577

LUPUS ERYTHEMATOSUSBy STEPHEN GOLD, M.R.C.P.

Physician to Skin Department, Hammersmith Hospital; Lecturer in Dermatology to Postgraduate WIedical School, etc.

. . . ..I

T.he wword 'lupus,' originally applied to anyulcerative lesion of the skin remotely resembling awolf bite, has been in current usage since the i3thcentury. With recognition of cancerous processesthe term was more specifically applied to tubercu-lous infection of the skin (lupus vulgaris), while the'red ' lupus probably first described in x827 bylRayer was termed lupus erythematosus byCazenave in 85 i. No recent observations haveadded to the morphological features described bythese earlier writers.

CUTANEOUS LUPUS ERYTHEMATOSUSThe earliest sign of such a process is an ery-

thema which at first is superficial and remains wellcircumscribed. With progress, scaliness occursand the scales so formed are adherent and tend toplug the dilated pilo-sebaceous orifices. When thescales. are removed, projecting spines may be seenon their under surfaces, the so-called 'tin-tack'plugging. Where scales are not evident, this plug-ging of follicles may still be obvious; the con-cretions are of cheesy sebaceous material whosesurfaces have' not been blackened as in the usualcomedo, give a stippled effect. It is usual to seepatches' enlarge centrifugally, the edge being raisedand scaly while the centre becomes atrophic;telangiectatic vessels are frequently seen coursingin these' aiiophic areas.

Frequently erythematous plaques do not pro-gress, to the atrophic stage, in which case they maydisappear without leaving any sign. It is theseearly, superficial lesions which present diagnosticditIicult4es. it may, in fact, be impossible to makea ~diagnosis, until after a period of observation,when other of the classical signs, such as plugging,scaling, telangiectasia and atrophy, may have be-come. apparent.

These, disoqid lesions may be discrete or con-fluent and appear usually on the exposed parts ofthe. skin.:. -Th.ey are characteristically seen on thefae,:.pa..icularly over the nose and: cheeks, givingthe well-known bat's wing' or ' butterfly'

appearance, but occur also on the forehead, eye-brows, ears and scalp. Occasionally the vermilionborder of the lips may be involved, giving astreaked silvery appearance. It is important toinspect the mucous membranes, particularly ofthe palate and tongue, which may present rederosions later becoming shrivelled and white. Theexposed part of the neck is often affected inwomen, while the dorsal surfaces of the handsfrequently show similar changes.

It is usual for a patient to develop a number ofsuch lesions, for the most part confined to theface and ears. In extensive cases, however, theymay be distributed widely over the body.The disease may occur at any age, but the

maximum incidence is in the third and fourthdecades. It affects females about five times morecommonly than males.

Precipitating FactorsSunlight is by far the most important factor in

determining the areas affected. It is obvious thatthese sites are the same as those involved inpellagra and in actinic' eruptions. It is not un-usual for patients to date the onset of their diseaseto a prolonged exposure to the sun, particularly atthe seaside. It is also common to notice theaggravating effect of sun on existing lesions.

Other types of physical trauma, particularlycold, may also be responsible. It has been shownthat most of the patients have a poor peripheralcirculation and are subject to chilblains. Changesconfined to the chilblain areas (fingers, nose andears) is a well recognized type, described byHutchinson as ' chilblain lupus,' Occasionally theprocess may,start at the site of a skin injury or as asequel to a subcutaneous injection.Aetiology

Earlier observations, particularly of Continentalworkers, led to the assumption that the conditionwas tuberculous in origin. Confusion between itand lupus vulgaris further supported this view. Itswas suggested that chronic lupus erythematosus

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represented a localized skin reaction to a tubercu-lous focus elsewhere in the body, a hypothesisbased on post-mortem evidence where associationof a tuberculous lesion in the lungs, glands orelsewhere was taken as proof of their intimateconnection. British workers suggested the culpa-bility of streptococcal infections. By removal ofseptic foci, Barber obtained resolution in somecases.Modern views on the aetiology remain mixed.

Most workers agree that some cases are un-doubtedly tuberculous in origin, the developmentof lupus erythematosus with other tuberculidesfollowing close upon a primary lung or gland in-fection having been seen too frequently to beinsignificant. There is much evidence, however, tosupport other cases as being due to a strepto-coccal focus. It is possible also that other focalabnormalities, conceivably not infectious in type,are at the basis of this process. It appears thatcertain conditioning factors are essential. A poorperipheral circulation has already been men-tioned, whilst another is endocrine imbalance.It is not unusual, for instance, to see lupus ery-thematosus or other collagenoses develop aftercastration.To suggest that two or more distinct organisms

can be responsible for the same morphologicalentity is not without precedent. Erythema in-duratum is accepted to be of a tuberculous naturein young girls, while in older age groups (Whitfieldtype, nodular vasculitis) it is of streptococcalorigin. Similarly, erythema nodosum is acceptedas being associated with primary tuberculous in-fection or with streptococcal tonsillitis. It seemsnot unreasonable to suggest that in lupus ery-thematosus these two organisms may also beculpable, the conditioning factors determining themorphological response (erythema induratum,erythema nodosum, lupus erythematosus) beingthe variants.

PrognosisIt has been stated that in one third of the

patients resolution is complete, one third are im-proved by treatment and one third progress un-changed. This is a fairly accurate assessment.Less than i per cent. progress to the ' systemic'form.

TreatmentEarly lesions should be soothed with simple

preparations containing calamine. It is importantto give strict advice on avoidance of sunlight; theuse of a wide brimmed hat and protective clothing,with the applications of various sun screen pre-parations, is helpful.The natural process of atrophy can be hastened

by the applications of caustic such as pure phenol.Local application of carbon dioxide snow is alsohelpful; it may be used as a solid stick or, withacetone, painted on as slush.On the assumption that some cases are strepto-

coccal in origin sulphonamides and other anti-biotics have been used. Early results with the.former suggested that they might be useful intreatment. It has now become apparent, however,that the danger of producing systematization is toogreat and should preclude their use completely.The results obtained with penicillin, streptomycinand more recent preparations have not been con-vincing.

Administration of bismuth either by injection orby mouth has been a safe and relatively helpfulprocedure. In this country bismuth is given incourses of eight or ten weekly intramuscular in-jections. Gold is used, probably with greatersuccess but certainly with more hazard. It may beadministered intramuscularly or intravenously;dosage is as for rheumatoid arthritis. It is usualfor courses to consist of eight injections and to befollowed by a period of rest from four to six weeks.Albuminuria, granulopenia, toxic rashes (exfolia-tive dermatitis) and systematization are possiblecomplications which must always be kept in mind.

SYSTEMIC LUPUS ERYTHEMATOSUSIt has been recognized since the earliest ob-

servations of Kaposi that occasionally discoidlupus erythematosus may assume an entirely newappearance, associated with severe bodily illness.It appears that few patients with the chronicdisease behave in this manner. Generally there isa provoking factor to account for it. Exposure tosunlight, drugs (particularly the heavy metals) andinfectious conditions are factors known to play a

part in causing dissemination.This alteration is characterized by a spreading

of the rash, severe prostration, high fever, pains inthe joints and other features to be discussed later.However, it should be clearly understood that ofall these ' systemic' types, only a minority havesuffered from preceding chronic lupus ery-thematosus, the majority occurring de novo. Itis the opinion of some that they do not evenrepresent the same process.

This condition is primarily one of women, oc-curring between puberty and the menopause. Itsoccurrence in men is extremely rare. The onsetmay be vague or it may be abrupt. In the former,general lassitude and rheumaticky pains are theusual premonitory symptoms, followed by feverwith blotchy erythematous rashes. In the latter,high fever with marked toxaemia, albuminuria,anaemia, leucopenia and pleural or pericardialeffusions lead on inexorably to death.

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November 1951 GOLD: Lupus Erythematosus 579

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FIG. i.-Chronic lupus erythematosus.

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FIG. 2.-Gross scarring in chronic lupus erythematosus.

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FIG. 3.-Chronic lupus erythematosus of superficial type.

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FIG. 4.-I,ichenoid lesions in chronic stage.

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580 POSTGRADUATE MEDICAL JOURNAL November 1951

FIG. 5

FIG. 6

FIGS. 5 AND 6.-Systemiclupus erythematosus (sub-acute) associated withthrombocytopenia.

SymptomatologyCutaneous ManifestationsThose patients who have suffered previously

from the chronic disease will show evidence ofdiscoid lesions which have increased in size andbecome redder. More commonly the rash is non-descript, though there are several well recognizedtypes. Again it is seen that the areas exposed tolight are those maximally affected; blotchy ery-thema of the face with slight scaling is usual.This type of eruption is commonly macular, thecentral area of the face being involved. Thecolour may vary from pink to red or a cyanotictint. When the rash is oedematous, individuallesions may be papular, vesicular or even bullous.A well recognized feature is erythema localized

around the nail folds, a sign also present indermatomyositis and scleroderma. Subacute typesoften reveal telangiectasia around the nails. Redmacules are seen on the palms and occasionallysmall, painful nodules, not unlike Osler's nodes.

' Erysipelas perstans faciei,' a papular rash oflivid hue affecting the face, was described byKaposi. Purpuric and petechial lesions are oftenseen and, in the absence of thrombocytopenia,indicate localized vascular damage; pigmentationis a common sequel where there has been muchextravasation of blood. Erythematous or petechialareas often occur in the mucous membranes of themouth; they soon develop into shallow ulcers.

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GOLD : Lupus Erythematosus

The rashes are therefore polymorphic. Theremay be urticaria, erythema, purpura, or bullousfeatures. A generalized alopecia is usual duringthe acute phase, unlike the cicatricial type seen inthe chronic form.

Joint SymptomsMost patients suffering from the systemic

disease have, at one time or another, painful andswollen joints. This arthritis subsides rapidly andthe association with periarthritis, synovitis andfibrositis may make differentiation from rheumaticfever difficult. If acute symptoms persist, theresidual arthritis may resemble the subacute infec-tive type. It is unusual to see radiographicchanges or permanent joint deformity. Thesesymptoms are often relieved by rest and salicy-lates, though the latter do not affect the fever.

Renal FindingsIt has long been recognized that renal disease is

a common association. Abnormal urinary findingsoccur in 75 per cent. of the patients, commonlywithout hypertension.

Albuminuria, casts and red and white cells arecommonly found in the urine. Renal failure isunusual. Even in the absence of albuminuria,renal function tests frequently show impairment.Cardiovascular Symptoms

Clinical enlargement of the heart is rare andcardiac murmurs cannot be taken as evidence ofverrucous endocarditis. Tacchycardia, arrhy-thmias and murmurs occur as in any severe illness.Pericarditis and pericardial effusions may. be de-tected. Cardiac failure, except as a terminal event,is not a feature. Electrocardiographic findings areagain not characteristic; it is usual to see lowvoltage curves and occasionally abnormal T waveformation; delay in conduction has been reported.

Gastrointestinal SymptomsDiarrhoea and vomiting may occur and the

simulation of an acute abdominal emergency is notunknown.

Central Nervous SystemEpileptiform seizures and toxic psychoses have

been reported and, in fact, any focal reaction mayoccur.

Reticulo-Endothelial SystemEnlargement of the liver is uncommon but when

it does occur is a result of cloudy swelling, pyle-phlebitis or abscess formation.

In the literature there have been numerous re-ports of splenomegaly and some authors havefound it regularly in their cases. In my own ex-

perience, enlargement of the spleen is uncommonexcept in children. Lesser degrees of splenomegalymay easily be missed through lack of regularexamination.Widespread enlargement of the lymphatic glands

is a common feature. It is probable that enlarge-ment of some glands is present in over 6o per cent.of cases; it has also been suggested that such afinding indicates chronicity. The glands, whenenlarged are discrete, soft and often tender; theydo not break down.

Serous MembranesInflammatory changes are most commonly

found in the pleura. Small effusions are not in-frequent; they may clear up spontaneously onlyto reappear later. At times the degree of effusionmay completely dominate the clinical picture; inothers obliterative changes occur which may beassociated with a similar process in the peri-cardium. Although pleural involvement is in-finitely more common than primary changes in thelung, small patches of pneumonia are not in-frequently to be found underlying a pleural re-action. Effusions in the pericardium, though lesscommon, may be as marked as those in the pleura;fibrosis occurring in small patches indicates pre-vious inflammation. Peritoneal effusions are rare.

Eye ChangesConjunctivitis of an allergic type occasionally

occurs. The injection is often violaceous. Retinallesions are well recognized but no single fundalpicture can be considered diagnostic. The featuresmost commonly noted include small white fluffyareas lying superficially in the retina (cytoidbodies), small superficial haemorrhages andpapilloedema. These fundal changes, probably amanifestation of widespread vascular injury,sharply distinguish the condition from rheumaticfever or rheumatoid arthritis.

DiagnosisDiagnosis of a typical case presents no difficulty.

The occurrence of a characteristic rash on theface and hands of a woman who is febrile andcomplains of pain and stiffness in various joints isan unforgettable picture. Should there be an as-sociated renal involvement or effusion from serousmembranes the syndrome is virtually complete.The majority of cases, however, particularly

those of insidious onset, never present such asimple problem. Similarity to other collagenosesis apparent and, in fact, mixed types are not in-frequent; there may well be a common de-nominator in these disorders. So long as thepossibility is present in the clinician's mind it isunlikely that the diagnosis will be missed. The

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following syndromes have been enumerated byGross (1940), as being symptom complexes inwhich such a diagnosis should be carefully con-sidered:-

1. ' Rheumatic fever' with pericarditis andpetechiae.

2. 'Rheumatic fever' with nephritis, raisedblood urea and normal blood pressure.

3. ' Rheumatic fever' with purpura.4. 'Rheumatic fever' with leucopenia in spite

of fever.5. ' Subacute bacterial endocarditis ' with nega-

tive blood culture and no embolic phenomena.

Pathological Findingsi. Haematological

(a) Hypochromic or normochromic anaemia isusual.

(b) Leucopenia is an important diagnostic sign.When there is a raised white count and no as-sociated infectious process to account for it, astrong doubt is cast on such a diagnosis. It isusual to see a relative lymphocytosis.

(c) The sedimenation rate is always increased,often to a marked degree.

(d) Diminlition of platelets is observed occasion-ally, particularly in those with an associatedpurpura.

(e) A positive direct Coomb's test occasionallyoccurs and an interesting and probably connectedfeature is the ability of these patients to formmultiple antibodies to transfused blood.

(f) Sternal marrow obtained from patients in anacute phase, particularly if heparinized, reveals apeculiar cell now known as the ' lupus erythema-tosus cell' (Hargraves et al., I946). This cellrepresents one of the granular series which hasingested round, amorphous, basophilic masses.The cell nucleus has frequently been pushed asideso as to envelop these ingested masses to give ahorseshoe appearance. In association with thesespecific cells the amorphous bodies are seen lyingfree; there is also a tendency of white cells toclump together.These lupus erythematosus cells have now been

demonstrated in peripheral blood. It appears thatheparin or other anticoagulants are unnecessaryfor their production. The ingested material isprobably nuclear in origin and is possibly derivedfrom degenerating lymphocytes. They are'seenin other conditions particularly where there iswholesale nuclear destruction as in leukaemia, butnever in such quantity as in acute lupus ery--thematosus. They have, therefore, been regardedas an important aid to diagnosis.

It has been possible, by using healthy whitecells and patients' serum to reproduce this effect,but when the serum is heated to 65° C. the effect

is lost. It seems probable that nuclear debrislying free in patients' serum soon becomes phago-cytosed by scavenging white cells, a process re-quiring some activity of the abnormal globulin (seebelow), as it will not occur after heating or specificabsorption of the globulin.

(g) Blood cultures are invariably sterile untilnear death, when a terminal septicemia is oftennoted.

2. Biochemical(a) The most striking feature of this condition

is the marked alteration of serum protein. dis-tribution; the albumin fraction is often,decreasedespecially if there is concomitant albuminuriawhilst the globulin fraction is increased so as toproduce reversal of the albumin-globulin ratio.This increase in globulin is largely due to a specificincrease of the y fraction which may diminishduring a remission and rise again in an exacerba-tion.

It is probable that this y globulin representsantibody, possibly produced in response to abacterial antigen or possibly to an auto-antigen.

(b) Cold agglutinins are frequently present andthey may be of such high titre as to cause im-mediate agglutination following venepuncture.

(c) A factor present in patients' serum willcause agglutination of sheeps' red cells which havebeen prEviously sensitized by the addition of' anti-sheeps' red cells serum.'

(d) Borrie (I95i) has demonstrated an unduetolerance to injected heparin and suggests thatthis was due to a neutralization of the heparin bythe y globulin.

Serological tests for the detection of syphilisfrequenfly give positive results, again probably dueto the presence of this abnormal globulin. If re-peated tests are made it is apparent that there is avariation in titre from time to time, a finding notapparent in untreated syphilis.

It is probable that all the findings in this groupare basically due to the presence of abnormalglobulin. Whether we are dealing with a conditionof hypersensitivity or altered immunity or acombination of the two is speculative.

(e) The serum calcium is usually slightly re-duced in acute cases.

(f) The excretion of ascorbic acid after largedoses by mouth is subnormal.

3. HistopathologicalAt post-mortem, macroscopic changes are re-

markable by their absence. In a small percentageof patients more especially thqse under 20, verru-cous endocarditis (Libman.Sacks) may be evident.These coarse vegetations are larger, more fragileand often have a broader base than those seen in

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rheumatic fever. Bacteriologically they are sterile.They may affect any or all of the four cardiacvalves and a characteristic feature is their tendencyto spread up on to the mural endocardium.Furthermore, patches of mural endocarditis, quitedistinct from the valvular lesions, are often seenin the right auricle or in either ventricle. Macro-scopic vegetations are present in 40 per cent. ofpatients and it is probable that microscopicevidence is present in a further 20 per cent.

Apart from associated lymphadenopathy, spleno-megaly and other non-specific findings, the onlyother striking gross abnormality is a peculiaralteration of the mediastinal and peritoneal fat.This is often of a peculiar, gelatinous consistencyand is particularly striking when present aroundthe pericardium. The kidneys, which are gener-ally of normal size, frequently show scatteredpetechial haemorrhages on their surfaces.When considering the microscopic changes of

all processes in which collagen is predominantlyaffected, it becomes apparent that, throughout, twodistinctive processes are in operation simul-taneously, the degenerative and the proliferative.Thus, in rheumatic fever and polyarthritis nodosa,cellular proliferation dominates the picture and' fibrinoid ' areas are soon converted into scartissue. In systemic lupus erythematosus ' fibrin-oid ' changes dominate the picture and cellularproliferation is minimal. The lesions are widelydistributed though there are definite sites of pre-dilection (skin, joints, serous membranes, etc.).As well as this ' fibrinoid ' change in collagen thereis a corresponding alteration in the intercellularcement substance. This is normally invisible inhealthy tissues but here it becomes apparent andstains metachromatically.As blood vessels contain all elements of connec-

tive tissues in their walls it is obvious that vascularlesions can occur at any site. This, in fact, explainsthe widespread and often focal reactions seen insuch sites as the gastro-intestinal tract. Vascularalteration may be the sole evidence of collagendamage. Changes vary from complete necrosis ofan arteriole involving all its coats to the slightestdeposition of ' fibrinoid ' material within the in-tima. There is always a simultaneous proliferationof fibroblasts, which in smaller vessels can lead toextreme narrowing. As the process progressesconcentric ' fibrinoid ' rings are laid down in theintima, raising the endothelium and causing

blocking of the lumen. Changes that are seen inindividual sites are all variations of this pattern.The typical ' onion skin ' appearance of the splenicvessels and the ' wire-looping ' of the glomerularcapillaries, the latter representing a ' fibrinoid 'change of basement membranes, are all examplesof this process.

TreatmentFrom the earliest observations it was apparent

that treatment was of little avail. At best relianceon good nursing and a relief of individual symp-toms was all that could be achieved. Variousdrugs have been tried and those perhaps whichhave found most favour are iodine and quinine bymouth and bismuth by injection. Reports of in-dividual cases benefiting from the use of sul-phonamides, penicillin, streptomycin and otherantibiotics are numerous, though the results arefar from consistent, and occasionally it appears thattheir use has aggravated the condition (Gold,195I).Blood transfusions and a high protein diet

are helpful supporting measures. Salicylates areuseful in controlling joint symptoms; anti-histamines have not proved of value and it shouldbe noted that these patients often display markedhypersensitivity to any drug taken internally. Theadministration of hormones or even castrationhave only proved temporarily helpful.With the advent of ACTH and cortisone it

appeared at first that the treatment of this uniform-ally fatal condition would be revolutionized. Itnow seems that their effect, though profound atfirst, is not permanent. When these drugs arewithdrawn the condition relapses often in a moreviolent form than before. At best it seems thatthey should be used only during an acute phase inthe hope of a natural remission. After theirinitial administration there is a striking responsein fever and joint symptoms, and later the rashmay disappear. A remarkable sense of well-beingdescends upon the victim, appetite improves andmild euphoria is frequent. The usual biochemicaland haematological responses are observed. Fre-quently the patients' hopes are buoyed up and theirrelations witness a dramatic recovery only to realizelater that the benefit is not maintained.

General opinion on the use of these substancesin the treatment of systemic lupus erythematosusis unfavourable.

BIBLIOGRAPHY

BORRIE, P. F. (i9Si), Brit. Y. Derm., 63, 21.GOLD, S. (I9SI), Lancet, 1, 268.GROSS, L. (1940), Am. Y. Path., I6, 37S.HARGRAVES, M. M., RICHMOND, H., and MORTON, R.

(It946), Proc. Mayo Cli?mC, 23, 25.

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