Bacterial and viral infections of the nail unit: Tips for diagnosis and management.

The nail unit is the most commonly affected area in hand infections, which can be primary infection or superinfection complicating other nail or skin disorders. Trauma, mechanical or chemical, is usually the trigger enabling infiltration of infectious organisms. Artificial nails and nail polish are also a possible cause of bacterial infection, harboring microorganisms. In severe acute bacterial infection, surgical intervention is often needed to prevent morbidity and disability. Abscess should always be drained, but viral infection such as herpetic whitlow, may mimic an abscess and, in contrast, requires non-operative treatment; to prevent sequelae. A more conservative approach is also generally advisable in less severe bacterial infection, other viral infections and in subacute or chronic nail infection. The present review deals with acute, subacute and chronic bacterial and viral infections of the nail unit, with a focus on diagnostic and treatment options. LEVEL OF EVIDENCE: III, systematic review of level III studies.

Reporting of outcomes in randomized controlled trials on nail psoriasis: a systematic review.

BACKGROUND: Harmonization of outcome measures is needed to increase the value of clinical trials on nail psoriasis. OBJECTIVES: To provide the first step in core outcome set (COS) development for nail psoriasis. METHODS: A systematic review was performed to identify outcome instruments and corresponding outcome domains used in (ongoing) randomized controlled trials. RESULTS: Identified outcome domains included clinical signs, quality of life, symptoms and delivery of care. The Nail Psoriasis Severity Index (NAPSI) was the most commonly used measure to assess clinical signs (74% of studies). Other outcome instruments used included the Nail Area Severity score, composite fingernail score, a Physician's Global Assessment, individual nail features or a combination of these. Heterogeneity in type and reporting (e.g. NAPSI 50, NAPSI 75) of outcome instruments was high and characteristics were often insufficiently reported. In total 43% of studies assessed quality of life, with 3% of studies using a nail psoriasis-specific tool. Assessment of symptoms and delivery of care was limited. CONCLUSIONS: Heterogeneity in the type and reporting of nail psoriasis outcome instruments needs to be addressed in the process towards COS development. Sufficient reporting of instrument characteristics should be encouraged. As nail psoriasis is generally assessed secondarily to psoriasis of the skin or joints, collaboration between different research groups in COS development is needed.

The effect of adalimumab on key drivers in the pathogenesis of psoriasis.

BACKGROUND: The use of recently introduced biologics targeting specific immune mechanisms has identified crucial steps in the pathogenesis of psoriasis. Studying the dynamics of changes of these target mechanisms in sequential skin biopsies during treatment with biologics may reveal potential biomarkers. Correlation between clinical parameters and the expression of specific genes during treatments may identify markers indicative of treatment response. OBJECTIVES: This observational open-label study aimed to provide an overview of important cell biological changes in lesional skin during treatment with adalimumab, and their relationship to clinical improvement. METHODS: Ten patients with moderate-to-severe plaque psoriasis were included and treated with adalimumab for 16 weeks. At baseline, and after 10 days and 16 weeks of treatment clinical scores were assessed and biopsies were taken to examine gene expression at the mRNA and protein level. RESULTS: The expression of marker genes for innate immunity, and epidermal differentiation and proliferation was rapidly restored to normal levels, whereas genes of the adaptive immune system showed a delayed decrease. The static and dynamic course of CD1a+ Langerhans cells and Ki67+ nuclei showed a significant strong correlation to the Psoriasis Area and Severity Index score. No correlation between interleukin-17 expression and clinical scores was found. CONCLUSIONS: The innate immune system is affected during adalimumab treatment well before the changes in the adaptive immune system become apparent. We may speculate that the addition of a treatment with an early effect on adaptive immunity to adalimumab may result in superior effectiveness compared with monotherapies.

Summary of the Dutch S3-guidelines on the treatment of psoriasis 2011. Dutch Society of Dermatology and Venereology.

This document provides a summary of the Dutch S3-guidelines on the treatment of psoriasis. These guidelines were finalized in December 2011 and contain unique chapters on the treatment of psoriasis of the face and flexures, childhood psoriasis as well as the patient's perspective on treatment. They also cover the topical treatment of psoriasis, photo(chemo)therapy, conventional systemic therapy and biological therapy.

Nail Psoriasis, the unknown burden of disease.

BACKGROUND: Psoriasis can be found at several different localizations which may be of various impact on patients' quality of life (QoL). One of the easy visible, and difficult to conceal localizations are the nails. OBJECTIVE: To achieve more insight into the QoL of psoriatic patients with nail psoriasis, and to characterize the patients with nail involvement which are more prone to the impact of the nail alterations caused by psoriasis. METHOD: A self-administered questionnaire was distributed to all members (n = 5400) of the Dutch Psoriasis Association. The Dermatology Life Quality Index (DLQI) and the Nail Psoriasis Quality of life 10 (NPQ10) score were included as QoL measures. Severity of cutaneous lesions was determined using the self-administered psoriasis area and severity index (SAPASI). RESULTS: Patients with nail psoriasis scored significantly higher mean scores on the DLQI (4.9 vs. 3.7, P = <0.001) and showed more severe psoriasis (SAPASI, 6.6 vs. 5.3, P = <0.001). Patients with coexistence of nail bed and nail matrix features showed higher DLQI scores compared with patients with involvement of one of the two localizations exclusively (5.3 vs. 4.2 vs. 4.3, P = 0.003). Patients with only nail bed alterations scored significant higher NPQ10 scores when compared with patients with only nail matrix features. Patients with psoriatic arthritis (PsA) and nail psoriasis experiences more impairments compared with nail psoriasis patients without PsA (DLQI 5.5 vs. 4.3, NPQ10 13.3 vs. 7.0). Females scored higher mean scores on all QoL scores. CONCLUSION: Greater attention should be paid to the possible impact nail abnormalities have on patients with nail psoriasis, which can be identified by nail psoriasis specific questionnaires such as the NPQ10. As improving the severity of disease may have a positive influence on QoL, the outcome of QoL measurements should be taken into account when deciding on treatment strategies.

The prevalence of onychomycosis in psoriatic patients: a systematic review.

We systematically reviewed all available literature concerning the prevalence of onychomycosis in patients with nail psoriasis and the distribution of pathogens causing onychomycosis in this specific group of patients. Databases searched were Pubmed, EMBASE and the Cochrane Controlled Clinical Trial Register. All studies reporting on the prevalence of onychomycosis in nail psoriasis were obtained, and quality assessment was determined by the STrengthening the Reporting of OBservational studies in Epidemiology checklist. Literature search revealed 720 studies, of which 10 studies met the inclusion criteria. The major limitation of the review was the heterogeneity of the included studies, which prevented the possibility to conduct a meta analysis. However, the average prevalence of 18.0% of onychomycosis in psoriatic patients seems to be increased when compared with control groups and literature on healthy population, even though the ultimate evidence remains lacking. As in the literature hypothesized shift in causative agents from dermatophytes to yeasts and/or moulds could not be confirmed. The clinical consequence of the relatively high prevalence of onychomycosis in psoriasis may be a general advice to rule out onychomycosis or concomitant onychomycosis in these patients with (suspected) nail psoriasis. This advice is stressed by the relative simplicity of treating the contribution of onychomycosis in the nail dystrophy but also the fact that nail psoriasis mostly is treated by immunosuppressive drugs, like steroids, methotrexate or biologics which may aggravate mycotic nail infections.

Nail psoriasis: a questionnaire-based survey.

BACKGROUND: Skin manifestations are the most characteristic finding of psoriasis. However, nail involvement is also a clinical feature of disease although it is often overlooked. The documented prevalence of nail psoriasis varies between 10·0% and 81·1%. OBJECTIVES: The aim of this investigation is to gain knowledge about the prevalence and clinical manifestations of nail psoriasis and patient experiences of treatment of nail psoriasis. METHODS: A structured, self-administered questionnaire was distributed to all members (n = 5400) of the Dutch Psoriasis Association. The questionnaire enquired about sociodemographic patient characteristics, disease-related data and treatment of nail psoriasis. Patients reported their nail manifestations with photographs after instruction. Patients with nail psoriasis were compared with patients without nail psoriasis. RESULTS: A response rate of 27% was achieved. The prevalence of nail psoriasis was 66·0%. The most frequently observed psoriatic nail manifestation was pitting (65·4%), whereas red spots in the lunula were infrequently seen (6·5%). Patients with nail psoriasis more frequently stated psoriasis capitis (75·8% vs. 65·7%), genital psoriasis (32·7% vs. 20·3%) and psoriatic arthritis (46·4% vs. 30·6%) compared with patients with psoriasis without nail involvement. Only 16·0% of patients received treatment for nail psoriasis. Systemic therapies were most frequently stated as being effective for nail lesions. CONCLUSIONS: Nail manifestations seem to be more prevalent in patients with psoriasis than previously thought. In addition, nail psoriasis is shown to be associated with widespread and more severe forms of psoriasis, and different treatment options are experienced as being effective for nail psoriasis. Notwithstanding, nail psoriasis is still an often overlooked feature of the disease.

High discordance between punch biopsy and excision in establishing basal cell carcinoma subtype: analysis of 500 cases.

BACKGROUND: Basal cell carcinoma (BCC) is the most frequently occurring cancer in humans. Worldwide incidences rise about 10% each year, increasing the burden on dermatologists, general practitioners and pathologists as well as increasing costs for the health care system. Increasingly non-surgical treatment options are used in the treatment of BCC, without histological confirmation of BCC subtype, potentially resulting in under-treatment. OBJECTIVE: We evaluated the diagnostic accuracy of a punch biopsy for the BCC histological subytpe in a primary BCC and the prevalence of biopsy-based under-diagnosis of aggressive subtypes. Accuracy of a punch biopsy was defined as concordance of the diagnosis of subtype of BCC at punch biopsy and excision. METHODS: A retrospective chart-review was performed of primary BCC, which were proven by punch biopsy and subsequently treated by excision. The first 100 consecutive BCCs per year during the years 2004-2009 were included, yielding a total of 500 evaluated BCCs. RESULTS: The overall accuracy of punch biopsy for BCC subtype at excision was 69%, in single-type BCC 83% (n = 343) and in mixed-type BCC 37% (n = 157). Accuracy varied substantially according to BCC subtype, being highest in the superficial subtype (84%) and subsequently in infiltrative (69%), nodular (63%) and micronodular subtype (38%). In 11% of all cases, an unsuspected more aggressive subtype was present. CONCLUSION: Punch biopsy has a high accuracy in single-type BCCs and a considerably lower accuracy in mixed-type BCCs for establishing BCC subtype compared to excision. The presence of an unsuspected aggressive subtype could explain therapy failure of non-surgical treatments like imiquimod or photodynamic therapy.

A double-blind, randomized quantitative comparison of calcitriol ointment and calcipotriol ointment on epidermal cell populations, proliferation and differentiation.

BACKGROUND: Calcitriol and calcipotriol are widely used in the topical treatment of psoriasis. However, studies comparing both treatment modalities are scarce. Especially, there are almost no studies comparing the effects on epidermal cell populations in a quantitative manner. OBJECTIVES: The aim of this study was to quantitatively compare the effects of topical calcitriol and topical calcipotriol on clinical scores and epidermal subpopulations. PATIENTS AND METHODS: From five patients with stable plaque psoriasis, skin biopsies were taken from two symmetrical regions on the trunk or extremities before and after treatment with either calcitriol or calcipotriol. Frozen sections were labelled immunofluorescently using direct immunofluorescence for beta-1 integrin and the Zenon labelling technique for keratin (K) 6, K10 and K15. The digital photographs of the stained sections were quantitatively analysed and the results of both treatments were compared. RESULTS: The clinical SUM-score improved significantly for both the calcitriol- and the calcipotriol-treated lesions. In the calcipotriol-treated group the expression of K10 and K15 increased and the expression of K6 decreased significantly. No changes were seen for the marker beta-1 integrin. In the calcitriol-treated group none of the markers changed significantly. A tendency towards significance was seen for the changes in the expression of K6 and K15 in favour of calcipotriol. CONCLUSIONS: Both calcitriol and calcipotriol gave a significant improvement in clinical scores. However, treatment with calcipotriol resulted in a normalization of K6, K10 and K15, whereas treatment with calcitriol did not. Comparison of both treatments showed a tendency towards significance for the above-mentioned markers for calcipotriol only.

Therapeutic effects of a 12-week course of alefacept on nail psoriasis.

BACKGROUND AND OBJECTIVES: Nail psoriasis is a common finding in psoriatic patients and it affects the quality of life in a great proportion of patients. Topical or systemic treatments have limited effectiveness or have a serious toxicity potential. Biologicals such as alefacept are the most recent treatment modalities for psoriasis. In the present study we evaluated changes in nail pathology in patients with plaque psoriasis and nail involvement during treatment with alefacept. PATIENTS AND METHODS: Digital photographs from eight patients were produced, which were analysed using the nail psoriasis severity index (NAPSI). A minimal NAPSI of 15 was chosen to divide patients into a moderate to very severe nail psoriasis group and a group with no or mild nail psoriasis. A decrease in NAPSI of at least 25% was considered a significant response to therapy. RESULTS: In the group with at least moderate nail psoriasis, two patients improved, in two patients the nail changes remained unchanged and in one patient the nail pathology was aggravated. The group with no or mild nail psoriasis showed variable results. CONCLUSIONS: Although alefacept showed some results in treating nail pathology in psoriasis, a more extensive study is required, covering both more patients and a more extensive time period. Furthermore, it would also be clinically relevant to compare the effects of alefacept on nail psoriasis with other biologicals.

Assessment of epidermal subpopulations and proliferation in healthy skin, symptomless and lesional skin of spreading psoriasis.

BACKGROUND: The margin zone in spreading psoriatic lesions has frequently been used as a model to study the changes in epidermal proliferation, keratinization and inflammation during the transition from symptomless to lesional skin. However, the dynamics of the changes in the epidermal subpopulations-basal cells, transit amplifying cells and differentiated cells-have not been studied in the transition between symptomless and lesional skin. OBJECTIVES: To quantify in a dynamic model of the margin zone in psoriasis the characteristics of these subpopulations with respect to epidermal proliferation and differentiation. METHODS: From seven patients with active psoriasis, biopsies were taken from the distant uninvolved skin, outer margin, inner margin and centre of a spreading psoriatic plaque. Frozen sections were labelled immunofluorescently using direct immunofluorescence for Ki-67 and beta1 integrin and the Zenon labelling technique for keratin 6, 10 and 15. Digital photographs of the stained sections were quantitatively analysed. RESULTS: In the distant uninvolved skin the expression of beta1 integrin was decreased and keratin 15 expression was lost. In this area suprabasal cells expressed beta1 integrin and in the outer margin suprabasal cells expressed Ki-67. From the outer to the inner margin of the psoriasis plaque, which coincided with the appearance of the clinical lesion, there was a significant change in the various markers. The patchy expression of keratin 6 in the inner margin became homogeneous in the centre of the psoriasis plaque and here was also coexpression of keratin 6 and keratin 10 in a single cell. CONCLUSIONS: The present study provides additional evidence that the distant uninvolved skin has a prepsoriatic phenotype, which is the first step in a psoriatic cascade. The cascade between symptomless and lesional skin comprises first an abnormality in inflammation with involvement of beta1 integrin-dim cells (transit amplifying cells) subsequently eliciting an enlarged germinative compartment with increased recruitment of cycling epidermal cells and focal expression of proliferation-associated keratins, ultimately culminating in a more-or-less homogeneous epidermis with massive recruitment of cycling epidermal cells and proliferation-associated keratinization.

Effect of calcipotriol on epidermal cell populations in alefacept-treated psoriatic lesions.

BACKGROUND AND OBJECTIVES: The effect of the established antipsoriatic treatment with topical calcipotriol (with a maximum of 100 g per week) in addition to systemic treatment with alefacept, a new biological agent for psoriasis, on epidermal cell populations in the psoriatic lesion was investigated using a combination of the Zenon labelling technique and microscopic image analysis. Epidermal cell populations were measured quantitatively with this sensitive method. PATIENTS/METHODS: Frozen sections of non-treated psoriatic epidermis and psoriatic epidermis treated with either alefacept intramuscular or alefacept intramuscular in combination with topical calcipotriol for 12 weeks were compared immunohistochemically. Antibodies against keratin 6, 10 and 15 were labelled with the Zenon technique, whereas antibodies against the Ki-67 antigen and beta-1 integrin were covalently Fluorescein Isothiocyanate (FITC)-labelled. Using image analysis, these markers were measured in the epidermis in a standardized manner. RESULTS AND CONCLUSIONS: Treatment of psoriasis with alefacept resulted in a good clinical response in several patients and in a normalization of epidermal expression of the immunohistochemical parameters for differentiation and proliferation. The addition of topical calcipotriol resulted in a faster clinical improvement with a similar overall clinical response and a similar response of epidermal cell populations as compared to treatment with alefacept monotherapy after 12 weeks of treatment. This study also suggests that the appearance of keratin 15 has a predictive value for the duration of remission. It can be concluded that the addition of a low-dose calcipotriol treatment does not contribute to the clinical efficacy of alefacept, both at the clinical level and with respect to markers for epidermal proliferation and differentiation.

Alefacept modifies long-term disease severity and improves the response to other treatments.

Alefacept treatment has been shown in several multicentre studies to result in prolonged post-treatment remission periods (median duration 241 days). This communication describes the clinical responses of 10 patients to multiple courses of 12 weekly intramuscular injections with alefacept given in combination with available antipsoriatic treatments. It was shown that in this group of 10 patients with moderate-severe psoriasis, 8 were no longer candidates for any more long-term continuous systemic treatment with methotrexate or acitretin, 7 had no options for UVB/PUVA courses and 8 were not suitable for treatment with cyclosporine. In 5 out of these 10 patients alefacept had resulted in a considerable long-term improvement with only mild disease expression, which lasted one year or longer. Patients indicated that these responses were outstanding as compared to the troublesome years before. Another patient reported a major improvement in the quality of life by reduction of itch. In two patients alefacept vastly enhanced the efficacy of dithranol treatment, as compared to previous treatments. Another patient was able to discontinue methotrexate without relapsing during alefacept, in contrast to severe rebound episodes following discontinuation of methotrexate in the past. The long-term responses of 8 out of the 10 patients described in this report indicate that alefacept, in the context of individualised care of patients with moderate to severe psoriasis, can have an important contribution. In particular, the long-term response after stopping alefacept makes this treatment a valuable tool, achieving prolonged disease control in at least some patients with moderate to severe psoriasis.

Acquired arteriovenous malformation induced by pressure: a case report.

Arteriovenous malformations may be congenital or acquired. In the latter case, usually a traumatic injury to the arteries precedes the arteriovenous anastomoses. Two elderly patients presented with large, purple-colored verrucous tumors on the buttocks. Both patients were obese and immobile, and reported repeated bleeding from the lesions after minor trauma. The tumors were soft and could be emptied by applying pressure. Doppler examination revealed arterial pulsations over the lesions. Both cases were diagnosed as pressure-induced arteriovenous malformations. The lesions are assumed to have been caused by tissue damage in the deep subcutis induced by decubitus.

Therapeutic inhibition of the complement system. Y2K update.

Activation of complement is an essential part of the mechanism of pathogenesis of a large number of human diseases; its inhibition by pharmacological means is likely to suppress disease processes in complement mediated diseases. From this point of view low molecular weight synthetic inhibitors of complement are being developed and high molecular weight natural inhibitors of human origin present in plasma or embedded in cell membrane are being purified or produced in their recombinant forms. This review is concerned with high molecular weight inhibitors, some of which are already in clinical use but may be efficacious in many other diseases in which they have not yet been tried. C1-esterase inhibitor (C1-INH) concentrate prepared from human plasma is being successfully used for the treatment of hereditary angioneurotic edema. Recently, C1-INH has been found to be consumed in severe inflammation and has been shown to exert beneficial effects in several inflammatory conditions such as human sepsis, post-operative myocardial dysfunction due to reperfusion injury, severe capillary leakage syndrome after bone marrow transplantation, reperfusion injury after lung transplantation, burn, and cytotoxicity caused by IL-2 therapy in cancer. Factor I has been used for the treatment of factor I deficiency. Recombinant soluble forms of membrane cofactor protein (MCP), and decay accelerating factor (DAF) have not yet been tried in humans but have been shown to be effective in immune complex mediate inflammation in animals. Organs of pigs transgenic for one or more of human membrane regulators of complement namely membrane cofactor protein (MCP), decay accelerating factor (DAF) or CD59, are being produced for transplantation into humans. They have been shown to be resistant to hyperacute rejection in non-human primates; acute vascular rejection is still a problem in their clinical use. It is hoped that these observations together with future developments will make xeno-transplantation in clinical practice a reality. Several recombinant variants of complement receptor 1 (CR1) have been produced. The most effective of these appears to be sCR1-SLe x, sCR1 part of which inhibits complement and carbohydrate Sle x moiety inhibits selectin mediated interactions of neutrophils and lymphocytes with endothelium. Although clinical trials of sCR1 in humans is eagerly awaited, several of the recombinant versions of sCR1 have been shown to suppress ischemia/reperfusion injury, thermal trauma, and immune complex mediated inflammation. They have also been shown to be effective in experimental models of systemic sclerosis, arthritis, myasthenia gravis, Guillain Barré syndrome and glomerulonephritis. Intravenous immunoglobulin, three of the most prominent properties of which are neutralization of autoantibody activity, suppression of autoantibody production and inhibition of complement activity, is being used in several diseases. These include autoimmune thrombocyopenic purpura, Kawasaki disease and several neurological diseases such as myasthenia gravis and Guillain Barre syndrome. In many uncontrolled small scale studies intravenous immunoglobulin has been shown to be effective in many immunological including dermatological diseases; controlled clinical trials in a large number of patients with these diseases is needed to establish the efficacy. It is hoped that in future therapeutic inhibition of complement will be one of the major approaches to combat many human diseases.

Synthesis of complement components C3 and factor B in human keratinocytes is differentially regulated by cytokines.

The complement system plays an important part in host defense and inflammation. Locally synthesized complement may perform these functions at tissue and organ level. In skin the keratinocyte is the major cell type, it is known to produce two soluble complement components, C3 and factor B. In this study we investigated the regulation of synthesis of these components in foreskin keratinocytes by cytokines. Human keratinocytes were cultured in the presence of supernatant of activated peripheral blood mononuclear cells, interleukin-1alpha, interleukin-2, interleukin-6, transforming growth factor-beta1, tumor necrosis factor-alpha, or interferon-gamma. C3 and factor B proteins were measured in culture supernatant by enzyme-linked immunosorbent assay and C3 and factor B transcripts in harvested cells by reverse transcriptase-polymerase chain reaction. Cultured keratinocytes constitutively produced C3 and factor B. Supernatant of activated mononuclear cells upregulated C3 and factor B production by 27- and 15-fold, respectively. interleukin-1alpha, interferon-gamma, and tumor necrosis factor-alpha upregulated C3 synthesis by 7-, 8-, and 22-fold, and interleukin-1alpha, interleukin-6, and interferon-gamma upregulated factor B synthesis by 3-, 3-, and 34-fold, respectively. Tumor necrosis factor-alpha induced production of C3 and interferon-gamma induced production of factor B were inhibited by cycloheximide. Cytokine induced upregulation of C3 and factor B proteins was always associated with the upregulation of levels of C3 and factor B mRNA. This indicated that, as expected, cytokine-induced enhancement in C3 and factor B levels was due to an increase in synthesis rather than their possible release from intracellular stores. In conclusion, synthesis of C3 and factor B in keratinocytes is regulated by some cytokines, known to be produced by inflammatory cells and keratinocytes.

Transforming growth factor-beta isoforms regulate the surface expression of membrane cofactor protein (CD46) and CD59 on human keratinocytes [corrected].

We studied the regulation of the expression of complement regulatory proteins, membrane cofactor protein (MCP), decay accelerating factor (DAF) and CD59, on human keratinocytes by supernatant of activated mononuclear cells and by some individual cytokines present therein. Cultured keratinocytes expressed MCP, DAF and CD59. Supernatant of activated mononuclear cells and recombinant forms of transforming growth factor (TGF)-beta variants (beta1, beta2 and beta3) up-regulated MCP and CD59 but not DAF. Recombinant IL-1alpha, IL-2, IL-6, TNF-alpha and IFN-gamma had no influence. TGF-beta present in the supernatant was likely responsible for up-regulation of MCP and CD59. A monoclonal anti-TGF-beta antibody, which neutralized TGF-beta1, -beta2 and -beta3, did not inhibit the up-regulation of MCP and CD59 by the supernatant. These results indicated that TGF-beta and an additional factor(s) present in the supernatant may be responsible for up-regulating the expression of MCP and CD59 on keratinocytes; both may be acting non-synergistically.