Remestemcel-L for the treatment of graft versus host disease.

INTRODUCTION: Remestemcel-L, a third-party, off-the-shelf preparation of bone-marrow derived mesenchymal stromal cells (MSCs), has been developed for experimental use in acute graft-versus-host disease (aGvHD) and other immune-mediated conditions. Several preclinical and clinical studies have indeed suggested the potential of human mesenchymal stromal cells (MSCs) as an effective treatment for steroid-refractory aGvHD. However, an unambiguous demonstration of efficacy is still lacking. Areas covered: This review critically examines the biologic rationale supporting MSCs use in aGvHD and analyzes the results of published clinical trials in this setting, with a particular focus on the potential benefits and drawbacks of Remestemcel-L. For this purpose, a systematic literature search was performed in PubMed using the following keywords: 'mesenchymal stromal cells', 'mesenchymal progenitor cells', 'multipotent stromal cells', 'mesenchymal cells', 'MSC', 'Remestemcel-L', 'Prochymal', and 'graft-versus-host disease' or 'GvHD'. Expert commentary: Remestemcel-L represents a promising alternative to second-line immunosuppressive agents for the treatment of steroid-refractory aGvHD. Despite the safety and the favorable risk/benefit profile of this cell product, which has been demonstrated in several phase I-II studies, large and prospective randomized trials are required to confirm its efficacy in aGvHD and to define the optimal schedule of administration in terms of infusion timing, cell dose and pharmacological synergism.

Neutrophilic dermatoses and inflammatory bowel diseases.

Pyoderma gangrenosum (PG) and Sweet's Syndrome (SS) are inflammatory skin diseases caused by the accumulation of neutrophils in the skin and, rarely, in internal organs, which led to coining the term of neutrophilic dermatoses (ND) to define these conditions. Recently, ND have been included among the autoinflammatory diseases, which are forms due to mutations of genes regulating the innate immune responses. Both PG and SS are frequently associated with inflammatory bowel diseases (IBD), a group of chronic intestinal disorders which comprises ulcerative colitis and Crohn's disease and whose pathogenesis involves both the innate and adaptive immunity in genetically prone individuals. Patients with IBD develop PG in 1-3% of cases, while SS is rarer. PG presents with deep erythematous-to-violaceous painful ulcers with undermined borders, but bullous, pustular, and vegetative variants can also occur. SS, also known as acute febrile neutrophilic dermatosis, is characterized by the abrupt onset of fever, peripheral neutrophilia, tender erythematous skin lesions and a diffuse neutrophilic dermal infiltrate. In this review that will be focused on PG and SS, we will describe also the aseptic abscesses syndrome, a new entity within the spectrum of ND which frequently occurs in association with IBD and is characterized by deep abscesses mainly involving the spleen and skin and by polymorphic cutaneous manifestations including PG- and SS-like lesions.

Evidence for vitamin D deficiency and increased prevalence of fractures in autoimmune bullous skin diseases.

BACKGROUND: Vitamin D deficiency plays a role in autoimmune diseases and risk of fractures. No data are available on vitamin D levels and vertebral fractures in autoimmune bullous skin diseases. OBJECTIVES: To assess serum vitamin D levels and the prevalence of vertebral fractures in patients with pemphigus vulgaris (PV) and bullous pemphigoid (BP), potentially fatal autoimmune bullous disorders. METHODS: We studied 13 consecutive inpatients with untreated active PV (six men and seven women, mean ± SD age 53·5 ± 14·3 years), 15 with BP (seven men and eight women, mean ± SD age 76·9 ± 12·4 years) and 28 age-, body mass index- and sex-matched controls. The 25-hydroxyvitamin D (25-OHD) levels and presence of vertebral fractures on spinal X-ray were assessed in all subjects. RESULTS: In patients with PV, 25-OHD levels were lower (mean ± SD 12 ± 4·4 ng mL(-1) ) and prevalence of severe hypovitaminosis D higher (62%) than in controls (mean ± SD 22·2 ± 11·7 ng mL(-1) , P = 0·012; 23%, P = 0·0047, respectively). The prevalence of fractures was 54% and 31% in patients with PV and controls, respectively. Patients with BP showed lower 25-OHD levels (mean ± SD 9·6 ± 7·2 ng mL(-1) ) and higher prevalence of severe hypovitaminosis D (73%) than controls (mean ± SD 22·6 ± 18·7 ng mL(-1) , P = 0·022; 27%, P = 0·01, respectively). The prevalence of fractures tended to be higher in patients with BP than in controls (67% vs. 33%, respectively, P = 0·068). CONCLUSIONS: The low 25-OHD levels found in PV and BP may suggest a role for this agent in their pathogenesis. The increased prevalence of fractures should be taken into consideration in patients who must be given corticosteroids.

Inflammatory cells, cytokines and matrix metalloproteinases in amicrobial pustulosis of the folds and other neutrophilic dermatoses.

Amicrobial pustulosis of the folds (APF) is a rare cutaneous disease characterized by relapsing sterile pustules frequently associated with autoimmune disorders. Although APF pathophysiology is still undefined, scattered reports suggest involvement of neutrophils. The aim of the present study is to evaluate the role of the skin inflammatory infiltrate, selected multifunctional cytokines and effectors of tissue damage in APF and other neutrophilic dermatoses. We studied, by immunohistochemical methods, inflammatory cell markers (CD3, CD163, myeloperoxidase), cytokines (TNF-alpha, IL-8, IL-17), metalloproteinases (MMP-2, MMP-9) and vascular-endothelial-growth-factor (VEGF) in lesional skin from six patients with APF, 11 with pyoderma gangrenosum (PG), 7 with Sweet's syndrome, and in 20 normal skin samples. Immunoreactivities of CD3, CD163, myeloperoxidase, TNF-alpha, IL-8, IL-17, MMP-2, MMP-9 and VEGF were significantly higher in APF, PG and Sweet's syndrome than in controls (p=0.0001). IL-8 was more expressed in PG than in APF (P=0.002) and Sweet's syndrome (p=0.001). In APF, MMP-9 reactivity was higher than in Sweet's syndrome (p=0.035), but less intense than in PG (p=0.020). Our study supports the role of proinflammatory cytokines/chemokines and MMPs as important effectors for the tissue damage in APF similarly to classic neutrophilic dermatoses.

Role of inflammatory cells, cytokines and matrix metalloproteinases in neutrophil-mediated skin diseases.

Pyoderma gangrenosum (PG) is a rare, immune-mediated inflammatory skin disease presenting with painful ulcers having undermined edges. Less commonly, bullous and vegetative variants exist. Histology consists of a neutrophil-rich dermal infiltrate. We characterized immunohistochemically the infiltrate in different variants of PG and in another neutrophilic dermatosis as Sweet's syndrome. We studied 21 patients with PG, eight with Sweet's syndrome and 20 controls, evaluating skin immunoreactivity for inflammatory cell markers (CD3, CD163 and myeloperoxidase), cytokines [tumour necrosis factor (TNF)-α, interleukin (IL)-8 and IL-17], metalloproteinases (MMP-2 and MMP-9) and vascular endothelial growth factor (VEGF). Immunoreactivities of CD3, CD163, myeloperoxidase, TNF-α, IL-8, IL-17, MMP-2, MMP-9 and VEGF were significantly higher in both PG and Sweet's syndrome than in controls (P=0·0001). Myeloperoxidase (neutrophil marker), IL-8 (cytokine chemotactic for neutrophils) and MMP-9 (proteinase-mediating tissue damage) were expressed more significantly in both ulcerative and bullous PG than in vegetative PG as well as in Sweet's syndrome (P=0·008-P=0·0001). In ulcerative PG, the expression of CD3 (panT cell marker) and CD163 (macrophage marker) were significantly higher in wound edge than wound bed (P=0·0001). In contrast, the neutrophil marker myeloperoxidase was expressed more significantly in wound bed than wound edge (P=0·0001). Our study identifies PG as a paradigm of neutrophil-mediated inflammation, with proinflammatory cytokines/chemokines and MMPs acting as important effectors for the tissue damage, particularly in ulcerative and bullous PG where damage is stronger. In ulcerative PG, the wound bed is the site of neutrophil-recruitment, whereas in the wound edge activated T lymphocytes and macrophages pave the way to ulcer formation.

The duration of clinical remission of photochemotherapy and narrow-band UV-B phototherapy in the treatment of psoriasis: a retrospective study.

PUVA and UVB-NB phototherapy have an established role in the treatment of moderate-to-severe psoriasis. Even though psoriasis patients often require continuous treatments, inadequate attention is devoted to the duration of remission after the treatment. The purpose of this retrospective study is to assess which phototherapeutic regimen induces a longer remission. Twenty patients with psoriasis were included: 10 patients received PUVA and 10 patients received UVB-NB. We consider as a cycle the therapeutic period needed to reach clinical remission. The comparison between the average number of days in remission revealed that PUVA induces a longer remission period than UVB-NB: PUVA 386 days (ds +/- 321), UVB-NB 298 days (ds +/- 257). Although the difference of the duration of remission is not statistically significant, a trend is seen and patients treated with PUVA remain clear for a period about 88 days longer than that of patients treated with UVB-NB. The differences in the duration of remission of psoriasis therapies must be considered in planning a patients course of treatment.

A telephone survey on the reasons for non-attendance in a dermatological clinic.

AIM: Long waiting time before obtain medical attention is a significant problem that affects all specialties and especially dermatology, where a quick observation is required because of the rapid mutation of skin lesions pattern. Non-attendance (NA) is one of the aspects that is most involved in the length of waiting lists. The aim of this study was to investigate the different reasons for NA in the dermatological clinic as to improve the booking system and allow patients to be visited in a shorter time. METHODS: All the patients who failed to attend a visit, booked in the dermatological service during a two months period, were contacted by telephone to determine the reasons for having missed the appointment. For each patient details as age, sex, kind of visit (initial visit, follow-up visit or visit with priority level) and type of clinic (general dermatology, second level dermatology or paediatric dermatology) were collected and analyzed. RESULTS: The overall NA rate was 11.19% and different reasons for NA were found, namely forgetfulness of the appointment, work-related problems and concomitant illness. CONCLUSION: The most frequent reason for NA is forgetfulness of the appointment and it could be explained by the long time elapsing between booking and visit. Different techniques to reduce forgetfulness have been suggested; in our case the use of a unique call centre that coordinates booking for all the health structures in Milan and the sending of a reminder mobile message have led to good results with a NA rate lower than in other studies.

Non-invasive evaluation of tacalcitol plus puva versus tacalcitol plus UVB-NB in the treatment of psoriasis: "right-left intra-individual pre/post comparison design".

Photochemotherapy with psoralen plus ultraviolet A(PUVA) and phototherapy with UVB narrow band (UVB-NB) are used in the treatment of psoriasis. Numerous studies have shown that the additional administration of either topical or systemic antipsoriatic agents may effectively increase the efficacy of these therapies. This study aimed to compare through objective data the efficacy of topical tacalcitol in combination with PUVA or UVB-NB versus PUVA and UVB-NB monotherapy in the treatment of mild to moderate chronic plaque psoriasis. Modified Psoriasis Area and Severity Index (PASI) score, transepidermal water loss (TEWL) and stratum corneum hydration were used to monitor the restoration of skin barrier in the psoriatic plaques of 40 patients during photochemotherapy. The study was a right-left, intra-individual, pre/post comparison trial. PUVAand UVB-NB treatments were given three times a week. On those plaques localized on the right side of the body tacalcitol ointment was applied once a day, in the evening. Corneometry, TEWL and modified PASI score were used to evaluate the response to the treatment at baseline, one month and two months. Thirty-six of the forty enrolled subjects completed the study. The comparison between combination treatments and the PUVA/UVB-NB monotherapy showed no significant differences with regard to modified PASI index. However, significant differences were recorded with regard to TEWL and corneometry. The combination of tacalcitol plus PUVA or tacalcitol plus UVB-NB restored epidermal barrier functions as well as skin hydration faster than PUVA or UVB-NB monotherapy (TEWL: p=0.0050 and corneometry: p=0.003). The combination of tacalcitol plus UVB-NB allowed a better restoration of skin barrier functions than tacalcitol plus PUVA (p=0.013). In conclusion, the combination of tacalcitol plus PUVA or plus UVB-NB improves the therapeutic result. In addition, the data from TEWL and skin hydration suggest a means in which tacalcitol plus UVB-NB induces a better normalization of skin biophysical parameters.