Rituximab in diffuse cutaneous systemic sclerosis: an open-label clinical and histopathological study.

OBJECTIVES: The safety and potential efficacy of rituximab was examined in diffuse cutaneous systemic sclerosis (dc-SSc). METHODS: A 24 week open-label study in which eight patients with dc-SSc received an infusion of 1000 mg rituximab administered at baseline and day 15, together with 100 mg methylprednisolone at each infusion. Assessment included CD19+ peripheral blood lymphocyte number, skin sclerosis score, indices of internal organ functioning, the health assessment questionnaire disability index, the 36-item Short Form health survey and histopathological evaluation of the skin. RESULTS: Ritixumab induced effective B-cell depletion in all patients (<5 CD19+ cells/microl blood). There was a significant change in skin score at week 24 (p<0.001). Also, significant improvements were measured in the dermal hyalinised collagen content (p = 0.014) and dermal myofibroblast numbers (p = 0.011). Two serious adverse events occurred, which were thought to be unrelated to the rituximab treatment. CONCLUSIONS: Rituximab appears to be well tolerated and may have potential efficacy for skin disease in dc-SSc.

Clinical and molecular abnormalities in lipoid proteinosis.

Lipoid proteinosis (hyalinosis cutis et mucosae) is a rare, autosomal recessive disease. The main clinicopathological features comprise skin and mucous membrane infiltration and scarring with deposition of hyaline material. In this report, we describe a 6-year-old boy in whom a diagnosis of lipoid proteinosis was first suspected when he presented with blisters and erosions at 4 years, a history of life-long dysphonia and a previous epileptic convulsion. The diagnosis was confirmed by histology and identification of a homozygous frameshift mutation, 501insC, in exon 6 of the gene encoding extracellular matrix protein 1, ECM1. Lipoid proteinosis may show protean clinical features and be difficult to diagnose on clinical grounds alone. This case report illustrates that lipoid proteinosis may show protean clinical features and yet remain undiagnosed for many years. Although the gold standard for definite diagnosis remains histology, molecular characterisation of the gene mutation will add to our understanding of genotype-phenotype correlation and perhaps to the development of a rationale for future therapeutics.

Genetic linkage between the collagen type VII gene COL7A1 and pretibial epidermolysis bullosa with lichenoid features.

Pretibial epidermolysis bullosa is a rare form of dominant dystrophic epidermolysis bullosa. The disease was diagnosed after considerable delay in a large Belgian family and was remarkable for its late age at onset and its misleading clinical presentation in the proband, which strongly resembled keratosis lichenoides chronica. Both recessively and dominantly inherited forms of dystrophic epidermolysis bullosa have been shown to be linked to the collagen type VII gene, COL7A1. Two-point linkage analysis with two intragenic polymorphisms (PvuII, AluI) in COL7A1 was performed. Strong genetic linkage between the disease in this family and COL7A1 was demonstrated by a lod score of 4.45 (theta = 0) for the AluI polymorphism. The observed intrafamilial variability of clinical phenotypes contradicts the presently proposed classification of dominantly inherited dystrophic epidermolysis bullosa.

Kinesin and kinectin can associate with the melanosomal surface and form a link with microtubules in normal human melanocytes.

Microtubuli play an important role in the organization of organelles and membrane traffic. They are present in melanocytic dendrites through which melanosomes are transported towards keratinocytes. Besides the actin-based motility systems, microtubuli-associated motor proteins also play a critical role in melanosome movement, as has recently been confirmed in mouse melanocytes. We investigated the in vitro expression of two forms of human conventional kinesin and its receptor kinectin in normal human epidermal melanocytes, keratinocytes, and dermal fibroblasts by reverse transcription polymerase chain reaction and northern blot analysis. In an attempt to gain insight into the subcellular distribution of kinesin and kinectin in melanocytes, double immunofluorescent staining and immunogold electron microscopy were performed. In all studied skin cells ubiquitous and neuronal kinesin are expressed, as well as the kinectin receptor. Immunofluorescent staining shows distinct but partially overlapping distributions for kinesin heavy chain and melanosomes, suggesting that kinesin is associated with some but not all of the melanosomes. Similar observations for kinectin indicate that this receptor can colocalize with melanosomes, which was confirmed by immunoelectron microscopy. The latter technique allowed us to demonstrate a close association between kinesin heavy chain, microtubuli, and melanosomes. The combined data from reverse transcription polymerase chain reaction, northern blot analysis, double immunofluorescent staining, and immunogold electron microscopy suggest that kinesins and kinectin have an important role in microtubuli-based melanosome transport in human melanocytes.

arg-cys substitution at codon 1246 of the human myosin Va gene is not associated with Griscelli syndrome.

Myosin Va is an actin-associated motor protein involved in organelle transport such as melanosomes and neuron synaptic vesicles and has always been proposed as the candidate gene for the autosomal recessive Griscelli-Pruniéras syndrome, one of the silvery hair syndromes, which is a lethal disease combining immunodeficiency and neurologic and pigmentary abnormalities. Thus far, two mutations in the myosin Va gene have been described to be associated with this syndrome. One of these mutations was a homozygous mis-sense mutation causing an arginine to cysteine alteration at codon 1246. Because we also found this particular substitution after mutation analysis of a Griscelli patient, we checked its relevance in a control group of 124 unrelated healthy individuals and found it to be present, even in homozygous state, in normal unaffected individuals. It is clear that this arg1246cys substitution is a polymorphism occurring in the human population and not occurring in association with Griscelli syndrome. Distinguishing a polymorphism from a bona fide mutation is of utmost importance and has major ethical implications with regard to prenatal genetic counseling in affected families.

Myosin V colocalizes with melanosomes and subcortical actin bundles not associated with stress fibers in human epidermal melanocytes.

Mutations of the gene encoding myosin V can produce a dilute or silvery hair color and various neurologic defects in mice and patients with Griscelli syndrome, leading to speculations that the myosin V motor protein plays a critical role in transporting melanosomes within melanocytes and neurosecretory vesicles within neurons. Therefore, we investigated the in vitro expression of myosin V in cultured normal human melanocytes, keratinocytes, and dermal fibroblasts using reverse transcriptase-polymerase chain reaction and northern blot analysis. Subcellular distribution of myosin V and proximity to actin bundles and melanosomes were determined by double indirect immunofluorescence labeling and immunogold electron microscopy. In all studied cells myosin V is expressed and treatment of melanocytes with the cyclic AMP-inducer 3-isobutyl-1-methylxanthine causes an induction of the myosin V message. In all cells myosin V colocalizes with actin bundles, concentrating in the subcortical cell zone. In the melanocyte it is closely associated with melanosomes. Quantitative analysis of myosin V labeling in melanocytes reveals a significantly higher (p < 0.005) presence of myosin V in the periphery of dendrites. These results suggest that myosin V is important in melanosome transport in human melanocytes. Possible roles in the other skin cells remain to be elucidated.

Time delays and related factors in the diagnosis of cutaneous melanoma.

Delay in melanoma diagnosis was investigated in a population-based sample of 130 patients. The median time elapsing from the first notice of the lesion to excision was 110.5 days. There was no linear correlation between total delay time and Breslow-thickness of the diagnosed melanomas (P=0.19). Patient delay, defined as the time from first notice of a (change in a) lesion to the first observation by a physician, exceeded 2 months in half of all patients. Only 41% of the patients consulted a doctor because they were worried about the lesion. Colour change and itch were associated with a longer patient delay. There was no correlation with age, gender, socio-economic factors, localisation of the lesion and the person who first noticed the lesion. In one quarter of all patients, the time from first observation by a physician to excision of the lesion exceeded 2.5 months. This physician delay seemed to be attributed to misdiagnosis and to a delay occurring during referral.

Trends in mortality from cutaneous malignant melanoma in Belgium.

BACKGROUND AND METHODS: Changes over time of mortality rates from cutaneous malignant melanoma (CMM) in Belgium were analysed, based on people (n = 3695) aged 25-84 years, who died of CMM from 1954 to 1992. All data were collected from the Belgian National Institute of Statistics. For the log-linear analysis and calculation of the average annual change, only the data from 1973 to 1992 were considered. RESULTS: The age-adjusted mortality rates (per 10(5)) for the age group 25-84 years old increased from 0.5 in 1954 to 3.0 in 1992 in men, and from 0.8 in 1954 to 2.2 in 1992 in women. The average annual percentage change in men (-0.003%) was stable over the period 1973-1982, and increased to 4.4% over the period 1983-1992. In women, the average annual increase was 4.6% over the period 1973-1982, and continued to increase to 6.8% over the period 1983-1992. Log-linear analysis showed that the change in rates for both men and women was mainly due to an age-'drift' effect, contrary to the results of the average annual percentage change in men. CONCLUSION: The risk of dying from CMM increased in men and women continuously over the whole period, irrespective of birth cohort. In both men and women, there was approximately a 20% increase in CMM mortality per 5-year period.

Multiple clear cell acanthomas. A clinical, histological, and ultrastructural report.

A case of multiple clear cell acanthomas in a 64-year-old woman is reported. The clinical and histological findings of this rare entity are consistent with the hypothesis that clear cell acanthomas are benign epidermal tumors. An ultrastructural study was performed with special emphasis on the melanocytic-keratinocytic interaction.

Gabapentin for pain control in cancer patients' wound dressing care.

A patient with mycosis fungoides illustrates the problem of pain management during wound care and suggests the utility of a novel treatment, gabapentin. Skin lesions, be they induced through necrosis of tumor, therapy (e.g., radiotherapy), or by pressure ulceration, are often the cause of continuous pain or acute wound dressing pain. Optimizing the analgesic treatment in those patients is thus of major importance. Anti-inflammatory drugs and opioids are the cornerstones in the treatment of cancer pain but are rarely sufficient to control wound pain. Different adjuvant techniques can be used, including topical analgesics, psychological distraction techniques, anxiolytics, and co-analgesics. There is growing evidence that anticonvulsants, and sodium channel blockers in particular, are effective not only in neuropathic but also in inflammatory pain. Gabapentin, a voltage sensitive sodium and calcium channel blocker, was used as a co-analgesic to supplement morphine in this case of cancer wound dressing pain.

Under-registration of melanoma in Belgium: an analysis.

The overall underestimation of incident cancer cases in the Belgian National Cancer Registry is estimated at about 20-25%, with a probable larger under-registration among males. Melanoma incidence is suspected to be underestimated even further because of the hospital-based reporting system of the National Cancer Registry. To investigate the suspected underestimation of melanoma in Belgium, the official data were compared with international data on melanoma incidence and the results of a melanoma registration programme launched in the province of East Flanders. The Eindhoven Cancer Registry, which covers a registration area near the Belgian border, was used as a reference to calculate the expected number of melanomas in East Flanders for 1995. The results indicate an ongoing under-registration of melanoma cases by the National Cancer Registry. Based on the Eindhoven Cancer Registry data, the under-registration in East Flanders is estimated at 43% for males and 36% for females. The East Flanders registration programme apparently obtains a better registration in females. This is mainly due to a higher registration in the younger age groups. In these groups a higher proportion of in situ melanomas and a thinner median Breslow thickness of the invasive melanomas is observed.

The melanoma burden in Belgium; premature morbidity and mortality make melanoma a considerable health problem.

The aim of this study was to investigate the impact of melanoma on public health in Belgium. Melanoma incidence and mortality rates were analysed relative to those of other cancers. These cancers were then evaluated for premature morbidity and mortality by studying age-specific incidence rates, years of potential life lost before 65, and years of potential life lost per death. Melanoma accounts for 1.23% of all incident cancer cases and 0.7% of all cancer deaths in Belgium. It is the seventeenth most common cancer in men and the sixteenth most common cancer in women. Compared with other, more frequent cancers, melanoma seems to affect patients at a younger age; in the 20-39 age group melanoma is the third most common cancer in both sexes. It is the second most important cancer in terms of years of potential life lost per death, preceded only by tumours of the central nervous system. These findings show that melanoma incidence and mortality rates are exceeded by many other cancers. Nevertheless, melanoma poses an important health problem because of its predilection for young and middle-aged people. We suspect that these observations are not specific for Belgium and will also apply to other European countries.

Etiological factors and underlying conditions in patients with leucocytoclastic vasculitis.

This study concerns a retrospective analysis of 63 consecutive patients presenting with leukocytoclastic vasculitis at the Departments of Dermatology or Rheumatology of the University Hospital Ghent (Belgium) (period 1988-1993). The diagnosis of leukocytoclastic vasculitis was confirmed by histopathology in all cases. All patients were screened for underlying causes, including drugs, infection, systemic autoimmune disease or neoplasia. In 34 patients, an etiological factor was identified: drugs (5 patients), infection (6 patients), drugs or infection (4 patients), systemic autoimmune disease (10 patients), Henoch Shönlein (6 patients), neoplasia (2 patients) and cryoglobulinemia (1 patient). In the group of patients with leukocytoclastic vasculitis in the context of systemic autoimmune disease, 4 patients suffered from systemic lupus erythematosus, 2 from Wegener's disease, 2 from Behçet's disease, 1 from polyarteritis nodosa and 1 from rheumatoid arthritis. In the remaining 29 patients, no cause for the vasculitis could be identified.

Immune-mediated pathology following hepatitis B vaccination. Two cases of polyarteritis nodosa and one case of pityriasis rosea-like drug eruption.

The association of hepatitis B virus infection and vasculitis or other immune-mediated manifestations is well documented. Reports on such manifestations in relation to hepatitis B vaccination are scarce, however. We report 2 patients who developed polyarteritis nodosa following vaccination against hepatitis B. In one patient this resulted in an ischemic and necrotic digital ulcus, necessitating surgical amputation. The other patient presented with typical cutaneous polyarteritis nodosa which responded well to corticosteroid treatment. A third patient developed a severe pityrias rosea-like eruption. He was treated with topical steroids with healing of the lesions, leaving only post-inflammatory hyperpigmentation. The literature on these associations is reviewed.

An imaging system with calibrated color image acquisition for use in dermatology.

We propose a novel imaging system useful in dermatology, more precisely, for the follow-up of patients with an increased risk of skin cancer. The system consists of a Pentium PC equipped with an RGB frame grabber, a three-chip charge coupled devices (CCD) camera controlled by the serial port and equipped with a zoom lens and a halogen annular light source. Calibration of the imaging system provides a way to transform the acquired images, which are defined in an unknown color space, to a standard, well-defined color space called sRGB. sRGB has a known relation to the CIE1 XYZ and CIE L*a*b* colorimetric spaces. These CIE color spaces are based on the human vision, and they allow the computation of a color difference metric called CIE deltaE*ab, which is proportional to the color difference, as seen by a human observer. Several types of polynomial RGB to sRGB transforms will be tried, including some optimized in perceptually uniform color spaces. The use of a standard and well-defined color space also allows meaningful exchange of images, e.g., in teledermatology. The calibration procedure is based on 24 patches with known color properties, and it takes about 5 minutes to perform. It results in a number of settings called a profile that remains valid for tens of hours of operation. Such a profile is checked before acquiring images using just one color patch, and is adjusted on the fly to compensate for short-term drift in the response of the imaging system. Precision or reproducibility of subsequent color measurements is very good with (deltaE*ab) = 0.3 and deltaE*ab < 1.2. Accuracy compared with spectrophotometric measurements is fair with (deltaE*ab) = 6.2 and deltaE*ab < 13.3.

Understanding the trends in melanoma incidence and mortality: where do we stand?

In previous decades melanoma incidence rates have risen spectacularly in white populations worldwide and a parallel - although more moderate - increase has been observed for melanoma mortality. More recently several reports have been made of a stabilization or decrease of mortality rates in the younger birth cohorts, resulting in a stabilization in the overall mortality in the 1980s for some populations. This article reviews past and current trends in melanoma epidemiology. It further handles the possible explanations for these trends and the currently available indications for or against these trends being brought about by real or artefactual influences. Time will undoubtedly reveal more about the truth.

Intercellular IgA dermatosis.

We report three cases of intercellular IgA dermatosis (IAD) and review the literature. IAD is a spectrum of vesiculobullous or vesiculopustular diseases mediated by intercellular IgA deposition. The clinical picture may vary from a vesiculopustular eruption with centrifugal evolution mainly involving the trunk and extremities, to the typical picture of classic pemphigus variants (foliaceus, vegetans). Histologically, infiltrating polymorphonuclear cells (mainly neutrophils) are observed in the epidermis with formation of pustules and bullae at various levels. However cases with typical histological features of pemphigus (variants) are described. Direct immunofluorescence on perilesonal skin typically displays intercellular IgA deposition at different levels or throughout the epidermis and indirect immunofluorescence often detects low levels of circulating antibodies. The disease has been repeatedly reported in association with monoclonal IgA gammopathy. Most cases respond to dapsone. In some cases IgA is directed against known pemphigus antigens whereas their targets in other cases are newly discovered antigens (105 kD, 115 kD, 120 kD). We observe a heterogeneity within the clinical, histological and immunological characteristics of the disease. Many reported cases feature various combinations of these characteristics. We therefore consider IAD as a disease spectrum with IgA pemphigus (clinical and histological pemphigus) at one end and intercellular IgA vesiculopustular dermatosis at the other end.

Autologous transplantation techniques for vitiligo: how to evaluate treatment outcome.

Effective methods for measuring treatment outcome in vitiligo are essential to accurately assess possible therapeutic modalities. This systematic review article aims to bring the problems concerning evaluation of treatment outcome in vitiligo studies using transplantation techniques to the attention of clinical investigators. Furthermore we highlight the interpretation of the achieved result from both physicians' and patients' view point using a questionnaire put to 558 dermatologists and 152 vitiligo patients in Belgium. There is no consensus about the choice of an evaluation method in surgical vitiligo studies. The interpretation of a 'successful' treatment result seemed to differ among dermatologists and vitiligo patients. We conclude that further research is needed to develop a universally accepted, objective, reliable and useful measurement method to evaluate the efficacy of surgical vitiligo treatments. A combination of both a clinical and a psychological measurement is likely to be the most appropriate choice.

The pathophysiology of lupus erythematosus.

Systemic lupus erythematosus disseminatus in addition to the more restricted, lupus-like syndromes, is the consequence of an attack by the immune system on the cellular and nuclear structures of the body. These disorders are also frequently associated with disturbances of the coagulation cascade. In this review paper, the factors that provoke or enhance these disturbances are considered, as well as the way by which this provocative effect is exerted. An intermutual relation between various elements is described, whereby congenital factors (heredity, race) and non-congenital factors (sex hormones, pregnancy, environment, ultraviolet light, drugs, infection) play a role. These factors induce the activation cascade of the disease, via two different axes: on the one hand modifications in the DNA structure, on the other immune stimulation. This eventually results in tissue damage.

Polyarteritis nodosa mimicking polymyalgia rheumatica.

We report a case of polyarteritis nodosa with a clinical presentation mimicking polymyalgia rheumatica, as well as pathological findings of non-giant-cell arteritis on temporal artery biopsy with symptoms of jaw claudication. Although certain clinical syndromes have been attributed to specific types of systemic vasculitis, considerable overlap occurs. Obtaining tissue biopsy in cases of vasculitis is mandatory for diagnosis and classification.