Summarized Definition of Pemphigus
Development of the Term Pemphigus
Similarities to other diseases
Genetic traits in common diseases
Causes of Allergy and Immunology
Dermatology Department: University of Iowa
Pemphigus is an autoimmune skin disorder characterized by blistering of the skin and mucous membrane. There are several types of Pemphigus, notably Pemphigus Vulgaris (PV), Pemphigus Foliaceous (PF) and Pemphigus Vegetans (Pvs). Pemphigus is Latin for "Blistering Skin."
Pemphigus involves blistering of the outer (epidermal) layer of the skin and mucous membrane. It is an autoimmune disorder where the immune system produces antibodies against specific proteins in the skin and mucous membrane. These antibodies produce a reaction that leads to a separation of epidermal cells (acantholysis). The exact cause of the development of antibodies against the body's own tissues (autoantibodies) is unknown. A few cases have occurred from reactions to medications, including penicillamine and captopril. More than 95% of people with pemphigus have specific HLA antigens.
Pemphigus is rare. It occurs almost exclusively in middle-aged or older people, of all races and ethnic groups. About one-half of the cases of pemphigus vulgaris begin with blisters in the mouth, followed by skin blisters. The blisters (bullae) are relatively asymptomatic, but the lesions become widespread and complications develop rapidly and may be debilitating or fatal.
Symptoms:
Diagnostic signs and tests:
Treatment:
Severe cases of pemphigus are treated similarly to severe burns. Treatment may require hospitalization, including care in a burn unit or intensive care unit. Treatment is aimed at reducing symptoms and preventing complications.
Intravenous fluids, electrolytes, and proteins may be required. Mouth ulcers may necessitate intravenous feedings, if severe. Anesthetic mouth lozenges may reduce pain of mild to moderate mouth ulcers. Antibiotics and antifungal medications may be appropriate to control/prevent infections.
Systemic therapy as early as possible is required to control pemphigus, but side effects from systemic therapy are a major complication. Treatment includes corticosteroids, medications containing gold, or medications that suppress the immune system (such as azathioprine, methotrexate, or others).
Plasmapheresis (antibody-containing plasma is removed from the blood and replaced with intravenous fluids or donated plasma) may be used in addition to the systemic medications to reduce the amount of antibodies in the bloodstream.
Localized treatment of ulcers and blisters may include soothing or drying lotions, wet dressings, or similar measures.
Expectations (prognosis):
If not treated, pemphigus vulgaris is usually fatal within 2 months to 5 years. This happens not because of the illness, but rather from complications arising from massive skin infections. Generalized infection is the most frequent cause of death. Treated, the disorder tends to be chronic in most cases. Side effects of treatment may be severe or disabling.
Complications:
I found this in a book while scouring the shelves at the University of British Columbia, in Canada. I forgot to write down the title or author, but do recall that it was written in 1961.
Hippocrates (460-370 B.C.), in enumerating different types of fever, referred to a pemphigoid fever (pemphigodes pyretoi) which he stated was terrible in its appearance. The disease which he thus designated did not, however, represent pemphigus since it was not characterized by blisters. A satisfactory interpretation of this pemphigoid fever is not possible because Hippocrates supplied no details. There are altogether four passages in the writings of Hippocrates which deal with blisters; but none of the bullous eruptions which he de- scribed were pemphigus since they were all of short duration.
Galen (A.D. 131-201) assigned the name febris pemphigodes to a disease which "by expansion of heat generates pustules in the mouth which are called phlyctides by the Greeks." Hebra assumed that the disease referred to probably was "herpes labialis seu facialis, so frequently seen on the lips in fevers."
Various medical writers of the ancient world and of the Middle Ages have described diseases with bullae, but none of the diseases resembled pemphigus. They probably represented herpes simplex, bullous impetigo, contact dermatitis or erythema multi forme.
The first author to revive the term febris pemphigodes after Hippocrates and Galen was Lusitanus Zacutus (Abraham Zacuto) (1575-1642). In 1637 he described an instance of "pemphigoid fever" in which the cutaneous lesions probably were blisters; but the disease did not represent pemphigus since the patient recovered after having had two attacks, both of which were of short duration.
In 1677, Seliger applied the term febris pemphygodes to an eruption that undoubtedly was bullous. He reported a case under the title "De febre pemphygode seu bullosa." The bullous eruption was, however, not pemphigus but erythema multi forme since the patient recovered on the eighth day of the disease.
De Sauvages (1706-1767), in 1760, created the word pemphigus; but the bullous eruption which he described as pemphigus maior probably represented erythema multi forme since it was accompanied by a high continuous fever and only lasted about two weeks. The definition given by de Sauvages to pemphigus maior, that of a bullous eruption of short duration, was widely accepted and most conditions described as pemphigus in the following years were of that type.
It was Wichmann (1740-1802) who in a lecture delivered and published in 1791 in Erfurt, Germany gave the word pemphigus its present meaning, that of a chronic bullous disease. For bullous eruptions of short duration he suggested the term febris bullosa. He was the first to describe a case of pemphigus vulgaris with the diagnosis of pemphigus.
In subsequent years the concept of pemphigus underwent repeated changes and the term became at times almost synonymous with vesicular or bullous disease. Thus, v on Martius arrived at the formidable number of ninety-seven types of pemphigus. However, Hebra, in 1860, reestablished Wichmann's concept of pemphigus by stating that pemphigus always was a chronic disease and that there was no acute form of this disease. This point of view has prevailed up to the present time.
Pemphigus Vulgaris. The first case in medical literature to which the diagnosis of pemphigus vulgaris may possibly be applied is that described in 1681 by Koenig of Berne, Switzerland. It is more likely, however, that the disease was bullous pemphigoid since the patient survived. No diagnosis was given by Koenig to this case. He merely referred to the disease as being strange and surprising.
" "A woman, twenty-five years of age, became afflicted with a very painful disease in 1678. Blisters the size of a hand and filled with a clear and burning water began to appear on different parts of the patient's body. Whenever the blisters disappeared in one area they reappeared in another. After eight months, the patient was able to leave the hospital. For nine months she remained well. Then blisters reappeared, but for only ten days."
The first author to report cases definitely identifiable as pemphigus vulgaris was Machride. In the second edition of his book, published in 1777, four instances of a bullous disease are described. He called the disease morbus vesicularis and stated that this disease had "hitherto entirely escaped the notice of observers." .All four patients were males and were sixty years of age or older. The description was as follows:
"The blisters and vesicles were perpetually coming and going... Two patients died.... The other two patients survived and recovered perfectly; one of them in ten months, while the other did not become entirely free of lesions until three years had elapsed... In the two patients who died the vesicles were filled with a bloody ichor, and the putrid ulcers that ensued were intolerably painful and livid, threatening mortification; but in the two patients who recovered the fluid contained in the blisters did not appear to be of so malignant a nature; being either a clear Iymph or yellow serum and the sores which followed were more tractable."
It is likely that the two patients who died had pemphigus vulgaris, as suggested by the refusal of the denuded areas to heal; whereas the two patients who survived probably had bullous pemphigoid.
The second author to report a case of true pemphigus vulgaris was Wichmann in 1791. He applied to his case the diagnosis of pemphigus and thus was, as already stated, the first to report a case of pemphigus with the diagnosis of pemphigus. The characteristic features of the case, as described by Wichmann in remarkable detail, were: flaccid bullae in some areas and detachment of the epidermis without the formation of bullae in others, resulting in large denuded areas of the skin; severe involvement of the oral mucosa with extension to the vermilion border of the lips; and a fatal outcome.
"The patient, sixty years of age, when first seen had already been ill for nine months. Large areas of the skin were deprived of their epithelium. The whole right leg from the knee down to the dorsum of the feet and large parts of the back and chest were denuded, like a scald. The mucous membrane of the mouth exhibited many wounds so that the patient could take only liquids. The lower lip was covered with crusts, which made the lip unshapely thick. The blisters were not raised but flat, the height and size of an almond and always broke soon. Even when the epidermis was not detached by the underlying moisture, it was loose and wrinkled, so that it could be moved; and so gradually it separated itself and left denuded areas. The patient died after having had the disease for fifteen months."
Pemphigus Foliaceus. Pemphigus foliaceus first was recognized as a special type of pemphigus by Cazenave in 1844. He stated in his textbook:
"The bullae follow each other so fast that there are no intervals. The bullae flow together, break as soon as they have formed and cover large areas with small scales, resembling the flakes of fine pastry. Attached to the skin at one side only, they are movable and have a peculiar foliaceous appearance, so remarkable that I believe that I should establish this type as a peculiar form of pemphigus."
In the literature prior to Cazenave's publication only two cases were found which probably were instances of pemphigus foliaceus. The first case in which a diagnosis of pemphigus foliaceus may be made was published by de la Motte in l772 under the heading: "Sur une maladie singuliere de l'epiderme." At the time of de la Motte's report the disease had persisted for four years.
"Blisters filled with serum arose.... The epidermis thus lifted detached itself in large pieces. New fluid lifted another layer without forming more bullae. This layer fell off and a third layer rose. The unfortunate sufferer changed his epidermis from head to foot every twenty-four to forty-eight hours. The whole body had the redness of a lobster. Every morning one removed from the bed sheet handfuls of pieces of epidermis. One may well believe that one could have filled two barrels with scales had one collected them since the beginning of the malady."
The Nikolsky sign was first described by Nikolsky as a characteristic sign of pemphigus foliaceus in a thesis on that disease published in 1895. In his textbook published in 1927 Nikolsky stated:
"The skin in pemphigus foliaceus shows a weakened coherence among its layers (especially between the horny and granular layers), even in places between lesions on the seemingly unaffected skin. This characteristic behavior of the skin may be demonstrated by two methods: First, by pulling the ruptured wall of a blister one can detach the horny layer for a long distance, even on a seemingly healthy skin; and second, by slightly rubbing the epidermis between blisters one exposes the moist surface of the granular layer."
Pemphigus Vegetans. This form of pemphigus was first described by Neumann in 1886. He stated in his original communication:
"When the wall of the bullae bursts their base becomes raised in the course of a few days and shows warty, densely set granulations. These areas of granulation increase in size and spread seriginously. The seriginous patches are limited by a shaggy undermined epidermis."
The literature before Neumann's report seems to contain descriptions of only two cases of pemphigus vegetans. The first case was described by Hebra in 1860 under the name of pemphigus diphthericus.
"By the bursting of the bullae the dermis forming the base was exposed, and on its surface was found a whitish yellow granulating substance so firmly attached that it could not be detached."
All current textbooks recognize the three forms of pemphigus just mentioned: pemphigus vulgaris, pemphigus foliaceus and pemphigus vegetans. Two additional variants of pemphigus were described in the early part of this century: benign mucosal pemphigus by Thost in 1911, and pemphigus erythematosus by Senear and Usher in 1926.
Pemphigus is an inflammatory auto-immune condition in which the immune system attacks the mucus membranes of the skin. Multiple Sclerosis is an auto-immune condition in which the immune system attacks the myelin sheath around the nerve endings. In Lupus, the immune system attacks muscle and rheumatoid arthritis attacks the joints.
As there is very little information or research about Pemphigus, we can learn a lot by reading what has been learned concerning other autoimmune conditions.
One of a large group of diseases characterized by the subversion or alteration of the function of the immune system of the body. Antigens normally present in the internal cells stimulate the development of antibodies, and the antibodies, unable to distinguish antigens of the internal cells from external antigens, act against the internal cell to cause localized and systemic reactions. These reactions affect the epithelial and the connective tissues of the body, causing a variety of diseases that can be divided into two general categories: the collagen diseases (including systemic lupus erythematosus, dermatomyositis, periarteritis nodosa, scleroderma, and rheumatoid arthritis) and the autoimmune hemolytic disorders (including idiopathic thrombocytopenic purpura, acquired hemolytic anemia, and autoimmune leukopenia).
The precise pathophysiologic processes and the origin of these diseases are unknown. * observations The manifestations and clinical characteristics depend on the specific disease and on the organ or systems affected.
Therapy includes corticosteroid, anti-inflammatory, and immuno suppressive drugs. The symptoms are treated specifically, such as a transfusion for hemorrhage, analgesics for pain, and physical therapy for the prevention of contracture. Diet may be regulated for specific needs; for example, iron might be increased to treat anemia in a person with thrombocytopenic purpura, or calories might be reduced in a weight-loss diet for a person with rheumatoid arthritis. Surgical treatment may be corrective or preventive, such as a hip replacement in rheumatoid arthritis or a splenectomy in thrombocytopenic purpura.
Many of these diseases are characterized by periods of crisis and periods of remission. During a crisis, the patient may be hospitalized and require extensive nursing care, with relief from pain, applications of heat or cold, range of motion exercises, or assistance in movement and ambulation. The nurse observes for signs of hemorrhage, puts side rails or a trapeze in place if necessary, protects the person from infection, and prevents chilling or overheating. Because the patient is in particular need of emotional support, the nurse helps the person verbalize feelings of anger and frustration, recognize limitations, focus on strengths, set realistic goals, and understand the disease process. It is important also to teach the patient and the family the side effects of the drugs being prescribed and how the drugs are to be taken.
(Editorial) by Anthony G. Wilson and Gordon W. Duff v310 British
Medical Journal June 10 '95 p1482(2)
COPYRIGHT 1995 British Medical Association (UK)
An important current topic of medical research is the localization of genes implicated in the susceptibility to common chronic diseases such as insulin dependent diabetes, rheumatoid arthritis, and multiple sclerosis. This has been greatly facilitated by the use of the polymerase chain reaction to characterize polymorphic microsatellite markers and the advent of automated technology and computer software to construct high resolution genetic maps covering the entire genome. A recent example of the success of these methods occurred in the genome-wide search in families for genes conferring susceptibility to insulin dependent diabetes. Population studies, based on epidemiological principles, test the association of disease with specific genetic markers, and recent advances have also been made with this approach.
Most of these common diseases are clearly polygenic, involving several loci, and many population association studies leave little doubt that an appreciable genetic component of immunopathology lies in the major histocompatibility complex. This is a four megabase stretch of DNA (about 0.1% of the human genome) located on the short arm of chromosome 6 and containing up to 200 genes, many of which are immunologically relevant. Within the major histocompatibility complex lies the gene for tumor necrosis factor [alpha], a potent proinflammatory cytokine implicated in the pathogenesis and clinical manifestations of many inflammatory and infectious conditions. In view of its chromosomal location and biological effects there has been speculation that polymorphism within the gene for tumor necrosis factor a may play a part in the genetic association of the major histocompatibility complex with at least some of these diseases.
A biallelic polymorphism has been described in the gene for tumor necrosis factor [alpha] in a region that controls transcription. The rarer allele, TNF2, is part of the HLA AL-B8-DR3-DQ2 haplotype, which is associated with many autoimmune diseases. A preliminary study in coeliac disease, which is strongly associated with HLA-DQ2, found carriage of TNF2 in 96% of patients compared with 21% of controls, suggesting that a second susceptibility locus on this haplotype may lie close to, or within, the locus for tumor necrosis factor. In malaria high plasma concentrations of tumor necrosis factor [alpha] are associated with more severe disease, with the highest concentrations occurring in fatal cases of cerebral malaria. A study of genotypes for tumor necrosis factor [alpha] in west African patients with malaria has shown that homozygosity for the TNF2 allele is associated with a sevenfold increased risk of death or severe neurological complications due to cerebral malaria. Furthermore, the TNF2 allele in gene assays directs higher levels of transcription of the gene compared with the common allele, suggesting that this polymorphism directly affects production of tumor necrosis factor [alpha]. Malaria or systemic lupus erythematosus?
An interesting observation is the apparent protection from autoimmune diseases in areas of west Africa where malaria is endemic, in contrast to the high incidence of systemic lupus erythematosus in Afro-American populations, who are mostly of west African descent. This has led to speculation that high concentrations of tumor necrosis factor [alpha] induced by malaria in west Africa may protect against systemic lupus erythematosus. In support of this idea, protective effects of recombinant tumor necrosis factor [alpha] in the (NZB x NZW)[F1] mouse model of lupus have been cited,[14] and infection of this strain with Plasmodium berghei prevents the development of the lupus-like disease. The TNF2 allele may be responsible for the lower incidence of lupus in Africa, resulting from endemic malaria, while the absence of this stimulant of the production of tumor necrosis factor [alpha] allows for the increased incidence of this disease in Afro-Americans. If this is correct it would be a good example of the old clinical adage that "autoimmunity is the price paid for eradicating infectious diseases."
Despite the adverse effects of homozygosity in malaria, TNF2 is maintained at a similar frequency in west African and northern European populations, which suggests that compensatory pressures in Africa exist to maintain the allele. Perhaps it has beneficial effects in other important infectious diseases such as measles, meningococcal disease, leprosy, or tuberculosis. There may also be heterozygous advantages. The efficacy of treatment with antibodies to tumor necrosis factor a is being investigated in several diseases and has been shown to be beneficial in rheumatoid arthritis.[16] Determining patients' genotype for tumor necrosis factor before starting treatment may permit the selection of patients who are genetically predisposed to produce high concentrations of this cytokine and who might therefore benefit most from this treatment. The prospect of targeting treatment at those predicted to gain most therapeutic benefit clearly has important clinical and economic consequences, particularly in diseases of high prevalence such as malaria. Clinical benefits may result from this research by the end of the decade.
by Charlotte Cunningham-Rundles v273 JAMA,
The Journal of the American Medical Association June 7 '95 p1659(2) 79G4882
COPYRIGHT 1995 American Medical Association
Cytokines are low-molecular-weight proteins secreted by many cells, which can function as immune mediators. (If the cell of origin is a lymphocyte, these proteins are usually called lymphokines.) Many cytokines were originally named on the basis of an observed biological activity (eg, tumor necrosis factor and interferon), but most are multi functional and act on a variety of target cells. These hormone like compounds are capable of a wide range of immunologic activities, including either stimulating or suppressing various cells of the immune system. Despite the powerful in vitro activities of cytokines and the demonstration of increased levels of cytokines role of cytokines in the pathogenesis of disease remains unknown but intensely investigated. One of the major controversies about assigning cytokines a role in disease pathogenesis is that there are still many questions about the optimum methods for measuring individual cytokines. The most commonly used methods are enzyme-linked immuno sorbent assay (ELISA) and, to a lesser extent, bioassays. Other methods include extraction of cells from blood or diseased tissues to assay for cytokine production in vitro or by studying tissues with cytokine-specific fluorescent-labeled monoclonal antibodies. An increasingly used method to measure cytokine gene expression in tissues is in situ hybridization, performed using cytokine-specific radioactively labeled complementary DNA probes. This method also provides information about the kind of cell producing the cytokine.
Each of these methods has intrinsic advantages and disadvantages. Bioassays are sensitive but are more frequently used in research studies, since growing cytokine-sensitive cell lines is not usually commercially practical. The ELISA kits have become popular, but there does not seem to be any ready means of standardizing these kits to ascertain their relative sensitivity and accuracy. Other problems stem from the biological samples themselves: cytokines in blood and other fluids may have a short half-life and may circulate bound to other plasma proteins (such as [beta.sub.2]-macroglobulin) or soluble cytokine receptors shed from Cells. These carrier proteins may interfere with biological function and/or cytokine detection. In situ hybridization is a powerful means of identifying locally produced cytokines but still not widely accessible. This method is probably best applied to freshly obtained, cypropreserved tissues. Despite the methodological reservations just mentioned, these assays are already being used to investigate the levels of cytokines in human disease and to draw conclusions about how these cytokines are involved in the disease process. In the next several years, cytokine measurements will most likely continue to thrive and become more standardized. In the meantime, further studies on the biological controls and functional activities of these complex proteins will elucidate how best to interpret the results of cytokine assays. Since an increasing number of cytokine antagonists will ultimately become available, the current hope is that where excess cytokine is proved to be disease producing, specific antagonists will be able to provide rational and specific treatments.
Why some individuals develop autoimmune disease while healthy people develop tolerance
to their own tissues, has always remained a mystery. For many years scientists assumed
that T cells capable of self-reactivity were deleted in the thymus, usually early in fetal
life. However, it is much more probable that maintenance of tolerance involves a number of
immunologic mechanisms that operate continually throughout life. For patients with
autoimmune disease, how to reestablish the normal state of tolerance to the patients' own
tissues has never been successfully addressed.
Almost 85 years ago Wells showed that feeding hen's egg protein to guinea pigs protected these animals from the fatal anaphylaxis usually induced by this protein. This protection, resulting in systemic unresponsiveness, has been called "oral tolerance." The induction of tolerance has been intermittently; investigated in a number of animal studies more recently. in this century, but the immunologic mechanisms underlying the development of tolerance remained elusive, and no application to human disease emerged.
In the past decade, a number of studies have shown that feeding the targeted protein antigen to animals with experimentally induced autoimmune disease could successfully treat the disease. Two of the main mechanisms for inducing tolerance in these situations have been elucidated: T-cell suppression (resulting from feeding lower doses of the antigen) and clonal anergy, in which there is deletion of immune T cells (usually resulting from feeding larger doses of the antigen). This interesting mode of therapy has recently been applied to several human autoimmune diseases. In pilot human studies, patients with multiple sclerosis were given bovine myelin, patients with rheumatoid arthritis were given chicken collagen, and patients with uveoretinitis were given bovine S-antigen. Clinically significant results have been seen in pilot studies, and no apparent toxicity or disease exacerbation has been observed. Several large clinical trials in rheumatoid arthritis and in uveitis are now ongoing to determine the ultimate utility of this novel approach.
During the past several years, another emerging theme in clinical immunology has been the investigation of individual immune components in model systems by targeted gene disruption. The development of a group of molecular techniques has made possible the deletion of specific genes of the immune system in mice (called gene "knockouts"). When the deleted gene is not required for survival, the resulting mutant mice can be used in studies to dissect the capabilities of the remaining immune system and to define the role of the deleted gene product. While antimicrobial immunity is generally defective in knockout mice, the intrinsically redundant nature of the immune system, or perhaps differences between mice and men, has provided a number of surprises in these knockout models.
In some cases, unexpected diseases emerge. Although interleukin-2 (IL-2) is believed to be an essential cytokine in human T-cell growth, the immune system of the IL-2-deficient mouse develops normally. However, after 10 weeks of life, if the IL-2-deficient mouse is housed in a non-germ-free environment, inflammatory bowel disease develops. Although there is no clear human counterpart to the IL-2-deficient mouse, infants with deficient IL-2 production have severe T-cell and B-cell defects and the diagnosis of severe combined immunodeficiency. The differences between the IL-2-deficient mouse and the human counterpart are not understood; perhaps in the human, additional defects lead to the more severe immune defects observed. In another knockout model, mice with no interleukin-10 (IL-10) appeared healthy and had good immunologic responses but later developed inflammatory bowel disease. These studies, coupled with other work showing that IL-10 can suppress several immune functions in vitro, provide a rationale for ongoing clinical trials of IL-10 in human inflammatory bowel disease. In other cases, the gene-knockout animals have unexpected immune defects. For example, when mice with no interferon gamma receptor are exposed to pseudorabies virus, antiviral T-cell and cytokine immunity is normal, but the animals do not develop protective antiviral titers and die after re exposure to the virus.
In the next several years, the further development of these knockout models will undoubtedly flourish. While mouse immunity and human immunity are certainly not identical, contrasting human immunodeficiency disease with genetically engineered models will likely lead to useful conclusions and uncharted avenues of investigation.
