 2.98). We further observed a consistent negative association of HLA-DRB1∗13 allele with SLE, Ps + PsA, RA, and SSc (18.3%, 19.3%, 16.3%, and 11.9%, resp., versus 29.8% in controls). HLA-DRB1∗13 frequency in the AIDs group was 20.0% (OR = 0.58). Although different alleles were associated with particular AIDs, the same allele, HLA-DRB1∗13, was underrepresented in all of the six diseases analysed. This observation suggests that this allele may confer protection for AIDs, particularly for systemic and rheumatic disease. The protective effect of HLA-DRB1∗13 could be explained by a more proficient antigen presentation by these molecules, favouring efficient clonal deletion during thymic selection.

EXPRESSION OF SIALYL-TN IN BREAST CANCER : CORRELATION WITH PROGNOSTIC PARAMETERS

To investigate the expression of a simple mucin-type carbohydrate antigen (Sialyl-Tn/STn) and its putative relationship with established or potentially useful clinico-pathologic prognostic parameters in breast cancer, we studied forty-six cases of invasive breast carcinoma in formalin-fixed, paraffin-embedded tissue sections. STn antigen was detected by the HB-STn antibody using an avidin-biotin-peroxidase method. The parameters studied were tumour size, histologic grade, nodal status, proliferative index (with MIB-1), ER expression, ploidy, c-erbB-2 and p53 expression. STn expression was observed in 18 cases (39%) of breast cancer. The expression of STn was associated with axillary node metastasis, ER negativity and c-erbB-2 expression. A tendency towards an association between STn immunoreactivity and high histologic grade was also found. No correlation was observed between STn immunoreactivity and age, tumour size, proliferative index, ploidy and p53 expression. We conclude that the detection of STn immunoreactivity may be useful for predicting the likelihood of lymph node metastasis and that the outcome of patients with breast cancer should be further investigated in order to find whether or not the data of the present study are confirmed in larger series.

Association between vitamin D receptor (VDR) gene polymorphisms and systemic lupus erythematosus in Portuguese patients

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown origin, in which both genetic and environmental factors are involved. One such environmental factor is vitamin D, a vital hormone that plays a specific function in the immune system homeostasis, acting through a nuclear receptor (VDR) expressed in all immune cells. Several polymorphisms of the gene that encodes this receptor have been described. Though inconsistently, these polymorphisms have been associated with clinical manifestations and SLE development. The aim of this study was to determine the possible association between VDR gene polymorphisms (BsmI, ApaI, TaqI e FokI) and SLE susceptibility and severity, in a cohort of lupus patients from the north of Portugal. A total of 170 patients (F = 155, M = 15; age = 45 ± 13.4 years) with SLE (diagnosed according the American College of Rheumatology criteria) with at least five years of disease evolution and followed in the Autoimmune Disease Clinical Immunology Unit of Centro Hospitalar do Porto were studied. Patients and 192 ethnicity-matched controls were genotyped for BsmI (rs1544410), ApaI (rs7975232), TaqI (rs731236) and FokI (rs2228570) polymorphisms by TaqMan allelic discrimination assay. Disease severity was assessed by SLICC damage score, number of affected organs, number of severe flares and pharmacological history. SLE patients with the CT genotype of FokI polymorphism have a higher SLICC value (p = 0.031). The same result was observed for the group of patients with the TT genotype of TaqI polymorphism (p = 0.046). No differences were observed in VDR genotype between patients and controls. Also, we observed that the other clinical features analysed were not influenced by VDR polymorphisms. Our study confirms a possible role of VDR gene polymorphisms in SLE. A positive association was found between VDR polymorphisms and SLE severity (chronic damage). The presence of CT genotype of FokI and TT genotype of TaqI seems to confer a worse prognosis and may constitute a risk factor for higher long-term cumulative damage in SLE patients.

Posterior Chamber Silicone Phakic Intraocular Lens

BACKGROUND We investigated the efficacy, safety, and stability of correction achieved with a silicone posterior chamber intraocular lens used to correct high myopia in phakic eyes. PATIENTS AND METHODS A silicone posterior chamber plate-style intraocular lens (Chiron, Adatomed) was implanted in 38 consecutive phakic eyes with high myopia (-7.00 to -28.00 diopters (D) over a period of 21 months. Follow-up ranged from 3 to 24 months. RESULTS Three months after surgery, refractions in 27 eyes (71%) ranged from -1.00 to +1.00 D and remained stable thereafter. Spectacle-corrected visual acuity improved at least two lines in 24 eyes (63%), and none was lost in any eye. Patient satisfaction was high (92%). The few complications that occurred were mostly related to imperfections in the surgical technique rather than lack of biocompatibility of the lens. No cataract or other vision-threatening complication was present at the end of the study. CONCLUSION This silicone posterior chamber plate-style intraocular lens provides a reasonably predictable, safe, and stable means of correcting high myopia.

Systemic Lupus Erythematosus, Progressive Multifocal Leukoencephalopathy, and T-CD4+ Lymphopenia

Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection caused by the reactivation of JC virus and occurs in patients with severe primary or secondary immunosuppression. Recently, PML is becoming relevant in autoimmune disorders, particularly in patients treated with biologic agents. However, systemic lupus erythematosus (SLE) appears to be associated with susceptibility to PML that cannot be entirely explained by the immunosuppressive therapy. The authors present two patients with the diagnosis of SLE and PML: One had a heavy immunosuppressive therapy history, and the other had never experienced biologic or cytotoxic therapeutics. Both patients had a profound T-CD4+ lymphopenia during their clinical history. These two cases emphasize the importance of CD4+ lymphopenia in SLE patients with and without immunosuppressors regarding opportunistic infections.

Evaluation of numerical abnormalities of chromosomes 1 and 17 in proliferative epithelial breast lesions using fluorescence in situ hybridization.

Our aim was to investigate the putative role of chromosome abnormalities of chromosomes 1 and 17 in the process of breast carcinogenesis. Numerical abnormalities of chromosomes 1 and 17 were investigated using fluorescence in situ hybridisation (FISH) in a series of 16 primary invasive breast carcinomas associated with intraductal proliferative epithelial lesions. Chromosome 1 aneusomy was detected in 55.6% of ductal hyperplasia (DH), 81.8% of ductal carcinomas in situ (DCIS) and 87.5% of invasive ductal carcinomas (IDC). Chromosome 17 aneusomy was not detected in the cases of DH and was present in 90.9% of DCIS and in 87.5% of IDC. Simultaneous aneusomy of chromosome 1 and 17 was found in 81.8% of DCIS and in 75.0% of IDC. Our results showed that the number of chromosome 1 and 17 copies increases from normal epithelium to invasive cancer. The numerical abnormalities of chromosome 1 were already detected in DH, suggesting that a gain in the copy number of chromosome 1 may be involved early in breast carcinogenesis.

Alveolar hemorrhage in systemic lupus erythematosus: a cohort review

Diffuse alveolar hemorrhage (DAH) is a rare but potentially catastrophic manifestation with a high mortality. Among rheumatologic diseases, it occurs most frequently in patients with systemic lupus erythematosus (SLE) and systemic vasculitis. Despite new diagnostic tools and therapies, it remains a diagnostic and therapeutic challenge. The aim of this work was to characterize the SLE patients with an episode of alveolar hemorrhage followed in our Clinical Immunology Unit (CIU). A retrospective chart review was carried out for all patients with SLE followed in CIU between 1984 and the end of 2013. We reviewed the following data: demographic characteristics, clinical and laboratory data, radiologic investigations, histologic studies, treatment, and outcome. We identified 10 episodes of DAH, corresponding to seven patients, all female. These represent 1.6% of SLE patients followed in our Unit. The age at DAH attack was 42.75 ± 18.9 years. The average time between diagnosis of SLE and the onset of DAH was 7.1 years. Three patients had the diagnosis of SLE and the DAH attack at the same time. Disease activity according to SLEDAI was high, ranging from 15 to 41. All patients were treated with methylprednisolone, 37.5% cyclophosphamide and 28.6% plasmapheresis. The overall mortality rate was 28.6%.

Idiopathic inflammatory myopathies: definition and management of refractory disease.

Adult idiopathic inflammatory myopathies, commonly referred to as myositis, are a heterogeneous group of diseases with an autoimmune etiology. In this review, the authors are going to focus on myositis excluding inclusion body myositis. They will review the prognostic factors (for mortality and response to steroids), define refractory disease, introduce a new concept (presumed refractory disease), analyze definitions of active disease, damage and improvement criteria, and summarize therapeutic alternatives for refractory patients, based on different disease phenotypes.

HLA in Portuguese systemic lupus erythematosus patients and their relation to clinical features.

Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease translating the different genetic and environmental factors involved. Polymorphisms at several loci, including the major histocompatibility complex (MHC), have been associated worldwide with SLE, although inconsistencies exist among these studies mainly due to genetic heterogeneity between populations and sample characteristics. The aim of the present study was to investigate in Portuguese SLE the association of HLA‐DRB1 alleles with clinical patterns of the disease and severity. Two hundred eighteen Portuguese patients with SLE—42% of whom had kidney involvement—were studied for HLA‐DRB1. Clinical and laboratory manifestations were correlated with HLA allele frequencies. HLA‐DRB1 * 03 allele frequency was significantly higher in SLE patients—as a whole and as either with or without renal involvement—compared to controls, while HLA‐DRB1 * 09 and DRB1 * 13 allele frequencies were decreased. Regarding the relationship with the presence or absence of specific clinical manifestations, it was only found that HLA‐DRB1 * 08 allele frequency was increased in patients with neurological involvement. No association with the presence or absence of anti‐dsDNA, anti‐sm or antiphospholipid antibodies, or antiphospholipid syndrome, was observed. These results were reproducible when analysis was repeated only with patients with more than 5 years of evolution. As in other populations HLA‐DRB1 * 03 is a susceptibility allele in Portuguese SLE patients, while HLA‐DRB1 * 09 and DRB1 * 13 alleles may be protective alleles, not only for the disease, but for the development of nephritis. No correlations with the different clinical manifestations were found, except with the neurological system.

Are Cognitive and Olfactory Dysfunctions in Neuropsychiatric Lupus Erythematosus Dependent on Anxiety or Depression

Objective. Depressed mood and cognitive impairments are common findings in systemic lupus erythematosus (SLE) and frequently coexist. We assessed the neuropsychological functioning of patients with SLE and investigated its association with psychopathological symptoms. Methods. A total of 85 patients with SLE (28 with neuropsychiatric syndromes: NPSLE) and 85 healthy control subjects with similar demographic characteristics were asked to perform a series of neuropsychological tests. A self-report questionnaire (the Hospital Anxiety and Depression Scale) was used to screen for psychopathology symptoms. Patients with SLE underwent a neurological examination. Results. Patients with NPSLE were more depressed and were more frequently impaired in cognitive and olfactory functions than controls or non-NPSLE patients. The NPSLE group remained statistically different from the other 2 groups on a series of neuropsychological measures (the Auditory Verbal Learning Test, Trail Making Test – Part A, Nine-Hole Peg Test, and Brief Smell Identification Test) even after control for elevated anxiety and depressed mood. Non-NPSLE and control groups were not significantly different regarding either psychopathological symptoms or neuropsychological functioning. Conclusion. Verbal memory, psychomotor speed, and olfaction are particularly vulnerable to dysfunction in NPSLE; impairment in these neuropsychological domains is not completely explained by psychopathology symptoms.