LRP1/CD91 is highly expressed in monocytes from patients with vitiligo - even after repigmentation.

Vitiligo pathophysiology is mediated by antigen-specific cytotoxic T cells. Environmental stressors cause susceptible melanocytes to secrete damage-associated molecular patterns (DAMPs). DAMPs are recognized by receptors such as the endocytic low-density lipoprotein receptor-related protein (LRP1/CD91), expressed in antigen-presenting cells, which activate self-reactive CD8+ T cells, leading to melanocyte destruction. Within this response, interferon gamma triggers production of cytokine CXCL10, recruiting more activated T cells causing further melanocytic damage. We hypothesized that expression of LRP1/CD91 was higher in vitiligo patients compared to non-vitiligo individuals. And further that levels/expression of CXCL10 in plasma were linked to disease severity. We enrolled forty individuals in this study: 18 patients with vitiligo and 22 healthy volunteers. We assessed LRP1/CD91 expression and plasma CXCL10 in patients with vitiligo and healthy volunteers. Additionally, vitiligo patients received combined treatment for 16 weeks following which the said parameters were reassessed. Vitiligo Area Scoring Index was calculated before and after treatment for these patients. Analysis of LRP1/CD91 MFI values in monocytes from vitiligo patients showed high surface levels of LRP1/CD91 than from healthy volunteers (10.50 ± 0.77 vs. 6.55 ± 0.77 MFI units, p < 0.001). This expression did not change after treatment. Plasma levels of CXCL10 were higher in vitiligo patients than healthy volunteers (93.78 ± 7.73 vs. 40.17 ± 6.25 pg/ml). The patients with a good clinical response to treatment had a parallel reduction in plasma CXCL10 levels (105.8 ± 18.44 vs. 66.13 ± 4.87 pg/ml) before and after treatment. LRP1/CD91 expression may reflect susceptibility to vitiligo. Plasma levels of CXCL10 can represent a biomarker for monitoring treatment response. LRP1 and CXCL10 may represent therapeutic targets.

Efficacy and Safety of Imiquimod 3.75% from Lmax in Actinic Keratosis According to Fitzpatrick Skin Type.

BACKGROUND: Imiquimod 3.75% is an effective actinic keratosis (AK) treatment that detects and clears clinical and subclinical lesions across an entire sun-exposed field such as the full face or balding scalp. OBJECTIVE: To determine the efficacy and safety of imiquimod 3.75% according to patients' Fitzpatrick skin type. METHODS: Data were pooled from two identical 14-week, double-blind studies. Patients were randomized to imiquimod 3.75% or placebo and applied study medication to the full face or balding scalp each day for 2 two-week treatment cycles separated by a two-week treatment-free interval. End of study (EOS) was eight weeks after the last treatment application. Patients were subgrouped according to whether they had Fitzpatrick skin types I or II (FST I/II), or types III or IV (FST III/IV). Efficacy was analyzed using the reduction in lesions from Lmax (maximum lesion count during treatment) to EOS. This assesses whether clinical lesions, and subclinical lesions which become detectable during treatment, are cleared. Safety was assessed by monitoring local skin reactions. RESULTS: In total, 173 patients with FST I/II and 142 with FST III/IV were included. The median percentage reductions in lesions from Lmax to EOS were similar in patients treated with imiquimod 3.75% with FST I/II and FST III/IV (94.2% and 89.7%, respectively) as were the median absolute reductions in lesions from Lmax to EOS (19.0 and 17.0, respectively). These reductions were significantly greater with imiquimod 3.75% versus placebo in the two respective FST subgroups (P<0.0001). The frequency of local skin reactions was similar in the two imiquimod 3.75% FST subgroups. CONCLUSIONS: Imiquimod 3.75% is well tolerated and effective at clearing clinical and subclinical lesions across large areas of sun-exposed skin in patients with FST I-IV, and so can be considered for AK patients with any of these skin types.

Atopic dermatitis: impact on quality of life and patients' attitudes toward its management.

This work studies atopic dermatitis in the following terms: impact on patients' life; patients' satisfaction and attitudes toward topical pharmacological treatment and medical recommendations (regarding hygienic and preventive strategies) and patients' and dermatologists' impressions of severity at the moment of consultation. To this end, an epidemiological, multicentre, cross-sectional study was carried out. In total, 191 dermatologists collected data from 322 patients (163 children, 159 adults). Poor agreement between specialists' and patients' criteria was found and patients with higher severity of affectation showed higher impacts on sleep/rest, emotional and school/ professional fulfillment (p<0.001). Moreover, reported compliance with pharmacological treatment and medical recommendations was high but patients' satisfaction with these recommendations was lower than with respect to pharmacological treatment. These results highlight that although reported compliance was high, there were still non-compliance attitudes and concerns about treatments that should be answered. Finally, a significant impact on patients' life was confirmed.

Acquired bullous dermatosis associated with IgA multiple myeloma: a case report.

We present the case of a patient with IgA paraprotein who developed hemorrhagic subepidermal vesicles and bullae with numerous neutrophils. Direct immunofluorescence test (DIF) showed weak deposits of IgA lambda paraprotein at the dermal-epidermal junction and at the intercellular level in the basal layer of the epidermis, and stronger deposits in a perivascular and diffuse pattern in the dermis. Indirect immunofluorescence (IIF) test revealed the presence of circulating IgA lambda antibodies reacting with the intercellular space of monkey and guinea pig esophagus and human skin. A blood test revealed an IgA lambda paraprotein and multiple myeloma stage I(0) was diagnosed in a later hematological study. Dapsone was prescribed and cutaneous lesions improved. This is the second report of subepidermal vesicles and bullae with dermal deposits of IgA paraprotein appearing prior to diagnosis of an IgA multiple myeloma, and it is a unique case with circulating IgA lambda antibodies reacting with the intercellular space of epithelia.

Treatment of psoriasis with anti-TNF drugs during pregnancy: case report and review of the literature.

Published experiences of TNF-alpha inhibition during pregnancy consist of a limited number of case reports, series and ongoing registry data in patients with arthritis and inflammatory bowel disease. A 28-year-old woman - with psoriasis vulgaris since she was 8 years of age and generalized pustular psoriasis during her first pregnancy (partially controlled with ciclosporin, oral prednisone and topical corticosteroids, when lupus anticoagulant was detected at another hospital) - presented 4 months after delivery with severe psoriasis (PASI = 15.4) that did not respond to ciclosporin (3 mg/kg/day). Ten days after the first infusion of infliximab (5 mg/kg), when the patient became aware that she was pregnant again, there was PASI75 response, and the patient wished to continue this treatment after being fully informed. Complete blanching was achieved by week 6 of treatment, and was maintained thereafter until the moment of writing (19 months after the start of treatment). She gave birth by caesarean delivery to a healthy female baby, who was breastfed for 1 month and has developed normally. The current report extends the available evidence on successful infliximab treatment in pregnant women, with the first case of a patient with psoriasis who presented impetigo herpetiformis during her previous pregnancy. No detectable adverse effects were detected in the neonate, despite potential exposure to infliximab throughout gestation and breastfeeding. Even though absolute safety is difficult to prove, available data suggest that women who become pregnant while taking infliximab or other anti-TNFalpha agents can be reassured regarding the continuation of pregnancy.

Treatment of acrodermatitis continua of Hallopeau with TNF-blocking agents: case report and review.

Acrodermatitis continua of Hallopeau (ACH) is a rare acropustular eruption, characterized by sterile pustules, paronychia and atrophic skin changes, onychodystrophy and osteolysis of the distal phalanges of the fingers and toes. It is considered to be a variant of pustular psoriasis with a chronic relapsing course and frequent refractoriness to many therapeutic modalities, which can be amenable to successful treatment by tumor necrosis factor alpha antagonists. We report 1 patient with pustular psoriasis and ACH whom we have treated successfully with etanercept (for 30 months) and then adalimumab (for 13 months and ongoing). Blanching was initially achieved with etanercept 50 mg twice a week, but suppression of periungual inflammation then required combination therapy with etanercept 50 mg twice a week and methotrexate 10 mg weekly; lower doses of both drugs did not allow complete control of the disease. Eventually, adalimumab 40 mg every 2 weeks has provided the most cost-effective response in this patient, allowing maintenance of response with partial nail regrowth under monotherapy.

Paraneoplastic pemphigus with negative direct immunofluorescence in epidermis or mucosa but positive findings in adnexal structures.

INTRODUCTION: Paraneoplastic pemphigus (PNP) is considered an autoimmune, multiorgan disease caused by antiplakin antibodies. We present three PNP patients who had negative epithelial direct immunofluorescence (DIF) findings in one or more biopsies. PATIENTS: An early lip biopsy of uninvolved oral epithelia in patient 1 was negative. A later biopsy from foreskin showed intense intercellular immunoglobulin G (IgG) deposits in the epithelia. In the early phase of the disease in patient 2, the intercellular fluorescence was negative in the epidermis, while intercellular IgG and C3 were observed in the sweat ducts. A later biopsy showed weak intercellular epidermal IgG and C3 fluorescence. Patient 3 showed intercellular IgG and/or C3 in follicular, sebaceous and sweat duct structures in several biopsies. No intercellular IgG or C3 was observed in the epithelia. DISCUSSION: The presence of immunoreactants in adnexal structures suggests that desmoplakins can be more strongly expressed in adnexa than in the epidermis, facilitating visualization of antibody deposits. CONCLUSIONS: Negative DIF findings in epithelia do not rule out the diagnosis of PNP, and the presence of IgG and/or C3 at the intercellular level of adnexal structures can help establish this diagnosis.

Double mucosal and myocutaneous island flap: a one-stage reconstruction for full-thickness lower eyelid defect.

BACKGROUND: Basal cell carcinomas (BCCs) on the lower eyelid are not uncommon, and depending on their histological type, they can be highly aggressive and difficult to eradicate. Numerous techniques have been proposed for the reconstruction of the lower lid margin after surgical excision of the lesion. OBJECTIVE: To describe a double-flap technique consisting of a mucosal and myocutaneous V-Y advancement flap to repair full-thickness lower lid margin defects in a one-stage procedure under local anesthesia. METHODS: Over a 12-year period (1995-2007), 33 patients with BCC underwent lower eyelid reconstruction. After tumor excision, a triangular mucosal flap with a central pedicle was used to repair the inner layer. A similar triangular-shaped myocutaneous flap was obtained from the inferior orbicularis oculus muscle and sutured in a V-Y fashion to build the outer layer. RESULTS: All 33 patients achieved satisfactory functional and cosmetic results. Slight scleral show and discrete rounded lower eyelid were the main adverse effects. No additional surgery was needed. CONCLUSION: This double V-Y advancement flap is a simple, useful alternative procedure to close full-thickness defects in the lower lid margin. Aesthetic and functional outcome is good.

Abortive or minimal-growth hemangiomas: Immunohistochemical evidence that they represent true infantile hemangiomas.

BACKGROUND: Infantile hemangiomas have a characteristic natural history of rapid proliferation in the first weeks of life followed by spontaneous involution. At birth, they may be present as a precursor lesion. Sometimes one may see precursor lesions that never undergo a growth phase or that undergo minimal growth. It is unclear the exact nature of these precursor-like lesions. OBJECTIVE: We sought to describe the morphology and histopathology of these precursor-like lesions. METHODS: We describe 4 patients with macules resembling precursor lesions of hemangiomas that did not show proliferation phase or minimal growth. The histopathologic and immunohistochemical study with glucose transporter-1 was performed in all of these cases. RESULTS: The skin biopsy specimen showed superficial ectatic vessels that reacted with anti-glucose transporter-1 antibodies. All skin biopsy specimens exhibited capillary lobules in papillary dermis and, in two of them, in the reticular dermis and subcutis. LIMITATIONS: This text is limited by the number of cases reported. CONCLUSIONS: Precursor lesions of hemangioma that do not show proliferation phase or minimal growth represent, in the view of glucose transporter-1 immunoreactivity, true hemangiomas of infancy with an aborted or arrested growth cycle.

Cutaneous adverse effects of biological therapies for psoriasis.

Psoriasis is a common immune-mediated disease that affects approximately 2% of the world's population. Most patients require lifelong treatment and many of the current systemic therapies are complicated by significant toxicities or inconvenience when administered long-term. New biological psoriasis therapies have been developed, which are thought to act through targeted molecular pathways, so as to administer them continuously without causing any relevant toxicity. Nevertheless, acute and chronic dermatological adverse effects are frequently observed, but knowledge about them is limited and the potential pathogenic mechanisms have not yet been identified. We present 7 patients from our dermatological department who presented different cutaneous adverse effects (2 erythrodermias, 1 palmoplantar pustulosis, 1 flexural psoriasis, 1 eczema, 1 neutrophilic dermatosis and 1 papular eruption) during treatment with biological drugs (4 patients with efaluzimab, 2 patients with infliximab and 1 patient with etanercept). The use of biological agents is expanding worldwide as new alternative treatments for psoriasis and other chronic inflammatory diseases. The increased use of these treatments has allowed identification of their acute and chronic systemic adverse events. Nevertheless, the dermatological adverse events of these biological drugs are less well known due to few reports about them and lack of information about their pathogenic mechanisms. Exact diagnosis of these cutaneous eruptions is very important in order to decide the need for discontinuation of the biological treatment.

Description and management of cutaneous side effects during cetuximab or erlotinib treatments: a prospective study of 30 patients.

BACKGROUND: Drugs such as cetuximab or erlotinib, which inhibit the epidermal growth factor receptor, are increasingly being used in treatment of solid tumors. This has led to the appearance of new secondary effects. OBJECTIVE: We sought to describe the cutaneous side effects and their management in patients with cancer treated with cetuximab or erlotinib. METHODS: We clinically examined 30 patients determining type, frequency, treatment, and evolution of side effects. RESULTS: Most patients presented with a cutaneous reaction consisting of a follicular eruption, typically appearing in seborrheic areas within the first 15 days of treatment. Painful fissures in palms and soles and paronychia were the second most common cutaneous toxicities. We also noticed an alteration in hair growth at several months' follow-up. As these secondary effects responded well to treatment, few patients discontinued the antineoplastic therapy because of cutaneous toxicity. LIMITATIONS: This was a prospective but uncontrolled study. CONCLUSION: Although these new targeted therapies have low systemic toxicity because of their high specificity, cutaneous side effects are common and may be serious.

Contact dermatitis due to para-phenylenediamine (PPD) on a temporal tattoo with henna. Cross reaction to azoic dyes.

Henna is used as a hair dye and to make temporary tattoos on the skin. It is usually mixed with p-phenylendiamine (PPD) to increase colour intensity and to reduce the time of fixation on the skin proteins. PPD can cross react with azoic dyes which are used as textile dyes. We studied a patient with skin eczema in the area of a henna temporary tattoo. The epicutaneous tests performed with the standard Trolab and Chemotecnique hair dressing and textile batteries, showed positive results to PPD, p-toluendiamine, 5-4aminophenol, Yellow 3, Orange Red and Red 1, and negative results to three types of henna. The eczema in this patient was due to sensitisation to PPD on a henna tattoo with cross reaction to azoic dyes. The recent fashion of applying temporal tattoos in occidental countries may produce an increase in the frequency of contact dermatitis due to henna mixtures with cross- reaction to related compounds and possibly producing permanent skin changes.

Cutaneous alternariosis in transplant recipients: clinicopathologic review of 9 cases.

OBJECTIVES: We sought to evaluate and review the clinical and histopathologic features of cutaneous infections caused by the environmental opportunistic fungus Alternaria observed in transplant recipients. METHODS: We conducted a retrospective study of cases of cutaneous alternariosis in transplant recipients given a diagnosis in 3 hospitals in Catalonia, Spain, between 1991 and 2001. The clinical and evolution features were reviewed. A panel of histopathologic features was evaluated by two independent observers in all cutaneous biopsy specimens. RESULTS: In all, 9 transplant recipients (8 men and 1 woman) presenting opportunistic cutaneous alternariosis were studied. The patients were 4 renal, 2 cardiac, 1 liver, and 2 lung transplant recipients. All patients were treated with different immunosuppressive therapeutic regimes. The lesions were solitary (3 patients) or multiple grouped (6 patients): papules (4 patients), plaques (5 patients), inflammatory nodules (2 patients), and recurrent cellulitis with secondary ulceration (1 patient), mainly located on the lower extremities. No extracutaneous involvement was detected. A previous traumatic event was recorded in two patients. A total of 12 cutaneous biopsy specimens were reviewed. Biopsy specimens from early lesions (<3 months evolution) were often characterized by the presence of epidermal changes (3/6 pseudoepitheliomatous hyperplasia; 50%), a diffuse dermal mixed inflammatory infiltrate of lymphocytes, plasma cells, histiocytes, neutrophils, and giant cells, and rare and focal granuloma formation. Dermal abscess or necrotizing folliculitis was occasionally noted. In biopsy specimens from more advanced lesions (>3 months evolution), the presence of a granulomatous inflammatory infiltrate was a constant feature. Suppurative granulomas (2/6; 33%) and sarcoidlike granulomas (2/6; 33%) were noted. In all biopsy specimens, fungal structures with a typical round-to-oval, thick refractile wall were identified. CONCLUSION: Different clinical and histopathologic patterns can be noted in cutaneous alternariosis. Clinically the lesions manifest as solitary or grouped papules, plaques, or nodules mainly involving the lower extremities. Histologically, a relationship between the evolution of the cutaneous lesions and granuloma formation is detected. An increased awareness regarding the clinical and histopathologic features of cutaneous alternariosis in transplant recipients is important to achieve early detection and treatment.

Cutaneous necrosis after injection of polyethylene glycol-modified interferon alfa.

Pegylated interferon alfa-2b is a formulation of recombinant human interferon conjugated with polyethylene glycol. Compared with standard interferon alfa injections, this preparation has a longer half-life allowing for once-weekly injections and superior antiviral efficacy in the treatment of hepatitis C when used in combination with ribavirin. Cutaneous side effects caused by interferon are well known. Cutaneous necrosis as a result of interferon alfa is an infrequent complication with unknown pathogenesis, in which a cutaneous local immune-mediated inflammatory process might be involved. We report 5 patients (3 patients with chronic hepatitis C treated with pegylated interferon alfa-2b in association with oral ribavirin and two patients with chronic myelocytic leukemia) who developed local cutaneous reactions at sites of injection after the administration of weekly subcutaneous injections of pegylated interferon alfa-2b at different doses. The ulcers slowly healed with local therapy, but two patients required dose modification of the pegylated interferon alfa-2b and one patient required treatment withdrawal. We review the literature on previously reported cases of cutaneous necrosis after injection of standard interferon alfa or pegylated interferon alfa-2b and discuss the different pathophysiologic mechanisms that might be involved.

Imiquimod 5% cream for the treatment of actinic keratosis: results from a phase III, randomized, double-blind, vehicle-controlled, clinical trial with histology.

BACKGROUND: Increasing evidence suggests imiquimod may be a safe therapeutic option for the treatment of actinic keratosis (AK). The diagnosis and assessment of most AK lesions is made clinically, without histologic confirmation. OBJECTIVE: A phase III, randomized, double-blind, parallel group, vehicle-controlled study evaluated the efficacy of imiquimod 5% cream compared with vehicle in the treatment of AK lesions on the face and balding scalp including pretreatment and posttreatment biopsy specimens. METHODS: A total of 286 patients at 18 centers in 6 European countries with histologically confirmed AK were randomized to either imiquimod 5% cream or vehicle cream. Study cream was applied once per day, 3 days per week, for 16 weeks. Clearance of AK lesions was clinically and histologically assessed at an 8-week posttreatment visit. RESULTS: The complete clearance rate for the imiquimod group was 57.1% versus 2.2% for the vehicle group (P <.001). The partial clearance rate (> or =75% reduction in baseline lesions) for the imiquimod group was 72.1% versus 4.3% for the vehicle group (P <.001). The most common side effects were erythema, scabbing/crusting, and erosions/ulceration. For the imiquimod group the incidence of severe erythema, scabbing/crusting, or erosions/ulceration was 30.6%, 29.9%, and 10.2%, respectively. CONCLUSION: Imiquimod 5% cream used 3 times per week for 16 weeks is an effective treatment for AK. Clinical clearance was established by both clinical observation and histologic analysis.

Acute generalized exanthematous pustulosis induced by terbinafine.

Terbinafine is an allylamine fungicidal agent that is widely used for the treatment of onychomycoses and other fungal infections. Adverse effects may occur in more than 10% of patients receiving oral terbinafine, with cutaneous reactions in 2.7%. We describe the development of acute generalized exanthematous pustulosis in a 36-year-old woman who took oral terbinafine.

Reduction in lesions from Lmax: a new concept for assessing efficacy of field-directed therapy for actinic keratosis. Results with imiquimod 3.75%.

BACKGROUND: Current parameters for assessing the efficacy of actinic keratosis (AK) treatments compare clinical lesions at the start and end of a study. However, the sun-exposed field also contains subclinical lesions which may become detectable during treatment. Lmax, the maximum lesion count during treatment, is a new concept to better assess the efficacy of field-directed AK therapies. Measuring efficacy using the reduction in lesions from Lmax includes for the first time the clearance of both subclinical and clinical lesions. OBJECTIVES: To evaluate the reduction of lesions from Lmax to study end and compare the results with traditional efficacy endpoints using imiquimod 3.75% (IQ3.75%) as an example of field-directed AK therapy. MATERIALS & METHODS: Pooled analysis of data from two 14-week, vehicle-controlled, double-blind studies of IQ3.75%. RESULTS: With IQ3.75%, the median number of lesions increased from 10 at baseline to an Lmax of 22. The median absolute reduction in lesions to study end was 18 from Lmax versus 7 from baseline. The median percentage reduction in AK lesions to study end was 92.2% from Lmax compared with 81.8% from baseline. CONCLUSIONS: The reduction in lesion count from Lmax is a novel efficacy parameter that should become the new way of evaluating field-directed AK therapies since it enables their efficacy against both clinical and subclinical lesions to be accurately determined. Together, the Lmax concept and IQ3.75% represent a new approach for the management of AK across a large sun-exposed field.