- Email: [email protected]
The Problem of Psoriasis
The Problem of Psoriasis PAUL GROSS, M.D.*
THE last decade has witnessed a concerted effort in basic dermatologic research concerned with or related to the pathogenesis of psoriasis. The biochemical, histochemical and refined histopathologic studies on keratinization and its abnormal form of parakeratosis have helped the understanding of this erythematosquamous dermatosis. The results of these studies and an analysis of the "Koebner phenomenon" reveal that the process of parakeratosis as it occurs in psoriasis consists of an acceleration of the keratinization process. This results in increased activity of cellular enzymes and abnormalities in the chemical composition of the parakeratotic epidermis. While this supplies evidence that the epidermis is the principal site of the pathologic changes in the target organ, the abnormalities of the papillary blood vessels and increased phosphorylase activity in the capillaries and arterioles point to humoral influences. These can be due to changes in carbohydrate, protein or lipid metabolism, based on a primary disturbance in the regulatory mechanism. The site and nature of this disturbance is the clue to the etiology of psoriasis, but the effort to localize it has so far been in vain. Progress in the knowledge of the interrelationship between the diencephalon and pituitary on one hand and intermediary metabolism on the other hand may eventually furnish some clue to the complexities of psoriasis. For the time being, we shall build on the knowledge available, and by correlating it with clinical experience, try to evolve a rational therapy of psoriasis. HISTOPATHOLOGY AND HISTOCHEMISTRY OF PSORIASIS
The tissue changes of psoriasis have been summarized by Lever22 as follows: (1) parakeratosis, (2) thinning of the suprapapillary portion of the rete Malpighii, (3) elongation of the rete pegs, (4) edema and clubbing of the papillae and (5) Munro micro-abscesses. Striking features in the cutis are the dilated and tortuous capillaries of the papillae and a moderate infiltration of the papillary portion of the corium with lymphocytes and monocytes. Variations in the degree of these microscopic findings explain some of the differences and at times atypical features which manifest themselves in the clinical appearance of the psoriatic lesion. From the Department of Dermatology, College of Physicians and Surgeons, Columbia University, New York, N. Y.
* Clinical Professor of Dermatology, College of Physicians and Surgeons, Columbia Un-iversity,. A ttending Dermatologist, Presbyterian Hospital.
903
Paul Gross
904-
The biochemical, histochemical and physiological changes in the psoriatic skin have been recently reviewed by Shelley and Arthur. 33 The bibliography of 169 references is a testimony to the data available in the literature and the exhaustive work performed by these authors in presenting and interpreting them critically. To understand the mechanism of keratinization and its functions helps to interpret the chemical abnormalities of parakeratosis. To quote Stiipel and Szakall :37 "Living ectodermal cells of the epidermis are transformed into flat, coherent, dry cells, which form an uninterrupted membrane spread over the entire body. This membrane has (although in moderate degree) a mechanically resistant structure and as a result of its structure it is endowded with the ability to form a protective barrier against mechanical influences of the outside world. Simultaneously with the formation of this solid structure a purposeful chemical change takes place in the living epidermal cells. It leads to the development of a number of well defined chemical substances which are able, due to their chemical qualities, to function against corresponding effects of the surrounding world, but are also capable of synthetic functions within the body." This, of course, refers to the distinction between structural keratin and the water-soluble extractives which are formed during keratinization. Most of the significant findings resulting from chemical studies of the psoriatic scale (Grueneberg and Szakall,l5 Flesch and Jackson-Esoda9, 10 and others) pertain to the water-soluble fraction. There is a decrease in the free amino nitrogen; an increase in the free sulfhydryl compounds and in the free and combined pentoses. These findings and the extensive histochemical studies by BraunFalc0 5 and Steigleder36 present a picture of the parakeratotic scale, which justifies the concept of accelerated keratinization as its cause. That this is a pathologic reaction is evidenced by the microscopic picture and by various abnormalities in the enzymes of the psoriatic efflorescence. The fact that they are not demonstrable in the normal skin of the psoriatic permits so far only the conclusion that they are the expression and not the cause of the metabolic disturbance of the skin in psoriasis. The significance of the findings of Paschoud, Keller and S,chmidli27 will also depend on the outcome of further research. These authors have demonstrated that the decrease of the water-soluble extractives in the psoriatic lesion is due to a 50 per cent reduction of polypeptides. They found the cause of this reduction in a decreased activity of the dipeptidases."(glycylglycin dipeptidase and leucylglycin dipeptidase). Further ingenious experiments revealed that these dipeptidases were not lacking, but were inhibited by a factor in the psoriatic scale. The search for this inhibitor is being continued by these authors, but their findings of increased dipeptidase activity in eczema may signify that the dipeptidase inhibitor is specific for the psoriatic process.
The sum total of the data accumulated by these biochemical and histochemical studies suggest strongly that a metabolic disturbance with its primary site in the epidermis explains the make-up of the psoriatic lesion. This concept is further supported by the Koebner phenomenon. THE KOEBNER PHENOMENON
Koebner,20 who described this behavior of the skin of the psoriatic in 1872, speaks of "a peculiar predisposition which in the psoriatic is present in the skin organ itself, and which is mostly hereditary, but at times acquired and may remain latent for years and may react to the most varying internal and local stimuli-just in this chronic pattern of
The Problem of Psoriasis
905
inflammation of the skin.... From this point of view there is an explanation for the sites of predilection, the first appearance of psoriasis and the only temporary result of local therapy." This broad statement is quoted in order to show that it holds true today and that the production of an isomorphous lesion by the scratch mark of a needle in the skin of a psoriatic who is in an active state is only one phase of the Koebner phenomenon. In previous publications12 , 13 I have referred to the pattern of distribution in widespread pellagra and its similarity to the localization of psoriasis. Since modern vitamin research has demonstrated the effect of nicotinic acid deficiency on cell metabolism, mediated by a defect in dehydrogenase activity, I have considered the Koebner phenomenon as a sign of diseased skin metabolism. The work by Bean, Spies and Vilter3 on asymmetric lesions in pellagra gives valuable insight into the mechanism of the Koebner reaction. The similarity of the Koebner phenomenon in psoriasis and the isomorphous reaction of pellagra is based on two common denominators. The trauma eliciting skin lesions in both diseases can be chronic mechanical irritation, caused by friction in intertriginous areas, or by tensile strain on the skin stretched over joints (especially elbows and knees). It may be a cellular injury produced by actinic or thermal energy, with the visible effect of sunburn or thermal burn; or at times it may consist of trophic changes in the skin due to stasis or scar tissue (Fig. 163). More subtle forms of trauma causing spreading of psoriasis, at times culminating in psoriatic erythroderma, are inflammatory reactions due to topical medicaments, as
Fig. IH3. Koebner phenomenon in pellagra. A, Dermatitis of hands at site of exposure to sun. B, Involvement of wrists due to flexion and friction. C, Lesions on elbows due to tensile strain. D, Butterfly lesion at site of intertriginous friction.
906
Paul Gross
seen in primary irritation or contact type allergic sensitivity. That systemic administration of drugs may act as a Koebner trauma is best demonstrated by the development of erythroderma after Atabrine,40 but also at times by acute exacerbations after therapy with arsenic, sulfonamides and gold injections. There is clinical evidence that this type of reaction is not due to an allergic mechanism but based on a biologic antagonism of these drugs to cellular enzymes. Bean and associates were able to demonstrate experimentally that skin lesions could only be produced during the active stage of pellagra and not during remission. Similarily, a positive Koebner phenomenon can only be produced when psoriasis is in a labile state, usually manifested by appearance of new lesions or spreading of older ones. While the differences between the cellular metabolism of the skin of active pellagra and pellagra in remission are known, no definite knowledge on this point exists concerning psoriasis. A comparative study of the blood chemistry, hormonal functions and physiologic behavior of the skin, including its capillaries and sweat glands during the eruptive stage on the one hand and during periods of remission or quiescence on the other hand, may be fruitful. The experimental work by Kuta and Neumann21 and most recently by Reinertson30 are revealing only by indicating that a mechanical trauma must reach the "living" layers of the epidermis and that the earliest metabolic disturbance measured by dehydrogenase activity occurs in the epidermis, before any significant inflammatory reaction has taken place in the cutis. This helps to understand why an increased demand on the metabolic function of the integument produced by any form of acute or chronic trauma may produce a pathologic response, if the site of trauma is in a state of metabolic insufficiency. What we do not know is the reason for this phasic behavior of the psoriatic skin. The adverse effect of systemic stress reactions on the activity of psoriasis (which include emotional stress, acute and chronic infection, intercurrent disease, unfavorable climatic conditions) make it probable that the skin is not the primary site of the pathologic changes causing psoriasis. The concept of a metabolic disease which has its roots in an abnormality of a central regulatory mechanism is by no means in contradiction to the hereditary pattern of psoriasis.
The conclusions of Hoede,17 that "Psoriasis is a hereditary disease and not some anomaly with occasional familial occurrence" seems incontestable on the basis of the data he has supplied. The peculiarity of the irregular dominant heredity, mentioned by him, emphasizes the need to broaden our concept of the pathologic constellation that is transmitted by heredity. Ashner, Curth and the author2 have pointed to the significant percentage of diabetes occurring in the families of psoriasis. The figure of 5.7 per cent of our psoriatic patients suffering simultaneously from diabetes becomes significant when we compare it with the findings of Joslin who reported 1.5 per cent diabetics in the general population aged 55 to 64 years. This makes it probable that our data obtained from 243 families with at least one psoriatic patient showing an incidence of 17.3 per cent diabetics among the relatives, may be significant statistically, although we lack comparative figures. In a recent communication from the island of Guam, Captain Samuel H. Horton, MC, USN,18 is impressed with the positive relationship between heredity and psoriasis. He finds that many of the psoriatic patients also have diabetes. (UThese
The Problem of Psoriasis
907
people are nearly all distantly kin, and the incidence of these two diseases is truly remarkable.") The advantages of investigating island populations regarding hereditary problems are reflected in Lomholt's23 studies on psoriasis in the Faeroe Islands. He concludes that the disease is inherited dominantly with failing manifestation and calculates the manifestation probability to be about 40 per cent. It would be an error of judgment to assume that the coincidence of psoriasis and diabetes and, for that matter, of psoriasis and arthritis is due to an identical pathogenesis. At best the hereditary studies point to a common denominator which lies in the genotype inheritance. GENERAL METABOLISM
The recognition that parakeratosis is a result of biochemical and enzymatic abnormalities concerned with the protein metabolism of the epidermis does not permit any conclusions regarding the nature of the disturbance of general metabolism. The theory of Schamberg32 that nitrogen retention is responsible for the development of the psoriatic lesions has not stood the test of careful studies employing modern methods. Block4 and his associates found no evidence of nitrogen retention or abnormal urinary sulfur distribution in a controlled study of two psoriatic patients. The therapeutic results attributed to low protein diets may have been due to other factors. Much work has been done on carbohydrate metabolism in psoriasis but evidence is lacking for a causal relationship between a disturbance of sugar metabolism and psoriasis. The genetic relationship which appears to exist between psoriasis and diabetes could be due to a common denominator in the area of lipid metabolism. It is not necessary to consider psoriasis as a lipoidosis of the skin, as Gruetz 16 suggested, in order to evaluate the evidence for a disturbance in lipid metabolism. Certainly the findings reported recently by Radl, I{raus and Tousek29 deserve further studies along these lines. Their averages in 80 cases of psoriasis showed a significant increase of total serum cholesterol. The determination of lipoproteins by paper electrophoresis revealed an increase of the beta fraction. Their work deserves attention since they attempted to correlate the findings of the blood chemistry with the clinical picture of the individual cases. Their statement that the metabolic changes were most pronounced in chronic cases during an acute flare-up, and in arthropathic subacute cases, but least pronounced in chronic cases, should be a guide to further investigative work. Many forms of approach ranging from the biochemical studies of the psoriatic lesion to the Koebner phenomenon, the physiologic behavior of the neurovascular system of the psoriatic and especially of unaffected skin of the psoriatic, may produce more consistent results if the findings are obtained during the eruptive stage of the disease. It should be remembered that the histologic and histochemical changes observed by Madden24 in the uninvolved skin were in cases of acute guttate and generalized psoriasis. CLINICAL PICTURE OF PSORIASIS26,28
The contrast between a chronic solitary plaque covered with heavy micaceous scales and a generalized guttate eruption of psoriasis is strik-
908
Paul Gross
ing. Nevertheless the diagnosis is simplified if we remember the erythematous squamous character of the disease. The early lesion may give the appearance of a brownish red papule but scraping with the fingernail will reveal the typical silvery scale. This so-called "candle-drop sign," together with the bleeding points produced by the systematic removal of
Fig. 164. A, Chronic generalized psoriasis (not a psoriatic erythroderma). B, Chronic psoriasis with acute exacerbation. C, Psoriasis of the hands (may indicate intolerance to sun rays). D, Psoriasis of the palms (should not be mistaken for dermatophytosis or occupational dermatitis). E, Psoriasis of the soles (predilection for pressure areas). F, Psoriasis of the toes (resembling dermatophytosis).
The Problem of Psoriasis
909
the scale, layer by layer (Auspitz sign), is a valuable diagnostic aid. There are instances when the scale may be lacking and a sharply demarcated border, absence of vesicles or oozing and the dusky red color are the only suggestive features of psoriasis. This happens in intertriginous areas, especially in the armpits, groin, anal region or in the interTable 1 SOME COMMON SKIN CONDITIONS TO BE DIFFERENTIATED FROM PSORIASIS
Scalp: Face: Ears: Elbows, knees: Hands, fingers: Palms, soles, toes: Axilla, groin, vulva, anus: Fingernails, toenails: Penis: Trunk and other sites:
Seborrheic dermatitis; lichen simplex chronicus lupus erythematosus Seborrheic dermatitis; lupus erythematosus Seborrheic dermatitis; otitis externa; lupus erythematosus; infectious eczematoid dermatitis Lichen simplex chronicus; asteatotic dermatitis Occupational dermatitis; nummular eczema; lichen planus; acrodermatitis perstans (Hallopeau) Dermatophytosis (especi~lly Trichophyton rubrum infection); syphiloderm; lichen simplex chronicus Pustular bacterids; acrodermatitis perstans (Hallopeau) Seborrheic dermatitis; intertrigo due to Candida albicans; tinea cruris; lichen simplex chronicus (pruritus ani and vulvae) Onychomycosis; onychia due to chemical irritants; traumatic onychia, chronic paronychia due to monilia fungi Lichen planus; erythroplasia; seborrheic dermatitis; distinctive exudative discoid and lichenoid chronic dermatosis (Sulzberger and Garbe) Mycosis fungoides; superficial basal cell epithelioma
digital spaces of the toes. A complete and thorough examination of the body surface, including the scalp and fingernails, may help to discover a typical lesion. The thickened horny layer of the palms and soles fre':' quently changes the appearance of the psoriatic lesion and produces a pale, hyperkeratotic, at times fissured plaque. Local conditions at the fingertips and dorsal aspects of the finger joints may cause a very atypical appearance of psoriasis. The dryness of these lesions, a tendency to fissuring, aggravated by cold weather and frequent exposure to soap, may lead to the mistaken diagnosis of an occupational eczema. The palms and soles and tips of the fingers and toes may also be the site of another atypical manifestation, known as pustular psoriasis. The presence of deep-seated small pustules in a circumscribed plaque covered with thin silvery scales and the presence of typical psoriasis in other sites leaves little doubt that these pustules are the result of the process which finds its histological expression in the Munro abscess. The situation is complicated by the fact that this pustular type of psoriasis frequently is the only manifestation and remains confined to the palms and soles. Even the experienced dermatologist will have difficulty in differentiating from a pustular bacterid or acrodermatitis perstans (Hallopeau). While this is a subject of much specialized discussion, the avoidance of a mistaken diagnosis of fungous infection is of sufficient importance to the welfare of the patient.
Paul Gross
910
The physical well-being of the patient afflicted with psoriasis is usually normal, but widespread eruptions, involvement of the scalp, face or hands and itching when present may cause great psychologic and social difficulties. Two complications, fortunately occurring only in a small number of cases, may cause prolonged confinement to the home or hospital and at times chronic invalidism. In patients who show a rapid spreading of the eruption, there exists the danger of the development of psoriatic erythroderma. The fact that a Koebner reaction produced by too active chemical or actinic therapy may be the trigger should make us conscious of the hazards involving this complication. Of course, there are sufficient instances of spontaneous psoriatic erythroderma and there is good reason to believe that among the stress reactions precipitating it, emotional factors play an important role. It is noteworthy that the other serious complication, namely, psoriatic arthropathy, is frequently associated with erythroderma. Fever may accompany the onset of erythroderma or may occur in its course as a result of a sweat retention syndrome, causing widespread pustular miliaria and secondary infection. The question whether the polyarthritis known as psoriatic arthropathy is distinct from rheumatoid arthritis is still awaiting an answer. It must be taken for granted that the arthritis as seen in psoriatic patients differs in some clinical, roentgenologic, histopathologic and serologic findings from rheumatoid arthritis. One could explain these atypical features by assuming that they are only alterations of rheumatoid arthritis based on the abnormal physiological and metabolic reactions which make up the "psoriatic disposition." The periodic exacerbations of psoriasis and arthritis which can be observed frequently as a concomitant occurrence may be due to the fact that both diseases are equally susceptible to the effect of stress. This seems to be less far-reaching than to seek a common etiology for psoriasis and rheumatoid arthritis, an argument used against the concept of the former disease as a metabolic disturbance. THERAPY OF PSORIASIS
The realization that an etiologic therapy for psoriasis is not available with our present day knowledge does not permit a defeatist approach to the management of the patient and his affliction. Even the limited data brought to light by modern research methods and a century of clinical observation point the way to a rational, though only symptomatic, therapy. That the local treatment should have as its object the disturbance of keratinization has been borne out by the studies described in the preceding discussion. The difference between antipsoriatic and anti-inflammatory therapy is best demonstrated by the results of topical corticosteroid therapy. The absence of a healing effect of hydrocortisone ointments on the typical lesion of psoriasis is in sharp contrast to the dramatic results obtained in the eczema-dermatitis group. The inhibition of dipeptidase activity in parakeratosis and its increase in inflammatory skin diseases27 may explain why measures producing an inflammatory reaction (chrysarobin and related compounds, sunburn, coal tar plus ultraviolet light therapy) induce the involution of the psoriatic lesion, when properly used. The time-honored use of salicylic acid ointments may have more value
The Problem of Psoriasis
911 Table 2
TOPICAL THERAPY OF PSORIASIS LOCATION OF LESIONS
RECOMMENDED THERAPY
A. Acute Attack or Acute Exacerbation (Positive Koebner Reaction) Trunk, extremities, face 1. Solution of aluminum subacetate 0.5% Aquaphor in equal parts 2. White petrolatum 3. Salicylic acid 3. 0 White petrolatum 120.0 4. Vioform 0.6 to 1.2 White petrolatum 120.0 Scalp 5. Salicylic acid 2 .4 Olive oil 120.0 Face, ears, intertriginous areas 6. Vioforrn 0 .45 Hydrocortisone 0 .3 Vanishing cream 30 .0 B. Subacute Stage (N 0 New Lesions Developing, No Increase in Size or Activity of Existing Eruption) 7. Vioform 2.0 Trunk, extremities White petrolatum 60.0 Localized psoriasis of trunk, extremities 8. Salicylic acid 0.6 and scalp Liquor carbonis detergens 2.0 Ammoniated mercury 0.6 to 1 .5 Hydrophilic petrolatum 30.0 9. P and S liquid (Chester Baker Co.) Scalp (ij 6, 8 or 10) 10. Cortarquin cream (Dome Chem., Inc.) Face, ears, intertriginous areas (!l6 or 10) 11. Allantoin = tar lotion (Alphosyl lotion, Scalp, trunk, extremities, hands Reed and Carnarick) C. Chronic or Quiescent Stage Start therapy as in D, if no response use the following: To remove scales from trunk and 6.0 12. Salicylic acid extremities 120.0 White petrolatum 13. :& 9, 11 or 13. Scalp 6.0 Salicylic acid 12.0 Castor oil 120.0 Olive oil q.s.ad 1.2 For scaly and fissured lesions on fingers, 14. Salicylic acid 60.0 palms and soles Diachylon ointment 4.0 Trunk and extremities (unless areas are 15. Crude coal tar 4.0 very hairy) Zinc oxide 4.0 Castor oil 20.0 Starch Hydrophilic petrolatum q .s. ad 60 .0 16. Coal tar 3% in vanishing cream (NuKol-Tar ointment, Benet Drug Co.) 17. Di-hydroxy-anthranol (Anthralin ointTrunk and extremities (avoid contact with eyes) ment, Abbott) 0.1,0.25,0.5 and 1.0% For the technique of chrysarobin and anthralin therapy and for the Goeckerman method of tar and ultraviolet light therapy, see Sulzberger and Wolf (re£. 38). Useful adjuncts to local therapy are colloid baths (oatmeal, Aveeno or Soyaloid) for the acute stages and tar baths for the subacute and chronic stages..A.ntiseborrheic shampoos are helpful in treatment of the scalp.
912
Paul Gross
than the mechanical removal of the psoriatic scale. The therapeutic effect of topical mercurial compounds and the lead-containing diachylon ointment has been attributed to the interaction of these metals with the sulfhydryl compounds much increased in parakeratosis. The therapeutic effect of systemic arsenic administration has been related to the same mechanism. The folic acid antagonists Aminopterin and Amethopterin owe their effectiveness to a competitive action with prosthetic groups of enzymes involved in purine and pyrimidine metabolism, but they are also inhibitors of Dopa decarboxylase and choline oxydase. 26 Their therapeutic action in psoriasis is confined to an effect on keratinization, resulting in reduced acanthosis and parakeratosis. 8 The knowledge that arsenic and the folic acid antagonists act directly on the epidermal cells in a manner similar to but more effective than that of the mercury compounds should make us consider carefully their toxicity before embarking on their use. The insidious late results of arsenic therapy has considerably reduced its application by American dermatologists. The acute toxicity of the folic acid antagonists can be reduced by changes in dosage and treatment schedule and strict supervision of the patient in the hospital or office. Their usefulness is impaired by their inability to prevent recurrences, as would be expected from such symptomatic therapy. The possibility of toxic side effects should not be overlooked when topical remedies are being used in widespread eruptions and over a long period. More important is the selection of local therapy or its omission, when their irritating action may produce a Koebner reaction and spreading of the eruption. A careful history and prophylactic patch tests will help prevent reactions of contact sensitivity. Primary irritation can be avoided by the proper selection and dosage of chemical and actinic therapy in the individual case. The difference between the eruptive stage and the chronic quiescent stage is not the only determinant in the choice of local therapy. We must make an effort to find and to influence the factors which are responsible for spreading of the eruption or its resistance to therapy. To do that we have to resort to a working hypothesis, which is founded in an unbiased interpretation of clinical observations and laboratory research. To understand the adverse effect of various types of stress on psoriasis we have to focus our attention on a central regulatory mechanism. 7 The pathway from this cerebral center to the skin leads through the pituitary adrenal system!' 39 and transmits abnormal responses to stress by humoral and neurovascular means to the target organ. A rise in the serum cholesterol and changes in the lipoproteins are part of this reaction 11 and by way of the papillary blood vessels precipitate metabolic changes in the skin manifested by abnormal keratinization. 'I'his approach makes it possible to understand the adverse influence of emotional stress, which may be acute, due to a severe psychic shock, or chronic due to anxiety, tension and overwork. Psychotherapy in its simplest form, establishing a good understanding between patient and physician, can be supported by the use of ataractic drugs. The proper selection of these drugs should take into account the mechanism of their action via the autonomic nerve centers of the diencephalon. 6, 35
The Problem of Psoriasis
913
Although the earlier studies on the role of the endocrine glands in psoriasis may have more than historic interest,31 attention has been focused in recent years on the therapeutic results obtained with the corticotropic hormone of the anterior pituitary gland and the corticosteroids. The nature of their action in psoriasis is not easily understood. The failure of topical applications containing hydrocortisone or its analogues to clear up psoriatic lesions makes it doubtful that the action of systemic corticosteroid therapy on psoriasis can be explained by its anti-inflammatory effect. A better understanding of the failures and shortcomings of this method may give us more insight into the pathology of psoriasis. The recurrence of lesions after cessation of therapy should dampen even the optimism concerning the value of triamcinolone, 34 which in equivalent biologic dosage undoubtedly is superior to other corticosteroids in its action on psoriasis. This should not tend to deny that benefits can be obtained from these drugs in special situations, for instance psoriatic erythroderma and psoriasis arthropathica. The objective of corticosteroid therapy should not be to control psoriasis but to overcome the acute stress situations and make the patient amenable to other forms of therapy. That increase of serum cholesterol and changes of lipoproteins can be brought about in predisposed individuals by emotional stress has been demonstrated by M. E. Grooverll in studies on atherosclerosis. These findings, together with the positive data on lipid metabolism in psoriasis, should give added value to the low jat diet and lipotropic therapy. The limitations of this therapy should not prompt us to discard it but rather to use it in conjunction with other measures indicated by the individual case and circumstances. The low fat diet can be carried out more easily with the addition of a margarine low in hydrogenated fats and high in unsaturated fatty acids, including linoleic caid. The lipotropic therapy found to be best suited for psoriasis by B. M. Kesten and the author12 • 14 consists of oral administration of a defatted soybean lecithin in doses of 30 to 45 Grams per day. This substance is composed of approximately equal amounts of lecithin, inositol phosphatid and cephalin. This represents a high content of choline and inositol in a natural foodstuff, rich in phosphorus; and this food supplement should be given in therapeutic and later maintenance doses over a period of many months. Its therapeutic effect apparently is complex, but its regulatory action on fat transport, fat metabolism and liver function has been fully substantiated. If used systematically, this therapy will help to arrest the spreading of the acute eruption or exacerbation. In the further course some cases will improve without active local therapy, others will react promptly to mild topical remedies. The dietary regimen and lipotropic therapy in combination with 8uberythema doses of ultraviolet light therapy or sun bathing is also recommended as prophylactic treatment. How far the beneficial effect of ultraviolet rays on psoriasis is related to the lowering of cholesterol and beta lipoproteins15 will deserve further study. Finally, topical therapy still remains an important part of the therapeutic armamentarium of psoriasis and the proper selection of these remedies is of utmost importance for the purpose of obtaining satisfactory results and avoiding aggravation of the eruption.
Paul Gross
914CONCLUSIONS
Psoriasis is a chronic disease of unknown etiology. The skin manifestations are attributable to a primary disturbance of keratinization. Changes in the cutaneous blood vessels indicate that neurovascular and humoral influences are responsible for the development and nature of the psoriatic lesion. The Koebner phenomenon should be interpreted as evidence of a metabolic disturbance and chemical studies of the blood point to abnormalities in lipid metabolism. Clinical observations support a hypotheses that a hypothalamic pituitary regulatory mechanism is the focus of the disturbance which results in these metabolic abnormalities. Such a concept explains the adverse effect of stress on the course of psoriasis. Emotional factors, climatic changes, acute and chronic infections, and other intercurrent diseases play an important role in this stress reaction. In view of the lack of specific therapy, treatment should attempt to reduce the adverse effect of stress, stabilize lipid metabolism and to correct the abnormal keratinization of the psoriatic lesion by local and systemic remedies. The need for proper therapeutic indications adjusted to the individual case and the stage of the disease should always be kept in mind, if exacerbations and at times serious complications are to be avoided. The shortcomings of the present therapy of psoriasis should limit the use of potentially dangerous drugs. REFERENCES 1. Anderson, E. and others: Effects of Midbrain and Spinal Cord Transection on Endocrine and Metabolic Functions with Postulation of a Midbrain HypothalamicoPituitary Activating System. R ecent Progress in Hormone Research 13: 21, 1957. 2. Aschner, B., Curth, H. O. and Gross, P.: Genetic Aspects of Psoriasis. Acta Genetic. 7: 197, 1957 (Proc. First International Congress of Human Genetics) . 3. Bean, W. B., Spies, T. D. and Vilter, R. W.: Asymmetric Cutaneous Lesions in Pellagra. Arch. Dermat. & Syph. 49: 335, 1944. 4. Block, W., Lea, W. A. Jr., Curtis, A. C. and Cannon, E. F.: Nitrogen Balance and Sulfur Excretion Studies in Psoriasis. J. Invest. Dermat. 6: 287, 1958. 5. Braun-Falco, 0.: Recent Histochemical Findings in Psoriasis. Conference on Psoriasis. New York Academy of Sciences. To be published. 6. Brodie, B. B.: Interaction of Psychotropic D11!gs: Physiological and Biochemical Mechanisms in Brain. Modern Med., August I, 1958. 7. Charpy, J.: Pathogenesis of Psoriasis. Excerpta Med. (Sect. XIII, Dermat. & Venereol.) 6: 310, 1952. 8. Edmundson, W. F . and Guy, W . B.: Treatment of Psoriasis with Folic Acid Antagonists. A.M.A. Arch. Dermat. 78: 200, 1958. 9. Flesch, P. and Jackson-Esoda, E. C.: Defective Epidermal Protein Metabolism in Psoriasis. A.M .A. Arch. Dermat. 76: 393, 1957. 10. Flesch, P. and Jackson-Esoda, E. C.: Deficient Water-Binding in Pathologic Horny Layers. J. Invest. Dermat. 28: 5, 1957. 1l. Groover, M. E.: Clinical Evaluation of a Public Health Program to Prevent Coronary Artery Disease. Tr. ColI. Physicians, Philadelphia 24: 105, 1957. 12. Gross, P. and Kesten, B.: Treatment of Psoriasis with Lipotropic Substances Derived from Foodstuffs. Arch. Dermat. & Syph. 47: 159, 1943. 13. Gross, P.: Significance of Nutritional Deficiencies in Practice of Dermatology. Clinics 3: 789, 1944. 14. Gross, P. and Kesten, B.: Treatment of Psoriasis as a Disturbance of Lipid Metabolism. New York J. Med. 50: 2683,1950. 15. Grilneberg, T. and Szakall, A.: Uber den Gehalt an Schwefel und Wasserloslichen Bestandteilen in der Verhornten Epidermis bei normal er und Pathologischer Verhornung (Psoriasis). Arch. klin. u. exper. Dermat. 201: 361,1955. 16. Grilt:t; 0.: Die Stellung der Psoriasis in Rahmen der Lipoidosen. Verhandl. Gesellsch. Verdau u. Stoffweckselker 14: 88, 1939 (Arch. Dermat. & Syph. 177: 246, 1938). 17. Hoede, K.: ZurFrage der Erblichkeit der Psoriasis. Hautarzt 8: 422,1957. 18. Horton, S. H.: Life on Guam. Bull. A. Military Dermatologists 7: 18, 1958. 19. Kalz, F., Quastel, J. H., Telner, P., Schafer, A. and MacIntyre, W.: Changes of
The Problem of Psoriasis
915
Electrophoretic Patterns of Sera of Psoriatics Under Various Forms of Therapy · J. Invest. Dermat. 31: 161, 1958. 20. Koebner, H.: Zur Aetiologie der Psoriasis. Vjschr. Dermat. 3: 559, 1876. 21. Kuta, A. and Newma nn, E.: Koebner's Phenomenon in Study Concerning Primary Epidermal Pathogenesis of Psoriasis. Dermatologica 115: 51, 1957. 22. Lever, W. F.: Histopathology of Skin. 1st Ed. Philadelphia, J. B. Lippincott Co., 1949. 23. Lomholt, G.: Psoriasis on Faeroe Islands. Acta dermat.-venereol. 34: 92, 1954. Also discussion of Ashner, Curth and Gross.2 24. Madden, J. F.: Histologic Studies of Uninvolved Skin of Patients with Psoriasis. Arch. Dermat. & Syph. #: 655, 1941. 25. Martin, G. J.: Biological Antagonism. New York, Blakiston Co., 1951. 26. Michelson, H. E.: The Unusual in Psoriasis. A.M.A. Arch. Dermat. 78: 9, 1958. 27. Paschoud, J. M., Keller, W . and Schmidli, B.: Untersuchungen uber Peptidasen in der gesunden und d er befallenen Haut von Psoriasis Kranken. Arch. klin. u. exper. Dermat. 203: 203 , 1956. 28. Pillsbury, D. M., Shelley, W . B. and Kligman, A. M . : Dermatology. Philadelphia, W. B. Saunders Co., 1956. 29. Radl, J., Kraus, Z. and Tousek, M.: Studien uber Blutlipide, Lipoproteine und Proteine bei Psoriasis. Dermat. Wchnschr. 135: 609, 1957. 30. Reinertson, R. P.: Vascular Trauma and Pathogenesis of Koebner Reaction in Psoriasis. J. Invest. Dermat. 30: 283, 1958. 31. Reiss, F.: Psoriasis and Adrenocortical Function. Arch. Derma t. & Syph. 59: 78, 1949. 32. Schamberg, J. F., Kolmer, J. A., Ringer, A. and Raiziss, G. W.: Protein Metabolism in Psoriasis. J. Cutan. Dis. 31: 803, 1913. 33. Shelley, W. B. and Arthur, R. P.: Biochemical and Physiological Clues to Nature of Psoriasis. A.M.A. Arch. Dermat. 78: 14, 1958. 34. Shelley, W. B., Harun, J. S. and PiUsbury, D. M . : Treatment of Psoriasis and Other Dermatoses with Triamcinolone (Aristocort) . J.A.M.A. 167: 959, 1958. 35. Shore, P. A. and Brodie, B. B.: Effect of Iproniacide on Brain Levels of Norepinephrine and Serotonin. Science 127: 704, 1958. 36. Steigleder, G. K.: Morphologische und histochemische Befunde in pathologischer Hornschicht, insbesondere bei Parakera tose . Arch. klin. u. exper. Dermat. 207: 209,1958. 37. Stupel, H. and Szakall, A.: Die Wirkung von Waschmitteln aui die Haut. H eidelberg, Dr. Alfred Huthig Verlag, 1957. 38. Sulzberger, M. B. and Wolf, J.: Dermatology. Essentials of Diagnosis and Treatment. Chicago, Year Book Publishers, 1952. 39. Szodoray, L.: Nervale Factoren im Pathomechanismus der Psoriasis. Arch. klin. u. exper. Dermat. 201: 581, 1955. 40. Witten, V. H. and Sulzberger, M. B.: Psoriasis: An Interesting and Perhaps Distinctive Response Following Quinacrine Therapy. A.M.A. Arch. Dermat. 73: 636,1956. 180 Fort Washington Avenue New York 32 N. Y.
THE last decade has witnessed a concerted effort in basic dermatologic research concerned with or related to the pathogenesis of psoriasis. The biochemical, histochemical and refined histopathologic studies on keratinization and its abnormal form of parakeratosis have helped the understanding of this erythematosquamous dermatosis. The results of these studies and an analysis of the "Koebner phenomenon" reveal that the process of parakeratosis as it occurs in psoriasis consists of an acceleration of the keratinization process. This results in increased activity of cellular enzymes and abnormalities in the chemical composition of the parakeratotic epidermis. While this supplies evidence that the epidermis is the principal site of the pathologic changes in the target organ, the abnormalities of the papillary blood vessels and increased phosphorylase activity in the capillaries and arterioles point to humoral influences. These can be due to changes in carbohydrate, protein or lipid metabolism, based on a primary disturbance in the regulatory mechanism. The site and nature of this disturbance is the clue to the etiology of psoriasis, but the effort to localize it has so far been in vain. Progress in the knowledge of the interrelationship between the diencephalon and pituitary on one hand and intermediary metabolism on the other hand may eventually furnish some clue to the complexities of psoriasis. For the time being, we shall build on the knowledge available, and by correlating it with clinical experience, try to evolve a rational therapy of psoriasis. HISTOPATHOLOGY AND HISTOCHEMISTRY OF PSORIASIS
The tissue changes of psoriasis have been summarized by Lever22 as follows: (1) parakeratosis, (2) thinning of the suprapapillary portion of the rete Malpighii, (3) elongation of the rete pegs, (4) edema and clubbing of the papillae and (5) Munro micro-abscesses. Striking features in the cutis are the dilated and tortuous capillaries of the papillae and a moderate infiltration of the papillary portion of the corium with lymphocytes and monocytes. Variations in the degree of these microscopic findings explain some of the differences and at times atypical features which manifest themselves in the clinical appearance of the psoriatic lesion. From the Department of Dermatology, College of Physicians and Surgeons, Columbia University, New York, N. Y.
* Clinical Professor of Dermatology, College of Physicians and Surgeons, Columbia Un-iversity,. A ttending Dermatologist, Presbyterian Hospital.
903
Paul Gross
904-
The biochemical, histochemical and physiological changes in the psoriatic skin have been recently reviewed by Shelley and Arthur. 33 The bibliography of 169 references is a testimony to the data available in the literature and the exhaustive work performed by these authors in presenting and interpreting them critically. To understand the mechanism of keratinization and its functions helps to interpret the chemical abnormalities of parakeratosis. To quote Stiipel and Szakall :37 "Living ectodermal cells of the epidermis are transformed into flat, coherent, dry cells, which form an uninterrupted membrane spread over the entire body. This membrane has (although in moderate degree) a mechanically resistant structure and as a result of its structure it is endowded with the ability to form a protective barrier against mechanical influences of the outside world. Simultaneously with the formation of this solid structure a purposeful chemical change takes place in the living epidermal cells. It leads to the development of a number of well defined chemical substances which are able, due to their chemical qualities, to function against corresponding effects of the surrounding world, but are also capable of synthetic functions within the body." This, of course, refers to the distinction between structural keratin and the water-soluble extractives which are formed during keratinization. Most of the significant findings resulting from chemical studies of the psoriatic scale (Grueneberg and Szakall,l5 Flesch and Jackson-Esoda9, 10 and others) pertain to the water-soluble fraction. There is a decrease in the free amino nitrogen; an increase in the free sulfhydryl compounds and in the free and combined pentoses. These findings and the extensive histochemical studies by BraunFalc0 5 and Steigleder36 present a picture of the parakeratotic scale, which justifies the concept of accelerated keratinization as its cause. That this is a pathologic reaction is evidenced by the microscopic picture and by various abnormalities in the enzymes of the psoriatic efflorescence. The fact that they are not demonstrable in the normal skin of the psoriatic permits so far only the conclusion that they are the expression and not the cause of the metabolic disturbance of the skin in psoriasis. The significance of the findings of Paschoud, Keller and S,chmidli27 will also depend on the outcome of further research. These authors have demonstrated that the decrease of the water-soluble extractives in the psoriatic lesion is due to a 50 per cent reduction of polypeptides. They found the cause of this reduction in a decreased activity of the dipeptidases."(glycylglycin dipeptidase and leucylglycin dipeptidase). Further ingenious experiments revealed that these dipeptidases were not lacking, but were inhibited by a factor in the psoriatic scale. The search for this inhibitor is being continued by these authors, but their findings of increased dipeptidase activity in eczema may signify that the dipeptidase inhibitor is specific for the psoriatic process.
The sum total of the data accumulated by these biochemical and histochemical studies suggest strongly that a metabolic disturbance with its primary site in the epidermis explains the make-up of the psoriatic lesion. This concept is further supported by the Koebner phenomenon. THE KOEBNER PHENOMENON
Koebner,20 who described this behavior of the skin of the psoriatic in 1872, speaks of "a peculiar predisposition which in the psoriatic is present in the skin organ itself, and which is mostly hereditary, but at times acquired and may remain latent for years and may react to the most varying internal and local stimuli-just in this chronic pattern of
The Problem of Psoriasis
905
inflammation of the skin.... From this point of view there is an explanation for the sites of predilection, the first appearance of psoriasis and the only temporary result of local therapy." This broad statement is quoted in order to show that it holds true today and that the production of an isomorphous lesion by the scratch mark of a needle in the skin of a psoriatic who is in an active state is only one phase of the Koebner phenomenon. In previous publications12 , 13 I have referred to the pattern of distribution in widespread pellagra and its similarity to the localization of psoriasis. Since modern vitamin research has demonstrated the effect of nicotinic acid deficiency on cell metabolism, mediated by a defect in dehydrogenase activity, I have considered the Koebner phenomenon as a sign of diseased skin metabolism. The work by Bean, Spies and Vilter3 on asymmetric lesions in pellagra gives valuable insight into the mechanism of the Koebner reaction. The similarity of the Koebner phenomenon in psoriasis and the isomorphous reaction of pellagra is based on two common denominators. The trauma eliciting skin lesions in both diseases can be chronic mechanical irritation, caused by friction in intertriginous areas, or by tensile strain on the skin stretched over joints (especially elbows and knees). It may be a cellular injury produced by actinic or thermal energy, with the visible effect of sunburn or thermal burn; or at times it may consist of trophic changes in the skin due to stasis or scar tissue (Fig. 163). More subtle forms of trauma causing spreading of psoriasis, at times culminating in psoriatic erythroderma, are inflammatory reactions due to topical medicaments, as
Fig. IH3. Koebner phenomenon in pellagra. A, Dermatitis of hands at site of exposure to sun. B, Involvement of wrists due to flexion and friction. C, Lesions on elbows due to tensile strain. D, Butterfly lesion at site of intertriginous friction.
906
Paul Gross
seen in primary irritation or contact type allergic sensitivity. That systemic administration of drugs may act as a Koebner trauma is best demonstrated by the development of erythroderma after Atabrine,40 but also at times by acute exacerbations after therapy with arsenic, sulfonamides and gold injections. There is clinical evidence that this type of reaction is not due to an allergic mechanism but based on a biologic antagonism of these drugs to cellular enzymes. Bean and associates were able to demonstrate experimentally that skin lesions could only be produced during the active stage of pellagra and not during remission. Similarily, a positive Koebner phenomenon can only be produced when psoriasis is in a labile state, usually manifested by appearance of new lesions or spreading of older ones. While the differences between the cellular metabolism of the skin of active pellagra and pellagra in remission are known, no definite knowledge on this point exists concerning psoriasis. A comparative study of the blood chemistry, hormonal functions and physiologic behavior of the skin, including its capillaries and sweat glands during the eruptive stage on the one hand and during periods of remission or quiescence on the other hand, may be fruitful. The experimental work by Kuta and Neumann21 and most recently by Reinertson30 are revealing only by indicating that a mechanical trauma must reach the "living" layers of the epidermis and that the earliest metabolic disturbance measured by dehydrogenase activity occurs in the epidermis, before any significant inflammatory reaction has taken place in the cutis. This helps to understand why an increased demand on the metabolic function of the integument produced by any form of acute or chronic trauma may produce a pathologic response, if the site of trauma is in a state of metabolic insufficiency. What we do not know is the reason for this phasic behavior of the psoriatic skin. The adverse effect of systemic stress reactions on the activity of psoriasis (which include emotional stress, acute and chronic infection, intercurrent disease, unfavorable climatic conditions) make it probable that the skin is not the primary site of the pathologic changes causing psoriasis. The concept of a metabolic disease which has its roots in an abnormality of a central regulatory mechanism is by no means in contradiction to the hereditary pattern of psoriasis.
The conclusions of Hoede,17 that "Psoriasis is a hereditary disease and not some anomaly with occasional familial occurrence" seems incontestable on the basis of the data he has supplied. The peculiarity of the irregular dominant heredity, mentioned by him, emphasizes the need to broaden our concept of the pathologic constellation that is transmitted by heredity. Ashner, Curth and the author2 have pointed to the significant percentage of diabetes occurring in the families of psoriasis. The figure of 5.7 per cent of our psoriatic patients suffering simultaneously from diabetes becomes significant when we compare it with the findings of Joslin who reported 1.5 per cent diabetics in the general population aged 55 to 64 years. This makes it probable that our data obtained from 243 families with at least one psoriatic patient showing an incidence of 17.3 per cent diabetics among the relatives, may be significant statistically, although we lack comparative figures. In a recent communication from the island of Guam, Captain Samuel H. Horton, MC, USN,18 is impressed with the positive relationship between heredity and psoriasis. He finds that many of the psoriatic patients also have diabetes. (UThese
The Problem of Psoriasis
907
people are nearly all distantly kin, and the incidence of these two diseases is truly remarkable.") The advantages of investigating island populations regarding hereditary problems are reflected in Lomholt's23 studies on psoriasis in the Faeroe Islands. He concludes that the disease is inherited dominantly with failing manifestation and calculates the manifestation probability to be about 40 per cent. It would be an error of judgment to assume that the coincidence of psoriasis and diabetes and, for that matter, of psoriasis and arthritis is due to an identical pathogenesis. At best the hereditary studies point to a common denominator which lies in the genotype inheritance. GENERAL METABOLISM
The recognition that parakeratosis is a result of biochemical and enzymatic abnormalities concerned with the protein metabolism of the epidermis does not permit any conclusions regarding the nature of the disturbance of general metabolism. The theory of Schamberg32 that nitrogen retention is responsible for the development of the psoriatic lesions has not stood the test of careful studies employing modern methods. Block4 and his associates found no evidence of nitrogen retention or abnormal urinary sulfur distribution in a controlled study of two psoriatic patients. The therapeutic results attributed to low protein diets may have been due to other factors. Much work has been done on carbohydrate metabolism in psoriasis but evidence is lacking for a causal relationship between a disturbance of sugar metabolism and psoriasis. The genetic relationship which appears to exist between psoriasis and diabetes could be due to a common denominator in the area of lipid metabolism. It is not necessary to consider psoriasis as a lipoidosis of the skin, as Gruetz 16 suggested, in order to evaluate the evidence for a disturbance in lipid metabolism. Certainly the findings reported recently by Radl, I{raus and Tousek29 deserve further studies along these lines. Their averages in 80 cases of psoriasis showed a significant increase of total serum cholesterol. The determination of lipoproteins by paper electrophoresis revealed an increase of the beta fraction. Their work deserves attention since they attempted to correlate the findings of the blood chemistry with the clinical picture of the individual cases. Their statement that the metabolic changes were most pronounced in chronic cases during an acute flare-up, and in arthropathic subacute cases, but least pronounced in chronic cases, should be a guide to further investigative work. Many forms of approach ranging from the biochemical studies of the psoriatic lesion to the Koebner phenomenon, the physiologic behavior of the neurovascular system of the psoriatic and especially of unaffected skin of the psoriatic, may produce more consistent results if the findings are obtained during the eruptive stage of the disease. It should be remembered that the histologic and histochemical changes observed by Madden24 in the uninvolved skin were in cases of acute guttate and generalized psoriasis. CLINICAL PICTURE OF PSORIASIS26,28
The contrast between a chronic solitary plaque covered with heavy micaceous scales and a generalized guttate eruption of psoriasis is strik-
908
Paul Gross
ing. Nevertheless the diagnosis is simplified if we remember the erythematous squamous character of the disease. The early lesion may give the appearance of a brownish red papule but scraping with the fingernail will reveal the typical silvery scale. This so-called "candle-drop sign," together with the bleeding points produced by the systematic removal of
Fig. 164. A, Chronic generalized psoriasis (not a psoriatic erythroderma). B, Chronic psoriasis with acute exacerbation. C, Psoriasis of the hands (may indicate intolerance to sun rays). D, Psoriasis of the palms (should not be mistaken for dermatophytosis or occupational dermatitis). E, Psoriasis of the soles (predilection for pressure areas). F, Psoriasis of the toes (resembling dermatophytosis).
The Problem of Psoriasis
909
the scale, layer by layer (Auspitz sign), is a valuable diagnostic aid. There are instances when the scale may be lacking and a sharply demarcated border, absence of vesicles or oozing and the dusky red color are the only suggestive features of psoriasis. This happens in intertriginous areas, especially in the armpits, groin, anal region or in the interTable 1 SOME COMMON SKIN CONDITIONS TO BE DIFFERENTIATED FROM PSORIASIS
Scalp: Face: Ears: Elbows, knees: Hands, fingers: Palms, soles, toes: Axilla, groin, vulva, anus: Fingernails, toenails: Penis: Trunk and other sites:
Seborrheic dermatitis; lichen simplex chronicus lupus erythematosus Seborrheic dermatitis; lupus erythematosus Seborrheic dermatitis; otitis externa; lupus erythematosus; infectious eczematoid dermatitis Lichen simplex chronicus; asteatotic dermatitis Occupational dermatitis; nummular eczema; lichen planus; acrodermatitis perstans (Hallopeau) Dermatophytosis (especi~lly Trichophyton rubrum infection); syphiloderm; lichen simplex chronicus Pustular bacterids; acrodermatitis perstans (Hallopeau) Seborrheic dermatitis; intertrigo due to Candida albicans; tinea cruris; lichen simplex chronicus (pruritus ani and vulvae) Onychomycosis; onychia due to chemical irritants; traumatic onychia, chronic paronychia due to monilia fungi Lichen planus; erythroplasia; seborrheic dermatitis; distinctive exudative discoid and lichenoid chronic dermatosis (Sulzberger and Garbe) Mycosis fungoides; superficial basal cell epithelioma
digital spaces of the toes. A complete and thorough examination of the body surface, including the scalp and fingernails, may help to discover a typical lesion. The thickened horny layer of the palms and soles fre':' quently changes the appearance of the psoriatic lesion and produces a pale, hyperkeratotic, at times fissured plaque. Local conditions at the fingertips and dorsal aspects of the finger joints may cause a very atypical appearance of psoriasis. The dryness of these lesions, a tendency to fissuring, aggravated by cold weather and frequent exposure to soap, may lead to the mistaken diagnosis of an occupational eczema. The palms and soles and tips of the fingers and toes may also be the site of another atypical manifestation, known as pustular psoriasis. The presence of deep-seated small pustules in a circumscribed plaque covered with thin silvery scales and the presence of typical psoriasis in other sites leaves little doubt that these pustules are the result of the process which finds its histological expression in the Munro abscess. The situation is complicated by the fact that this pustular type of psoriasis frequently is the only manifestation and remains confined to the palms and soles. Even the experienced dermatologist will have difficulty in differentiating from a pustular bacterid or acrodermatitis perstans (Hallopeau). While this is a subject of much specialized discussion, the avoidance of a mistaken diagnosis of fungous infection is of sufficient importance to the welfare of the patient.
Paul Gross
910
The physical well-being of the patient afflicted with psoriasis is usually normal, but widespread eruptions, involvement of the scalp, face or hands and itching when present may cause great psychologic and social difficulties. Two complications, fortunately occurring only in a small number of cases, may cause prolonged confinement to the home or hospital and at times chronic invalidism. In patients who show a rapid spreading of the eruption, there exists the danger of the development of psoriatic erythroderma. The fact that a Koebner reaction produced by too active chemical or actinic therapy may be the trigger should make us conscious of the hazards involving this complication. Of course, there are sufficient instances of spontaneous psoriatic erythroderma and there is good reason to believe that among the stress reactions precipitating it, emotional factors play an important role. It is noteworthy that the other serious complication, namely, psoriatic arthropathy, is frequently associated with erythroderma. Fever may accompany the onset of erythroderma or may occur in its course as a result of a sweat retention syndrome, causing widespread pustular miliaria and secondary infection. The question whether the polyarthritis known as psoriatic arthropathy is distinct from rheumatoid arthritis is still awaiting an answer. It must be taken for granted that the arthritis as seen in psoriatic patients differs in some clinical, roentgenologic, histopathologic and serologic findings from rheumatoid arthritis. One could explain these atypical features by assuming that they are only alterations of rheumatoid arthritis based on the abnormal physiological and metabolic reactions which make up the "psoriatic disposition." The periodic exacerbations of psoriasis and arthritis which can be observed frequently as a concomitant occurrence may be due to the fact that both diseases are equally susceptible to the effect of stress. This seems to be less far-reaching than to seek a common etiology for psoriasis and rheumatoid arthritis, an argument used against the concept of the former disease as a metabolic disturbance. THERAPY OF PSORIASIS
The realization that an etiologic therapy for psoriasis is not available with our present day knowledge does not permit a defeatist approach to the management of the patient and his affliction. Even the limited data brought to light by modern research methods and a century of clinical observation point the way to a rational, though only symptomatic, therapy. That the local treatment should have as its object the disturbance of keratinization has been borne out by the studies described in the preceding discussion. The difference between antipsoriatic and anti-inflammatory therapy is best demonstrated by the results of topical corticosteroid therapy. The absence of a healing effect of hydrocortisone ointments on the typical lesion of psoriasis is in sharp contrast to the dramatic results obtained in the eczema-dermatitis group. The inhibition of dipeptidase activity in parakeratosis and its increase in inflammatory skin diseases27 may explain why measures producing an inflammatory reaction (chrysarobin and related compounds, sunburn, coal tar plus ultraviolet light therapy) induce the involution of the psoriatic lesion, when properly used. The time-honored use of salicylic acid ointments may have more value
The Problem of Psoriasis
911 Table 2
TOPICAL THERAPY OF PSORIASIS LOCATION OF LESIONS
RECOMMENDED THERAPY
A. Acute Attack or Acute Exacerbation (Positive Koebner Reaction) Trunk, extremities, face 1. Solution of aluminum subacetate 0.5% Aquaphor in equal parts 2. White petrolatum 3. Salicylic acid 3. 0 White petrolatum 120.0 4. Vioform 0.6 to 1.2 White petrolatum 120.0 Scalp 5. Salicylic acid 2 .4 Olive oil 120.0 Face, ears, intertriginous areas 6. Vioforrn 0 .45 Hydrocortisone 0 .3 Vanishing cream 30 .0 B. Subacute Stage (N 0 New Lesions Developing, No Increase in Size or Activity of Existing Eruption) 7. Vioform 2.0 Trunk, extremities White petrolatum 60.0 Localized psoriasis of trunk, extremities 8. Salicylic acid 0.6 and scalp Liquor carbonis detergens 2.0 Ammoniated mercury 0.6 to 1 .5 Hydrophilic petrolatum 30.0 9. P and S liquid (Chester Baker Co.) Scalp (ij 6, 8 or 10) 10. Cortarquin cream (Dome Chem., Inc.) Face, ears, intertriginous areas (!l6 or 10) 11. Allantoin = tar lotion (Alphosyl lotion, Scalp, trunk, extremities, hands Reed and Carnarick) C. Chronic or Quiescent Stage Start therapy as in D, if no response use the following: To remove scales from trunk and 6.0 12. Salicylic acid extremities 120.0 White petrolatum 13. :& 9, 11 or 13. Scalp 6.0 Salicylic acid 12.0 Castor oil 120.0 Olive oil q.s.ad 1.2 For scaly and fissured lesions on fingers, 14. Salicylic acid 60.0 palms and soles Diachylon ointment 4.0 Trunk and extremities (unless areas are 15. Crude coal tar 4.0 very hairy) Zinc oxide 4.0 Castor oil 20.0 Starch Hydrophilic petrolatum q .s. ad 60 .0 16. Coal tar 3% in vanishing cream (NuKol-Tar ointment, Benet Drug Co.) 17. Di-hydroxy-anthranol (Anthralin ointTrunk and extremities (avoid contact with eyes) ment, Abbott) 0.1,0.25,0.5 and 1.0% For the technique of chrysarobin and anthralin therapy and for the Goeckerman method of tar and ultraviolet light therapy, see Sulzberger and Wolf (re£. 38). Useful adjuncts to local therapy are colloid baths (oatmeal, Aveeno or Soyaloid) for the acute stages and tar baths for the subacute and chronic stages..A.ntiseborrheic shampoos are helpful in treatment of the scalp.
912
Paul Gross
than the mechanical removal of the psoriatic scale. The therapeutic effect of topical mercurial compounds and the lead-containing diachylon ointment has been attributed to the interaction of these metals with the sulfhydryl compounds much increased in parakeratosis. The therapeutic effect of systemic arsenic administration has been related to the same mechanism. The folic acid antagonists Aminopterin and Amethopterin owe their effectiveness to a competitive action with prosthetic groups of enzymes involved in purine and pyrimidine metabolism, but they are also inhibitors of Dopa decarboxylase and choline oxydase. 26 Their therapeutic action in psoriasis is confined to an effect on keratinization, resulting in reduced acanthosis and parakeratosis. 8 The knowledge that arsenic and the folic acid antagonists act directly on the epidermal cells in a manner similar to but more effective than that of the mercury compounds should make us consider carefully their toxicity before embarking on their use. The insidious late results of arsenic therapy has considerably reduced its application by American dermatologists. The acute toxicity of the folic acid antagonists can be reduced by changes in dosage and treatment schedule and strict supervision of the patient in the hospital or office. Their usefulness is impaired by their inability to prevent recurrences, as would be expected from such symptomatic therapy. The possibility of toxic side effects should not be overlooked when topical remedies are being used in widespread eruptions and over a long period. More important is the selection of local therapy or its omission, when their irritating action may produce a Koebner reaction and spreading of the eruption. A careful history and prophylactic patch tests will help prevent reactions of contact sensitivity. Primary irritation can be avoided by the proper selection and dosage of chemical and actinic therapy in the individual case. The difference between the eruptive stage and the chronic quiescent stage is not the only determinant in the choice of local therapy. We must make an effort to find and to influence the factors which are responsible for spreading of the eruption or its resistance to therapy. To do that we have to resort to a working hypothesis, which is founded in an unbiased interpretation of clinical observations and laboratory research. To understand the adverse effect of various types of stress on psoriasis we have to focus our attention on a central regulatory mechanism. 7 The pathway from this cerebral center to the skin leads through the pituitary adrenal system!' 39 and transmits abnormal responses to stress by humoral and neurovascular means to the target organ. A rise in the serum cholesterol and changes in the lipoproteins are part of this reaction 11 and by way of the papillary blood vessels precipitate metabolic changes in the skin manifested by abnormal keratinization. 'I'his approach makes it possible to understand the adverse influence of emotional stress, which may be acute, due to a severe psychic shock, or chronic due to anxiety, tension and overwork. Psychotherapy in its simplest form, establishing a good understanding between patient and physician, can be supported by the use of ataractic drugs. The proper selection of these drugs should take into account the mechanism of their action via the autonomic nerve centers of the diencephalon. 6, 35
The Problem of Psoriasis
913
Although the earlier studies on the role of the endocrine glands in psoriasis may have more than historic interest,31 attention has been focused in recent years on the therapeutic results obtained with the corticotropic hormone of the anterior pituitary gland and the corticosteroids. The nature of their action in psoriasis is not easily understood. The failure of topical applications containing hydrocortisone or its analogues to clear up psoriatic lesions makes it doubtful that the action of systemic corticosteroid therapy on psoriasis can be explained by its anti-inflammatory effect. A better understanding of the failures and shortcomings of this method may give us more insight into the pathology of psoriasis. The recurrence of lesions after cessation of therapy should dampen even the optimism concerning the value of triamcinolone, 34 which in equivalent biologic dosage undoubtedly is superior to other corticosteroids in its action on psoriasis. This should not tend to deny that benefits can be obtained from these drugs in special situations, for instance psoriatic erythroderma and psoriasis arthropathica. The objective of corticosteroid therapy should not be to control psoriasis but to overcome the acute stress situations and make the patient amenable to other forms of therapy. That increase of serum cholesterol and changes of lipoproteins can be brought about in predisposed individuals by emotional stress has been demonstrated by M. E. Grooverll in studies on atherosclerosis. These findings, together with the positive data on lipid metabolism in psoriasis, should give added value to the low jat diet and lipotropic therapy. The limitations of this therapy should not prompt us to discard it but rather to use it in conjunction with other measures indicated by the individual case and circumstances. The low fat diet can be carried out more easily with the addition of a margarine low in hydrogenated fats and high in unsaturated fatty acids, including linoleic caid. The lipotropic therapy found to be best suited for psoriasis by B. M. Kesten and the author12 • 14 consists of oral administration of a defatted soybean lecithin in doses of 30 to 45 Grams per day. This substance is composed of approximately equal amounts of lecithin, inositol phosphatid and cephalin. This represents a high content of choline and inositol in a natural foodstuff, rich in phosphorus; and this food supplement should be given in therapeutic and later maintenance doses over a period of many months. Its therapeutic effect apparently is complex, but its regulatory action on fat transport, fat metabolism and liver function has been fully substantiated. If used systematically, this therapy will help to arrest the spreading of the acute eruption or exacerbation. In the further course some cases will improve without active local therapy, others will react promptly to mild topical remedies. The dietary regimen and lipotropic therapy in combination with 8uberythema doses of ultraviolet light therapy or sun bathing is also recommended as prophylactic treatment. How far the beneficial effect of ultraviolet rays on psoriasis is related to the lowering of cholesterol and beta lipoproteins15 will deserve further study. Finally, topical therapy still remains an important part of the therapeutic armamentarium of psoriasis and the proper selection of these remedies is of utmost importance for the purpose of obtaining satisfactory results and avoiding aggravation of the eruption.
Paul Gross
914CONCLUSIONS
Psoriasis is a chronic disease of unknown etiology. The skin manifestations are attributable to a primary disturbance of keratinization. Changes in the cutaneous blood vessels indicate that neurovascular and humoral influences are responsible for the development and nature of the psoriatic lesion. The Koebner phenomenon should be interpreted as evidence of a metabolic disturbance and chemical studies of the blood point to abnormalities in lipid metabolism. Clinical observations support a hypotheses that a hypothalamic pituitary regulatory mechanism is the focus of the disturbance which results in these metabolic abnormalities. Such a concept explains the adverse effect of stress on the course of psoriasis. Emotional factors, climatic changes, acute and chronic infections, and other intercurrent diseases play an important role in this stress reaction. In view of the lack of specific therapy, treatment should attempt to reduce the adverse effect of stress, stabilize lipid metabolism and to correct the abnormal keratinization of the psoriatic lesion by local and systemic remedies. The need for proper therapeutic indications adjusted to the individual case and the stage of the disease should always be kept in mind, if exacerbations and at times serious complications are to be avoided. The shortcomings of the present therapy of psoriasis should limit the use of potentially dangerous drugs. REFERENCES 1. Anderson, E. and others: Effects of Midbrain and Spinal Cord Transection on Endocrine and Metabolic Functions with Postulation of a Midbrain HypothalamicoPituitary Activating System. R ecent Progress in Hormone Research 13: 21, 1957. 2. Aschner, B., Curth, H. O. and Gross, P.: Genetic Aspects of Psoriasis. Acta Genetic. 7: 197, 1957 (Proc. First International Congress of Human Genetics) . 3. Bean, W. B., Spies, T. D. and Vilter, R. W.: Asymmetric Cutaneous Lesions in Pellagra. Arch. Dermat. & Syph. 49: 335, 1944. 4. Block, W., Lea, W. A. Jr., Curtis, A. C. and Cannon, E. F.: Nitrogen Balance and Sulfur Excretion Studies in Psoriasis. J. Invest. Dermat. 6: 287, 1958. 5. Braun-Falco, 0.: Recent Histochemical Findings in Psoriasis. Conference on Psoriasis. New York Academy of Sciences. To be published. 6. Brodie, B. B.: Interaction of Psychotropic D11!gs: Physiological and Biochemical Mechanisms in Brain. Modern Med., August I, 1958. 7. Charpy, J.: Pathogenesis of Psoriasis. Excerpta Med. (Sect. XIII, Dermat. & Venereol.) 6: 310, 1952. 8. Edmundson, W. F . and Guy, W . B.: Treatment of Psoriasis with Folic Acid Antagonists. A.M.A. Arch. Dermat. 78: 200, 1958. 9. Flesch, P. and Jackson-Esoda, E. C.: Defective Epidermal Protein Metabolism in Psoriasis. A.M .A. Arch. Dermat. 76: 393, 1957. 10. Flesch, P. and Jackson-Esoda, E. C.: Deficient Water-Binding in Pathologic Horny Layers. J. Invest. Dermat. 28: 5, 1957. 1l. Groover, M. E.: Clinical Evaluation of a Public Health Program to Prevent Coronary Artery Disease. Tr. ColI. Physicians, Philadelphia 24: 105, 1957. 12. Gross, P. and Kesten, B.: Treatment of Psoriasis with Lipotropic Substances Derived from Foodstuffs. Arch. Dermat. & Syph. 47: 159, 1943. 13. Gross, P.: Significance of Nutritional Deficiencies in Practice of Dermatology. Clinics 3: 789, 1944. 14. Gross, P. and Kesten, B.: Treatment of Psoriasis as a Disturbance of Lipid Metabolism. New York J. Med. 50: 2683,1950. 15. Grilneberg, T. and Szakall, A.: Uber den Gehalt an Schwefel und Wasserloslichen Bestandteilen in der Verhornten Epidermis bei normal er und Pathologischer Verhornung (Psoriasis). Arch. klin. u. exper. Dermat. 201: 361,1955. 16. Grilt:t; 0.: Die Stellung der Psoriasis in Rahmen der Lipoidosen. Verhandl. Gesellsch. Verdau u. Stoffweckselker 14: 88, 1939 (Arch. Dermat. & Syph. 177: 246, 1938). 17. Hoede, K.: ZurFrage der Erblichkeit der Psoriasis. Hautarzt 8: 422,1957. 18. Horton, S. H.: Life on Guam. Bull. A. Military Dermatologists 7: 18, 1958. 19. Kalz, F., Quastel, J. H., Telner, P., Schafer, A. and MacIntyre, W.: Changes of
The Problem of Psoriasis
915
Electrophoretic Patterns of Sera of Psoriatics Under Various Forms of Therapy · J. Invest. Dermat. 31: 161, 1958. 20. Koebner, H.: Zur Aetiologie der Psoriasis. Vjschr. Dermat. 3: 559, 1876. 21. Kuta, A. and Newma nn, E.: Koebner's Phenomenon in Study Concerning Primary Epidermal Pathogenesis of Psoriasis. Dermatologica 115: 51, 1957. 22. Lever, W. F.: Histopathology of Skin. 1st Ed. Philadelphia, J. B. Lippincott Co., 1949. 23. Lomholt, G.: Psoriasis on Faeroe Islands. Acta dermat.-venereol. 34: 92, 1954. Also discussion of Ashner, Curth and Gross.2 24. Madden, J. F.: Histologic Studies of Uninvolved Skin of Patients with Psoriasis. Arch. Dermat. & Syph. #: 655, 1941. 25. Martin, G. J.: Biological Antagonism. New York, Blakiston Co., 1951. 26. Michelson, H. E.: The Unusual in Psoriasis. A.M.A. Arch. Dermat. 78: 9, 1958. 27. Paschoud, J. M., Keller, W . and Schmidli, B.: Untersuchungen uber Peptidasen in der gesunden und d er befallenen Haut von Psoriasis Kranken. Arch. klin. u. exper. Dermat. 203: 203 , 1956. 28. Pillsbury, D. M., Shelley, W . B. and Kligman, A. M . : Dermatology. Philadelphia, W. B. Saunders Co., 1956. 29. Radl, J., Kraus, Z. and Tousek, M.: Studien uber Blutlipide, Lipoproteine und Proteine bei Psoriasis. Dermat. Wchnschr. 135: 609, 1957. 30. Reinertson, R. P.: Vascular Trauma and Pathogenesis of Koebner Reaction in Psoriasis. J. Invest. Dermat. 30: 283, 1958. 31. Reiss, F.: Psoriasis and Adrenocortical Function. Arch. Derma t. & Syph. 59: 78, 1949. 32. Schamberg, J. F., Kolmer, J. A., Ringer, A. and Raiziss, G. W.: Protein Metabolism in Psoriasis. J. Cutan. Dis. 31: 803, 1913. 33. Shelley, W. B. and Arthur, R. P.: Biochemical and Physiological Clues to Nature of Psoriasis. A.M.A. Arch. Dermat. 78: 14, 1958. 34. Shelley, W. B., Harun, J. S. and PiUsbury, D. M . : Treatment of Psoriasis and Other Dermatoses with Triamcinolone (Aristocort) . J.A.M.A. 167: 959, 1958. 35. Shore, P. A. and Brodie, B. B.: Effect of Iproniacide on Brain Levels of Norepinephrine and Serotonin. Science 127: 704, 1958. 36. Steigleder, G. K.: Morphologische und histochemische Befunde in pathologischer Hornschicht, insbesondere bei Parakera tose . Arch. klin. u. exper. Dermat. 207: 209,1958. 37. Stupel, H. and Szakall, A.: Die Wirkung von Waschmitteln aui die Haut. H eidelberg, Dr. Alfred Huthig Verlag, 1957. 38. Sulzberger, M. B. and Wolf, J.: Dermatology. Essentials of Diagnosis and Treatment. Chicago, Year Book Publishers, 1952. 39. Szodoray, L.: Nervale Factoren im Pathomechanismus der Psoriasis. Arch. klin. u. exper. Dermat. 201: 581, 1955. 40. Witten, V. H. and Sulzberger, M. B.: Psoriasis: An Interesting and Perhaps Distinctive Response Following Quinacrine Therapy. A.M.A. Arch. Dermat. 73: 636,1956. 180 Fort Washington Avenue New York 32 N. Y.