Dermatomyositis/polymyositis associated with internal malignancy: a consequence of how neoplasms alter generalized extracellular matrix in the host.

The mechanism of dermatomyositis/polymyositis (DM/PM) is unknown. There are multiple probable trigger mechanisms. Internal malignancy is a specific trigger for some cases of DM/PM. It is known that there are marked changes in the extracellular matrix around tumors and that various fractions of depolymerized glycosaminoglycans enter the circulation. Circulating ECM fractions are known to incorporate in the extracellular matrix (ECM). Skin changes in DM include mucin formation, edema, and atrophy. These are not post inflammatory changes. These changes could be a consequence of the tumor's effect in the generalized ECM. Many factors influence ECM. Infections are another probable trigger for DM/PM. Infections induce extracellular matrix changes. It is likely that a role for infectious agents in DM/PM will eventually be defined. The drug D-penicillamine is also a trigger for DM/PM. Understanding the mechanism of any one trigger might aid in helping define other triggers. Four other cutaneous signs of internal malignancy can be explained by the mechanism used to explain DM/PM.

The sign of Leser-Trélat: a cutaneous sign of internal malignancy: weakened subepithelial matrix from the effect of neoplasms on the extracellular matrix of the host.

The sudden onset of many seborrheic keratoses (SK) associated with an internal malignancy (most commonly adenocarcinoma) is called the sign of Leser-Trélat. It is associated with acanthosis nigricans (AN) in 20% of the cases. There are marked changes in the extracellular matrix (ECM) around tumors. Various fractions and depolymerized glycosaminoglycans enter circulation. They can incorporate in the general extracellular matrix. Mechanical factors present in AN produce extrusions of this poor quality ECM in the form of papillae and folds. The poor quality of subepithelial extracellular matrix produces the marked epithelial changes of acanthosis nigricans which shows hyperkeratosis, papillomatosis, slight irregular acanthosis, and keratin material formation. The neoplasm can produce the same qualitative changes in the subepithelial ECM on otherwise normal appearing skin. When the altered same epithelial changes occur on this biologically altered skin the result is many SK (the sign of Leser-Trélat).

Pellagra--increased viscosity of extracellular matrix.

Pellagra is the result of increased viscosity of extracellular matrix (ECM). The skin changes in pellagra localize at sites of sun exposure or trauma because the mediators which are released cannot diffuse from the area. Edema is reported as the first clinical and microscopic change. Changes in the ECM are not directly visible. Increased viscosity of ECM in the gastrointestinal tract would decrease absorption of fluid and nutrients from the bowel resulting in diarrhea. In the tongue the excess ECM viscosity holds water producing swelling. The effect of climate and seasons relates to the increased demand for ECM repair on sunlight exposed areas. Infections increase the severity of pellagra by requiring increased tissue repair. Local infections are often unusually severe. Infections have a greater inflammatory component at sites of high ECM viscosity. Nicotinic acid reverses the neurologic and gastrointestinal changes of pellagra in 24 h. This suggests a simple rapid mode of action. Nicotinic acid plays a major role in tissue respiration which is essential for tissue repair and degradation of glycosaminoglycans. Altering ECM viscosity is a method of modulating inflammation, immunity, and normal tissue physiology.

Acanthosis nigricans--decreased extracellular matrix viscosity: cancer, obesity, diabetes, corticosteroids, somatotrophin.

Acanthosis nigricans is a reaction pattern to over a dozen different causes. The skin, most classic in the axilla, is dark, soft, velvet-like with fine folding and papillae. The mechanism of this skin change is decreased viscosity of extracellular matrix (ECM) combined with mechanical extrusion of ECM into papillae extending out from the upper dermis. It occurs in obesity (increased mechanical pressure on ECM), diabetes (decreased quality of glycosaminoglycans) (GAG), excess corticosteroids (decreased quality of GAG), pineal tumors (increased ECM and edema), other endocrine disorders (alterations in the quality of GAG), multiple genetic variants (structural and chemical change), from drugs such as nicotinic acid, estrogens, corticosteroids (weakened or altered GAG) and adenocarcinoma (fractions of depolymerized or altered GAG released from the tumor area are incorporated into and weaken the skin GAG). Acanthosis nigricans was first reported in 1890 as a cutaneous sign of internal malignancy. Acanthosis nigricans presents an opportunity to better understand what is occurring in the ECM in many disorders. The understanding of the association of AN and internal malignancy will expand our understanding of how a neoplasm decreases generalized ECM viscosity.

Inducing viral immunity without a vaccine--possible use with human immunodeficiency virus.

Induction of allergic contact dermatitis over warts (verrucae vulgaris) causes viral immunity and resolution of the warts in a large percentage of cases. Human immunodeficiency virus could be removed, concentrated, and placed back into the patient's own skin at a site of contact dermatitis.

Aphthous stomatitis (canker sores): a consequence of high oral submucosal viscosity (the role of extracellular matrix and the possible role of lectins).

Recurrent aphthous stomatitis (RAS) or canker sores occur in 20-60% of all persons. The lesion occurs because of increased viscosity of oral submucosal extracellular matrix (ECM). The lesions begin in the second decade and peak in the third decade. Sex hormones are an important influence on fibroblasts, especially in the early phase of exposure. Sex hormones are known to concentrate, to a degree, in the bucal mucosa in animals. Lesions of RAS localize clinically and experimentally at sites of trauma. In the skin, edema is known to trigger early cellular inflammation. Increased viscosity of ECM heightens the response. The histopathology of the ulcerated lesions is similar to that which occurs under sites of acute inflammation in the skin. Systemic corticosteroids completely supress the lesions. Caustics, such as silver nitrate and phenol, stop the growth and pain of lesions. Irritants are known to break ECM viscosity. The oral mucosa exerts some control on underlying ECM. Substances such as lectins influencing the mucosa could influence ECM. Soluble substances in food or organisms could also penetrate to influence ECM. A number of different foods have been incriminated as trigger agents in individual cases. This includes gluten in patients with gluten sensitive enteropathy. Gluten is known to alter the mucosa of the small intestine in persons with celiac disease.

To wall off neoplasms with more viscous extracellular matrix.

Normal inflammatory and immune mechanisms would destroy most neoplasms if the neoplasm did not alter its immediate environment to weaken the host defenses. Based on factors that seem to increase extracellular matrix viscosity, methods of enhancing host resistance in the vicinity of the tumor are suggested by the author. This includes adjuvant therapy, pyridoxine antagonist, cytokines, beta carotene, retinoids, vitamin C, iodides, bromides, and pellagragenic substances. Hyperthermia may also have an effect.

Autoimmunity as a secondary phenomenon in scleroderma (and so-called human adjuvant disease).

Autoantibodies form under diverse circumstances. Some autoantibodies are clearly secondary phenomena in response to tissue injury. When there is defective microdebridement, tissue antigens will persist and will produce even more autoantibody. Scleroderma is classified as an autoimmune disease but autoantibodies are not always present. There is extensive literature on the early role of vascular changes and the presence of connective tissue active substances. There are clinical cases of scleroderma following implants of silicone, paraffin injections, and occupational silica or polyvinyl chloride exposure. It would be hard to describe a worse group of nondegradable substances capable of overloading the debridement system. It has been demonstrated that macrophages that ingest silica release factors that increase biosynthesis by fibroblasts. There may be many methods of arriving at the clinical pattern of scleroderma. Elimination of autoantibodies as a primary etiologic consideration will allow concentration on the other known physiologic factors. There is, in some cases, a secondary injury of the kidney from immune complexes. Autoimmunity, when it occurs, is a secondary phenomenon in scleroderma, or so-called 'human adjuvant disease'.

Dermatitis herpetiformis and gluten sensitive enteropathy (including celiac disease)--increased subepithelial extracellular matrix viscosity due to gliadin.

It is now firmly established that dermatitis herpetiformis (DH) is associated with gluten sensitive enteropathy (GSE), although the GSE of DH is generally milder than that form which occurs in celiac disease. The toxic fraction of gluten is in the gliadin, a protein fraction. Gliadin is absorbed in GSE and antigliadin antibodies are present in both DH and celiac disease. There is a question of a cross reactivity between reticulin and gliadin. Gliadin is reported to bind to reticulin. Reticulin has a glycosaminoglycan component. Fibronectin, another component of ground substance, also binds to reticulin. Reticulin and fibronectin are important in basement membrane areas and play a role in basement membrane attachment. Gluten may also exert a lectin effect on gastrointestinal mucosa which contributes to the underlying extracellular matrix. DH and GSE have different pathologies because of their different anatomical sites. The pathomechanisms of both diseases can be explained by one mechanism. Gliadin, or a peptide fraction from it, enters or combines with the extracellular matrix and increases tissue viscosity. The protein fraction of glycosaminoglycans in the extracellular matrix is known to control viscosity. In DH the increased extracellular matrix viscosity would interfere with the diffusion of tissue fluid in the dermal papillae and leads to vesicle formation. The intestinal villi serve a very different function. In GSE the increased extracellular matrix viscosity would decrease adsorption from the intestinal tract producing villi with less volume (shortened or atrophic). The shortened villi decrease the production of digestive enzymes and the absorptive surface. The decreased movement of nutrient tissue fluid supplied to the intestinal epithelial cells also eliminates the microvilli.(ABSTRACT TRUNCATED AT 250 WORDS)

Herpes gestationis--bullae from hormones that cause increased extracellular matrix (autoantibodies to epidermal basement membrane as a secondary phenomenon).

Herpes gestationis is a bullous skin disease clearly secondary to the hormones of pregnancy and other hormonal influences. It is the result multiple hormones. No one hormone is specific. The hormones increase ground substance viscosity in the skin and this induces edema and bullae formation. Only 10 to 20% of the patients demonstrate IgG formation by indirect immunofluorescence. By direct immunofluorescent studies 30 to 40% of the patients demonstrate deposition of IgG in the basement membrane zone. Other variations of immune factors are present in most cases but they are weak by titers usually present in most so called autoimmune disorders. Many bullous diseases of the skin, including herpes gestationis, are considered autoimmune. It is known that trauma to cells and tissues can induce autoantibodies to form. It is proposed that autoantibodies can form as a secondary phenomenon in bullous skin disorders. The authors who have proposed an autoimmune etiology of herpes gestationis do not attempt to explain the clear association of the disease with the hormones of pregnancy, other female hormones, chorio-carcinoma, or hydatidiform mole.

High viscosity of newborn extracellular matrix is the etiology of erythema toxicum neonatorum: neonatal jaundice?: hyaline membrane disease?

At the time of birth, the fetal ground substance is under the influence of maternal and placental hormones. Hormones are known to exert significant effect on ground substance. The ground substance viscosity that is ideal for intrauterine life is too viscous for the newborn. Sites of minor skin trauma develop swelling, inflammation and pustules. Dilution of tissue fluids causes formation of some of the mediators of inflammation including those responsible for intraepidermal pustule formation. The newborn responds to inflammation with eosinophilic granulocyte. The clinical lesions referred to as erythema toxicum neonatorum are known to localize at pressure sites. The skin lesions correct as maternal and placental hormone influence weakens. The entity occurs in 31 to 72% of white infants. The hormone induced viscosity changes may aid in better understanding some aspects of neonatal physiology; such as jaundice of the neonatal period, the eosinophilic granulocyte inflammatory response of the neonatal period and hyaline membrane disease.

Autoantibodies in aging: an attempt to correct a weakening debridement mechanism.

Autoantibodies are present in small quantities throughout most of the host life but increase with aging. It is unlikely they are the etiologic cause of aging. They probably do contribute to some of the pathologic changes seen in aging such as amyloid deposits. Autoantibodies, when they are part of a functioning microdebridement system, like other antibodies, are one method of increasing tissue debridement. Autoantibodies are a broad biologic phenomenon capable of doing far more good than harm. Inflammation weakens with aging and thus microdebridement is weakened. The immune system weakens with aging but is stimulated by the increasing accumulation of antigen derived from tissue debris. Autoantibodies are an attempt to enhance debridement in a weakening system. The autoantibody should not be condemned because of the failure of other aspects of the debridement system. Improving tissue debridement would not stop eventual senescence but it might decrease some of the pathologic and physiologic changes of aging and improve the quality of life. Improving tissue debridement is currently more attainable than altering the etiology of senescence. Factors promoting immunologic stimulation by tissue fractions are reviewed. The possible value of increasing tissue debridement in damage preceding arteriosclerotic vascular change is discussed. The role of the aging extracellular matrix in the weakening of ground substance and decreasing early cellular inflammation is reviewed.

Defective generalized extracellular matrix in the neoplasm bearing host: decreased inflammation, immunity and resistance.

Neoplasms have extensive qualitative and quantitative changes in their extracellular matrix. Lytic factors from neoplasms breakdown extracellular matrix of the areas adjacent to the neoplasms and fibroblasts in these areas produce increased extracellular matrix. Some of the extracellular matrix fractions are normally present in serum. Multiple fractions derived from extracellular matrix are present in the serum of tumor patients. Tumor patients often have decreased early cellular inflammation and immunity. These reactions depend on a normal extracellular matrix. A number of known facts about the tumor bearing host can be explained by the concept that the host's generalized extracellular matrix is altered by circulating fractions of extracellular matrix. These could be qualitative or quantitative defects as well as an abundance of depolymerized fractions. The beneficial effects of cytokines, streptococcal infections and pyridoxine deficiency on tumors can be explained by this concept.

Sulfapyridine and sulfones decrease glycosaminoglycans viscosity in dermatitis herpetiformis, ulcerative colitis, and pyoderma gangrenosum.

Shortly after the introduction of sulfa drugs, sulfapyridine was found to have unique therapeutic properties, unrelated to antibacterial activity. Later, sulfones were found to share the same properties. The disorders initially improved were dermatitis herpetiformis, pyoderma gangrenosum, subcorneal pustular dermatosis, acrodermatitis continua, impetigo herpetiformis and ulcerative colitis. They were also sometimes helpful in many other disorders. They are effective in select disorders characterized by edema followed by granulocytic inflammation or edema followed by vesicle or bullae formation. The sulfones work in low doses in leprosy and their mode of action is not fully understood. Several pieces of experimental information are available. It is proposed that these drugs are entering or influencing the protein moiety of glycosaminoglycans and decreasing tissue viscosity. This decreased tissue viscosity prevents edema and dilution of tissue fluid and decreases acute inflammation and vesicle and bullae formation.

Psoriasis: highly reactive early cellular inflammation.

Psoriasis is the result of highly reactive early cellular inflammation. Psoriasis simultaneously has a rapidly proliferating epidermis, a vigorous acute inflammatory reaction, an accelerated rate of dermal breakdown and repair, and vascular and fibroblast proliferation. Understanding the primary role of early cellular inflammation allows explanation of other factors. All clinical, experimental and therapeutic facts can be explained on this basis. There are extensive biologic changes. Early cellular inflammation is influenced by genetic and environmental factors. It is proposed that the defect is quantitative rather than qualitative. Psoriasis commonly localizes at sites of injury. Several authors have noted that the first histologic change in psoriasis is the spurting of granulocytes from the dermal papillae. This is a cyclical event. Connective tissue-active peptides released from granulocytes produce a ninefold increase in the size of the dermal papille. This results in a ninefold increase in the size of the germinative cell base of the epidermis. The vast literature on rapid epithelial proliferation in psoriasis measures a secondary phenomenon. The concept presented does not provide an answer to the biochemistry of early cellular inflammation except to point out the initial importance of dilution of tissue fluids. The author considers early cellular inflammation to result from multiple, simultaneous, overlapping, amplifying and inhibitory systems. There are multiple ways to arrive at the final biologic effect which is too essential to depend on a single series of events. There is a large amount of empiric knowledge on psoriasis which can aid in understanding early cellular inflammation.

Pyridoxine deficiency and antagonism produce increased ground substance viscosity with resulting seborrheic dermatitis and increased tumor resistance.

Pyridoxine deficiency and 4'-deoxypyridoxine produce acrodynia in rats and seborrheic dermatitis in man. They also produce tumor inhibition in man and animals. Pyridoxine is extensively involved in metabolism and its relationship to the inhibitor 4'-deoxypyridoxine is complex. Pyridoxine deficiency and antagonism increases ground substance viscosity. This increase the inflammatory reactivity of the skin to produce acrodynia in rats and seborrheic dermatitis in man. The increase in ground substance viscosity would explain the increased resistance to tumors in man and animals. Pyridoxine is important in protein metabolism. The protein moiety of glycosaminoglycans in ground substance is small but plays a major role in tissue viscosity. Pyridoxine deficiency or antagonism by itself does not offer a definitive answer for tumors. Combined with substances that stimulate fibroblast or glycosaminoglycans production it may have a significant additive effect.

A mechanism of peripheral spread or localization of inflammatory reactions--role of the localized ground substance adaptive phenomenon.

It is known that connective tissue-active peptides (CTAP) are released at sites of inflammation. Some of this material diffuses to immediately adjacent tissue and increases ground substance viscosity and fibroblast proliferation. This contributes to host protection against spread of infections and tumors. In a person with normal inflammatory reactivity, it should prevent spread of mediators and products of local inflammation. However, the host with an increased reactivity in sites of increased ground substance viscosity or who is highly reactive to dilution of tissue fluid would respond with more inflammation. A non-infectious, non-malignant process in a host with a highly reactive inflammatory or immune response could end up with peripheral spread. This could occur in any tissue but it occurs with great vigor in the skin. It could present as a peripheral extension of a local disease process, such as psoriasis, or the migration of cyclic lesions with clearing of the central area. There are over a dozen variants of peripherally spreading, ringed lesions described in the dermatologic literature. This includes erythema marginatum of rheumatic fever, erythema gyratum repens associated with cancer, and erythema annulare centrificum associated with allergic reactions to fungi. Many of the ringed dermatologic lesions have an immunologic component. They tend to be associated with inflammatory immune reactions at distant sites. Dermatologists have been gathering information on the ringed phenomenon at least since Hebra in 1854. The acute localized ground substance adaptive phenomenon is a broadly beneficial biologic response.(ABSTRACT TRUNCATED AT 250 WORDS)

Commonsense advice on treating nail disorders.

Most nail disorders seen by primary care physicians are due to maceration, dryness, trauma, or infection. Some cases may be treated simply by having the patient remove a bandage to allow the skin to dry; other cases, such as subungual abscess, require local anesthesia and drainage for relief. Fungal infections may need to be treated for as long as a year. Patients with a tumor under the nail should be referred to a specialist.

Lupus erythematosus and rheumatoid arthritis--groups of defects in microdebridement (polygenetic defects exceeding the fault tolerance threshold--a consequence of natural defense mechanisms).

Lupus erythematosus (LE) and rheumatoid arthritis (RA) are groups of defects in microdebridement of tissue which includes removal of infectious agents and cellular debris. They are the phenotypic response to a number of polygenetic and/or induced defects. The recognized clinical patterns of these disorders are the responses to accumulated tissue debris and complications of secondary debridement mechanisms that cannot function properly due to basic defects in the debridement system. The series of events that occurs after infection or tissue damage is polygenetic and involve multiple pathways. Genetic polymorphism of this group of mechanisms increases survival against a wider variety of infections. An organism capable of bypassing or destroying a specific step in the host defense is still eliminated by the host in spite of the created defect (a fault tolerant system). However, a single mutant error of this same step creating the same defect will not disrupt the host to the point of clinical illness or death. The pathways are broad enough to bypass some mutant errors. It is the same fault tolerant system. Increased pressure on the system from infection or tissue damage or a combination of multiple genetic defects results in enough faults to exceed the threshold of fault tolerance and produce clinical patterns of disease. The large number of possible combinations of defects gives rise to marked disease variation among patients. The higher frequency of some defects or combination of defects ces subsets. Inbred strains of animals have less polymorphism and thus some strains have a greater susceptibility to infections, LE and RA. Many of the phenomena that occur in LE and RA are secondary to the basic defect of inadequate tissue debridement. Rheumatoid factor (RF) is generally a normal beneficial phenomenon of increasing particle size so that immune complexes can more readily be removed by the reticuloendothelial system. In the presence of defective microdebridement the system is overloaded and no longer effective. This results in circulating RF. There are clearly multiple basic genetic defects. For example, the known multiple genetic defects in complement in LE are relevant to the systems involved. They are important ligands for defense and debridement mechanisms. A null allele is not likely to be a secondary phenomenon. It might be in a fault tolerant site and contribute to disease in one host, and yet not contribute to disease in another host.(ABSTRACT TRUNCATED AT 400 WORDS)