Anti-Tumor Necrosis Factor Alpha-Induced Drug Eruptions: One Patient, More Than a Pattern

Background: Tumor necrosis factor alpha (TNFα) antagonists are effective in treating several immune-inflammatory diseases, including psoriasis and inflammatory bowel disease. The paradoxical and unpredictable induction of psoriasis and psoriasiform skin lesions is a recognized adverse event, although of unclear aetiology. However, histological analysis of these eruptions remains insufficient, yet suggesting that some might constitute a new pattern of adverse drug reaction, rather than true psoriasis. Case report: The authors report the case of a 43-year-old woman with severe recalcitrant Crohn disease who started treatment with infliximab. There was also a personal history of mild plaque psoriasis without clinical expression for the past eight years. She developed a heterogeneous cutaneous eruption of psoriasiform morphology with pustules and crusts after the third infliximab infusion. The histopathological diagnosis was of a Sweet-like dermatosis. The patient was successfully treated with cyclosporine in association with both topical corticosteroid and vitamin D3 analogue. Three weeks after switching to adalimumab a new psoriasiform eruption was observed, histologically compatible with a psoriasiform drug eruption. Despite this, and considering the beneficial effect on the inflammatory bowel disease, it was decided to maintain treatment with adalimumab and to treat through with topicals, with progressive control of skin disease. Discussion: Not much is known about the pathogenesis of psoriasiform eruptions induced by biological therapies, but genetic predisposition and Koebner phenomenon may contribute to it. Histopathology can add new facets to the comprehension of psoriasiform reactions. In fact, histopathologic patterns of such skin lesions appear to be varied, in a clear asymmetry with clinical findings. Conclusion: The sequential identification in the same patient of two clinical and histopathologic patterns of drug reaction to TNFα antagonists is rare. Additionally, to the authors’ knowledge, there is only one other description in literature of a TNFα antagonist-induced Sweet-like dermatosis, emphasizing the singularity of this case report.

Propriedades Psicométricas da Versão Portuguesa do Kansas City Cardiomyopathy Questionnaire na Miocardiopatia Dilatada com Insuficiência Cardíaca Congestiva

Several studies have shown that patients with congestive heart failure (CHF) have a compromised health-related quality of life (HRQL), and this, in recent years, has become a primary endpoint when considering the impact of treatment of chronic conditions such as CHF. OBJECTIVES: To evaluate the psychometric properties of the Portuguese version of a new specific instrument to measure HRQL in patients hospitalized for CHF: the Kansas City Cardiomyopathy Questionnaire (KCCQ). METHODS: The KCCQ was applied to a sample of 193 consecutive patients hospitalized for CHF. Of these, 105 repeated the assessment 3 months after admission, with no events during this period. Mean age was 64.4 +/- 12.4 years (21-88), and 72.5% were 72.5% male. CHF was of ischemic etiology in 4% of cases. RESULTS: This version of the KCCQ was subjected to statistical validation, with assessment of reliability and validity, similar to the American version. Reliability was assessed by the internal consistency of the domains and summary scores, which showed similar values of Cronbach alpha (0.50-0.94). Validity was assessed by convergence, sensitivity to differences between groups and sensitivity to changes in clinical condition. We evaluated the convergent validity of all domains related to functionality, through the relationship between them and a measure of functionality, the New York Heart Association (NYHA) classification. Significant correlations were found (p < 0.01) for this measure of functionality i patients with CHF. Analysis of variance between the physical limitation domain, the summary scores and NYHA class was performed and statistically significant differences were found (F = 23.4; F = 36.4; F = 37.4, p = 0.0001) in the ability to discriminate severity of clinical condition. A second evaluation was performed on 105 patients at the 3-month follow-up outpatient appointment, and significant changes were observed in the mean scores of the domains assessed between hospital admission and the clinic appointment (differences from 14.9 to 30.6 on a scale of 0-100), indicating that the domains assessed are sensitive to changes in clinical condition. The correlation between dimensions of quality of life in the KCCQ is moderate, suggesting that the dimensions are independent, supporting the multifactorial nature of HRQL and the suitability of this measure for its evaluation. CONCLUSION: The KCCQ is a valid instrument, sensitive to change and a specific measure of HRQL in a population with dilated cardiomyopathy and CHF.

Evaluation of Bone Remodeling in Hemodialysis Patients: Serum Biochemistry, Circulating Cytokines and Bone Histomorphometry

BACKGROUND: To optimize the noninvasive evaluation of bone remodeling, we evaluated, besides routine serum markers, serum levels of several cytokines involved in bone turnover. METHODS: A transiliac bone biopsy was performed in 47 hemodialysis patients. Serum levels of intact parathyroid hormone (iPTH; 1-84), total alkaline phosphatases (tAP), calcium, phosphate and aluminum (Al) were measured. Circulating levels of interleukin-6 (IL-6), IL-1 receptor antagonist (IL-1Ra) and soluble IL-6 receptor (sIL-6r) were determined using ELISA. Circulating IL-1beta, IL-6, IL-8, IL-10, IL-12p70 and tumor necrosis factor-alpha (TNF-alpha) were simultaneously quantified by flow cytometric immunoassay. RESULTS: Patients with low/normal bone formation rate (L/N-BFR) had significantly lower serum iPTH (p<0.001) and tAP (p<0.008) and significantly higher Al (p<0.025) than patients with high BFR. Serum calcium and phosphorus, however, did not differ (p=NS). An iPTH >300 pg/mL in association with tAP >120 U/L showed low sensitivity (58.8%) and low negative predictive value (44.0%) for the diagnosis of high BFR disease. An iPTH <300 pg/mL in association with normal or low tAP, <120 U/L, was associated with low sensitivity (66.7%) but high specificity (97.1%) for the diagnosis of L/N-BFR. Serum IL-1, IL-6, IL-12p70 and TNF-alpha were positively correlated with BFR, serum IL1-Ra and IL-10 with bone area, and by multiple regression analysis, tAP and IL-6 were independently predictive of BFR. CONCLUSIONS: Significant associations were found between several circulating cytokines and bone histomorphometry in dialysis patients. The usefulness of these determinations in the noninvasive evaluation of bone remodeling needs to be confirmed in larger dialysis populations.

Rastreio Neonatal de Hemoglobinopatias numa População Residente em Portugal

The primary objective of newborn screening of hemoglobinopathies is the early identification of infants with sickle cell disease, as they are at increased clinical risk. Other goals include the identification of other types of clinically significant hemoglobinopathies and the detection of heterozygous carriers followed by the screening and counselling of family members. We performed a pilot study for the neonatal screening of hemoglobinopathies in 400 samples of cord blood taken from a maternity in Lisbon. We did not find any newborn with sickle cell disease. Six samples were from sickle cell heterozygotes, the respective families were studied and informed. We looked for the presence of alpha-thalassemia at birth in 100 consecutive samples of cord blood, by the presence of Hb Bart's, abnormal red blood cell indices and alpha-globin genotype. The results show an incidence of 10% of alpha-thalassemia (-alpha) carriers and 4% of triple alpha-globin gene carriers. The authors discuss the feasibility of neonatal screening of hemoglobinopathies in a Portuguese-speaking population consisting of a low prevalence of Hb S trait autoclonous group and a high prevalence immigrant minority

Impact of Donor and Recipient Cytokine Genotypes on Renal Allograft Outcome

Allelic differences in gene promoter or codifying regions have been described to affect regulation of gene expression, consequently increasing or decreasing cytokine production and signal transduction responses to a given stimulus. This observation has been reported for interleukin (IL)-10 (-1082 A/G; -819/-592 CT/CA), transforming growth factor (TGF)-beta (codon 10 C/T, codon 25 G/C), tumor necrosis factor (TNF)-alpha (-308 G/A), TNF-beta (+252 A/G), interferon (IFN)-gamma (+874 T/A), IL-6 (-174 G/C), and IL-4R alpha (+1902 G/A). To evaluate the influence of these cytokine genotypes on the development of acute or chronic rejection, we correlated the genotypes of both kidney graft recipients and cadaver donors with the clinical outcome. Kidney recipients had 5 years follow-up, at least 2 HLA-DRB compatibilities, and a maximum of 25% anti-HLA pretransplantation sensitization. The clinical outcomes were grouped as follows: stable functioning graft (NR, n = 35); acute rejection episodes (AR, n = 31); and chronic rejection (CR, n = 31). The cytokine genotype polymorphisms were defined using PCR-SSP typing. A statistical analysis showed a significant prevalence of recipient IL-10 -819/-592 genotype among CR individuals; whereas among donors, the TGF-beta codon 10 CT genotype was significantly associated with the AR cohort and the IL-6 -174 CC genotype with CR. Other albeit not significant observations included a strong predisposition of recipient TGF-beta codon 10 CT genotype with CR, and TNF-beta 252 AA with AR. A low frequency of TNF-alpha -308 AA genotype also was observed among recipients and donors who showed poor allograft outcomes.

Clinical and Pathological Findings in Women with Fabry Disease

Introduction. Fabry disease is a rare metabolic disorder caused by the genetic deficiency of the lysosomal hydrolase alpha-galactosidase A, located on chromosome X. Females with the defective gene are more than carriers and can develop a wide range of symptoms. Nevertheless, disease symptoms generally occur later and are less severe in women than in men. The enzyme deficiency manifests as a glycosphingolipidosis with progressive accumulation of glycosphingolipids and deposit of inclusion bodies in lysosomes giving a myelinlike appearance. Patients and Methods. Records of renal biopsies performed on adults from 1st January 2008 to 31st August 2011, were retrospectively examined at the Renal Pathology Laboratory. We retrieved biopsies diagnosed with Fabry disease and reviewed clinical and laboratory data and pathology findings. Results. Four female patients with a mean age of 49.3±4.5 (44-55) years were identified. The mean proteinuria was 0.75±0.3 g/24h (0.4-1.2) and estimated glomerular filtration rate (CKD EPI equation) was 71±15.7 ml/min/1.73m2 (48-83). Three patients experienced extra-renal organ involvement (cerebrovascular, cardiac, dermatologic, ophthalmologic and thyroid) with distinct severity degrees. Leukocyte α-GAL A activity was below normal range in the four cases but plasma and urinary enzymatic activity was normal. Light microscopy showed predominant vacuolisation of the podocyte cytoplasm and darkly staining granular inclusions on paraffin and plastic-embedded semi-thin sections. Electron microscopy showed in three patients the characteristic myelin-like inclusions in the podocyte cytoplasm and also focal podocyte foot process effacement. In one case the inclusions were also present in parietal glomerular cells, endothelial cells of peritubular capillary and arterioles. Conclusion. Clinical signs and symptoms are varied and can be severe among heterozygous females with Fabry disease. Intracellular accumulation of glycosphingolipids is a characteristic histologic finding of Fabry nephropathy. Since this disease is a potentially treatable condition, its early identification is imperative. We should consider it in the differential diagnosis of any patient presenting with proteinuria and/or chronic kidney disease, especially if there is a family history of kidney disease.

Tumores Cardíacos. Experiência de 17 Anos num Serviço de Cardiologia Pediátrica

Introdução: Os tumores cardíacos primários podem ser benignos ou malignos, ter origem no endocárdio, miocárdio ou pericárdio. São raros em crianças, com uma prevalência descrita em séries de autópsia de 0,0017 a 0,28%; a maioria são benignos, representando os malignos cerca de 10% do total. Material e Métodos: Com o objectivo de avaliar a apresentação clínica e a evolução das crianças assistidas num centro de Cardiologia Pediátrica com este diagnóstico, procedeu-se à revisão retrospectiva dos processos clínicos dos doentes com tumores cardíacos primários observados nos últimos 17 anos (1989-2006). Determinou-se a forma de apresentação, diagnóstico morfológico, complicações e evolução ao longo do período de seguimento. Resultados: Identificaram-se 12 doentes, cuja idade média à data do diagnóstico foi de 23 meses. Em dois casos o diagnóstico foi pré-natal. A causa mais frequente de referenciação foi a esclerose tuberosa, seguida de sopro cardíaco. O ecocardiograma e a ressonância magnética permitiram o diagnóstico em todos. Todos os doentes realizaram electrocardiograma e registo Holter e o achado mais frequente foram as alterações inespecíficas da repolarização. O tumor mais frequente foi o rabdomioma (67%), na maioria associado a esclerose tuberosa; seguido do fibroma em (17%) e do fibroelastoma (8%). Apesar da biópsia ser o exame de eleição para a confirmação diagnóstica, realizou-se apenas em dois doentes. A excisão cirúrgica do tumor foi efectuada num doente (fibroelastoma), por risco de embolia pulmonar. Discussão e Conclusões: Na população estudada o tumor cardíaco mais frequente foi o rabdomioma associado à esclerose tuberosa. A maioria dos doentes não apresentava sintomas cardiovasculares, sendo o seu diagnóstico geralmente efectuado em observações de rotina para esclarecimento de sopro cardíaco ou devido ao diagnóstico de esclerose tuberosa. O exame histológico justifica-se apenas nos tumores mais raros.

Phototherapy in Childhood: a 17-Year Retrospective Study Regarding Effectiveness and Safety

Introduction: Skin diseases in paediatric age are often distressing conditions with significant impact in children’s psychosocial development. Additionally, systemic therapeutic options are often limited in childhood, due to its potential toxicity in this vulnerable group. Phototherapy is therefore an endorsed option for photo-responsive dermatological conditions. Objective and Methods:This observational retrospective study aims to access efficacy and safety of Phototherapy in our paediatric population. Relevant clinical data from 1996 to present concerning patients aged 18 years or less was collected. Results: 78 patients were included, of which64,1%was female. Mean age was 12,9 years (range 2-18). Distribution according to diagnosis was:47,4%psoriasis, 34,6% alopecia areata, 9,0% vitiligo, 9,0% other diagnosis. Mean number of cycles was 1,5 (range 1-7), with an average of 16,3 treatments per cycle and mean cumulative dose 134 J/cm2. 70,5% was treated with one single cycle. Topic and systemic PUVA were the first choice in 37,2% and 39,7%, respectively, while UVB TL01 and broadband UVB were used in 11,5% each. On the first cycle 67,5% improved, 14,3% showed no sustained clinical response and 19,5% were lost to follow-up. Psoriasis patients had the best response rates (81,8%), followed by alopecia areata (59,3%). Side effects occurred in 21%, being erythema the most common (12%). None led to therapeutic interruption. Discussion: Phototherapy is a safe and effective option in childhood, yet the withdraw rate might be an important limitation.

The HIF1A Functional Genetic Polymorphism at Locus +1772 Associates with Progression to Metastatic Prostate Cancer and Refractoriness to Hormonal Castration

The hypoxia inducible factor 1 alpha (HIF1a) is a key regulator of tumour cell response to hypoxia, orchestrating mechanisms known to be involved in cancer aggressiveness and metastatic behaviour. In this study we sought to evaluate the association of a functional genetic polymorphism in HIF1A with overall and metastatic prostate cancer (PCa) risk and with response to androgen deprivation therapy (ADT). The HIF1A +1772 C>T (rs11549465) polymorphism was genotyped, using DNA isolated from peripheral blood, in 1490 male subjects (754 with prostate cancer and 736 controls cancer-free) through Real-Time PCR. A nested group of cancer patients who were eligible for androgen deprivation therapy was followed up. Univariate and multivariate models were used to analyse the response to hormonal treatment and the risk for developing distant metastasis. Age-adjusted odds ratios were calculated to evaluate prostate cancer risk. Our results showed that patients under ADT carrying the HIF1A +1772 T-allele have increased risk for developing distant metastasis (OR, 2.0; 95%CI, 1.1-3.9) and an independent 6-fold increased risk for resistance to ADT after multivariate analysis (OR, 6.0; 95%CI, 2.2-16.8). This polymorphism was not associated with increased risk for being diagnosed with prostate cancer (OR, 0.9; 95%CI, 0.7-1.2). The HIF1A +1772 genetic polymorphism predicts a more aggressive prostate cancer behaviour, supporting the involvement of HIF1a in prostate cancer biological progression and ADT resistance. Molecular profiles using hypoxia markers may help predict clinically relevant prostate cancer and response to ADT.

A Novel Autosomal Recessive GJA1 Missense Mutation Linked to Craniometaphyseal Dysplasia

Craniometaphyseal dysplasia (CMD) is a rare sclerosing skeletal disorder with progressive hyperostosis of craniofacial bones. CMD can be inherited in an autosomal dominant (AD) trait or occur after de novo mutations in the pyrophosphate transporter ANKH. Although the autosomal recessive (AR)form of CMD had been mapped to 6q21-22 the mutation has been elusive. In this study, we performed whole-exome sequencing for one subject with AR CMD and identified a novel missense mutation (c.716G>A, p.Arg239Gln) in the C-terminus of the gap junction protein alpha-1 (GJA1) coding for connexin 43 (Cx43). We confirmed this mutation in 6 individuals from 3 additional families. The homozygous mutation cosegregated only with affected family members. Connexin 43 is a major component of gap junctions in osteoblasts, osteocytes, osteoclasts and chondrocytes. Gap junctions are responsible for the diffusion of low molecular weight molecules between cells. Mutations in Cx43 cause several dominant and recessive disorders involving developmental abnormalities of bone such as dominant and recessive oculodentodigital dysplasia (ODDD; MIM #164200, 257850) and isolated syndactyly type III (MIM #186100), the characteristic digital anomaly in ODDD. However, characteristic ocular and dental features of ODDD as well as syndactyly are absent in patients with the recessive Arg239Gln Cx43 mutation. Bone remodeling mechanisms disrupted by this novel Cx43 mutation remain to be elucidated.

Exacerbation of Recalcitrant Cutaneous Sarcoidosis with Adalimumab - a Paradoxical Effect? A Case Report

The paradoxical adverse effects of tumor necrosis factor-alpha (TNF-alpha) antagonists have been described frequently as a result of the widespread use of these drugs. Among the TNF-alpha blocking agents, few reports exist relating the use of adalimumab in cutaneous sarcoidosis, although all of them show good results. More recently, sarcoidosis onsets have been reported with various TNF-alpha inhibitors. The current case is, to our knowledge, the first to describe the exacerbation of cutaneous lesions of sarcoidosis treated with adalimumab.

The HIF1A Functional Genetic Polymorphism at Locus +1772 Associates with Progression to Metastatic Prostate Cancer and Refractoriness to Hormonal Castration

The hypoxia inducible factor 1 alpha (HIF1a) is a key regulator of tumour cell response to hypoxia, orchestrating mechanisms known to be involved in cancer aggressiveness and metastatic behaviour. In this study we sought to evaluate the association of a functional genetic polymorphism in HIF1A with overall and metastatic prostate cancer (PCa) risk and with response to androgen deprivation therapy (ADT). The HIF1A +1772 C>T (rs11549465) polymorphism was genotyped, using DNA isolated from peripheral blood, in 1490 male subjects (754 with prostate cancer and 736 controls cancer-free) through Real-Time PCR. A nested group of cancer patients who were eligible for androgen deprivation therapy was followed up. Univariate and multivariate models were used to analyse the response to hormonal treatment and the risk for developing distant metastasis. Age-adjusted odds ratios were calculated to evaluate prostate cancer risk. Our results showed that patients under ADT carrying the HIF1A +1772 T-allele have increased risk for developing distant metastasis (OR, 2.0; 95%CI, 1.1-3.9) and an independent 6-fold increased risk for resistance to ADT after multivariate analysis (OR, 6.0; 95%CI, 2.2-16.8). This polymorphism was not associated with increased risk for being diagnosed with prostate cancer (OR, 0.9; 95%CI, 0.7-1.2). The HIF1A +1772 genetic polymorphism predicts a more aggressive prostate cancer behaviour, supporting the involvement of HIF1a in prostate cancer biological progression and ADT resistance. Molecular profiles using hypoxia markers may help predict clinically relevant prostate cancer and response to ADT.

Transthyretin Amyloidosis: Chaperone Concentration Changes and Increased Proteolysis in the Pathway to Disease

Transthyretin amyloidosis is a conformational pathology characterized by the extracellular formation of amyloid deposits and the progressive impairment of the peripheral nervous system. Point mutations in this tetrameric plasma protein decrease its stability and are linked to disease onset and progression. Since non-mutated transthyretin also forms amyloid in systemic senile amyloidosis and some mutation bearers are asymptomatic throughout their lives, non-genetic factors must also be involved in transthyretin amyloidosis. We discovered, using a differential proteomics approach, that extracellular chaperones such as fibrinogen, clusterin, haptoglobin, alpha-1-anti-trypsin and 2-macroglobulin are overrepresented in transthyretin amyloidosis. Our data shows that a complex network of extracellular chaperones are over represented in human plasma and we speculate that they act synergistically to cope with amyloid prone proteins. Proteostasis may thus be as important as point mutations in transthyretin amyloidosis.

Clinical and Genetic Characterization of Portuguese Patients with Pseudohypoparathyroidism Type Ib

Patients with pseudohypoparathyroidism type Ib (PHP-Ib) present hypocalcemia and hyperphosphatemia, as a consequence of a resistance to PTH action, through its G-protein-coupled receptor, in the renal tubules. This resistance results from tissue-specific silencing of the G-protein alpha-subunit (G(s)α), due to imprinting disruption of its encoding locus--GNAS. In familial PHP-Ib, maternally inherited deletions at the STX16 gene are associated to a regional GNAS methylation defect. In sporadic PHP-Ib, broad methylation changes at GNAS arise from unknown genetic causes. In this study, we describe the clinical presentation of PHP-Ib in four Portuguese patients (two of whom were siblings), and provide further insight for the management of patients with this disease. The diagnosis of PHP-Ib was made after detection of GNAS imprinting defects in each of the cases. In the siblings, a regional GNAS methylation change resulted from a known 3.0 kb STX16 deletion. In the other two patients, the broad methylation defects at GNAS, which were absent in their relatives, resulted from genetic alterations that remain to be identified. We report the first clinical and genetic study of Portuguese patients with PHP-Ib. The genetic identification of a hereditary form of this rare disease allowed an early diagnosis, and may prevent hypocalcemia-related complications.

Undetectable Levels of CSF Amyloid-β Peptide in a Patient with 17β-Hydroxysteroid Dehydrogenase Deficiency

17β-hydroxysteroid dehydrogenase 10 (HSD10) deficiency is a rare X-linked inborn error of isoleucine catabolism. Although this protein has been genetically implicated in Alzheimer's disease pathogenesis, studies of amyloid-β peptide (Aβ) in patients with HSD10 deficiency have not been previously reported. We found, in a severely affected child with HSD10 deficiency, undetectable levels of Aβ in the cerebrospinal fluid, together with low expression of brain-derived neurotrophic factor, α-synuclein, and serotonin metabolites. Confirmation of these findings in other patients would help elucidating mechanisms of synaptic dysfunction in this disease, and highlight the role of Aβ in both early and late periods of life.