Vitamin D and skeletal health in autoimmune bullous skin diseases: a case control study.

BACKGROUND: The presence of hypovitaminosis D in patients with autoimmune bullous skin diseases, such as pemphigus vulgaris (PV) and bullous pemphigoid (BP), is debated. In a previous study we found an increased prevalence of vertebral fractures (VFx) and hypovitaminosis D in PV and BP patients. The present study extends the sample size of the previous one, for investigating the 25-hydroxyvitamin D (25OHVitD) levels in relation with the skeletal health and disease intensity in these patients. METHODS: The previous study was performed in 13 PV and 15 BP patients and 28 controls. Data from 39 additional patients (22 PV and 17 BP) were now added. Eventually, we studied 67 patients (35 PV, 32 BP, 51 females), aged 64.7 ± 16.9 years and 67 age- gender- and body mass index-matched controls. In all subjects, serum 25OHVitD, calcium and alkaline phosphatase (ALP) levels were measured, bone mineral density (BMD) was evaluated by Dual-energy X-ray. Absorptiometry at lumbar spine (LS) and femoral neck (FN) and the presence of VFx were ascertained by visual assessment from spinal radiographs. In patients, the disease intensity was evaluated by the autoimmune bullous skin disorder intensity score (ABSIS). RESULTS: As compared with controls, both PV and BP patients showed lower 25OHVitD (22.2 ± 11.1 vs 13.9 ± 8.3 ng/mL, p < 0.001 and 22.4 ± 14.9 vs 9.5 ± 7.7 ng/mL, p < 0.0001, respectively) and higher prevalence of severe hypovitaminosis D (22.9 vs 48.6%, p < 0.02 and 31.1 vs 75.0%, p < 0.0001, respectively) and VFx (28.6 vs 57.1%, p = 0.03 and 34.4 vs 62.5%, P = 0.02, respectively). In both PV and BP patients, LS and FN BMD did not differ from controls. In the whole patients' group, ABSIS score was inversely associated with 25OHVitD levels (R = -0.36, p < 0.005), regardless of age (ß = -3.2, P = 0.009). CONCLUSIONS: PV and BP patients have an increased prevalence of hypovitaminosis D and VFx. The extended study shows, for the first time, that the 25OHVitD levels are inversely associated with disease intensity and that VFx occur in spite of a not reduced BMD.

Association of pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH) shares genetic and cytokine profiles with other autoinflammatory diseases.

The association of pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH) has recently been described and suggested to be a new entity within the spectrum of autoinflammatory syndromes, which are characterized by recurrent episodes of sterile inflammation, without circulating autoantibodies and autoreactive T-cells. We conducted an observational study on 5 patients with PASH syndrome, analyzing their clinical features, genetic profile of 10 genes already known to be involved in autoinflammatory diseases (AIDs), and cytokine expression pattern both in lesional skin and serum. In tissue skin samples, the expressions of interleukin (IL)-1ß and its receptors I and II were significantly higher in PASH (P = 0.028, 0.047, and 0.050, respectively) than in controls. In PASH patients, chemokines such as IL-8 (P = 0.004), C-X-C motif ligand (CXCL) 1/2/3 (P = 0.028), CXCL 16 (P = 0.008), and regulated on activation, normal T cell expressed and secreted (RANTES) (P = 0.005) were overexpressed. Fas/Fas ligand and cluster of differentiation (CD)40/CD40 ligand systems were also overexpressed (P = 0.016 for Fas, P = 0.006 for Fas ligand, P = 0.005 for CD40, and P = 0.004 for CD40 ligand), contributing to tissue damage and inflammation. In peripheral blood, serum levels of the main proinflammatory cytokines, that is, IL-1ß, tumor necrosis factor-α, and IL-17, were within the normal range, suggesting that in PASH syndrome, the inflammatory process is mainly localized into the skin. Four out of our 5 PASH patients presented genetic alterations typical of well-known AIDs, including inflammatory bowel diseases, and the only patient lacking genetic changes had clinically evident Crohn disease. In conclusion, overexpression of cytokines/chemokines and molecules amplifying the inflammatory network, along with the genetic changes, supports the view that PASH syndrome is autoinflammatory in origin.

Immune-mediated inflammatory reactions and tumors as skin side effects of inflammatory bowel disease therapy.

All drugs currently used for treating patients with inflammatory bowel disease (IBD - including Crohn's disease and ulcerative colitis) have the potential to induce skin lesions ranging from mild eruptions to more serious and widespread clinical presentations. The number of cutaneous adverse reactions due to IBD therapies is progressively increasing and the most frequently involved drugs are thiopurines and biologics like tumor necrosis factor (TNF)-α antagonists. The main drug-induced cutaneous manifestations are non-melanoma skin cancer (NMSC), notably basal cell and squamous cell carcinomas, and viral skin infections for thiopurines and psoriasiform, eczematoid and lichenoid eruptions as well as skin infections and cutaneous lupus erythematosus for biologics. Cutaneous manifestations should be promptly recognized and correctly diagnosed in order to quickly establish an adequate therapy. The main treatment for NMSC is surgical excision whereas the management of immune-mediated inflammatory skin reactions varies from topical therapy for mild presentations to the shift to another drug alone or in combination with corticosteroids for extensive eruptions.

Cutaneous manifestations in patients with inflammatory bowel diseases: pathophysiology, clinical features, and therapy.

The skin is one of the most common extraintestinal organ system affected in patients with inflammatory bowel disease (IBD), including both Crohn's disease and ulcerative colitis. The skin manifestations associated with IBD are polymorphic and can be classified into 4 categories according to their pathophysiology: (1) specific, (2) reactive, (3) associated, and (4) induced by IBD treatment. Cutaneous manifestations are regarded as specific if they share with IBD the same granulomatous histopathological pattern: perianal or metastatic Crohn's disease (commonly presenting with abscesses, fistulas or hidradenitis suppurativa-like features) is the prototype of this setting. Reactive cutaneous manifestations are different from IBD in the histopathology but have close physiopathological links: pyoderma gangrenosum, a neutrophil-mediated autoinflammatory skin disease typically manifesting as painful ulcers, is the paradigm of this group. Among the cutaneous diseases associated with IBD, the most commonly seen are erythema nodosum, a form of panniculitis most commonly involving bilateral pretibial areas, and psoriasis, a T helper 1/T helper 17-mediated erythematous squamous inflammatory disease. Finally, the number of cutaneous adverse reactions because of IBD therapies is progressively increasing. The most frequent drug-induced cutaneous manifestations are psoriasis-like, eczema-like, and lichenoid eruptions, as well as cutaneous lupus erythematosus for biologics, and nonmelanoma skin cancer, mainly basal cell and squamous cell carcinomas for thiopurines.

Autoinflammatory skin disorders in inflammatory bowel diseases, pyoderma gangrenosum and Sweet's syndrome: a comprehensive review and disease classification criteria.

Pyoderma gangrenosum (PG) and Sweet's syndrome (SS) are skin diseases usually presenting with recurrent ulcers and erythematous plaques, respectively. The accumulation of neutrophils in the skin, characteristic of these conditions, led to coin the term of neutrophilic dermatoses to define them. Recently, neutrophilic dermatoses have been included in the group of autoinflammatory diseases, which classically comprises genetically determined forms due to mutations of genes regulating the innate immune response. Both PG and SS are frequently associated with inflammatory bowel diseases (IBDs); however, IBD patients develop PG in 1-3 % of cases, whereas SS is rarer. Clinically, PG presents with deep erythematous-to-violaceous painful ulcers with well-defined borders; bullous, pustular, and vegetative variants can also occur. SS is characterized by the abrupt onset of fever, peripheral neutrophilia, tender erythematous skin lesions, and a diffuse neutrophilic dermal infiltrate. It is also known as acute febrile neutrophilic dermatosis. Treatment of PG involves a combination of wound care, topical medications, antibiotics for secondary infections, and treatment of the underlying IBD. Topical therapies include corticosteroids and the calcineurin inhibitor tacrolimus. The most frequently used systemic medications are corticosteroids and cyclosporine, in monotherapy or in combination. Dapsone, azathioprine, cyclophosphamide, methotrexate, intravenous immunoglobulins, mycophenolate mofetil, and plasmapheresis are considered second-line agents. Hyperbaric oxygen, as supportive therapy, can be added. Anti-TNF-α agents such as etanercept, infliximab, and adalimumab are used in refractory cases. SS is usually responsive to oral corticosteroids, and the above-mentioned immunosuppressants should be considered in resistant or highly relapsing cases.

Basosquamous cell carcinoma: a survey of 76 patients and a comparative analysis of basal cell carcinomas and squamous cell carcinomas.

BACKGROUND: Basosquamous carcinoma (BSC) is a rare epithelial tumor with a still confusing terminology. Since 2005 a more comprehensive and broader classification has existed. AIM: To retrospectively review our cases of BSC according to the new WHO definition and to re-evaluate their clinical and demographic characteristics and the margin involvement after traditional surgical excision. The data were compared with the same results obtained by basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs). PATIENTS AND METHODS: Histologically confirmed carcinomas observed in our Department during a sixteen-year period (1994-2011) were studied. Surgical excision was evaluated following the international guidelines. Histopathologic subtypes of BSC were classified in accordance with accepted criteria. RESULTS: Seventy-six patients had a BSC, 305 a SCC, 3,643 a BCC. There were significant differences among the median age of BSCs, the total BCCs and Non-Aggressive BCCs (74.7, 68.8 and 68.3 years respectively; p<0.05). BSC was more significantly located on head-neck region than Non-Aggressive BCC (p<0.04), and less on trunk than Mixed Histology BCC (p<0.01) and Non-Aggressive BCC (p<0.005). BSC has higher prevalence of positive margins after excision than total (p<0.03) and Non-Aggressive BCC (p<0.001). CONCLUSION: Basosquamous carcinoma fits to a tumor type with a different behavior pattern from non-aggressive basal cell carcinoma and more similar to squamous cell carcinoma or aggressive variants of basal cell carcinoma. Its infiltrative growth and the stromal reaction patterns give enough evidence to support the notion of considering basosquamous carcinoma as a relatively aggressive tumor.

Pyoderma gangrenosum, acne and suppurative hidradenitis syndrome following bowel bypass surgery.

The clinical triad of pyoderma gangrenosum (PG), acne and suppurative hidradenitis (PASH) has recently been described as a new disease entity within the spectrum of autoinflammatory syndromes, which are an emerging group of inflammatory diseases distinct from autoimmune, allergic and infectious disorders. PASH syndrome is similar to PAPA (pyogenic arthritis, acne and PG), but it differs in lacking the associated arthritis and on a genetic basis. PAPA syndrome is caused by mutations in a gene involved in the regulation of innate immune responses, the PSTPIP1, while no mutations have been detected to date in patients with PASH syndrome. We report a young male patient who developed coexisting disseminated PG, typical suppurative hidradenitis and acneiform eruption on the face, after he had undergone bowel bypass surgery for obesity. The cutaneous manifestations associated with bowel bypass syndrome often mimic PG or other neutrophilic dermatoses, suggesting a pathogenesis related to neutrophil-mediated inflammation for this condition. This is the first report describing PASH syndrome after bariatric surgery, and we propose to include such neutrophilic dermatoses in the list of complications occurring after bowel bypass surgery. Extensive genetic studies may help to clarify the etiopathogenesis of PASH as well as of autoinflammatory diseases in general.

Vulvar pyoderma gangrenosum with renal involvement.

Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis of unknown etiology which usually occurs over the lower extremities; however, unusual presentations such as that involving the genital region have been described. Extracutaneous involvement of PG in the form of sterile neutrophilic infiltrates in various organs has infrequently been reported. We hereby describe a case of PG that was limited to the vulvar and perianal area in a 37-year-old female, with associated renal involvement in the form of a slight increase in the serum creatinine, microhematuria of glomerular origin and proteinuria. The patient had a rapid response of both her mucocutaneous lesions and renal dysfunction after the initiation of systemic steroids. The present case highlights the importance of evaluating all patients with PG for extracutaneous disease to avoid potentially harmful diagnostic or therapeutic procedures. Two other reasons for interest are the localized presentation of disease on the genital region and the presence of vascular involvement, albeit without signs of true vasculitis, vascular changes possibly being a histological hallmark of PG involving genitalia.

Tomesa balneophototherapy in mild to severe psoriasis: a retrospective clinical trial in 174 patients.

Psoriasis is a chronic inflammatory skin disease with a high social and psychological impact on the quality of life of patients. Tomesa balneophototherapy is based on bathing in a magnesium-rich salt solution combined with exposure to narrowband ultraviolet B phototherapy. We conducted a retrospective clinical trial on 174 patients affected by mild to severe psoriasis undergoing Tomesa balneophototherapy. The basal course consisted of three to five sessions per week for a total of 30 sessions. Subsequently, patients could continue with a maintenance course of one session per week for a total of 30 sessions. We recorded a significant reduction of the mean Psoriasis Area and Severity Index (PASI) index with an achievement of at least PASI 75 in 52.1% of the 119 patients who completed the basal course and an improvement of the 'quality of life' of patients. The good efficacy obtained by this treatment, and the psychological impact on the quality of life of patients, demonstrated that Tomesa balneophototherapy could be a good option for the treatment of a chronic disease associated with psychological distress, like psoriasis.

Interactions between inflammation and coagulation in autoimmune and immune-mediated skin diseases.

Inflammation and coagulation systems are simultaneously activated in autoimmune and immune-mediated skin disorders, and the cross-talk that amplifies and maintains their activation seems to have both local and systemic implications. This interplay occurs in bullous pemphigoid (BP), the prototype autoimmune blistering disease in which eosinophil recruitment and thrombin generation locally contribute to the formation of bullae and inflammatory tissue damage. Moreover, the systemic activation of coagulation may explain the increased thrombotic risk observed in BP patients. Atopic dermatitis (AD), a chronically relapsing immune-mediated inflammatory skin disease, also involves the local and systemic activation of coagulation, which means that a prothrombotic state could theoretically develop, although the incidence of thrombosis is not increased in AD patients probably because of their young age. In psoriasis, a erythematous-squamous inflammatory immune-mediated skin disorder, the activation of coagulation seems to be mainly systemic and related to systemic inflammation, thus potentially contributing to the disease-related increase in cardiovascular risk in this disease. The activation of coagulation has also been suggested an additional pathomechanism in dermatitis herpetiformis (DH), a chronic-relapsing autoimmune skin disease associated with gluten sensitivity and celiac disease, but its precise role has not yet been defined. Taken together, these data provide the rationale for controlled clinical trials aimed at evaluating the usefulness of anticoagulant treatment in autoimmune skin disorders to counteract the local and systemic effects of coagulation activation.

Three cases of primary cutaneous lymphoblastic lymphoma: microarray-based comparative genomic hybridization and gene expression profiling studies with review of literature.

Lymphoblastic lymphoma (LBL) is a neoplasm of precursor B- or T-lymphocytes, and primary skin involvement is uncommon. The aim of the study was to review all reported primary cutaneous (PC)-LBLs and to examine three new cases to better characterize this neoplasm. Two of our patients showed a pre-B phenotype (PC-B-LBL) and one a never-reported pre-T phenotype (PC-T-LBL). The patient with PC-T-LBL showed an aggressive course, while those with PC-B-LBL showed a complete remission (CR) after polychemotherapy. Cytogenetic analysis and gene expression profiling (GEP) were performed on one case of PC-B-LBL and on that of PC-T-LBL. A specimen of PC-B-LBL and two specimens (early and late stage) of PC-T-LBL were investigated by microarray-based comparative genomic hybridization (CGH). All specimens revealed trisomy of chromosome 4. PC-T-LBL showed a gain of 1p36.33-p22.1 in the early stage and multiple chromosome gains/losses in the late stage. Our data suggest that trisomy 4 could be detected early in LBL and gain of 1p36.33-p22.1 could be an interesting marker in PC-T-LBL. LBL is an aggressive disease but, only in B-LBL, the cutaneous presentation seems to be a favorable prognostic factor and polychemotherapy is the best therapeutic approach. We suggest that PC-LBL should be included as a provisional clinicopathologic entity in future cutaneous lymphoma classification.

Cutaneous T-cell/histiocyte-rich B-cell lymphoma: a case report and review of the literature.

BACKGROUND: T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) primarily presenting on the skin is an extremely rare entity with only sporadic cases reported in the literature. METHODS: We here report an extraordinary case of primary cutaneous THRLBCL with self-healing and 24 months of follow-up. RESULTS: The lesion was a dermohypodermal/subcutaneous circumscribed ulcerated nodosity. Histological examination with immunohistochemical, molecular analysis and comparative genomic hybridization were performed. A complete staging was negative for secondary involvement. CONCLUSION: Our case is remarkable because it is the second well-documented primary cutaneous THRLBCL in which we observed a complete self-regression of skin lesions without recurrences or dissemination of the disease. According to the literature, we highlight that the tumoral microenvironment, in our case, could play a relevant role in stopping lymphoma growth. Furthermore, this case supports the observation that THRLBCL primarily presenting on the skin shows an overall good prognosis.