Genoa and leprosy: from the Middle Ages to the present.

During the Middle Ages, leprosy sufferers could not live in the city and were forced outside the walls. In the centuries, the Genoese area dedicated several hospitals to lepers, such as S. Lazzaro and Pammatone Hospital, a small leprosarium in the Tigullio area and San Martino Hospital from 1935. The first doctor who recognized to cure leprosy in Genoa was Goffredo, who later was also nominated rector of the community. In the early 1900's, Radaeli promoted the construction of a leprosarium behind the San Martino hospital. In 1936 Giuseppe Mariani was known for using the leprosarium to hide Italian Jews during deportation to the extermination camps. Later, Professor Aldo Baccaredda-Boy instituted the graduate school in "Leprosy and Tropical Dermatology", continued by professor Enrico Nunzi until 1990. The leprosarium was then transformed into the Department of Tropical Dermatology and finally into the Operative Unit of Social Dermatology, a national reference center.

Autoantibody Profile of a Cohort of 54 Italian Patients with Linear IgA Bullous Dermatosis: LAD-1 Denoted as a Major Auto-antigen of the Lamina Lucida Subtype.

Linear IgA bullous dermatosis (LABD) is characterized by presence of multiple IgA autoantibodies, and a comparatively lesser number of IgG antibodies, directed against different hemidesmosomal antigens. The main autoantigens are LAD-1, LABD-97, BP180 and BP230, type VII collagen and laminin 332. We retrospectively studied the serology of 54 Italian patients with LABD using enzyme-linked immunosorbent assay (ELISA), immunoblotting assay, and indirect immunofluorescence on monkey oesophagus and salt-split skin. Among these, indirect immunofluorescence of salt-split skin elicits the greatest sensitivity. Sixty-three percent of the sera were observed to be positive, with a lamina lucida pattern observed in 48%, a sub-lamina densa pattern in 2% and a mixed pattern in 13% of the cases. IgA reactivity to LAD-1 on immunoblotting was found in 52% of sera, to BP180-NC16A by ELISA in 32% and to BP230 in 26%. Only 17% of patients possessed circulating IgG autoantibodies. LAD-1 was determined to be a major autoantigen of the lamina lucida subtype. Combined serological assays demonstrated a high sensitivity (82%), suggesting that this approach could support diagnosis when a biopsy is not feasible or direct immunofluorescence results are negative.

Synergy among non-desmoglein antibodies contributes to the immunopathology of desmoglein antibody-negative pemphigus vulgaris.

Pemphigus vulgaris (PV) is a potentially lethal mucocutaneous blistering disease characterized by IgG autoantibodies (AuAbs) binding to epidermal keratinocytes and inducing this devastating disease. Here, we observed that non-desmoglein (Dsg) AuAbs in the sera of patients with Dsg1/3 AuAb-negative acute PV are pathogenic, because IgGs from these individuals induced skin blistering in neonatal mice caused by suprabasal acantholysis. Serum levels of AuAbs to desmocollin 3 (Dsc3), M3 muscarinic acetylcholine receptor (M3AR), and secretory pathway Ca2+/Mn2+-ATPase isoform 1 (SPCA1) correlated with the disease stage of PV. Moreover, AuAb absorption on recombinant Dsc3, M3AR, or SPCA1 both prevented skin blistering in the passive transfer of AuAbs model of PV in BALB/c mice and significantly decreased the extent of acantholysis in a neonatal mouse skin explant model. Although acantholytic activities of each of these immunoaffinity-purified AuAbs could not induce a PV-like phenotype, their mixture produced a synergistic effect manifested by a positive Nikolskiy sign in the skin of neonatal mice. The downstream signaling of all pathogenic non-Dsg AuAbs involved p38 mitogen-activated protein kinase (MAPK)-mediated phosphorylation and elevation of cytochrome c release and caspase 9 activity. Anti-Dsc3 and anti-SPCA1 AuAbs also activated SRC proto-oncogene, nonreceptor tyrosine kinase (SRC). Of note, although a constellation of non-Dsg AuAbs apparently disrupted epidermal integrity, elimination of a single pathogenic AuAb could prevent keratinocyte detachment and blistering. Therefore, anti-Dsg1/3 AuAb-free PV can be a model for elucidating the roles of non-Dsg antigen-specific AuAbs in the physiological regulation of keratinocyte cell-cell adhesion and blister development.

Mechanisms of pathogenic effects of eosinophil cationic protein and eosinophil-derived neurotoxin on human keratinocytes.

Cutaneous deposition of eosinophil degranulation proteins is a major feature of eosinophil-rich cutaneous diseases including bullous pemphigoid (BP). We sought to better understand the effect of two of these proteins - eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN), on human keratinocytes using the Het-1A cell line. To evaluate expression of key cytokines and chemokines observed in BP as well as metal metalloprotease 9 (MMP9), we performed qPCR and in-cell Western assays on cells treated with either ECP or EDN. We further evaluated the effect of ECP and EDN on keratinocyte survival, generation of reactive oxygen species (ROS) and apoptosis. Lastly, we assessed ECP and EDN's ability to induce keratinocyte detachment from provisional matrix. Treatment of keratinocytes with ECP and EDN resulted in significant increases in IL-5, eotaxin-1 and CCL5 (RANTES) expression at both mRNA and protein levels, but not IL-17 or IL-31. ECP and EDN also upregulate MMP9 production. Inhibiting MMP9, we confirmed that keratinocyte expression of IL-5, eotaxin-1 and RANTES was independent from MMP9. Both ECP and EDN were cytotoxic to keratinocytes, inducing ROS formation and apoptosis through a mitochondrion-dependent pathway as evidenced by results of terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) and cytochrome c release assays, respectively. ECP but not EDN led to significant keratinocyte detachment from provisional matrix. These findings demonstrate that the pathogenic effects of ECP and EDN in BP may result from their direct action on keratinocytes, and as such may became a target for future therapies in eosinophil-rich cutaneous diseases.

Determining the Incidence of Pneumocystis Pneumonia in Patients With Autoimmune Blistering Diseases Not Receiving Routine Prophylaxis.

Importance: Pneumocystis pneumonia (PCP) is a potentially lethal opportunistic infection that primary prophylaxis can help prevent. The risk of prophylactic therapy must be weighed against the incidence of PCP in the patient population. Prophylaxis most frequently involves trimethoprim-sulfamethoxazole, with second-line therapies, including atovaquone, dapsone, and pentamide. The indication for prophylaxis in immunocompromised patients without HIV is less well defined. Previously, an incidence of at least 3.5% has been proposed as a cutoff to justify prophylaxis. Objective: To assess the incidence of PCP in patients with autoimmune blistering diseases receiving no routine prophylaxis. Design, Setting, and Participants: This was a retrospective analysis of patient medical records to determine the incidence of PCP infections. The multicenter study was performed at tertiary care centers that provide care for patients with autoimmune blistering disease in Germany, Italy, Singapore, Israel, and the Netherlands. Patients had a confirmed diagnosis of pemphigus vulgaris/foliaceus, bullous pemphigoid, epidermolysis bullosa acquisita, mucous membrane pemphigoid/cicatricial pemphigoid, or anti-p200 pemphigoid. Main Outcomes and Measures: To determine the incidence of PCP defined as patients with the International Classification of Diseases, Ninth Revision (ICD-9), code 136.3, for PCP, or free text documentation of PCP occurring based on characteristic radiographic findings with elevated lactate dehydrogenase, or hospitalization for pneumonia with bronchioalveolar lavage demonstrating Pneumocystis jiroveci on confirmatory stains. Results: A total of 801 patients with autoimmune blistering diseases were included in this study; their mean (SD) age was 66.5 (17.6) years, and a total of 465 (58%) were female. Only 1 patient developed PCP, resulting in an incidence rate of 0.1%. This incidence significantly fell below the recommended threshold of 3.5% (0.1% vs 3.5%, χ21 = 27.0; P < .001). This incidence was significantly lower than the previously reported incidence of PCP in all immunosuppressed dermatologic patients (0.1% vs 1.3%; χ21 = 8.2; P = .004). Conclusions and Relevance: Routine Pneumocystis prophylaxis for patients with autoimmune blistering diseases does not seem to be warranted. Patients with autoimmune blistering disease seem to have a lower risk of PCP than the general population of immunosuppressed dermatology patients. Risks of routine prophylaxis include hyperkalemia, hypoglycemia, photosensitivity, thrombocytopenia, and more rare adverse reactions.

Etiopathogenesis of rosacea: a prospective study with a three-year follow-up.

BACKGROUND: The aim of this study was to investigate the role of Demodex folliculorum (DF), Helicobacter pylori (HP), and small intestine bacterial overgrowth (SIBO) in the development of rosacea. METHODS: A case-control study including 60 patients with rosacea and 40 healthy controls was performed. All the patients underwent standardized skin surface biopsy to investigate DF, urea breath test for HP and lactulose breath test and glucose breath test for SIBO. Etiological therapy was started in the following order: acaricidal treatment, antibiotics for SIBO and HP. These exams were repeated after 3 years. Statistical analysis was performed. RESULTS: As regards the 88 patients who completed the entire follow-up, DF positivity was found in 47.7% of the patients, SIBO in 25.0%, and HP in 21.6%. SIBO significantly prevailed in papulopustular rosacea, while HP in erythrosis. At the 6-month follow up, the 61% of patients were in remission. After 3 years, 18% of patients dropped out, while the remaining patients repeated all the investigations. The majority of patients were still in remission and negative for HP while only 5 were positive for DF and 4 for SIBO. CONCLUSIONS: SIBO was the most relevant factor in papulopustular rosacea. Its treatment was crucial in improvement and in maintaining the clinical remission.

Neuro sweet syndrome: a systematic review. A rare complication of Sweet syndrome.

Sweet's syndrome (SS) is an inflammatory disease characterized by fever, leucocytosis and distinctive skin lesions that histologically consist of a dermal infiltrate of neutrophils with nuclear fragmentation. Aseptic neutrophilic inflammation may occur also in other organs. Central nervous system involvement in SS, Neuro-Sweet's syndrome (NSS), is rare and reported especially among Asian patients. A systematic review of the literature has been performed to find articles reporting cases of SS with neurological involvement. The search terms: "Sweet's syndrome/disease with neurological involvement, Neuro Sweet Syndrome/Disease" were used in the Pubmed Database. Sixty-nine NSS patients including 46 males and 23 females, more Asian than Caucasian, have been described from 1983 to date. The average age was 48.7 year-old. The most representative neurologic symptom was the altered state of consciousness, followed by headache and memory disorders. Differently from SS with skin or other district involvement, NSS appears to be more common in Asian patients than in Caucasian ones and affects mainly the male sex in the third or fourth decade of life. A very wide range of symptoms and signs can occur, depending on which part of the nervous system is affected. Initial presentation is usually with the SS typical skin lesions followed by neurological involvement. However, also an opposite presentation or a simultaneous skin and nervous involvement may happen. Awareness of the possible neurological complications in SS is important to avoid unnecessary therapies for other forms of meningoencephalitis and lead to successful treatment with systemic corticosteroids.

The high incidence of anti-Ro/SSA and anti-p200 antibodies in female patients with connective tissue diseases confirms the importance of screening for congenital heart block-associated autoantibodies during pregnancy.

It is known that anti-Ro/SSA positivity leads to higher risk of miscarriage and fetal cardiac malformations. Particularly, anti-p200 antibodies against a finer specificity of the Ro/SSA antigen, have been associated with congenital heart block. The aim of the study was to assess the frequency of anti-p200 among female patients with different connective tissue diseases and, among these, the relevance of anti-p200 values in patients with cutaneous diseases compared to systemic diseases. Anti-p200 were investigated in 110 anti-Ro/SSA positive female sera, sent to our laboratory between 2008 and 2014 with suspect of connective disease, by using ELISA testing. Positivity was found in 40.9 % samples, 34 of them showed a strong positivity (values ≥ 1.0, cut off = 0.7). Patients with systemic diseases were anti-p200 positive in the 45.9 % of cases while patients with cutaneous diseases were positive in the 24.0 % of cases. Positivity for anti-p200 antibodies was revealed in 24.0 % of patients with discoid lupus erythematosus; 100 % of patients with dermatomyositis; 40.0 % of patients with mixed connective tissue disease; 25.0 % of patients with rheumatoid arthritis; 100 % of patients with Sjögren's syndrome; 33.3 % of patients with subacute cutaneous lupus erythematosus; 42.9 % of patients with systemic lupus erythematosus; 80.0 % of patients with systemic sclerosis. No significant difference in anti-p200 prevalence was found between systemic and cutaneous involvement, nevertheless, considering only positive sera, the antibody titer was higher in systemic diseases rather than in cutaneous diseases (2.6 ± 1.7 and 1.7 ± 1.9; p = 0.041). The authors think screenings for anti-Ro/SSA and anti-p200 antibodies should be included in the laboratory checklist for pregnancy.

Epidemiological study of onychomycosis in older adults with onychodystrophy.

AIM: To identify the prevalence of onychomycosis and epidemiological features in older adults (>65%) with toenail onychodystrophy. In particular, the aim of the study was to analyze risk factors/protective factors, clinical manifestations, comorbidities and etiological agents. METHODS: A prospective study was carried out from February 2012 to May 2012 at San Martino-IST of Genoa, Italy. The inclusion criteria for enrolment were the presence of onychodystrophy of one or more toenails and age >65 years. The exclusion criteria were systemic/topical antifungal treatments in the previous 6 months, drilling of the nail plate in the previous 6 months and a specialist's diagnosis or suspicion of onychomycosis. A database was created for the patients' anamnesis, the clinics and testing results. Several statistical analyses were carried out. RESULTS: A total of 100 patients fulfilled the inclusion criteria. A total of 35 cases had positive results, and the etiological agent was isolable in 14 cases. The most represented was Trichophyton mentagrophytes followed by Trichophyton rubrum and others. Multivariate logistic regression analysis showed the significant roles of sex and diabetes as risk factors, and the use of statins as a protective factor. CONCLUSIONS: Onychomycosis has a high prevalence in older adults with onychodystrophy. It is important not to overlook onychodystrophy, and to carry out laboratory testing to exclude a fungal infection. In fact, as older patients often cannot undergo systemic antifungal therapies, it is fundamental to treat them early and avoid the spread of infection.

Remitting seronegative symmetrical synovitis with pitting edema associated with parvovirus B19 infection: two new cases and review of the comorbidities.

BACKGROUND: Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is a rare syndrome consisting of acute symmetrical tenosynovitis of the hands and wrists associated with pain and marked pitting edema of the dorsum of the hands or the feet. Persistent rheumatoid factor seronegativity and elevated acute phase reactants are the rule, while radiographic findings are characterized by the absence of bony erosions. The syndrome has occasionally been associated with a wide range of diseases including solid and hematological malignancies, polymyalgia rheumatica, and other inflammatory rheumatic diseases. METHODS: Two patients with skin eruption on hands and feet associated with arthromyalgias have been investigated to confirm diagnosis of RS3PE and to detect comorbidities. A revision of all the possible medical conditions correlated to RS3PE has been performed. RESULTS: We report two cases of RS3PE associated with Parvovirus B19 infection/reactivation. There are very few reports on the association between RS3PE and infectious agents, and in only one case the syndrome has been correlated to parvovirus infection. CONCLUSIONS: We want to underline the importance for patients with RS3PE to be seen by dermatologists who should become familiar with this syndrome and remark that Parvovirus B19 infection may be a potential cause of RS3PE.

A retrospective study of cutaneous drug reactions in an outpatient population.

BACKGROUND: Adverse cutaneous drug reactions (ACDR) are unexpected cutaneous changes occurring at drug dosages that are normally used for disease prophylaxis, diagnosis or treatment. OBJECTIVE: The aim of the study was to determine the clinical types of ACDR, the causative agents, the latency time between drug intake and onset of ACDR and the recovery time in an outpatient population. METHOD: Ninety-five patients diagnosed with ACDR at the Department of Dermatology of the University of Genoa between 2003 and 2012 were retrospectively studied. RESULTS: Antimicrobials, especially cephalosporins, were the most responsible for ACDR, followed by non-steroidal anti-inflammatory drugs and antihypertensives. The most common clinical manifestations were exanthema (42.1%), erythema multiforme (10.53%) and vasculitis (9.53%). Patients with peripheral eosinophilia showed a more severe clinical manifestation, they were treated with systemic therapies and their recovery time was longer. CONCLUSION: It is important to have an appropriate clinical approach according to the ACDR severity degree. We think that eosinophilia may characterise severe cutaneous eruptions and that it should always be investigated when ACDR is suspected in order to manage the patient with the appropriate treatment.