IgA nephropathy in adults with epidermolysis bullosa.

Epidermolysis bullosa (EB) is a devastating genetic condition caused by mutations in genes that give rise to aberrant proteins. There are 16 different such proteins implicated in EB that are important in maintaining the integrity of the dermoepidermal junction. It is classified into four major subtypes: (i) EB simplex; (ii) junctional EB (JEB); (iii) dystrophic EB (DEB); and (iv) Kindler EB. Renal disease is a recognized complication of EB and the aetiology is complex. We describe our experience of managing five patients with EB and IgA nephropathy. We recommend that patients with recessive DEB and JEB routinely have the following monitored: renal function, urinary albumin/creatinine ratio, urine analysis, serum albumin levels and immunoglobulins; specifically serum IgA. Management of IgA nephropathy in the context of EB should be tailored to the individual and be carried out within a specialist multidisciplinary team. Our case series provides important insights into the treatment of IgA nephropathy in patients with EB and will help inform treatment in this rare genetic disease. Case series and reports like ours are key in gaining real-life data to quantify the actual risk of morbidity and mortality from each of the treatment modalities discussed.

Altered balance of epidermis-related chemokines in epidermolysis bullosa.

BACKGROUND: Epidermolysis bullosa (EB) is a congenital, refractory skin disease and there are no fundamental treatments. Recently, allogenic cell therapies are beginning to be applied as potential treatments, that are based on the concept that the allogenic cells can migrate into the skin and reconstitute the skin components. Although the mechanisms of cell migration into skin are not fully understood, chemokines are regarded as key factors in recruiting bone marrow-derived cells. OBJECTIVES: Our study aims to elucidate the expression of chemokines in the EB patients. METHODS: We determined the expression of wound-healing related chemokines in the sera, keratinocytes, and skin tissues of EB patients and compared them to those of healthy volunteers by enzyme-linked immunosorbent assays, quantitative reverse transcription PCR, and immunofluorescence staining. RESULTS: The serum levels of CXCL12 and HMGB1 were found to be significantly elevated in the EB patients. Conversely, the serum levels of CCL21 were found to be lower in the EB patients than in healthy controls. In addition, the serum levels of CXCL12 tended to increase and the serum levels of CCL27 tended to decrease with an increase in the affected body surface areas. To detect the origin of the circulating chemokines, we performed immunofluorescence staining. CCL21, CCL27, HMGB1 and CXCL12 were stained more broadly in the EB patient tissues than those in the control tissues. CONCLUSIONS: These results suggest that fluctuations in chemokine levels may contribute in a coordinated way to the wound-healing process and lend clues toward efficient cell therapies for EB.

Birmingham epidermolysis severity score and vitamin D status are associated with low BMD in children with epidermolysis bullosa.

Bone status impairment represents a complication of generalized forms of epidermolysis bullosa (EB); however, the prevalence and the main determinants of this event in localized forms remain poorly defined. Birmingham epidermolysis bullosa severity (BEBS) score and 25-hydroxyvitamin D levels are strongly associated with low bone mass, suggesting that vitamin D may play a potential beneficial role in bone health. Further longitudinal studies are needed in order to confirm this hypothesis. INTRODUCTION: Bone status impairment represents a complication of generalized forms of EB; thus, we aimed to estimate the prevalence of low bone mass, to examine mineralization differences in various EB subtypes and to identify the most important determinants of bone impairment in children with either generalized or localized EB. METHODS: An observational study of 20 children (11 males; mean age ± standard deviation, 11.7 ± 3.9 years) with EB was performed. Clinical history, physical examination, laboratory studies, X-ray of the left hand and wrist for bone age, and dual energy X-ray absorptiometry scans of the lumbar spine were obtained. Areal bone mineral density (aBMD Z-scores) and bone mineral apparent density were related to the BEBS score. RESULTS: Areal BMD Z-score (mean -1.82 ± 2.33, range, -7.6-1.7) was reduced (<-2 SD) in 8 patients (40%), whereas aBMD Z-score adjusted for bone age was low in 7 patients (35%). BEBS score and 25-hydroxyvitamin D serum levels were the most important elements associated with aBMD (P = 0.0001 and P = 0.016, respectively). A significant correlation between the aBMD Z-score and area of skin damage, insulin-like growth factor-1, C-reactive protein, and sodium serum levels was also found. CONCLUSIONS: Low aBMD can be considered a systemic complication of EB, primarily associated with BEBS score and 25-hydroxyvitamin D levels. Therefore, longitudinal evaluation of bone status is ongoing in these patients to define whether vitamin D supplementation would prevent, or at least reduce, bone status impairment.

Homocysteine metabolism in children and adolescents with epidermolysis bullosa.

BACKGROUND: Epidermolysis bullosa (EB) belongs to a family of rare heterogeneous, genetic disorders characterized by blistering of the skin and mucous membranes in response to minor mechanical trauma. The involvement of the oral mucosa and oesophagus stenosis is suggested to be responsible for severe nutritional deficiencies, but few studies have till now considered this aspect. This observational study aimed to evaluate homocysteine status in children and adolescents with EB by assessing total plasma homocysteine (tHcy) and metabolically related vitamins (B6, B12, folate) concentrations. METHODS: Twenty EB patients (12 M; age range 0.5-19 years) were evaluated for: plasma tHcy, serum B12 and holotranscobalamin (HoloTC, the active fraction of B12), serum and erythrocyte folate (s-F and Ery-F, respectively), plasma B6 and serum high sensitive C-reactive-protein (hsCRP) levels. Clinical severity was also evaluated through the Birmingham Epidermolysis Bullosa Severity (BEBS) score. A sex and age well-matched population was also enrolled. RESULTS: EB patients showed tHcy levels higher (p = 0.04) and B6 levels lower (p = 0.03) than controls. B12, HoloTC, s-F and ery-F concentrations did not differ between patients and controls. Multiple linear regression analysis showed that tHcy levels were independent of the metabolically related vitamins levels. In addition, serum hsCRP levels were higher in EB patients than in controls (p = 0.003) and correlated negatively with B6 concentrations (r = -0.6; p = 0.009). BEBS score correlated negatively with HoloTC (p = 0.022) and B6 (p = 0.005) levels and positively with age (p = 0.031) and hsCRP levels (p < 0.001). CONCLUSIONS: The assessment of tHcy and metabolically related vitamin levels describes an important aspect of EB patients' nutritional status which can result essential for their long term care. Monitoring B6 levels in EB patients could be particularly important in order to prevent several complications associated with B6 deficiency and to avoid a B6 excess which sustains an inflammatory condition.

Proinflammatory Cytokines and Antiskin Autoantibodies in Patients With Inherited Epidermolysis Bullosa.

Epidermolysis bullosa (EB) is a rare disorder characterized by inherited skin adhesion defects with abnormal disruption of the epidermal-dermal junction in response to mechanical trauma. Our aim was to investigate a set of cytokine levels in serum samples from patients suffering from epidermolysis bullosa simplex (EBS), dystrophic epidermolysis bullosa (DEB), and healthy controls (HCs), exploring their potential correlations with antiskin autoantibody titers and disease activity. Forty patients afferent to the Dermatological Ward of Bari City Hospital and 9 HCs were enrolled and subdivided according to the dystrophic (DEB) and simplex forms (EBS). We found a significant increase in interleukin (IL)-1ß plasmatic levels of DEB (P = 0.0224) and EBS (P = 0.0465) patients compared to HCs; IL-6 levels were significantly higher in DEB than in EBS patients (P = 0.0004) or HCs (P = 0.0474); IL-2 levels were significantly increased in DEB compared with EBS (P = 0.0428). Plasmatic tumor necrosis factor-ß and interferon-γ were higher in DEB patients than in HCs (P = 0.0448 and 0.0229). Conversely, tumor necrosis factor-α was significantly decreased in DEB (P = 0.0034). IL-5 correlated with anti-BP180 (r = -0.5018, P = 0.0338), anti-BP230 (r = -0.6097, P = 0.0122), and anticollagen VII (r = -0.5166, P = 0.0405) autoantibodies; interferon-γ correlated with anti-BP180 (r = 0.9633, P < 0.0001), anti-BP230 (r = 0.9071, P < 0.0001), and anticollagen VII (r = 0.8619, P = 0.0045) autoantibodies. Score of disease severity was significantly correlated with IL-6 (r = 0.6941, P = 0.029) and IL-12 (r = 0.5503, P = 0.0272). The present study supports that EB might be considered a systemic inflammatory disease rather than a skin-limited disorder; clinical disease activity scores could be also integrated by laboratory data such as IL-6 and IL-12 dosage; biotherapies targeting specific cytokine networks probably represent a way to go in the future.

Correlation between nutritional, hematological and infectious characteristics and classification of the type of epidermolysis bullosa of patients assisted at the Dermatology Clinic of the Hospital Universitário de Brasília.

Epidermolysis bullosa comprises a group of phenotypically different genodermatosis, hereditary or acquired, characterized by skin fragility and subsequent formation of blisters in response to mechanical trauma, and which may also affect mucous membranes. This study aimed to analyze the relation between the nutritional, hematologic, infectious characteristics and the type of epidermolysis bullosa, through a descriptive case study based on data from medical records of 10 patients with epidermolysis bullosa assisted regularly at the Dermatology Clinic of the Hospital Universitário de Brasília. The old classification of the type of epidermolysis bullosa, weight and height, blood count, white blood cell count, platelet count and description of the type and frequency of secondary infections during the service were considered. We verified a predominance of iron deficiency anemia, chronic leukocytosis, thrombocytosis, chronic malnutrition, low height for age and thinness, and people with epidermolysis bullosa simplex exhibited appropriate relation between height/age and BMI/age. The non-specific skin infection was the most prevalent in both sexes. The severity of the type of epidermolysis bullosa and frequency of secondary infections did not form a directly proportional relation. The absence of direct proportion in all cases between the type of epidermolysis bullosa and the analysis parameters suggest a possible significant interference from other aspects such as the extent of the affected skin area, extracutaneous type of engagement and specific genetic mutation. The inclusion of these factors in the new classification proposed by Fine et al can contribute significantly to a better correlation of clinical parameters and appropriate preventive and therapeutic approaches.

Correlates of low bone mass in children with generalized forms of epidermolysis bullosa.

BACKGROUND: Epidermolysis bullosa (EB) is a family of rare, heterogeneous, genetic disorders characterized by fragility of the skin and mucous membranes. Reduced bone mass and fractures have been recognized as complications of generalized forms of EB. OBJECTIVES: We sought to describe the range and to estimate the prevalence of low bone mass in children with generalized EB, and to identify correlates of low bone mass in this population. METHODS: This was a prospective, observational study of 24 patients with generalized EB. Each patient completed a history, physical examination, laboratory studies, bone age, and x-rays of the lumbar spine. Those aged 6 years and older underwent dual energy x-ray absorptiometry scans of the lumbar spine. Primary outcomes were areal bone mineral density (aBMD) based on chronologic age, bone age, and adjusted for height Z-score. Descriptive statistics were used to summarize results, and linear regression was used to determine factors associated with low aBMD. RESULTS: Mean lumbar spine aBMD Z-scores ± SD were: -2.6 ± 1.4 for chronologic age, -1.7 ± 1.3 for bone age, and -1.0 ± 1.2 after adjusting for height Z-score. aBMD Z-scores were less than or equal to -2 in 64% for chronologic age, 50% for bone age, and 28% after adjusting for height Z-score. aBMD correlated with height Z-score, weight Z-score, extensive blistering, immobility, albumin, hemoglobin, iron, erythrocyte sedimentation rate, and c-reactive protein values. LIMITATIONS: Small sample size was a limitation. CONCLUSIONS: Children with severe, generalized recessive dystrophic EB have low aBMD for age. Deficits in aBMD were reduced after adjusting for delayed skeletal maturation and small body size.

Multicentric Castleman's disease associated with inherited epidermolysis bullosa.

Multicentric Castleman's disease (MCD) is a rare disorder characterized by fever, polyclonal hypergammaglobulinemia, and generalized lymphadenopathy. It has three histological characteristics: a recognizable architecture, germinal center abnormalities, and plasmacytosis. Inherited epidermolysis bullosa (EB) is also a rare disorder caused by a genetic defect. We report a 43-year-old patient with dystrophic EB, non-Hallopeau-Siemens recessive type or dominant type, displaying clinicopathologic features of MCD. In addition, his serum interleukin-6, which is thought to be responsible for the clinical symptoms in MCD, was elevated.

Blood vitamin and trace metal levels in epidermolysis bullosa.

Plasma or erythrocyte levels of ten nutrients (vitamins A, C, B12 and B6; folate; thiamine; riboflavin; zinc; copper; iron) were assayed in 73 patients with various forms of inherited epidermolysis bullosa (EB). Whereas the mean level for each nutrient was within its normal range, deficient levels were noted in individual EB subsets for selected nutrients. Notable abnormalities included low levels of plasma iron and zinc (in junctional EB and recessive dystrophic EB), vitamin C (primarily in EB simplex), vitamin A (in junctional and recessive dystrophic EB), vitamin B12 (primarily in EB simplex), and vitamin B6 (especially in recessive dystrophic EB). With the exception of low plasma iron and zinc levels in junctional and recessive dystrophic EB, however, only a minority of patients in any of the EB subsets had low levels of most of the other nutrients, and an apparent correlation with malabsorption was possible with only selected nutrients.

Abnormalities of plasma and erythrocyte essential fatty acid composition in epidermolysis bullosa: influence of treatment with diphenylhydantoin.

The fatty acid composition of plasma and erythrocyte phospholipids was determined in children with various subtypes of epidermolysis bullosa (EB) and in their parents. Patients with recessive dystrophic, dominant dystrophic, simplex, or junctional forms of EB had a higher percentage composition of arachidonic acid in plasma and/or erythrocyte phospholipids compared to age-matched controls. Epidermolysis bullosa patients treated with diphenylhydantoin had lower levels of arachidonic acid in plasma and erythrocyte phospholipids than did untreated EB patients. Parents of children with the recessive dystrophic or junctional EB subtypes had higher linoleic and arachidonic acids in plasma and erythrocyte phospholipids than did controls. Plasma and erythrocyte total lipids were within the normal range in children with EB. Plasma zinc was also normal but plasma copper was elevated in children with recessive dystrophic EB. We conclude that higher arachidonic acid in plasma and erythrocytes may be related to the pathology of EB.

Elevated serum chymotrypsin levels in a patient with junctional epidermolysis bullosa. Normalization after UVB therapy with good clinical response.

A 36-year-old Hispanic woman, covered with blisters since birth, was found to have markedly elevated chymotrypsin levels in her serum. This proteolytic enzyme is thought to digest laminin, thus causing separation of the basement membrane at the level of the lamina lucida, corroborating findings on electron microscopy. On the basis that the sun-exposed areas of the skin were relatively less involved, she received a course of UVB therapy, with total clinical clearance of her lesions after 3 weeks. A repeat estimation of serum chymotrypsin at this time revealed normal levels of this enzyme. It is thought that the elevated chymotrypsin levels were either released from the Langerhans cells themselves or from lymphocytes or keratinocytes as a result of Langerhans cell activity, and that the suppression of Langerhans cell activity by UVB inhibited the release of this proteolytic enzyme, resulting in the suppression of blister formation in our patient.

Basement membrane reactivity of antisera to type IV collagen and sera from patients with bullous pemphigoid and epidermolysis bullosa acquisita.

The basement membrane antigenic specificities of antibodies to Type IV collagen were compared to naturally occurring antibodies in sera from patients with bullous pemphigoid and epidermolysis bullosa acquisita (EBA) by indirect immunofluorescence, mixed immunofluorescence and immunoabsorption. Results suggested that the three sera reacted with three different basement membrane antigens. In addition, absorption with Types I, II, III, or IV collagen failed to reduce the basement membrane reactivities of bullous pemphigoid or EBA sera. The antibodies to the basement membrane components should be useful in studying skin and mucous membrane diseases including periodontal diseases.

The activity of arylsulphatases in serum of patients with several bullous diseases.

Spectrophotometric estimations of levels of activities of arylsulphatases A and B in serum of patients with several bullous diseases were carried out. The activities of these enzymes in cases of bullous pemphigoid were at high levels in comparison with those in cases of other bullous diseases and in the control group. Especially, the activity of arylsulphatase B was remarkably increased. It seems likely that there is some relationship between these disturbances and the pathogenesis of bullous pemphigoid.

Nonlinear kinetics of phenytoin in children.

The nonlinear kinetics of phenytoin were evaluated in 54 children by measuring phenytoin concentrations at steady state at three or more doses. There was good correlation between phenytoin doses and concentrations when a nonlinear kinetic model was used (r = 0.896). Increasing age was associated with a reduction in the apparent Vmax. The apparent Km was influenced primarily by drug interactions. Phenobarbital increased the Km and Vmax for phenytoin. Carbamazepine reduced both Km and Vmax. Valproic acid reduced the Km. The low Km (less than 2.6 mg per liter) found in 28% of patients makes titration of the phenytoin dose to therapeutic levels difficult.