Sexto reporte de eventos adversos con tratamientos biológicos en Argentina: Informe del registro BIOBADASAR / Sixth report of adverse events with biological treatments in Argentina: Report of the BIOBADASAR registry

Objetivo: Actualizar los resultados del registro BIOBADASAR sobre seguridad, duración y causas de interrupción del tratamiento luego de 8 años de seguimiento. Métodos: BIOBADASAR es un registro de seguridad de terapias biológicas establecido por la Sociedad Argentina de Reumatología. Se presenta la descripción de BIOBADASAR 3.0, una cohorte compuesta por 53 centros de Argentina seguidos prospectivamente desde agosto de 2010 hasta enero de 2018. Resultados: Se registraron 4656 pacientes, 6234 tratamientos [3765 casos (terapia con biológicos) y 2469 controles (terapia no biológicos)]. Se interrumpió el tratamiento en el 44,6% en los casos vs. 27,9% en los controles. Causa principal de discontinuación fue por ineficacia (40% casos vs. 32% controles). Se presentaron 3154 eventos adversos (2230 en casos vs. 924 en controles), de los cuales el 13,6% fueron graves (9,8% en casos y 3,7% en controles). El evento adverso (EA) más frecuente en ambos grupos fueron las infecciones (43,56% en casos vs. 34,31% en los controles, RR: 3,42; IC 95%: 3,02-3,88), y de ellas las de vías aéreas superiores (14,5%). Las neoplasias se presentaron en 78 casos vs. 45 en controles (RR: 1,98; IC 95%: 1,37-2,86). Conclusiones: En este sexto reporte no se observan tendencias diferentes sobre seguridad, duración y causas de interrupción del tratamiento respecto a informes previos. Las infecciones fueron el principal EA y la ineficacia, seguido por EA y la pérdida de pacientes las principales causas de suspensión del tratamiento. El advenimiento de nuevos agentes biológicos y la necesidad de control en seguridad a largo plazo, fortalece el uso de este tipo de registro.

Objective: Update the results of the BIOBADASAR registry on safety, duration and causes of treatment interruption after 8 years of follow-up. Methods: BIOBADASAR is a safety record of biological therapies established by the Argentine Society of Rheumatology. The description of BIOBADASAR 3.0 is presented, a cohort of 53 centers in Argentina followed prospectively from August 2010 to January 2018. Results: 4656 patients were registered, 6234 treatments [3765 cases (therapy with biologicals) and 2469 controls (non-biological therapy)]. Treatment was interrupted in 44.6% in cases vs. 27.9% in controls. Main cause of discontinuation was due to inefficiency (40% cases vs. 32% controls). There were 3154 adverse events (2230 in cases vs. 924 in controls), of which 13.6% were tombs (9.8% in cases and 3.7% in controls). The most frequent adverse event (AE) in both groups were infections (43.56% in cases vs. 34.31% in controls, RR: 3.42, 95% CI: 3.02-3.88), and the upper airway pathways (14.5%). Neoplasms were published in 78 cases versus 45 controls (RR: 1.98, 95% CI: 1.37-2.86). Conclusions: In this article, there are no different trends regarding safety, duration and causes of interruption of treatment compared to previous reports. Infections were the main causes of treatment discontinuation. The advent of new biological agents and the need for control over long-term security, strengthens the use of this type of registration.

Granulomatous reactions after injections of multiple aesthetic micro-implants in temporal combinations: a complication of filler addiction.

BACKGROUND: Granulomatous reaction is a well-known complication following soft filler procedures. However, the diagnosis of filler-induced granulomas may be challenging because of the occasional reluctance of patients to report the previously performed aesthetic procedure. OBJECTIVE: To describe a new clinical situation in which some patients, in the quest for physical perfection, become addicted to multiple sequential cosmetic injections, increasing the risk of adverse reactions. METHODS: We describe three women who developed diffuse facial nodular tumefaction after multiple procedures of filler injections into their face that occurred at different times in the previous years. RESULTS: Histopathology showed a granulomatous reaction including different combined substances that were identified with different types of micro-implants in the same biopsy. CONCLUSIONS: Excessive demand of multiple cosmetic injections may increase the frequency of skin granulomatous reactions and can be included in the spectrum of similar addictive dysmorphophobic behaviours. Histopathology is the best mean to achieve the diagnosis.

Diffuse dermal angiomatosis: a clinical mimicker of vasculitis associated with calciphylaxis and monoclonal gammopathy.

Diffuse dermal angiomatosis is a form of cutaneous reactive angiomatosis characterized clinically by painful erythematous or violaceous lesions with ulcers that may mimic cutaneous vasculitis/vasculopathy. Histologically it shows a benign, diffuse proliferation of endothelial cells with tiny blood vessels in the papillary and reticular dermis. Herein, we report four patients with diffuse dermal angiomatosis in the setting of calciphylaxis and monoclonal gammopathy and review the cases previously published in the literature. Comorbidities and management will also be discussed.

Vasotocin mRNA expression is sensitive to testosterone and oestradiol in the bed nucleus of the stria terminalis in female Japanese quail.

Vasotocin-producing parvocellular neurones in the medial part of the bed nucleus of the stria terminalis (BSTM) of many species of birds and mammals show sexual dimorphism and great plasticity in response to hormonal and environmental stimuli. In the BSTM of Japanese quail, vasotocin-immunoreactive neurones are visible and sensitive to testosterone exclusively in males. In males, gonadectomy decreases and testosterone restores vasotocin-immunoreactive cells and fibres by acting on vasotocin mRNA transcription. The insensitivity of female vasotocin-immunoreactive neurones to the activating effects of testosterone is the result of organisational effects of early exposure to oestradiol. Female quail also show vasotocin mRNA-expressing neurones in the BSTM, although it is not known whether the insensitivity of the vasotocinergic neurones to testosterone originates at the level of vasotocin gene transcription in this sex. Therefore, initially, the present study analysed the effects of acute treatment with testosterone on vasotocin mRNA expression in the BSTM of gonadectomised male and female quail using in situ hybridisation. Gonadectomy decreased (and a single injection of testosterone increased) the number of vasotocin mRNA-expressing neurones and intensity of the vasotocin mRNA hybridisation signal similarly in both sexes. Notably, testosterone increased vasotocin mRNA expression in ovariectomised females over that shown by intact quail. However, this treatment had no effect on vasotocin immunoreactivity. A second experiment analysed the effects of testosterone metabolites, oestradiol and 5α-dihydrotestosterone, on vasotocin mRNA expression in female quail. Oestradiol (but not 5α-dihydrotestosterone) fully mimicked the effects of testosterone on the number of vasotocin mRNA-expressing neurones and the intensity of the vasotocin mRNA hybridisation signal. Taken together, these results show, for the first time, that gonadal steroids strongly activate vasotocin mRNA expression in the BSTM of female quail.

Tinea atypica.

Although usually simple, the diagnosis of dermatophyte infection is sometimes neglected. Variations in clinical presentation (tinea atypica), mimicking other skin diseases depend on many factors, partially due to the dermatophyte's characteristics, and a combination of patient's pathological but often physiological conditions, such as excessive washing or sun exposure. The physician's misdiagnosis and eventual prescription of steroids or other incongruous treatments further induce pathomorphosis (tinea incognito), longstanding disease and delayed recovery. This review describes the morphology of some atypical dermatophyte infections, in an attempt to compare and correlate changes to the normal features of the disease by site of involvement. The risk factors and predisposing conditions are also analysed to provide a reasoned interpretation of morphology and therefore evoke the diagnostic suspect in atypical cases. Periodical training is the clue to improve dermatologist expertise in what is the first-sight ability to make a diagnosis, perform the correct assessments and consequent therapy in daily practice.

Upper eyelid necrosis and reconstruction after spider byte: case report and review of the literature.

Spider bites are not very common, especially in the Mediterranean area, and those affecting the ocular-palpebral region involving reconstructive surgery are particularly rare. In May 2010, the case of a Caucasian 24-year-old female patient was brought to the attention of the Dermatology Department, University of Cagliari, Italy. The patient reported she woke up feeling an intense pain with itching and that also she had noticed a spider of an unknown species on her bed. The dermatosis had affected the right orbital region, where there was a considerable red and violet erythema and a hard edema, not foldable. When the necrosis appeared the patient was treated at the Plastic Surgery Unit where she underwent a reconstruction of the eyelid with a full thickness skin graft from the retroauricular area. The post-operative course was regular with a perfect in-take of the skin graft. When the patient was discharged she was sent to an Entomological University Centre to identify the spider species and the possible venom which caused the skin lesion. The spider which caused the injury has been a Loxosceles rufescens (Dufour, 1820). Loxoscelism is a necrotic arachnoidism caused by the poisonous bite of spiders belonging to the Loxosceles species. It is very important to identify what sort of lesion it is and to treat it in a combined way in order to choose the proper timing for surgery to avoid damages to the eyelid functioning.

Cutaneous adverse drug reactions to allopurinol: 10 year observational survey of the dermatology department--Cagliari University (Italy).

BACKGROUND: Allopurinol is extensively prescribed for conditions associated with urate excess, despite being responsible for severe cutaneous adverse drug reactions (ADR). OBJECTIVE: A cross-sectional survey of allopurinol cases observed at the main Dermatology Department with inpatients facilities in southern Sardinia. (approx 560,836 inhabitants). MATERIAL AND METHODS: Data collection of all consecutive patients referred for ADR between 2001 and 2010. Causality assessment followed the WHO Collaborating Centre for Drug Monitoring criteria; illness severity score was adopted for toxic epidermal necrolysis (SCORTEN). RESULTS: Allopurinol was the culprit drug in 84 of 780 cutaneous ADR cases (10.7%; 8.4 cases/year). Mean age was 74 years, 58% of the patients were female, 95% of patients required hospitalization. Clinical forms were maculo-papular eruptions (34 cases), Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (31 cases), vasculitis (six cases), Drug Rash Eosinophilia and Systemic Symptoms (DRESS) (three cases), Acute Generalized Exanthematous Pustolosis (AGEP) (three cases), Pityriasis rosea-like eruption (three cases), lichenoid dermatitis (two cases), fixed drug eruption (one case), erythroderma (one case). The indication for allopurinol prescription was asymptomatic hyper-uricemia in 95% of the patients. Twelve patients were under allopurinol dosage adjustment according to creatinine clearance. Final causality assessment was definite for 12% of the cases and probable for the remaining 88%. Full recovery was achieved in 88% of subjects; ten SJS/TEN patients died (12% overall mortality; 32% mortality of the SJS/TEN cases). CONCLUSION: Considering the populations size of Southern Sardinia, is plausible that 1.5/100,000 Sardinian will be affected by allopurinol related ADR per year. Advanced age, and inappropriate allopurinol prescription were the main conditions affecting morbidity and mortality.

A case of bullous pemphigoid in infancy treated with local corticosteroids.

Bullous pemphigoid (BP) is an immune-mediated subepidermal vesiculobullous eruption, whose true incidence is unknown, but it is considered extremely rare in children, with a usually indolent course and rare relapses. Diagnosis is often belated, because of the invasive assessment with biopsy for typical immune-pathologic findings to differentiate it from Dermatitis Herpetiformis and Linear IgA bullous dermatosis (LABD), more common in children. A 4-year-old girl presented with one year history of erythematous-edematous and erythematous-bullous eruptions on the genitalia, periocular regions, dorsal and palmo-plantar surfaces. At onset erosions of the month and lips where considered a primary herpes simplex infection from the pediatrician, but repeated courses of systemic antivirals were completely ineffective, while application of a antibiotic-steroidal cream was of partial benefit. Histopathology showed a dermo-epidermal blistering, with a marked eosinophilic infiltrate. Direct immunofluorescence showed a characteristic positive linear IgG and C3 band at the basement membrane zone (BMZ). Complete hematic-chemical and instrumental examinations gave normal results, excluding associated pathologies. Due to paucity of lesions and good response to local treatment with moderate potency cortisones, in agreement with the parents, no systemic therapy was started. No recurrence occurred in the 2 year follow-up after complete remission. The case is reported for the rarity of the childhood form, and the importance of the differential diagnosis for management and treatment. Good response to topical treatment is stressed, avoiding the risks of long-term systemic drug administration.

Clinical outcome evaluation following cyclosporine a treatment in moderate to severe psoriasis: a retrospective study.

This retrospective study was conducted on 193 patients treated in three Italian Psoriasis Units with the aim of evaluating the evolution of psoriasis severity and the safety of cyclosporin A (Sandimmun Neoral) in moderate to severe psoriasis, at the regimens usually employed in common clinical practice. Cyclosporin A (CyA) was administered for a mean period of 14 months, the mean number of treatment courses was 1.6 (range 1-4), and the mean dosage ranged from 1.5 to 3.1 mg/kg/die. Ninety percent of patients obtained complete therapeutic success or clinical remission, defined as complete clearance of lesions or clearance of lesions with residual minor pigmentations respectively, when treated with CyA in monotherapy. The mean Psoriasis Area and Severity Index (PASI) decreased from 23.31 before CyA administration to 5.64 at the end of treatment. The clinicians judgement on CyA tolerability was good/very good in 90 percent of cases. Adverse events occurred in 36 percent of patients, with hypertension being the most commonly reported (17.6 percent). The results of this study indicate that in the common clinical practice CyA in moderate to severe psoriasis is usually employed at low doses, resulting both safe and effective.

Immunoreactivity for alpha-smooth muscle actin characterizes a potentially aggressive subgroup of little basal cell carcinomas.

Basal cell carcinoma (BCC) is a very common malignant skin tumor that rarely metastatizes, but is often locally aggressive. Several factors, like large size (more than 3 cm), exposure to ultraviolet rays, histological variants, level of infiltration and perineural or perivascular invasion, are associated with a more aggressive clinical course. These morphological features seem to be more determinant in mideface localized BCC, which frequently show a significantly higher recurrence rate. An immunohistochemical profile, characterized by reactivity of tumor cells for p53, Ki67 and alpha-SMA has been associated with a more aggressive behaviour in large BCCs. The aim of this study was to verify if also little (<3 cm) basal cell carcinomas can express immunohistochemical markers typical for an aggressive behaviour.

Functional analysis of neurosteroidal oestrogen using gene-disrupted and transgenic mice.

The brain aromatase (oestrogen synthase) hypothesis predicts that oestrogen plays important roles in both sexual behaviours and brain sexual differentiation. To elucidate the functions of oestrogen in the brain, we generated aromatase knockout (ArKO) mice, which showed undetectable oestrogen and enhanced androgen levels in blood. These ArKO mice exhibited an enhanced appetite and disorders in sexual motivation, sexual partnership preference, sexual performance, aggressive behaviour, parental behaviour, infanticide behaviour and exploratory (anxiety) behaviour. We characterised the brain-specific promoter of the mouse aromatase gene, and identified several crucial cis-acting elements and the minimal essential promoter region for brain-specific expression. Next, we introduced a transgene of human aromatase, controlled by the minimal promoter region, into the ArKO mouse. The resulting mouse (ArKO/hArom), whose preoptic area, hypothalamus and amygdala were exposed to oestrogens only in the perinatal period, and then to enhanced androgens and no oestrogens in adulthood, showed near recovery from behavioural disorders. These results suggest that local oestrogens acting in specific brain regions are involved in the organisation of sex-specific neural networks during the perinatal period. Finally, we examined effects of oestrogens on gene expression within specific brain regions in mice during the perinatal period using DNA microarray analysis. This assay revealed both up-regulated and down-regulated brain-specific genes, including those related to neuronal function. Specifically, genes involved in energy metabolism, cell proliferation/apoptosis and secretory/transport system were altered in ArKO mice compared to wild mice. These results suggest that brain oestrogens participate in the sexual differentiation of the brain by influencing gene expression.

Immunoreactivity for alpha-smooth muscle actin characterizes a potentially aggressive subgroup of little basal cell carcinomas.

Basal cell carcinoma (BCC) is a very common malignant skin tumor that rarely metastatizes, but is often locally aggressive. Several factors, like large size (more than 3 cm), exposure to ultraviolet rays, histological variants, level of infiltration and perineural or perivascular invasion, are associated with a more aggressive clinical course. These morphological features seem to be more determinant in mideface localized BCC, which frequently show a significantly higher recurrence rate. An immunohistochemical profile, characterized by reactivity of tumor cells for p53, Ki67 and alpha-SMA has been associated with a more aggressive behaviour in large BCCs. The aim of this study was to verify if also little (<3 cm) basal cell carcinomas can express immunohistochemical markers typical for an aggressive behaviour.

Enzyme-linked immunosorbent assay in autoimmune blistering diseases: preliminary experience of the Dermatology Department of Cagliari.

AIM: Recent insights on the pathogenesis of autoimmune blistering diseases have pointed out the opportunity of new diagnostic tools, such as enzyme-linked immunosorbent assay (ELISA) for Desmogleins 3 and 1 (Dsg3, Dsg1), and bullous pemphigoid (BP) 180 antigen auto-antibodies. The aim of the present prospective study was to evaluate the diagnostic values of these tests in blind with histopathology and direct immunofluorescence (DIF), the assessment of correlation with clinical presentation and severity of disease, as well as eventual modifications of serum auto-antibodies titres in course of treatment. METHODS: From June 2005 to June 2007, all consecutive patients with clinically blistering diseases presenting to the Dermatology Department of Cagliari were enrolled in the study. Biopsy specimens were performed in all cases and sent for histopathological examinations including haematoxylin-eosin stain and DIF to the Unit of Pathological Anatomy of the same University. Serum samples were tested with Dsg3, Dsg1 and BP180 ELISA in the internal laboratory of the Dermatology Department, and results were worked out many days before histopathology reports. Final diagnosis was established on clinical, histological and immunopathological findings. A selected sample of patients with active autoimmune blistering disease underwent repeated immunosorbent assays at 1-2-6 months from first diagnosis and treatment introduction. RESULTS: Forty-two patients (23 men, 19 women) were enrolled in the study and divided into three groups: pemphigus (N=17), pemphigoid (N=19) and other diseases (OD; N=6), depending on the final diagnosis assessed by histological, immunopathological and serological examinations. In pemphigus group ELISA showed circulating antibodies against Dsg3 in all patients (100%) and against Dsg1 in 13 patients (76.5%). In the pemphigoid group, 16 of 19 sera showed positive scores above the cut-off value (84.2%), but sensibility was higher if considering only the bullous pemphigoid final diagnosis (16/17). None of the other bullous diseases (0%) exceeded the cut-off value for Dsg1, Dsg3 and BP180 ELISA. Correlation with histopathology and direct immunofluorescence was excellent for pemphigus and very good for pemphigoid. Eight patients (6 P; 2 BP) underwent a serial measurement of the autoantibodies levels: two patients (1 PV and 1 BP) showed an ELISA antibodies titres decrease after two months of treatment, in parallel with an excellent clinical response. Whereas in six cases (5 PV and 1 BP) the ELISA titres overstayed high at I and II month. Clinically the disease was active in all six patients, and a treatment adjustment was performed (increased corticosteroid dosage and/or azathioprine initiation in all cases, high dose intravenous immune globulin in one case). At month VI, a decrease on ELISA antibody levels was documented in three patients (3 PV), parallel to a clinical remission. Whereas in other three patients (2 PV, 1 BP), persistent high Dsg3 ELISA titres were related to a still active disease: although clinically improved, blisters flared up at any attempt to taper drugs dosage. CONCLUSION: Dsg3, Dsg1 and BP ELISA is a sensitive, easy and quick reading tool for the diagnosis of the main autoimmune blistering diseases: pemphigus and bullous pemphigoid. More over, autoantibodies titre correlate with disease severity, and is useful to monitor treatment response.

Effect of hyperosmotic stimulation on aquaporins gene expression in chick kidney.

Birds can produce hyperosmotic urine, but their renal morphology differs from that of mammals. Recent studies in mammals, suggested that various aquaporins (AQPs) are present in the kidney and play crucial roles in urine production. To elucidate the role of AQPs in the avian kidney, we first examined for the presence of AQP1, 2, 3, 4, 7 and 9 mRNAs in the chick (Gallus gallus) kidney by RT-PCR analysis. Next, we quantified variations of AQPs mRNAs levels in chick kidney after hyperosmotic stimulation (water-deprivation or salt-loading) by real-time RT-PCR analysis. Our study showed that in addition to AQP1, 2, 3, 4 and 7, chick kidney also expressed AQP9 and that hyperosmotic stimulation induced changes in AQPs expression. In particular, water-deprivation increased AQP2 and AQP3 mRNAs levels, whereas salt-loading induced a significant increase in AQP1, AQP2 and AQP9 mRNAs levels. AQP4 and AQP7 mRNA levels were not affected by any hyperosmotic stimulation. Taken together, these results indicated that the presence of AQPs in chick kidney is similar to that in mammals, that the chick kidney has an additional AQP9 and that AQP1, 2, 3 and 9 may play a crucial but different role in water permeability in this organ.

Tinea manuum bullosa.

We report a case of tinea manuum bullosa in a 36-year-old male, a crop and livestock farmer by trade. The lesion, resembling contact dermatitis, was located in the palm of the right hand. We isolated Trichophyton verrucosum. No other skin lesion was detected. Blood chemistry and immunology test results were normal. Treatment with terbinafine 250 mg day(-1) led to clinical and mycological healing.

Classic Kaposi's sarcoma in southern Sardinia, Italy.

The first examination of classical Kaposi's sarcoma incidence in southern Sardinia (Italy) in 1998-2002 found the highest rate recorded in the island of 2.49 per 100 000 per year (standardised).

Leishmaniasis of the lip in a patient with Down's syndrome.

Cutaneous leishmaniasis is an endemic protozoan infection in Sardinia, one of the major islands of the Mediterranean Basin. The main causative strain in this country is Leishmania infantum, which rarely involves mucocutaneous areas, but has the potential to cause visceral leishmaniasis. An atypical leishmaniasis involving the inferior lip of a 57-year-old female with Down's syndrome was observed at the Dermatology Department of Cagliari (italy). The diagnosis was mainly based upon histopathological examination, revealing intra- and extra-cellular leishmania amastigotes. The leishmania infantum zymodeme MON-111 was identified by isoenzymatic characterization. Laboratory investigations revealed a normal complete blood count and biochemistry profile, except for an inverted CD4/CD8 ratio. Treatment with meglumine antimoniate 60 mg/kg/day (Glucantime) intramuscularly for 15 days, followed by intralesional administration 1 ml weekly for 4 weeks led to complete recovery. No relapses were observed at 6-month follow-up. The unusual localization is likely to be a reflection of the uncommon site of inoculation of the protozoa, transmitted by bites from flying vectors. Nevertheless, the presence of Down's syndrome in our patient may have contributed to the atypical presentation by traumatic exacerbation of the lesion, due to repeated auto-induced microtraumas of the inferior lip accompanied by subclinical immunodeficiency. In fact, the specific immune response to Leishmania infection depends on a host-cell-mediated immune response, reported as defective in Down's syndrome patients. Differential diagnosis and early detection of the infection are necessary in order to start effective treatment and prevent more serious complications.