Recent Advances: DermatologyBMJ 1995; 311 doi: https://doi.org/10.1136/bmj.311.7020.1615 (Published 16 December 1995) Cite this as: BMJ 1995;311:1615
- aDepartment of Dermatology, University of Maryland School of Medicine, 405 W Redwood St, Baltimore, MD 21201-1703, USA
- b Division of General Internal Medicine, Johns Hopkins Bayview Medical Center, Baltimore, MD 2122, USA
- Correspondence to: Dr M H Lowitt
Recent advances in dermatology and related fields have brought new answers to some old questions and new treatment options for some traditionally vexing diseases of the skin. This review focuses on several important reports of the past year, including progress in the understanding of pathogenesis, prevention, diagnosis, and treatment of some of the most difficult dermatologic maladies.
Since the discovery of its association with human immunodeficiency virus infection, Kaposi's sarcoma (1) has remained one of the most puzzling entities in the cutaneous repertoire of patients infected with HIV. An exhausting array of potential aetiological agents has been proposed.1 Until recently, even the basic categorisation of the condition (malignancy, reactive process, infection) has remained uncertain. Reports of Kaposi's sarcoma in homosexual men negative for HIV,2 coupled with the observation that among patients positive for HIV Kaposi's sarcoma was more common in homosexual men than in injecting drug users,3 led to the suspicion that the condition was sexually transmitted, presumably by a virus distinct from but often transmitted with HIV.
During the past year, several reports have emerged documenting the discovery of herpesvirus-like DNA sequences within Kaposi's sarcoma lesions.4 5 6 The DNA sequences (sometimes referred to as KS330(233) or KSHV) have been identified by polymerase chain reaction and by Southern blot hybridisation. These bits of DNA have been discovered in tissue from the lesions of patients with epidemic (HIV associated) Kaposi's sarcoma as well as classic Kaposi's sarcoma (on the legs of immunocompetent elderly men of Mediterranean descent) and African endemic Kaposi's sarcoma.5 The additional finding of similar sequences in tissue from some lymphomas in patients infected with HIV7 and in Kaposi's sarcoma from homosexual men negative for HIV6 lends support to the hypothesis that a novel group of herpesviruses may be the major aetiological agent of all forms of Kaposi's sarcoma as well as some lymphomas in the immunocompromised host.
One of the time honoured scourges of the playground, varicella (chickenpox), is now threatened by the development of a live attenuated varicella vaccine. Although varicella is usually a benign affliction, characterised by a miserably pruritic child and a temporarily housebound parent, infection with varicella zoster virus may infrequently lead to severe sequelae such as pneumonitis, encephalitis, and even death, particularly when acquired in adulthood or by immunocompromised individuals. Arguments for and against universal vaccination have raged, alternately citing the rare but serious risks of the disease, the loss of parental productivity in the workplace, the high prevalence of infection, and the possible eradication of herpes zoster infections--against the high costsof widespread vaccination, generally trivial nature of the illness, uncertain long term degrees ofimmunity from the vaccine, and risks to unvaccinated individuals who might tend to acquire the infection later in life when the danger of serious sequelae would be greater. After healthy debate, the American Academy of Pediatrics has recently adopted a position in support of universal vaccination of healthy non-immune children and adults.8
Recent advances in dermatology Infectious disease
Herpesvirus-like sequences are associated with Kaposi's sarcoma
A live attenuated vaccine is now recommended for prevention of varicella zoster virus infection Inflammatory dermatoses
Topical calcipotriol is effective in treatment of psoriasis
Topical doxepin is effective in treatment of atopic dermatitis
An autoimmune mast cell mechanism is proposed for chronic urticaria Cutaneous neoplasms
A candidate gene for the familial atypical molemelanoma syndrome may be the growth regulator p16 on chromosome 9
Tumour thickness, level of invasion, sex, and anatomic location are independent prognostic factors in survival with melanoma
Topical calcipotriol for psoriasis
Topical calcipotriol (vitamin D3) ointment is a new treatment for psoriasis with great promise.Several studies have confirmed the effectiveness of this agent in the treatment of moderate plaque-type psoriasis 2).9 10 11 12 Although its mechanism of action is not entirely understood, vitamin D3 is known to act locally to increase extracellular calcium concentrations, which leads to increased keratinocyte differentiation and decreased proliferation and scaling. Topical calcipotriol has been found to be superior in the treatment of chronic plaque-type psoriasis in comparison with placebo,9 10 15% coal tar,11 and topical clobetasol propionate 0.05%.12 With the exception of rare skin irritation, calcipotriol ointment was well tolerated, effective, and safe. Monitoring of serum calcium concentration may be appropriate in selected patients with known or suspected baseline hypercalcaemia. Topical calcipotriol is a welcome addition to the palette of antipsoriatic drugs because it is effective and an excellent alternative to topical steroids.
Topical doxepin for atopic dermatitis
The degree of disfigurement and debilitation caused bythe pruritus of atopic dermatitis cannot be overestimated. Although topical steroids, emollients, and oral antihistaminic agents are often of great benefit, many patients suffer from intractable itch. Ultraviolet treatment, cyclosporine, and systemic corticosteroids, while effective for some patients, are impractical, ineffective, or unsafe in the long term for many others. Because of its antihistaminic activity (both H1 and H2) and its efficacy in the treatment of itch whentaken orally, a topical formulation of doxepin, the tricyclic antidepressant, has been introduced. When administered in a placebo controlled, double blind fashion to 270 patients with active atopic dermatitis, doxepin 5% ointment gave significantly greater relief of itch than did the vehicle alone.13 Mild localised burning (30%) and mild drowsiness during the first three days of treatment (28%) were the most common adverse effects in the group treated with doxepin.
Pathogenesis of chronic urticaria
Physicians and patients alike dread the diagnosis of chronic urticaria (hives) in light of its persistence, association with life threatening angio-oedema, erratic response to treatment, and infrequent identification of a causative factor. After exclusion of physical causes of urticaria (cold, pressure, sunlight, heat, water), drugs (particularly aspirin and nonsteroidal anti-inflammatories), foods, infections (hepatitis, chronic sinusitis), and autoimmune connective tissue disease, the remaining majority of patients are relegated to the “idiopathic” category.14
New information may now help to identify a subset of urticaria sufferers whose condition may actually represent a form of autoimmune mast cell disease.14 15 An IgG autoantibody with the ability to bind and cross link IgE receptors on mast cells has been identified in the serum of some patients with chronic urticaria. In one study, 98 of 163 patients (60%) with chronic urticaria developed wheals after intradermal injection of their own (autologous) serum. These same samples were able to elicit the release of histamine from basophils of healthy controls. The chronic production of these autoantibodies may therefore explain the long term nature of the illness. Experimental treatments with plasmapheresis, intravenous immunoglobulin, and cyclosporin have been effective in a small number of patients. This exciting new finding may shed light on and lead to further understanding of this heretofore unexplained condition.
Familial atypical mole-melanoma gene
The hunt for the genetic basis of the familial syndromeof atypical moles and malignant melanomahas advanced rapidly in the past several years. After theinitial observations that people with many large atypical moles had an increased risk of melanoma, the name for this syndrome has varied; names including dysplastic nevus syndrome, familial atypical mole and melanoma syndrome (FAMMM), and B-K mole syndrome.
Early evidence pointed towards a locus on the short arm of chromosome 1, but several other possible sites had been identified. Some recent studies point towards an area on the short arm of chromosome 9.16 Within this chromosomal segment (9p21) resides p16, a gene which codes for a protein that regulates cell replication.16 The normal protein product of this gene inhibits mitosis and DNA synthesis, maintaining a baseline inhibitory tone in cells by blocking progression of the cell cycle. A mutation or deletion of the inhibitory p16 gene therefore results in uncontrolled cellular replication and consequent neoplasia. Deletions in the p16 gene have been identified in a wide spectrum of malignancies.
In studies of some families prone to melanoma, uniform deletions in the gene have been detectedamong affected members.17 As this abnormality is not present in many other kindreds prone to melanoma,17 investigation will need to continue in the search for other genes or regulators involved in the genetic predisposition to melanoma. Taken in sum, however, these early data promise much for our future understanding of the genetic basis for this deadly cutaneous neoplasm.
Prognostic factors in malignant melanoma
Since the pioneering work of Clark and Breslow, the depth of dermal invasion by melanoma cells has been considered to be the most important prognostic factor in long term survival for patients with this disease. Two recent large studies conclude that some additional factors may prove to be independent predictive factors in survival.18 19 In an 18 year follow up of 5264 patients with primary cutaneous melanoma (3), four independently significant prognostic factors were found: tumour thickness, level of invasion, sex, and anatomic location (table). As expected, Breslow tumour thickness was the most powerful prognostic factor for 10 year survival. Tumours with thicknesses of from 1.01-2.0 mm and 2.01-4.0 mm portended a much higher risk of death than those of 1.00 mm or less. The Clarks level (a classification based on the anatomic level of the skin to which the tumour cells extend) proved to be an independent variable, distinguishing particularly between patients with level II disease (full involvement of the papillary dermis) and those with level III or greater (extension into or deeper than the reticular dermis). This finding may be a blow for patients with melanomas on areas of particularly thin skin, where the Breslow thickness may be thin but the anatomic depth of invasion is greater. Men were found to have a greater relative risk of 10 year mortality than women, independent of other variables such as tumour thickness. The anatomical location of the tumour was also important in prognosis: melanomas in the “TANS” areas (thorax, upper arms, neck, and scalp) showed a higher relative risk. Although more confirmatory studies are needed, these data may allow physicians to provide more accurate information on survival to their patients with melanoma.
Conflict of interest None