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MEDICAL BIOLOGY: ON PSORIASIS

The following points are made by M.P. Schoen and W-H. Boehncke (New Engl. J. Med. 2005 352:1899):

1) Although psoriasis is a common skin disease, its definition by Ferdinand von Hebra (1816-1880) as a distinct entity dates back only to the year 1841, and estimates of its prevalence --approximately 2 percent, according to standard textbooks -- stem from only a few population-based studies. Perhaps the most comprehensive field study was performed in the Faroe Islands, where 2.8 percent of the inhabitants were reported to be affected.[1] This prevalence rate is higher than that in central Europe, where prevalence is approximately 1.5 percent, according to a more recent analysis.[2] Ethnic factors also appear to influence the prevalence of psoriasis, which ranges from no cases in the Samoan population to 12 percent in Arctic Kasach'ye.[2] The influence of ethnic factors is particularly evident when one compares prevalence rates within the United States. The prevalence among blacks (0.45 to 0.7 percent)[3] is far lower than that in the remainder of the U.S. population (1.4 to 4.6 percent).[4]

2) Numerous family studies have provided compelling evidence of a genetic predisposition to psoriasis, although the inheritance pattern is still unclear.[5] The illness develops in as many as half of the siblings of persons with psoriasis when both parents are affected, but prevalence falls to 16 percent when only one parent has psoriasis and to 8 percent when neither parent is affected. The concordance rate for monozygotic twins is around 70 percent, as compared with some 20 percent for dizygotic twins, a finding that further supports the concept of genetic predisposition. As many as 71 percent of patients with childhood psoriasis have a positive family history.

3) Within the past decade, several putative loci for genetic susceptibility to the disease have been reported on the basis of genome-wide linkage studies, but there has not been widespread replication of the results -- a problem that has also been encountered in the investigation of other complex diseases. However, one locus in the major-histocompatibility-complex (MHC) region on chromosome 6 has been replicated in several populations. This locus, termed psoriasis susceptibility 1 (PSORS1), is considered the most important susceptibility locus. On the basis of association studies of three tightly linked susceptibility alleles, PSORS1 appears to be associated with up to 50 percent of cases of psoriasis.

4) People with psoriasis typically have sharply demarcated chronic erythematous plaques covered by silvery white scales, which most commonly appear on the elbows, knees, scalp, umbilicus, and lumbar area. An inverse type of psoriasis spares these sites and instead appears in intertriginous areas, where scaling is minimal. Eruptive guttate psoriasis, which may be the initial manifestation of the disease and is often preceded by streptococcal infection by two to three weeks, exhibits small, disseminated erythematosquamous papules and plaques. Psoriatic diaper rash appears to be the most common type of psoriasis in children under the age of two years.

5) Psoriasis is an instructive model for studying interactions of immigrating immunocytes with resident epithelial and mesenchymal cells. This disease vividly highlights the pathogenic importance of T cells and simultaneously illustrates how advances in our understanding of molecular immune mechanisms can be translated into innovative therapies. Although many factors that contribute to the generation of psoriatic lesions remain obscure, compelling circumstantial and experimental evidence suggests a primary T-lymphocyte-based immunopathogenesis. The response of psoriasis to treatment with compounds that act on lymphocytes, such as cyclosporine, first described for use in psoriasis in 1979, is an early example. More recently, other compounds specifically targeting T-cell functions were found to alleviate psoriasis.

References (abridged):

1. Lomholt G. Prevalence of skin diseases in a population; a census study from the Faroe Islands. Dan Med Bull 1964;11:1-7

2. Farber EM, Nall ML. Epidemiology: natural history and genetics. In: Roenigk HH, Maibach HI, eds. Psoriasis. New York: Marcel Dekker, 1998:107-58

3. Kenney JA. Psoriasis in the American black. In: Farber EM, Cox AJ, eds. Psoriasis: proceedings of the International Symposium, Stanford University. Stanford, Calif.: Stanford University Press, 1971:49-52

4. Christophers E. Psoriasis -- epidemiology and clinical spectrum. Clin Exp Dermatol 2001;26:314-320

5. Henseler T, Christophers E. Psoriasis of early and late onset: characterization of two types of psoriasis vulgaris. J Am Acad Dermatol 1985;13:450-456

New Engl. J. Med. http://www.nejm.org

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INFECTIONS AND SUSCEPTIBILITY TO AUTOIMMUNE AND ALLERGIC DISEASES

The following points are made by Jean-Francois Bach (New Engl. J. Med. 2002 347:911):

1) Infectious agents can induce autoimmune diseases in several experimental settings, some of which have clinical counterparts. A variety of mechanisms have been invoked to explain these observations, including molecular mimicry and an increase in the immunogenicity of autoantigens caused by inflammation in the target organ.(1) Paradoxically, infectious agents can also suppress allergic and autoimmune disorders. The author summarizes the evidence that the main factor in the increased prevalence of these diseases in industrialized countries is the reduction in the incidence of infectious diseases in those countries over the past three decades. This concept is not new. In 1966, for example, Leibowitz et al. suggested that the risk of multiple sclerosis is increased among persons who spent their childhood in a home with a high level of sanitation.(2) About 20 years later, Strachan observed that the risk of allergic rhinitis was inversely linked to birth order and the size of the family. He proposed that infections within households in early childhood have a role in preventing allergic rhinitis.(3) Since then, numerous epidemiologic and experimental studies have sought to clarify and extend this so-called "hygiene hypothesis" concerning asthma and other allergic diseases and autoimmune disorders.

2) In general, epidemiologic data provide strong evidence of a steady rise in the incidence of allergic and autoimmune diseases in developed countries over the past three decades. The incidence of many diseases of these two general types has increased: asthma,(4) rhinitis,(5) and atopic dermatitis, representing allergic diseases, and multiple sclerosis, insulin-dependent diabetes mellitus (type 1 diabetes) --particularly in young children -- and Crohn's disease, representing autoimmune diseases. The prevalence of asthma, hay fever, and atopic dermatitis doubled in Swedish schoolchildren between 1979 and 1991, and in Lower Saxony, Germany, the incidence of multiple sclerosis also doubled from 1969 to 1986. The incidence of Crohn's disease more than tripled in northern Europe from the 1950s to the 1990s. The incidence of these disorders apparently began to increase in the 1950s and continues to do so today, although the incidence of some of these diseases may have plateaued.

3) Concomitantly, there has been an obvious decrease in the incidence of many infectious diseases in developed countries as a result of antibiotics, vaccination, or more simply, improved hygiene and better socioeconomic conditions. Intestinal infections are notable, because their frequency has decreased in developed countries as compared with less-developed countries, particularly among children. Moreover, the age at which colonization of the intestinal flora occurs differs among countries: intestinal colonization with gram-negative bacteria, for instance, occurs later in developed than in less-developed countries, both quantitatively and qualitatively. The high prevalence of parasitic infections, notably with plasmodia and schistosoma in southern countries, contrasts with the absence of these diseases in developed countries. Furthermore, the frequency of infestation by minor parasites such as Enterobius vermicularis (pinworms) over the past decade has decreased in developed countries.

4) Clinical implications: The relation between the reduction in the incidence of infectious diseases and the increase in the incidence of allergic and autoimmune diseases, on the one hand, and the apparent protective effect of infections against immune-mediated diseases, on the other hand, have clear clinical implications. A major problem with these correlations is that the infections contributing to protection or susceptibility are ill defined. Moreover, certain infectious agents can trigger allergic or autoimmune diseases.

References (abridged):

1. Olson JK, Croxford JL, Miller SD. Virus-induced autoimmunity: potential role of viruses in initiation, perpetuation, and progression of T-cell-mediated autoimmune disease. Viral Immunol 2001;14:227-250.

2. Leibowitz U, Antonovsky A, Medalie JM, Smith HA, Halpern L, Alter M. Epidemiological study of multiple sclerosis in Israel. II. Multiple sclerosis and level of sanitation. J Neurol Neurosurg Psychiatry 1966;29:60-68.

3. Strachan DP. Hay fever, hygiene, and household size. BMJ 1989;299:1259-1260.

4. Woolcock AJ, Peat JK. Evidence for the increase in asthma worldwide. CIBA Found Symp 1997;206:122-34.

5. Upton MN, McConnachie A, McSharry C, et al. Intergenerational 20 year trends in the prevalence of asthma and hay fever in adults: the Midspan family study surveys of parents and offspring. BMJ 2000;321:88-92.

New Engl. J. Med. http://www.nejm.org

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AUTOIMMUNE DISEASES

The following points are made by A. Davidson and B. Diamond (New Engl. J. Med. 2001 345:340):

1) These diseases, with the exception of rheumatoid arthritis and autoimmune thyroiditis, are individually rare, but together they affect approximately 5 percent of the population in Western countries. Currently, an "autoimmune disease" is defined as a clinical syndrome caused by the activation of T cells or B cells or both, the activation in the absence of an ongoing infection or other discernible cause.

2) For many years the central dogma of immunology focused on the idea that the clonal deletion of autoreactive cells leaves a repertoire of T cells and B cells that recognize specific foreign antigens. The current consensus, however, is that a low level of autoreactivity of the immune system is physiologic and crucial to normal immune function. Autoantigen helps to form the repertoire of mature lymphocytes, and the survival of naive T cells and B cells in the periphery requires continuous exposure to autoantigens.

3) Since there is no fundamental difference between the chemical structure of self-antigens (autoantigens) and that of foreign antigens, lymphocytes apparently evolved not to distinguish self from foreign, as some have speculated, but to respond to antigens only in certain microenvironments, generally in the presence of inflammatory cytokines. Since autoreactivity is physiologic, the challenge in the context of autoimmune diseases is to understand how it becomes a pathologic process and how T cells and B cells contribute to tissue injury.

New Engl. J. Med. http://www.nejm.org

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