dermatology - postgraduate medical journal · dermatology 895 functionin atopicdermatitis thereis...

Postgrad Med J (1990) 66, 894 - 905 © The Fellowship of Postgraduate Medicine, 1990

Reviews in Medicine

DermatologyM.H.A. Rustin

The Royal Free Hospital, Pond Street, London NW3 1QG, UK.

Introduction

Over the last ten years there has been a dramaticsurge in scientific research in dermatology and thisspecialty has benefited from advances in molecularbiology, cell biology, immunology and pharma-cology. The realization that the skin functions as animmunological organ and that mediators releasedfrom cells within the epidermis and dermis can actin an endocrine, autocrine and paracrine mannerhave had a major impact on our understanding ofthe pathogenesis ofnumerous inflammatory derma-toses, skin tumours and the wound repair pro-cesses. The use of immunohistochemical andimmunoblotting techniques in the prenatal diag-nosis of and the classification and diagnosis ofmany blistering disorders have become familiar.However, the genetic basis of many common skindiseases such as atopic dermatitis and psoriasis stillremains unknown; a goal that may be realized bythe accurate mapping of the human genome.

In this review of advances in dermatology someof these developments are brought out in thedescription of the following disease states, atopicdermatitis, acne and Raynaud's phenomenon andin the mode of action of two pharmacologicalagents, cyclosporin and essential fatty acids.

Atopic dermatitis

Atopic dermatitis may be defined as a specificdermatitis in the abnormally reacting skin of theatopic, resulting in itch with sequelae as well asinflammation. The incidence of this dermatosis inchildren aged 0-7 years has increased dramaticallyfrom approximately 3% in the period 1960-1964to 10% from 1970-1974' and the incidence ofatopy in the general population may now be as highas 30-40%. The cause of this is not known.Undoubtedly atopic dermatitis has a genetic com-ponent, evidenced by the high concordance rate inmonozygotic twins (a risk of0.86 compared to 0.21in dizygotic partners) and recent work in asthma

has suggested an autosomal dominant inheritanceof a defect on chromosome 1 lq.2A unifying concept in the pathogenesis of atopic

dermatitis has to explain the fact that the skin isabnormal in many ways.3 The skin is invariablyitchy and dry which is due to a combination ofincreased water loss, a decreased number ofsebaceous glands, reduced sebum excretion rateand reduced sweating. Patients have abnormalvascular reactivity evidenced by white dermo-graphism during an exacerbation of atopic derma-titis and a flush reaction which may be localized orgeneralized and precedes the itching. Furthermorethese patients have increased colonization withStaphylococcocus aureus. There is also abundantevidence that immunological factors are con-tributory especially as this dermatosis hasdeveloped in recipients of bone marrow trans-plants4 and the atopic dermatitis-like eruptionassociated with the Wiskott-Aldrich syndromeresolves after bone marrow transplantation.

Further evidence of immunological involvementin atopic dermatitis is that the cellular infiltrate inthe skin consists of predominantly 'activated'CD4+, HLA-DR + lymphocytes and the ratio ofhelper/suppressor is three times more than that inthe peripheral blood.5 Furthermore keratinocytesin lesional and clinically normal skin are HLA-DR+ and there may be deposition of IgG at thedermo-epidermal junction in involved and unin-volved skin.6 Another abnormality found in over80% of patients is raised serum IgE levels and thisis associated with Type I immediate hypersen-sitivity reactions to various inhalant or foodallergens on skin prick testing.7 Serum IgE levelsappear to correlate with the extent and severity ofthe disease but there is debate as to whether theraised IgE levels represent an epiphenomenon. Thisis because some patients with atopic dermatitishave normal IgE levels, that patients with X-linkedagammaglobulinaemia develop atopic dermatitisin the absence of demonstrable immediate skinreactivity8 and that elevated IgE occurs in otherdermatoses and lymphomas.9

Together with an abnormality of B lymphocyteCorrespondence: M.H.A. Rustin, B.Sc., M.D., M.R.C.P.

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DERMATOLOGY 895

function in atopic dermatitis there is also evidenceof impaired cell mediated immunity.'°"' Patientshave an increased susceptibility to eczema herpe-ticum, impaired mitogenic responses of lympho-cytes to several mitogens which normalizes duringclinical remission, reduced incidence of allergiccontact dermatitis, a reduced ability to inducesensitization to an antigen such as dinitro-chlorobenzene and cutaneous anergy to microbialantigens. In contrast many authors have shownthat application of patch tests, solutions or oint-ments containing a variety of aeroallergens (housedust mite, tree, grass and weed pollens, animaldanders and molds) to the skin of patients withatopic dermatitis results in the clinical and histo-logical features of an acute eczema.12-'5 Both thetime course and the cellular infiltrate have sug-gested that a form of delayed hypersensitivity hadoccurred. 6-17

Percutaneous entry of applied aeroallergencould allow binding to the increased numbers ofantigen presenting epidermal Langerhans cells inthe skin of patients with atopic dermatitis.18Recently, IgE has been identified on the surface ofcutaneous dendritic cells (principally Langerhanscells and interdigitating reticulum cells) in bothlesional and nonlesional skin ofpatients with activeatopic dermatitis.19'20 Therefore the capacity ofantigen trapping via the surface bound IgE and theability of Langerhans cells to induce T lymphocyteactivation and the generation of cytotoxic T lym-phocytes could be the initiating events in thedelayed hypersensitivity reaction.Low affinity cell surface receptors for the Fc

fragments of IgE (FceR) have been identified on Tand B lymphocytes, monocytes, platelets andeosinophils2'-23 and the FceR on B cells is identicalto the CD23 antigen earlier described as a Bcell-activation marker.24 Investigators have pro-vided evidence that Langerhans cells also expressCD23 in the skin of patients with atopic derma-titis.25 The CD23 molecule not only acts as areceptor but a 32- to 35-kDa soluble form of theCD23 molecule (sCD23), otherwise known as IgEbinding factor, is spontaneously shed from CD4+ Tcells and activated B cells26 and causes proliferationofCD23- B cells27. It would be interesting to knowin the context of atopic dermatitis if the autocrineeffect of sCD23 could upgrade the afferent arm ofthe immune response by allowing a greater numberof CD23 molecules to be expressed on cutaneousLangerhans cells or whether there is an effect onIgE synthesis by B lymphocytes.A consequence of the recruitment of activated T

lymphocytes into the dermis during a flare ofatopicdermatitis might be the release of interferon-y(IF-y) and interleukin 4 (IL-4). Since it has beenshown that keratinocytes in lesional skin expressHLA-DR5 and that IF-y can induce the expression

of HLA-DR on keratinocytes,28 it would seemextremely likely that release of IF-y does occur. Ithas also been shown that IL-4 and IF-y have asynergistic effect on the induction of CD23 oncultured Langerhans cells.29 In addition keratino-cytes may release several cytokines includinginterleukin 1 (IL-1), interleukin 6 (IL-6), tumournecrosis factor (TNF) and granulocyte mac-rophage colony stimulating factor (GMCSF)30 buta possible role for these mediators in thepathogenesis of the inflammatory response orindeed in regulating Langerhans cell CD23 expres-sion in atopic dermatitis has so far not beenpublished. Thus there appear to be several explana-tions for upgrading the immunological/inflam-matory response in atopic dermatitis but so farlittle progress has been made on the downgradingprocess although it is known that topically appliedcorticosteroids decrease not only the number butalso the antigen-presenting capacity of epidermalLangerhans cells.31'32A possible biochemical explanation for the

immunological abnormalities seen in atopic der-matitis is that there is a defect of intracellularsecondary messenger systems.33'34 In particular,elevated cyclic AMP-specific phosphodiesteraseactivity causing cyclic AMP hyporesponsivenesshas been found in peripheral blood mononuclearleucocytes from patients with atopic dermatitis andabnormalities of protein kinase C and of inositolactivation also have been described. However, it isnot known whether these abnormalities allowfurther mediator release or whether these findingsare secondary to chronic exposure to low levels ofinflammatory mediators since similar findings havebeen found in psoriasis.

Acne

Acne is a chronic inflammatory disease which ischaracterized by the formation of comedones,erythematous papules, pustules, nodules and cysts.The pathogenesis is undoubtedly multifactorialwith the abnormalities centred on the pilo-sebaceous unit. There may be increased sebumexcretion, obstruction of the pilosebaceous ductdue to hypercornification, altered bacterial colon-ization and inflammation. Whatever the import-ance of the individual aetiological factors anabsolute prerequisite for the development ofacne isactive sebaceous glands.

Sebaceous glands are under the influence of sexhormones. Androgens increase gland size andsebum secretion and at puberty when the glandsincrease dramatically in size, the sebum output alsoincreases.3 Because there is a good correlationbetween severity of acne and the level of sebumexcretion,36 an obvious suggestion was that abnor-

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mally high levels of sebum secretion resulted fromhigh circulating androgens. A number of studieshave documented raised androgen levels (elevatedfree testosterone and lowered sex hormone bindingglobulin) in women with acne but these findingshave usually been limited to those over the age of20and in selected severe or therapy resistantcases.37-39 In general there appears to be no correla-tion between acne severity and plasma androgenlevels or clinical markers of androgenicity (hir-sutes, excessive body hair, male pattern alopecia,hidradenitis suppurativa) in women.40'41 This takentogether with the poor correlation between acneseverity at different sites suggests that in most casesthe acne does not result from a systemic hyper-androgenaemia but rather from an abnormalitylocally with greater conversion ofandrogens in skincontaining active sebaceous glands. Indeed thelocal conversion oftestosterone to the more andro-genic 5-a-dihydrotestosterone by the enzyme 50-reductase is increased in acne skin compared tonormals.42 Furthermore the finding that 83% offemales with acne vulgaris have polycystic ovariesand that these patients lacked the features usuallyassociated with the polycystic ovary syndrome alsosuggests an alteration in local steroid metabolismor steroid hormone receptors rather than asystemic abnormality.43'44 This hypothesis is sup-ported by increased urinary Sa-tetrahydrocortisolin patients with the polycystic ovary syndromeindicating increased conversion of cortisol to 5a-dihydrocortisol by Sa-reductase in either the skinor liver.45 Clearly, exciting work has yet to be doneto elucidate the factors controlling cutaneous an-drogen metabolism and such research may providethe realization of topical antiandrogenic drugs inthe treatment of acne.Although there is evidence that patients with

acne have an increased sebum excretion rate, theseborrhoea persists after resolution of the acne.There must therefore be other factors necessary forthe development of the condition and one of theseis ductal hypercornification. This involves asignificant change in the formation and desquama-tion of the keratinized cell layer inside the infrain-fundibulum (the lower four-fifths) of the pilo-sebaceous orifice.4 The granular layer becomesmore prominent and the horny cells become moredistinct and stick together so that instead ofsloughing into a loose disorganizing mass, thehorny cells pack together into lamellae of denseeosinophilic horn. Thus the accumulation ofhornycells distends the pilosebaceous canal, producingfirst a microcomedo and then a clinically obviouslesion. As the comedone enlarges sebum continuesto be produced, becoming mixed in with thecorneocytes and eventually a stage is reached whenthere is obstruction of the pilosebaceous duct andthe sebum becomes dammed up.47

The pathogenesis ofthe abnormal ductal cornifi-cation in acne is not fully understood. It may resultfrom hyperproliferation of the ductal epidermisand/or an increased cohesiveness of the corneo-cytes. Since not all ducts in an acne-prone individ-ual form comedones, a local change affecting somebut not all follicles must occur. Proposed factorsthat modulate the cornification include alterationsin skin surface fatty acids48'49 and squalene,50bacterial colonization51 and the degree of hydra-tion of the pilosebaceous duct. Squalene, in partic-ular its oxide and peroxides, is implicated as beingcomedogenic and the surface lipids ofpatients withacne have an increased squalene content comparedwith controls.5 The theory that bacteria are insome way involved in comedogenesis appearsunlikely however since a large proportion ofclosedand open comedones are totally free of bacteria.53The observation that acne may flare premenstru-ally can be explained by changes in pilosebaceousduct size and measurement of the orifice size hasshown a reduction between the 15 and 20th daysand a deterioration in the acne on the 22nd day ofthe cycle.5 Whether this is due to hydration of theductal corneocytes or direct hormonal influenceshas not yet been established.A role for micro-organisms in the genesis ofacne

was initially proposed by Unna in 189655 but it isstill not known whether the microflora are initi-ators of the lesions or whether their presence isdependent upon the local environment. The com-mensal flora of healthy or acne-affected pilo-sebaceous follicles consists of Propionibacteriumacnes, Staphylococcus epidermidis and Pityros-porum ovale.56'57 It has been shown that P. acnes aredistributed at skin sites with high numbers ofsebaceous follicles58 but there does not appear to bea direct relationship between the severity of acneand the bacterial population density.59 Never-theless the efficacy of antibiotic therapy in thetreatment of acne strongly suggests that bacteriaare involved in the pathogenesis of the diseasealthough it is now known that tetracyclines haveother actions such as interfering with proteinsynthesis and having an anti-inflammatory action.60

Further evidence for the involvement of micro-organisms comes from the fact that nascent sebumis high in triglycerides and devoid of free fattyacids.6' Lipases produced by P. acnes act on thesebum to yield long chain fatty acids, glycerol andmono- and diglycerides and the free fatty acids areboth irritant and comedogenic.62-64 A recenthypothesis suggests that the follicular anaerobicflora produce porphyrins which catalyse the oxida-tion of squalene.65 This oxidation product is notonly comedogenic but the reaction reduces fol-licular oxygen levels and encourages the coloniza-tion of further anaerobes such as P. acnes. Thevariability in the microenvironment of the individ-

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ual follicles might then explain the highly localnature of acne and why some follicles becomeinflamed and others not.The inflammatory component of acne is almost

certainly ofgreatest concern to the patient and maybe the precursor of persistent scars. Inflammatorylesions consist of macules, papules, pustules,nodules and cysts. Through careful mapping ofdeveloping lesions it was found that the earliestinflammatory cells consisted of a predominantly Thelper lymphocytic periductal and perivascularlymphocytic infiltrate.66 Polymorphonuclear leuco-cytes were present at later stages (72 hours) andwere more evident when there was disruption oftheduct wall. Interestingly, these authors refuted thecurrently held dogma that disruption of the fol-licular wall is a necessary requirement for theinflammatory process since this was only found in14% ofinflamed lesions at 6 hours and in 18% at 72hours. Immunofluorescent studies have shown thatactivation ofcomplement accompanies the cellularinfiltrate since there is deposition ofC3 in the wallsof small dermal blood vessels and at the dermo-epidermal junction in early inflamed lesions.67

There has been great interest in unravelling thepathogenesis of the inflammatory process and tounderstand how drugs such as antibiotics and thesynthetic retinoids are so successful in reversingthese changes. The main focus has been on medi-ators released by the micro-organisms within thepilosebaceous duct and the effect of these medi-ators on polymorphonuclear leucocytes ratherthan the lymphocyte. It has been shown that P.acnes produce cytotaxins68 (compounds whichstimulate chemotactic activity and do not requirethe presence of serum factors) some of which havebeen identified as lipases,69 a prostaglandin-likesubstance and a low molecular weight substance.70The cell wall of P. acnes stimulates in vitro theclassical and alternate complement pathways7' andother comedonal contents of non-bacteriologicalorigin may be important in acting as cytotaxins andactivating complement.

There is also evidence of a host response in acnewith some patients having antibodies to P. acnesand others demonstrating delayed skin test reac-tivity to P. acnes, both ofwhich correlate with acneseverity.7273 Furthermore investigators have de-monstrated lymphocyte transformation to P. acnesand increased cellular immunity using the leuco-cyte migration inhibition test.The precise pathogenesis ofacne remains unclear

and the reason why the disease is usually selflimiting also is not known at present. Fortunatelythe disease responds satisfactorily to availabletreatment.

Cyclosporin

Cyclosporin is a lipophilic cyclic undecapeptidecomposed of 11 aminoacids produced by a strain ofFungi Imperfecti, Tolypocladium inflatum Gamsand was first isolated from samples of soil inWisconsin and the Hardanger Vidda in Norway in1969. The antilymphocytic action of cyclosporinwas first described by Borel in 197675 and the drugwas first used in human organ transplantation in1978. Its possible role as a dermatological treat-ment was first appreciated in 1979 when 4 patientswith psoriatic arthritis noticed a rapid clearing oftheir psoriasis and an improvement of theirarthritis following treatment with cyclosporin.76 In1984 administration of cyclosporin to a patientwith crippling psoriatic arthritis resulted inmobilization together with clearing of the psoria-sis.77 Subsequent studies have established thatlow-dose cyclosporin induces remission in severepsoriasis and that this is maintained with continuedtherapy.78'79 Tachyphylaxis does not occur andafter stopping the drug the skin conditiongradually deteriorates to its pre-treatment statewith 2 to 8 weeks. Rebound worsening does notusually occur although there have been a fewreports of such a phenomenon including reboundpustular psoriasis in the literature.80Cyclosporin in open, and in a few double-blind,

studies has also been shown to be of benefit in thetreatment of many other diseases including atopicdermatitis81'82 lichen planus,83 alopecia areata,84pemphigoid,85'86 pemphigus,87 polymyositis,88dermatomyositis,89 pyoderma gangrenosum90 andBehcet's disease91'92 but at present its use should bereserved for severe conditions in which standardtreatments have been unsuccessful. An initiallyencouraging report of cyclosporin improvingichthyosis vulgaris93 was not substantiated by itsfurther use in the treatment oflamellar ichthyosis.94Cyclosporin has also been shown to improve thecutaneous sclerosis, heal persistent digital ulcersand to lower levels of serum aminoterminal pro-peptide of type III procollagen in patients withsystemic sclerosis.95 However, in an earlier report inthe treatment of patients with systemic sclerosis,one of four patients treated with cyclosporin diedofacute renal failure96 and in the most recent study2 of 10 patients had abnormal post-treatment renalbiopsies.From experience obtained in the treatment of

psoriasis, cyclosporin should be started at an initialdaily oral dose of 3.0mg/kg/day taken in twoequally divided doses. If there has been no im-provement after 2 weeks the dose should beincreased by 0.5 mg/kg/day every 2 weeks to amaximum dose of 5 mg/kg/day. Doses above thiscarry increased risks of side effects. It is advisedthat topical treatment of the psoriasis be continued

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so that the dose of cyclosporin may be reduced tothe lowest necessary to maintain remission.

Cyclosporin is absorbed in the small intestineand peak blood concentrations are reached within1 and 8 hours after oral administration.97 The drugis metabolized in the liver by the cytochrome P450system and is excreted predominantly into thebiliary system. Several drugs are known to interferewith cyclosporin metabolism. Those that inducethe cytochrome P450 dependent liver enzymes(rifampicin, phenytoin, phenobarbitone, carba-mazepine) lower cyclosporin blood levels and thosethat inhibit the P450 enzyme system (ketoconazole,corticosteroids, oral contraceptives, calcium chan-nel blocking drugs, erythromycin) increase cyclo-sporin blood levels.? These may be rapidlymeasured by radioimmunoassay.The most frequent side effects of cyclosporin are

hypertension and nephrotoxicity, both of whichare dose-related. It is essential therefore thatmonthly trough blood cyclosporin levels be per-formed, that blood pressure should be regularlymonitored and that glomerular filtration rate bemeasured at least every 3-4 months since a rise inserum creatinine may be a late manifestation ofimpaired renal function. Nephrotoxic drugs poten-tiate the renal toxicity of cyclosporin and thereforethese should be avoided. Hypertension occurs in asmany as 25% ofpatients though the blood pressurenormalizes after the drug is stopped and if con-tinued therapy with cyclosporin is required then acalcium channel blocking drug may be an appro-priate antihypertensive agent. Other side effectsinclude hypertrichosis, gum hyperplasia, paraes-thesiae, elevated potassium and uric acid levels anddecreased serum magnesium.98 A worry about thelong term immunosuppressant effect ofcyclosporinis the possible increased risk of malignancies andbecause of this it would be unwise to start this drugin any patient who has had a past or presentmalignancy.To minimize systemic side effects the use of

topical cyclosporin in the treatment ofpsoriasis hasbeen explored. Unfortunately this has been unsuc-cessful but a recent report of intralesional cyclo-sporin showed a beneficial effect which suggeststhat the drug may be acting by a local mechanism."Interestingly, application of a 10% gel did signifi-cantly improve the severity of atopic dermatitisin a double-blind placebo-controlled study'° andthere are reports of topical cyclosporin underocclusion flattening hypertrophic lichen planus andof a cyclosporin wash improving oral lichenplanus.'0'The mode of action of cyclosporin has mostly

been studied in psoriasis and can be divided into itsimmunological/anti-inflammatory and anti-pro-liferative actions.'02 The predominant immuno-logical effects are the reversible inhibition of T

lymphocyte activation probably as a result of areduced responsiveness of helper T cells tointerleukin 1 and a reduction in the subsequentrelease of many of its cytokines and lymphokines,interleukin 2 and gamma interferon. Other effectsinclude an inhibition ofMHC II expression, inhibi-tion of antigen presenting capacity, interferencewith cell surface receptors, inhibition ofcalmodulin-dependent binding processes and in-hibition of phospholipase A2. Cyclosporin mayalso have a direct effect on the epidermis throughinhibition of proliferation and epidermal enzymes.In psoriasis the earliest effects of cyclosporin,before any clinical improvement has been ob-served, are those involving loss of gammainterferon inducable surface molecules onkeratinocytes, such as HLA-DR and intercellularadhesion molecule-l. This suggests that inter-ference with lesional T cell lymphokine release is animportant early event in the resolution of psoriaticplaques.

Cyclosporin is therefore a potent therapy ofmany dermatological disorders but as yet it is notlicensed for the treatment ofany these diseases andbecause of its nephrotoxic capacity, long termtreatment must be carefully supervised. Thedevelopment ofappropriate epicutaneous prepara-tions may overcome these concerns and they areeagerly awaited.

Raynaud's phenomenon

Raynaud's phenomenon is defined as episodicdiscolouration and ischaemia of the digits of thehands and feet in response to cold or emotionalstress, often accompanied by feelings ofnumbness,tingling and pain. It is manifested by pallor fol-lowed by cyanosis and then redness; these changesreflect respectively the underlying ischaemia,venostasis and reactive hyperaemia. The symptomcomplex is relatively common with a prevalence inthe general population reported as being between3_22%.103-105Raynaud's phenomenon can be subdivided into

an isolated or primary disorder or it may besecondary, when it precedes or accompanies asystemic disorder, or be caused by drugs. Themajority of cases of primary Raynaud's phenome-non can be diagnosed by a modification of Allenand Brown's criteria."06 Such patients haveepisodes of bilateral vasospastic colour changeprovoked by cold or emotional stress, normalperipheral artery pulsations, absence of gangreneor digital pulp loss, absence of any obvious causaldisease on history or examination, a minimumduration of symptoms of 2 years, age of onsetunder 25 and negative investigations for secondaryRaynaud's phenomenon. These would include

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negative anti-nuclear antibodies, anti-DNA anti-bodies, cryoglobulins and cold agglutinins, normalESR, immunoglobulin and creatine phospho-kinase levels and normal lung function tests, nail-fold capillaroscopy, chest and hand radiographs.The causes of secondary Raynaud's phenomenonare listed in Table I.The pathogenesis of Raynaud's phenomenon is

still unknown but several theories exist. MauriceRaynaud thought that the abnormality was centralor, in his own words, due to 'increased irritability ofthe central parts of the cord presiding over vascularinnervation'.107 However, direct microneurograph-ic recordings of median nerve sympathetic activityin normals and patients with Raynaud'sphenomenon before and after a cold challengeshowed no increased sympathetic outflow to thehand nor more profound or more prolongedvasoconstriction elicited by single, strong sym-pathetic bursts.'08 Further evidence that increasedsympathetic tone does not entirely provide thebasis of the attacks of Raynaud's phenomenoncomes from the disappointing results of sym-pathetic denervation.'09

Angiographic studies have shown that the digitalarteries are the major vessels affected in Raynaud'sphenomenon with severe narrowing and eventualabsence of filling."° In contrast there is onlyattenuation of the palmar arches and occasionalspasm of the forearm arteries. Lewis believed thatthere was a local fault of the vessels rather thaninappropriate vasomotor impulses causing spasmof the digital arteries. This was based upon studiesin which the sympathetic nerve supply to the digitswas interrupted by injection of local anaestheticaround the ulnar nerve at the elbow. Thisinvariably caused an initial rise in digitaltemperature but did not prevent local cold-inducedvasospasm in the anaesthetized ulnar innervatedarea of the hand."' Recent advances in knowledgeabout the role of the endothelium in modulatingvascular smooth muscle tone may define the abnor-malities that may be the cause of Lewis's localfault."2 There may be defective release of endo-thelial vasodilator mediators such as prostaglandinI2 (PGI2), E2 or endothelium-derived relaxing fac-

tors (EDRF). Alternatively there may be increasedrelease of vasoconstrictor mediators such as endo-thelin or altered neurovascular control mediated bythe serotininergic, cholinergic, peptidergic oradenosinergic nerves.

There is evidence to suggest that altered prosta-glandin release occurs in patients with Raynaud'sphenomenon and there might be an imbalancebetween the release of the vasoconstrictor throm-boxane A2 and the vasodilator PGI2.'"3'14 Indeed a

factor, present in the serum of patients withprimary and secondary Raynaud's phenomenon,has been found which inhibits the release of PGI2from cultured human endothelial cells."' It is notknown whether there is a similar mechanismaffecting the release of EDRF which is also aninhibitor of platelet aggregation.

Endothelin is a 21 amino acid peptide (mol.wt.2,492) that has recently been isolated andsequenced."6 It is synthesized and released byendothelial cells and has been shown to have potentvasoconstricting properties."7 Moreover, intra-venous administration of endothelin causes a longlasting pressor response in rats and such a responsemay account for the long lasting vasospasm ob-served during an attack of Raynaud's pheno-menon.

Cutaneous arterioles and arterio-venous anasto-moses are supplied by adrenergic vasoconstrictorneurones and there may be increased sensitivity or

density of the peripheral alpha-adrenoceptors.There is already evidence to suggest alpha-adrenergic hyper-responsiveness in primary Ray-naud's phenomenon"8 and other investigatorshave shown increased platelet alpha2-adrenergicreceptors in patients with primary and secondaryRaynaud's phenomenon.19 There also may be an

abnormality ofneurally mediated vasodilatation inRaynaud's phenomenon, a nocioceptive reflexinduced by contact with cold and carried proxi-mally by thin (Ab) afferent fibres and centrifugallyin contralateral (?afferent) non-myelinated fi-bres.'20 In addition, in normal people there isevidence of a local vasodilatation induced by anaxon reflex on stimulation ofcutaneous polymodalnocioceptor fibres.'21'122 It is thought that the

Table I Causes of secondary Raynaud's phenomenon

Connective tissue diseases Drugs Others

Systemic sclerosis P-blockers Thoracic outlet syndromeSystemic lupus erythematosus Ergotamine VibrationDermatomyositis Bleomycin AtherosclerosisRheumatoid arthritis Cisplatin Thromboangiitis obliteransMixed connective tissue disease Nicotine Direct arterial trauma

Sjogren's syndrome Bromocriptine Cold agglutininsCryoglobulinaemia

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dilatation is due to antidromic impulses releasinghistamine, substance P or calcitonin gene-relatedpeptide (CGRP). Recently one group of inves-tigators has showed a suprasensitivity to int-ravenous CGRP with a greater increase in bloodflow in the hands of patients with Raynaud'sphenomenon than normal controls.'23 This sug-gested a deficiency ofendogenous CGRP release inthe patients. However, another group of inves-tigators has shown no difference in the response tointradermal injections of histamine and CGRP inpatients with Raynaud's phenomenon comparedto the controls at room temperature'24 and asomewhat attenuated response to CGRP in thepatients at 5°C.'25

In addition to the above proposed pathogeneticmechanisms for Raynaud's phenomenon there arealso a number of other well documented abnorm-alities which may account for the reduced digitalblood flow'26"'27 and reactive hyperaemia128 in suchpatients but probably are not so important in thedynamic sequence of events that lead to an attackof Raynaud's phenomenon. Viscosity of bloodfrom patients with primary Raynaud's phenome-non is normal at 37°C but at 27°C it is increasedcompared to normal controls.129 In most patientswith secondary Raynaud's phenomenon, especiallythose with an underlying connective tissue disease,blood viscosity is increased probably as a result ofincreased levels of fibrinogen and gamma-globulins.13013 However, since blood viscosityrepresents a sum of many interacting factors themeasurement of red blood cell deformability hasbeen performed. This was found to be normal inpatients with primary Raynaud's phenomenon butreduced in patients with Raynaud's phenomenonassociated with systemic sclerosis.'32 Moreover,these investigators showed that red blood cellsfrom the latter patients had a reduced negativesurface charge which, through increasedadhesiveness to the blood vessel wall, might be afurther factor in reducing digital blood flow.The earlier suggestion that endothelial cell dys-

function may be one of the fundamental abnor-malities in Raynaud's phenomenon is supported bymeasurement of von Willebrand Factor (vWF)antigen levels. The circulating protein Factor VIIIis a complex of two factors, Factor VIIIC which islinked by non-covalent bonds to a high molecularweight polymeric glycoprotein vWF which ismainly synthesized by endothelial cells and to alesser extent by platelets and megakaryocytes. It isknown that disturbances of endothelial cell integ-rity in vitro can stimulate the release ofvWFAg andit has been on the basis of this fact that measure-ment of circulating vWFAg has been measured inseveral diseases in which microvascular injuryoccurs. Raised levels have been found in patientswith primary Raynaud's phenomenon'33 and in

patients with Raynaud's phenomenon associatedwith systemic sclerosis.'34 Furthermore, a coldchallenge increased these levels still further. Itwould have been interesting to compare this datawith an histological assessment of the digitalarteries in primary Raynaud's phenomenon butunfortunately the only ultrastructural study thathas been performed on such patients examinedsalivary gland blood vessels and these were nor-mal.'35 Although much has been learnt about thepathogenesis of Raynaud's phenomenon it is stillnot known why the attacks of digital ischaemia aremore common in women and even less is knownabout the role ofenvironmental temperature versusthe rate of heat loss from the skin in triggeringattacks.

Essential fatty acids and dermatologyThere is increasing awareness that there may be alink between the diet and skin disease,136 and nowseveral studies have shown that increasing the oralintake of essential fatty acids has a beneficial effecton a variety of dermatoses.'37 In order to under-stand the rationale for using these agents, it is firstnecessary to outline the biochemistry of essentialfatty acids.'38There are two types of essential fatty acids

known as the 06 and 03 series and this nomen-clature is based upon the position ofthe first doublebond relative to the methyl end of the molecule;thus the 06 series have their first double bond at 6carbon atoms along the carbon chain. Mammalsare incapable of introducing double bonds at thesepositions and rely upon marine sources (a-linolenicacid) for the o3 series of fatty acids and plantsources for the 06 fatty acids (linoleic acid). Bothtypes of fatty acids appear to be metabolized by thesame or a closely related enzyme sequence and anoutline of the products is shown in Figure 1.The metabolism of essential fatty acids in the

skin is different from that in most other tissues sincethe epidermis lacks both the 65- and 66-desaturaseenzymes.'39'40 Thus linoleic acid cannot be con-verted to y-linolenic acid nor dihomo-y-linolenicacid to arachidonic acid and because the epidermisturns over rapidly it is likely that storage of thesemetabolites is minimal. Therefore the epidermis isdependent upon the continual formation of thesemetabolites in other organs, principally the liver,'4'and on their transport to the skin by the blood.The effects of essential fatty acid deficiency on

the skin have mostly been studied in animals sincesuch a pure deficiency in the absence ofvitamin andother deficiencies is rare in humans. In the animalsthe skin becomes erythematous and scaly, the hairbecomes thin and lost, transepidermal water loss isgreatly increased and normal healing of wounds

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06 FATTY ACIDS

Linoleic acid

y-linolenic acid

03 FATTY ACIDS

a-linolenic acid

+,66-Desaturase +Stearidonic acid

Dihomo-y-linolenic acid+4 Elongase +4

4 65-Desaturase +Arachidonic acid

Eicosatetraenoic acid

Eicosapentaenoic acid

Figure 1 Outline of metabolism of w3 and 06 essential fatty acids.

fails to occur, possibly as a result of defectivecollagen formation.142'143 On histology the epider-mis becomes thickened and the thickened stratumcorneum instead of being made up of the normalclosely-packed layers consists of loosely packedlayers of keratin. Furthermore, the hair follicles arefrequently plugged with keratin, the sebaceousglands hypertrophy and there are increasednumbers of phospholipid granules throughout thestratum corneum. Similar cutaneous changes havebeen observed in humans deficient ofessential fattyacids secondary to intestinal resection, chylousascites and prolonged parenteral feeding.144-146 Thediagnosis can be established by the very lowconcentrations of arachidonic and linoleic acids inthe dermis in the presence of appreciable amountsof eicosatrienoic acid.147'148The clinical similarity between the skin changes

of essential fatty acid deficiency and atopic derma-titis led to the measurement of unsaturated fats inthe blood of children suffering from this der-matosis. It was found that there was a deficiency ofunsaturated fats and subsequent feeding with fatsupplements produced clinical improvement.149'150However subsequent studies produced inconsistentresults and it was not until 1981 when administra-tion of evening primrose oil (rich in linoleic andgamma-linolenic acid) in a controlled study pro-duced a modest but significant improvement inatopic dermatitis that further interest in essentialfatty acids was rekindled.'5Measurement of plasma phospholipids in

patients with atopic dermatitis has shown normallevels of linoleic and linolenic acid but levels of themetabolites of the 03 and 06 essential fatty acidswere low, suggesting a possible block at the level ofthe 66-desaturase enzyme.'52'53 Other workers haveshown plasma dihomo-y-linolenic acid andarachidonic acid levels are lower than normal inthese patients.154 If impaired 66-desaturation isimportant in atopic dermatitis, then administration

of gamma-linolenic acid should produce clinicalbenefit by bypassing the block.

Gamma-linolenic acid is present in human milkand in variable quantities in the seed oil of theevening primrose Oenothera biennis.'55 Epogamcapsules containing 500 mg ofevening primrose oil(40 mg of gamma-linolenic acid) have producedclinical improvement in atopic dermatitis and ameta-analysis of nine multi-centre trials showed asubstantial and significant reduction in itch and anon-significant clinical improvement in the cross-over trials.'56 There also was a positive correlationbetween the improvement of the atopic dermatitisand changes in dihomogamma-linolenic acid andarachidonic acid levels in plasma phospholipids.Other workers do not believe that the efficacy ofthis preparation has been proved'57 but never-theless Epogam is now licensed for the treatment ofatopic dermatitis in the UK at the dose of 4-6capsules twice daily in adults and 2-4 capsulestwice daily for children.The mechanism by which evening primrose oil

produces improvement in atopic dermatitis is notknown but it is possible that the elongation productof gamma-linolenic acid serves as a precursor forprostaglandin El (PGEi) synthesis and it has beenreported that plasma PGE, levels increase twofoldduring administration ofevening primrose oil.'52 '58PGE, seems to be a crucial mediator for lym-phocyte, mast cell and basophil function, theregulation of arachidonic acid metabolism andsuppression of diverse effector systems ofinflammation.'59 This prostaglandin activatesadenylate cyclase, thereby increasing cAMP levelsand causes a dose-dependent inhibition of hista-mine release from basophils and mast cells.160'161

There has been considerable interest in the roleof 5- and 12-lipoxygenase products in the patho-genesis of the inflammatory process in psoriasis.'62Eskimos appear to be completely clear of psori-asis'62 and because their diet is high in

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eicosapentenaenoic acid which competes witharachidonic acid and reduces its conversion topotentially inflammatory metabolites, attemptshave been made to treat psoriasis with concen-trated fish oil. Several open studies showed that fishoil supplements produced some improvement inplaque psoriasis and these results were confirmed ina double blind trial.64 Furthermore this treatmentresulted in a substantial inhibition ofleukotriene B4production by the peripheral blood polymorpho-nuclear leucocytes in vitro.'65

There has also been speculation that essentialfatty acid deficiency may be involved in thepathogenesis of acne. Levels of linoleic acid insebum decrease progressively as the severity ofacne

increases'66 and such a deficiency in the pilo-sebaceous epithelium might account for the charac-teristic follicular hyperkeratosis of acne.'67 How-ever, administration of evening primrose oil in onestudy did not produce clinical benefit'68 although inanother study essential fatty acid supplementsneeded to be continued for 6 months before animprovement was observed.'69

Clearly, the role ofessential fatty acids in the skinis only slowly being understood and the oppor-tunity to modulate inflammatory eicosanoid pro-duction and the second messenger cell signallingsystem is an exciting challenge in the treatment ofseveral common skin disorders.

References

Atopic dermatitis1. Larsen, F.S. & Holm, N.V. Atopic dermatitis: a genetic-

epidemiologic study in a population-based twin sample. JAm Acad Dermatol 1986, 15: 487-494.

2. Cokson, W.O.C.M., Sharp, P.A., Faux, J.A. & Hopkin,J.M. Linkage between immunoglobulin E responses under-lying asthma and rhinitis and chromosome llq. Lancet1989, i: 1292-1295.

3. Hanifin, J.M. Pharmacophysiology of atopic dermatitis.Clin Rev Allergy 1986, 4: 43-65.

4. Saarinen, U.M. Transfer of latent atopy by bone marrowtransplantation: a case report. J Allergy Clin Immunol 1984,74: 196-200.

5. Lever, R., Turbitt, M., Sanderson, A. & MacKie, R.Immunophenotyping of the cutaneous infiltrate and of themononuclear cells in the peripheral blood in patients withatopic dermatitis. J Invest Dermatol 1987, 89: 4-7.

6. Bieber, T., Dannenberg, B., Ring, J. & Braun-Falco, O.Keratinocytes in lesional skin of atopic eczema bear HLA-DR, CD a, and IgE molecules. Clin Exp Dermatol 1989,14:35-39.

7. Stone, S.P., Muller, S.A. & Gleich, G.F. IgE levels in atopicdermatitis. Arch Dermatol 1973, 108: 806-811.

8. Peterson, R.O.A., Page, A.R. & Good, R.A. Wheal anderythema allergy in patients with agammaglobulinemia. JAllergy Clin Immunol 1962, 33: 406-411.

9. O'Loughlin, S., Diaz-Perez, J.L., Gleich, G. & Winkelmann,R.K. Serum IgE in dermatitis and dermatosis. Arch Derma-tol 1977, 113: 309-315.

10. Leung, D.Y.M. & Geha, R.S. Immunoregulatory abnorm-alities in atopic dermatitis. Clin Rev Allergy 1986, 4: 67-86.

11. Clark, R.A.F. Cell-mediated and IgE-mediated immuneresponses in atopic dermatitis. Arch Dermatol 1989, 125:413-416.

12. Reitamo, S., Visa, K., Kahonen, K. et al. Eczematousreactions in atopic patients caused by epicutaneous testingwith inhalant allergens. Br J Dermatol 1986, 114: 303-309.

13. Norris, P.G., Scohfield, O. & Camp, R.D.R. A study of therole of house dust mite in atopic dermatitis. Br J Dermatol1988, 118: 435-440.

14. Adinoff, A.D., Tellez, P. & Clark, R.A.F. Atopic dermatitisand aeroallergen contact sensitivity. J Allergy Clin Immunol1988, 4: 736-742.

15. Gondo, A., Saeki, N. & Tokuda, Y. Challenge reactions inatopic dermatitis after percutaneous entry of mite antigen.Br J Dermatol 1986, 115: 485-493.

16. Mitchell, E.B., Crow, J., Chapman, M.D. et al. Basophils inallergen-induced patch test sites in atopic dermatitis. Lancet1982, i: 127-130.

17. Platts-Mills, T.A.E., Mitchell, E.B., Rowntree, S. et al. Therole of dust mite allergens in atopic dermatitis. Clin ExpDermatol 1983, 8: 233-247.

18. Zachary, C.B., Allen, M.H. & MacDonald, D.M. In situquantification of T-lymphocyte subsets and Langerhanscells in the inflammatory infiltrate of atopic eczema. Br JDermatol 1985, 112: 149-156.

19. Bruynzeel-Koomen, C., van Wichen, D.F., Toonstra, J.,Berrens, L. & Bruynzeel, P.L.B. The presence of IgEmolecules on epidermal Langerhans cells in patients withatopic dermatitis. Arch Dermatol Res 1986, 278: 199-205.

20. Barker, J.N.W.N., Alegre, V.A. & MacDonald, D.M.Surface-bound immunoglobulin E on antigen-presentingcells in cutaneous tissue of atopic dermatitis. J InvestDermatol 1988, 90: 117-121.

21. Bonnefoy, J.Y., Aubry, J.P., Peronne, C. et al. Productionand characterization of a monoclonal antibody specific forthe human lymphocyte low affinity receptor for IgE: CD23 isa low affinity receptor for IgE. J Immunol 1987, 138:2970-2978.

22. Yukawa, K.H., Kikutani, H., Owaki, K. et al. A Bcell-specific differentiation antigen, CD23, is a receptor forIgE (FceR) on lymphocytes. J Immunol 1987, 138:2576-2580.

23. Capron, M., Jouault, T.H., Prin, L. et al. Functional studyof a monoclonal antibody to IgE Fc receptor (FceR2) ofeosinophils, platelets and macrophages. J Exp Med 1986,164: 72-89.

24. Thorley-Lawson, D.A., Nadler, L.M., Bhan, A.K. &Schooley, R.T. BLAST-2 [EBVCS], an early cell surfacemarker of human B cell activation, is superinduced byEpstein Barr virus. J Immunol 1985, 134: 3007-3012.

25. Bruynzeel-Koomen, C., van der Donk, E.M.M., Bruynzeel,P.L.B., Capron, M., De Gast, G.C. & Mudde, G.C.Associated expression of CDI antigen and Fc receptor forIgE on epidermal Langerhans cells from patients with atopicdermatitis. Clin Exp Immunol 1988, 74: 137-142.

26. Delespesse, G., Sarfati, M. & Hofstetter, H. Human IgE-binding factors. Immunol Today 1989, 10: 159-164.

27. Armitage, R.J. & Goff, L.K. Functional interaction betweenB cell subpopulations defined by CD23 expression. Eur JImmunol 1988, 18: 1753-1760.

28. Basham, T.Y., Nickoloff, B.J., Merigan, Th.C. & Morhenn,V.B. Recombinant gamma interferon induces HLA-DRexpression on cultured human keratinocytes. J Invest Der-matol 1984, 83: 88-90.

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DERMATOLOGY 903

29. Bieber, T., Rieger, A., Neuchrist, C. et al. Induction ofFceR2/CD23 on human epidermal Langerhans cells byhuman recombinant interleukin 4 and y interferon. J ExpMed 1989, 170: 309-314.

30. Sauder, D.N., Wong, D., McKenzie, R. et al. The pluri-potent keratinocyte: molecular characterization of epider-mal cytokines. J Invest Dermatol 1988, 90: 605.

31. Ashworth, J., Booker, J. & Breathnach, S.M. Effects oftopical corticosteroid therapy on Langerhans cell antigenpresenting function in human skin. Br J Dermatol 1988, 118:457-470.

32. Furue, M. & Katz, S.I. Direct effect of glucocorticosteroidson epidermal Langerhans cells. J Invest Dermatol 1989, 92:342-347.

33. Holden, C.A. Atopic dermatitis: a defect of intracellularsecondary messenger systems? Clin Exp Allergy 1990, 20 inpress.

34. Hanifin, J.M. Phosphodiesterase and immune dysfunctionin atopic dermatitis. J Dermatol Sci 1990, 1: 1-6.

Acne35. Cunliffe, W.J. & Shuster, S. The rate of sebum excretion in

man. Br J Dermatol 1969, 81: 697-704.36. Cunliffe, W.J. & Shuster, S. The pathogenesis of acne.

Lancet 1969, i: 685-687.37. Darley, R., Kirby, J., Besser, G.M. et al. Circulating

testosterone, sex hormone binding globulin and prolactin inwomen with late onset of persistent acne vulgaris. Br JDermatol 1982, 106: 517-522.

38. Lawrence, D.M., Katz, M., Robinson, T.W.E. et al.Reduced sex hormone binding globulin and derived freetestosterone levels in women with severe acne. Clin Endo-crinol 1981, 15: 87-91.

39. Schiavone, F.E., Rietschel, R.L., Sgoutas, D. et al. Elevatedfree testosterone levels in women with acne. Arch Dermatol1983, 119: 799-802.

40. Levell, M.J., Cawood, M.L., Burke, B. & Cunliffe, W.J.Acne is not associated with abnormal plasma androgens. BrJ Dermatol 1989, 120: 649-654.

41. Sheehan-Dare, R.A., Hughes, B.R. & Cunliffe, W.J. Clinicalmarkers of androgenicity in acne vulgaris. Br J Dermatol1988, 119: 723-730.

42. Hay, J.B. & Hodgins, M.B. Metabolism of androgens byhuman skin in acne. Br J Dermatol 1974, 91: 123-133.

43. Luck, A.W. Androgens and the skin: another journeyaround the circle. Arch Dermatol 1987, 123: 193-195.

44. Bunker, C.B., Newton, J.A., Kilbor, J. et al. Most womenwith acne have polycystic ovaries. Br J Dermatol 1989, 121:675-680.

45. Stewart, P.M., Shakleton, C.H.L., Beastall, G.H. &Edwards, C.R.W. 5a-reductase activity in polycystic ovarysyndrome. Lancet 1990, 335: 431-433.

46. Kligman, A.M. An overview of acne. J Invest Dermatol1974, 62: 268-287.

47. Knutson, D.D. Ultrastructural observations in acne vul-garis. The normal sebaceous follicle and acne lesions. JInvest Dermatol 1974, 62: 288-307.

48. Gloor, M., Graumann, U., Kionke, M. et al. Menge undzusammensetzung der hautoberflachenlipide bei patientenmit acne vulgaris und gesunden vergleichspersonen. ArchDermatol Forsch 1972, 242: 316-322.

49. Kanaar, P. Lipolysis of skin-surface lipids in acne vulgarispatients and healthy controls. Dermatologica 1971, 143:121-129.

50. Motoyoshi, K. Enhanced comedo formation in rabbit earskin by squalene and oleic acid peroxides. Br J Dermatol1983, 109: 191-198.

51. Puhvel, S.M. & Amirian, D.A. Bacterial flora ofcomedones.Br J Dermatol 1979, 101: 543-548.

52. Cotterill, J.A., Cunliffe, W.J., Williamson, B. et al. Furtherobservations on the pathogenesis of acne. Br MedJ 1972, 3:444-446.

53. Leeming, J.P., Holland, K.T. & Cunliffe, W.J. Thepathological and ecological significance of microorganismscolonising acne vulgaris comedones. J Med Microbiol 1985,20: 11-16.

54. Williams, M. & Cunliffe, W.J. Explanation for premenstrualacne. Lancet 1973, ii: 1055-1057.

55. Unna, P.J. Histopathology of the Diseases of the Skin. W.F.Clay, Edinburgh, 1896.

56. Leeming, J.P., Holland, K.T. & Cunliffe, W.J. The microbialecology of pilosebaceous units from human skin. J GenMicrobiol 1984, 130: 803-807.

57. Leeming, J.P., Holland, K.T. & Cunliffe, W.J. The microbialcolonisation ofinflamed acne vulgaris lesions. Br JDermatol1988, 118: 205-208.

58. McGinley, K.J., Webster, G.F. & Leyden, J.J. Regionalvariation of cutaneous propionibacteria. Appl Environ Mic-robiol 1978, 35: 62-66.

59. Leyden, J.J., McGinley, K.J. & Mills, O.H. Pro-pionibacterium levels in patients with and without acnevulgaris. J Invest Dermatol 1975, 65: 382-384.

60. Eady, E.A., Holland, K.T. & Cunliffe, W.J. The use ofantibiotics in acne therapy: oral or topical administration. JAntimicrob Chemother 1982, 10: 89-115.

61. Cunliffe, W.J. Biochemistry of the pilosebaceous unit. In:Cunliffe, W.K. (ed.) Acne. Martin Dunitz, London, 1989,p. 164.

62. Shalita, A.R. Genesis of free fatty acids. J Invest Dermatol1974, 62: 332-335.

63. Kanaar, R. Follicular-keratogenic properties of fatty acidsin the external ear canal of the rabbit. Dermatologica 1971,142: 14-22.

64. Freinkel, R.K. Pathogenesis of acne vulgaris. N Engl J Med1969, 280: 1161-1163.

65. Saint-Leger, D., Bague, A., Lefevre, E. et al. A possible rolefor squalene in the pathogenesis of acne. In vivo study ofsqualene oxides in skin surface and intracomedonal lipids ofacne patients. Br J Dermatol 1986, 114: 543-552.

66. Norris, J.F.B. & Cunliffe, W.J. A histological andimmunocytochemical study of early acne lesions. Br JDermatol 1988, 118: 651-659.

67. Dahl, M.G.C. & McGibbon, D.H. Complement C3 andimmunoglobulin inflammatory acne vulgaris. Br J Dermatol1979, 101: 633-640.

68. Puhvel, S.M. & Sakamoto, M. Cytotoxin production bycomedonal bacteria (Propionibacterium acnes, Propioni-bacterium granulosum, and Staphylococcus epidermis). JInvest Dermatol 1980, 74: 36-39.

69. Lee, W.L., Shalita, A.R., Suntharalingam, K. et al. Neutro-phil chemotaxis by Propionibacterium acnes lipase and itsinhibition. Infect Immun 1982, 35: 71-78.

70. Webster, G.F. & Leyden, J.J. Characterization of sebumand comedones. Histologic observations. Arch Dermatol1965, 92: 443-456.

71. Webster, G.F., Leyden, J.J., Norman, M.E. et al. Comple-ment activation in acne vulgaris: in vitro studies withPropionibacterium acnes and Propionibacterium granulosum.Infect Immun 1978, 22: 523-529.

72. Puhvel, S.M., Hoffman, I.K. & Sternberg, T.H. Coryne-bacterium acnes: presence of complement fixing antibodiesto Corynebacterium acnes in the sera of patients with acnevulgaris. Arch Dermatol 1966, 93: 364.

73. Kersey, P., Sussman, M. & Dahl, M. Delayed skin testreactivity to P. acnes correlates with the severity ofinflammation in acne vulgaris. Br J Dermatol 1980, 103:651-655.

74. Saint-Leger, D., Bague, A., Lefevre, E. et al. A possible rolefor squalene in the pathogenesis of acne. In vitro study ofsqualene oxidation. Br J Dermatol 1986, 114: 535-542.

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904 M.H.A. RUSTIN

Cyclosporin75. Borel, J.F., Feurer, C., Gubler, H.U. & Stachelin, H.

Biological effects of cyclosporin A: a new antilymphocyticagent. Agents Actions 1976, 6: 468.

76. Mueller, W. & Herrmann, B. Cyclosporin A for psoriasis. NEngl J Med 1979, 301: 555.

77. Harper, J.I., Keat, A.C.S. & Staughton, R.C.D. Cyclosporinfor psoriasis. Lancet 1984, ii: 981-982.

78. Ellis, C.N., Gorsulowsky, D.C., Hamilton, T.A. et al.Cyclosporin improves psoriasis in a double-blind study.JAMA 1986, 256: 3110-3116.

79. Bos, J.D., Meinardi, M.M.H.M., Van Joost, Th. et al. Use ofcyclosporin in psoriasis. Lancet 1989, ii: 1500-1502.

80. Heidenheim, M., Oxholm, A. & Da Cunha Bang, F.Generalized pustular psoriasis in relation to withdrawal ofcyclosporin A. Br J Dermatol 1990, 122: 719.

81. Van Joost, T., Stolz, E. & Heule, F. Efficacy of low dosecyclosporine in severe atopic skin disease. Arch Dermatol1987, 123: 166-167.

82. Taylor, R.S., Cooper, K.D., Headington, J.T. et al. Cyclo-sporine therapy for severe atopic dermatitis. J Am AcadDermatol 1989, 21: 580-583.

83. Pigatto, P.D., Chiappino, G., Bigardi, A. et al. CyclosporinA for treatment of severe lichen planus. Br J Dermatol 1990,122: 121-123.

84. Gupta, A.K., Ellis, C.N. Tellner, D.C. & Voorhees, J.J.Cyclosporine A in the treatment of severe alopecia areata.Transplant Proc 1988, 20 (Suppl 4): 105-108.

85. Thivolet, J., Barthelmy, H., Rigot-Muller, G. et al. Effects ofcyclosporine on bullous pemphigoid and pemphigus. Lancet1985, i: 334-335.

86. Cunliffe, W.J. Bullous pemphigoid and response to cyclo-sporin. Br JDermatol 1987, 117: 113-114.

87. Barthelemy, H., Frappaz, A., Cambazard, F. et al. Treat-ment of nine cases ofpemphigus vulgaris with cyclosporine.J Am Acad Dermatol 1988, 18: 1262-1266.

88. Jones, D.W., Snaith, M.L. & Isenberg, D.A. Cyclosporintreatment for intractable polymyositis. Arthritis Rheum1987, 30: 959-960.

89. Heckmatt, J., Hasson, N., Saunders, C. et al. Cyclosporin injuvenile dermatomyositis. Lancet 1989, i: 1063-1066.

90. Curley, R.K., Macfarlane, A.W. & Vickers, C.F.H.Pyoderma gangrenosum treated with cyclosporin A. Br JDermatol 1985, 113: 601-604.

91. Nussenblatt, R.B., Palestine, A.G., Chan, C.-C. et al.Effectiveness of cyclosporin therapy for Behcet's disease.Arthritis Rheum 1985, 28: 671-679.

92. Masuda, K., Nakajima, A., Urayama, A. et al. Double-masked trial of cyclosporin versus colchicine and long-termopen study ofcyclosporin in Behcet's disease. Lancet 1989, i:1093-1096.

93. Velthius, R.J. & Jesserun, R.F.M. Improvement of ich-thyosis by cyclosporin. Lancet 1985, i: 335.

94. Ho, V.C., Gupta, A.K., Ellis, C.N. et al. Cyclosporin A inlamellar ichthyosis. Arch Dermatol 1989, 125: 511-514.

95. Zachariae, H., Halkier-Sorensen, L., Heickendorff, L. et al.Cyclosporin A treatment of systemic sclerosis. Br J Derma-tol 1990, 122: 677-681.

96. Frances, C., Branchet, M.C., Bletry, O. et al. Skin collagenfrom scleroderma patients before and after cyclosporin Atreatment. Clin Exp Dermatol 1988, 13: 1-3.

97. Meinardi, M.M.H.M. & Bos, J.D. Immunopharmaco-logical properties of ciclosporin in psoriasis. In: van Joost,Th., Heule, F. & Bos, J.D. (eds) Ciclosporin (Sandimmune)in Psoriasis. Acta Sandoz no 13. Alphen aan de Rijn, theNetherlands: Samson Stafleu, 1988, pp. 26-49.

98. Gupta, A.K., Brown, M.D., Ellis, C.N. et al. Cyclosporinein dermatology. J Am Acad Dermatol 1989, 21:1245-1256.

99. Ho, V.C., Griffiths, C.E.M., Ellis, C.N. et al. Intralesionalcyclosporine in the treatment of psoriasis. J Am AcadDermatol 1990, 22: 94-100.

100. De Prost, Y., Bodemer, C. & Teillac, D. Randomiseddouble-blind placebo-controlled trial of local cyclosporin inatopic dermatitis. Acta Derm Venereol 1989, 144 (Suppl):136-138.

101. Eisen, D., Griffiths, C.E.M., Ellis, C.N. et al. Cyclosporinwash for oral lichen planus. Lancet 1990, 335: 535-536.

102. Bos, J.D. The pathomechanisms of psoriasis: the skinimmune system and cyclosporin. Br J Dermatol 1988, 118:141-155.

Raynaud's phenomenon103. Maricq, H.R., Weinrich, M.C., Keil, J.E. & LeRoy, E.C.

Prevalence of Raynaud's phenomenon in the generalpopulation. J Chron Dis 1986, 39: 423-427.

104. Heslop, J., Coggon, D. & Acheson, E.D. The prevalence ofintermittent digital ischaemia (Raynaud's phenomenon) in ageneral practice. J R Coll Gen Pract 1983, 33: 85-89.

105. Olsen, N. & Nielsen, S.L. Prevalence of primary Raynaud'sphenomena in young females. ScandJ Clin Lab Inv 1978,37:761-764.

106. Allen, E.V. & Brown, G.E. Raynaud's disease: A criticalreview of minimal requisites for diagnosis. Am J Med Sci1932, 183: 187-200.

107. Raynaud, M. Local asphyxia and symmetrical gangrene ofthe extremities and new researches on the nature andtreatment of local asphyxia of the extremities. In: SelectedMonographs (Translated by Thomas Barlow). The NewSydenham Society, 1988: pp. 1-150.

108. Fagius, J. & Blumberg, H. Sympathetic outflow to the handin patients with Raynaud's phenomenon. Cardiovasc Res1985, 19: 249-253.

109. Birnstingl, M. The Raynaud syndrome. Postgrad Med J1971, 47: 297-310.

110. Rosch, J., Porter, J.M. & Gralino, B.J. Cryodynamic handangiography in the diagnosis and management of Ray-naud's syndrome. Circulation 1977, 55: 807-814.

111. Lewis, T. Experiments relating to the peripheral mechanisminvolved in spasmodic arrest of the circulation in the fingers,a variety of Raynaud's disease. Heart 1929-1931, 15:7-100.

112. Vanhoutte, P.M. The endothelium - modulator of vascularsmooth-muscle tone. N Engl J Med 1988, 319: 512-513.

113. Reilly, I.A.G., Roy, L. & Fitzgerald, G.A. Biosynthesis ofthromboxane in patients with systemic sclerosis andRaynaud's phenomenon. Br Med J 1986, 292: 1037-1039.

114. Deray, G., Le Hoang, P., Achour, L. et al. Cyclosporin andRaynaud's phenomenon. Lancet 1986, ii: 1092-1093.

115. Rustin, M.H.A., Bull, H.A., Machin, S.J. et al. Serum frompatients with Raynaud's phenomenon inhibits prostacyclinproduction. J Invest Dermatol 1987, 89: 555-559.

116. Yanagisawa, M., Kurihara, H., Kimura, S. et al. A novelpotent vasoconstrictor peptide produced by vascularendothelial cells. Nature 1988, 332: 411-415.

117. Brain, S.D., Tippins, J.R. & Williams, T.J. Endothelininduces potent microvascular constriction. Br J Pharmacol1988, 95: 1005-1007.

118. Freedman, R.R., Sabharwal, S.C., Desair, N. et al. In-creased alpha-adrenergic responsiveness in idiopathicRaynaud's disease. Arthritis Rheum 1989, 32: 61-65.

119. Edwards, J.M., Phinney, E.S., Taylor, L.M. et al. a2-adrenergic receptor levels in obstructive and spastic Ray-naud's syndrome. J Vasc Surg 1987, 5: 38-45.

120. Blumberg, H. & Wallin, B.G. Direct evidence of neurallymediated vasodilatation in hairy skin of the human foot. JPhysiol 1987, 382: 105-121.

121. Lewis, T. The Blood Vessels of the Human Skin and theirResponses. Shaw and Sons, London, 1927.

122. Foremann, J. & Jordan, C. Histamine release and vascularchanges induced by neuropeptides. Agents Actions 1983, 13:105-116.

copyright. on M


http://pmj.bm

j.com/

Postgrad M


ovember 1990. D

ownloaded from

http://pmj.bmj.com/

DERMATOLOGY 905

123. Shawket, S., Hazleman, B., Dickerson, C. & Brown, M.J.Selective suprasensitivity to calcitonin-gene-related peptidein the hands in Raynaud's phenomenon. Lancet 1989, ii:1354-1357.

124. Bunker, C.B., Foreman, J.C. & Dowd, P.M. Digitalcutaneous vascular responses to histamine, compound 48/80and neuropeptides in normal subjects and Raynaud'sphenomenon. J Invest Dermatol 1989, 92: 409.

125. Bunker, C.B., Foreman, J.C. & Dowd, P.M. Digital vascularresponses to neuropeptides and histamine at low tempera-tures in Raynaud's phenomenon. J Invest Dermatol 1990,94:511.

126. Peacock, J.H. A comparative study of the digital cutaneoustemperatures and hand blood flows in the normal hand,primary Raynaud's disease and primary acrocyanosis. ClinSci 1959, 18: 25-33.

127. Coffman, J.D. & Cohen, A.S. Total and capillary fingertipblood flow in Raynaud's phenomenon. N Engl J Med 1971,285: 259-263.

128. Lee, P., Sarkozi, J., Bookman, A.A. et al. Digital blood flowand nailfold capillary microscopy in Raynaud's pheno-menon. J Rheumatol 1986, 13: 564-569.

129. Jahnsen, T., Nielsen, S.L. & Skovborg, F. Blood viscosityand local response to cold in primary Raynaud's pheno-menon. Lancet 1977, ii: 1001-1002.

130. Blunt, R.J., George, A.J., Hurlowe, R.A. et al. Hypervis-cosity and thrombotic changes in idiopathic and secondaryRaynaud's syndrome. Br J Haematol 1980, 45: 651-658.

131. Dintenfass, L. Haemorheological factors in Raynaud'sphenomenon. Angiology 1977, 28: 472-481.

132. Rustin, M.H.A., Kovacs, I.B., Sowemimo-Coker, S.O. et al.Differences in red cell behaviour between patients withRaynaud's phenomenon and systemic sclerosis and patientswith Raynaud's disease. Br J Dermatol 1985, 113: 265-272.

133. Kahaleh, M.B., Osborn, I., LeRoy, E.C. Increased FactorVIII/von Willebrand factor antigen and von Willebrandfactor activity in scleroderma and Raynaud's phenomenon.Ann Intern Med 1981, 94: 482-484.

134. Lee, P., Norman, C.S., Sukenik, S. & Alderdice, C.A. Theclinical significance ofcoagulation abnormalities in systemicsclerosis (scleroderma). J Rheumatol 1985, 12: 514-517.

135. Camilleri, J.P., Fiessinger, J.N., Debure, C. et al. Finestructural capillary changes and basal lamina thickening inscleroderma (progressive systemic sclerosis) and Raynaud'sdisease. Path Res Pract 1984, 178: 230-236.

Essential fatty acids and dermatology136. Burton, J.L. Diet and dermatology. Br Med J 1989, 298:

770-771.137. Burton, J.L. Dietary fatty acids and inflammatory skin

disease. Lancet 1989, i: 27-31.138. Horrobin, D.F. Essential fatty acids in clinical dermatology.

J Am Acad Dermatol 1989, 20: 1045-1053.139. Chapkin, R.S. & Ziboh, V.A. Inability of skin enzyme

preparations to biosynthesize arachidonic acid from linoleicacid. Biochem Biophys Res Commun 1984, 124: 784-792.

140. Chapkin, R.S., Ziboh, V.A., Marcelo, C.L. et al. Humanepidermal preparations can elongate gamma-linolenic acidinto gamma-homolinolenic acid. J Invest Dermatol 1986, 86:468.

141. Ziboh, V.A. & Chapkin, R.S. Biologic significance ofpolyunsaturated fatty acids in the skin. Arch Dermatol 1987,123: 1686-1690.

142. Sinclair, H.M. Essential fatty acids and the skin. Br MedBull1958, 14: 258-262.

143. Sheretz, E.F. The skin in essential fatty acid deficiency. In:Roe, D.A. (ed.) Nutrition and the Skin. Alan R. Liss, NewYork, 1986, pp. 117-130.

144. Hansen, A.E. & Wiese, M.F. Clinical and blood lipid studiesin a child with chylous ascites. Am J Dis Child 1944, 68:350-355.

145. Wene, J.D., Connor, W.E. &den Besten, L. Development ofessential fatty acid deficiency in healthy men fed fat-freediets intravenously and orally. J Clin Invest 1975, 56:127-133.

146. Paulsrud, J.R., Pensler, L., Whitten, C.F. et al. Essentialfatty acid deficiency in infants induced by fat-free feeding.Am J Clin Nutr 1972, 25: 897-904.

147. Fulco, A.J. & Mead, J.F. Metabolism ofessential fatty acids.VII. Origin of 5,8,11, eicosatrienoic acid in the fat-deficientrat. J Biol Chem 1959, 234: 1411-1416.

148. Prottey, C., Hartop, P.J. & Press, N. Correction of thecutaneous manifestations of essential fatty acid deficiency inman by the application of sunflower seed oil to the skin. JInvest Dermatol 1975, 64: 228.

149. Hansen, A.E. Serum lipid changes and therapeutic effects ofvarious oils in infantile eczema. Proc Soc Exp BiolMed 1933,31: 160-161.

150. Hansen, A.E. Serum lipids in eczema and other pathologicalconditions. Am J Dis Child 1937, 53: 933-946.

151. Lovell, C.R., Burton, J.L. & Horrobin, D.F. Treatment ofatopic eczema with evening primrose oil. Lancet 1981, i: 278.

152. Manku, M.S., Horrobin, D.F., Morse, N.L. et al. Reducedlevels of prostaglandin precursors in the blood of atopicpatients: defective delta-6-desaturase function as abiochemical basis for atopy. Prostaglandins LeukotrienesMed 1982, 9: 615-628.

153. Manku, M.S., Horrobin, D.F., Morse, N.L. et al. Essentialfatty acids in the plasma phospholipids of patients withatopic eczema. Br J Dermatol 1984, 110: 643-648.

154. Burton, J.L. Essential fatty acids and the skin. In: Champ-ion, R.H. & Pye, R.J. (eds) Recent Advances in Dermatology8. Churchill Livingstone, Edinburgh, London, 1990,pp. 129-145.

155. Hudson, B.J.F. Evening primrose (Oenothera spp) oil andseed. J Am Oil Chem Soc 1984, 61: 540-543.

156. Morse, P.F., Horrobin, D.F., Manku, M.S. et al. Meta-analysis of placebo-controlled studies of the efficacy ofEpogam in the treatment of atopic eczema. Relationshipbetween plasma essential fatty acid changes and clinicalresponse. Br J Dermatol 1989, 121: 75-90.

157. Sharpe, G.R. & Farr, P.M. Evening primrose oil andeczema. Lancet 1990, 335: 667-668.

158. Melnik, B.C. & Plewig, G. Is the origin of atopy linked todeficient conversion of o-5-fatty acids to prostaglandin El? JAm Acad Dermatol 1989, 21: 557-563.

159. Samuelsson, B., Goldyne, M., Granstrom, E. et al. Prostag-landins and thromboxanes. Ann Rev Biochem 1978, 47:997-1029.

160. Bourne, H.R., Lichtenstein, L.M. & Melmon, K.L. Phar-macologic control of allergic histamine release in vitro:evidence for an inhibitory role of 3', 5'-adenosinemonophosphate in human leukocytes. J Immunol 1972, 108:695-705.

161. Grewe, S.R., Chan, S.C. & Hanifin, J.M. Elevated leukocytecyclic AMP-phosphodiesterase in atopic disease: a possiblemechanism for cAMP-agonist hyporesponsiveness. JAllergy Clin Immunol 1982, 70: 452-457.

162. Camp, R. & Greaves, M.W. Inflammatory mediators in theskin. Br Med Bull 1987, 43: 401-444.

163. Kromann, N. & Green, A. Epidemiological studies in theUpernavik District, Greenland. Acta Med Scand 1980, 208:401-406.

164. Bittiner, S.B., Tucker, W.F.G., Cartwright, I. & Bleehen,S.S. A double-blind randomised placebo-controlled trial offish oil in psoriasis. Lancet 1988, i: 378-380.

165. Maurice, P.D.L., Allen, B.R., Barkley, A.S.J. et al. Theeffects of dietary supplementation with fish oil in patientswith psoriasis. Br J Dermatol 1987, 117: 599-606.

166. Morello, A.M., Downing, D.T. & Strauss, J.S.Octadecadienoic acids in the skin surface lipids of acnepatients and normal subjects. J Invest Dermatol 1976, 66:319-323.

167. Downing, D.T., Stewart, M.E., Wertz, P.W. & Strauss, J.S.Essential fatty acids and acne vulgaris. JAm Acad Dermatol1986, 14: 221-225.

168. Rustin, M.H.A. Unpublished data.169. Downing, D.T. The effect of sebum on epidermal lipid

composition. Acne and Related Disorders: an internationalsymposium, Cardiff 1988.

copyright. on M


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Postgrad M


ovember 1990. D

ownloaded from

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