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obstruction, was seen. Case 3 was known to haveharboured threadworms for two years and presumablythese were responsible for the changes seen in her

appendix. Case 4 had a definite catarrhal appendicitis.Whether the changes found in his appendix began asthe follicular appendicitis mentioned by Aird (1949),which he says may accompany a non-specific mesentericadenitis, is an interesting question. Certainly the glandsseen in the mesentery in case 4 resembled those in non-specific adenitis, but in that condition there is usually ahigher temperature and more severe pain.

REFERENCE

Aird, I. (1949) Companion in Surgical Studies. Edinburgh; p. 707.

Medical Societies

HEBERDEN SOCIETY

THIS society met in London on Dec. 7 and 8, underthe presidency of Sir HENRY COHEN.

ANAEMIA OF RHEUMATOID ARTHRITIS

Dr. M. R. JEFFREY (Bath) said that the anaemia, ofrheumatoid arthritis was essentially a normocyticanaemia with decrease in the number of red cells andin their haemoglobin content ; red-cell fragility, haemo-lysis, and hsemodilution probably played no part in it. Theansemia varied with the activity of the rheumatoid

process but not with the patient’s age or sex or withthe duration of the disease. Over three hundred testshad shown a low plasma-iron level which could not becorrected by short courses of cortisone but could becorrected-sometimes for months-by intravenous iron.He and his associates had used a kind of " iron tolerancetest " in which gr. 9 of ferrous iron and a large dose ofascorbic acid were given by mouth to the fasting patient,whose plasma-iron content was subsequently measured.Some patients, mostly women, quickly responded witha large rise of plasma-iron ; but others who had, he con-sidered, a specific abnormality of iron metabolism did not.It was unlikely that decreased iron availability in thegut explained this failure ; there was no change in theplasma level of the specialised globulin responsible foriron transport, nor was there evidence of significantlyincreased removal of iron from the plasma. He con-cluded that in this disease there must be impairedabsorption of iron from the gut. Even when the levelof plasma-iron was corrected, however, the anaemia didnot always improve.

Dr. J. J. R. DUTHIE (Edinburgh) remarked that thepossibility of refractory protein-iron binding might beinvestigated ; and Dr. J. H. H. GLYN stated that inhis experience intravenous iron therapy sometimes pro-duced a rapid rise of haemoglobin before there wasevidence of bone-marrow response.

PRIMARY OSTEO-ARTHRITIS

Dr. ROBERT MooRE (Manchester) made a plea forthe recognition of a certain kind of osteo-arthritis as adistinct disease. Although degenerative joint diseasewas regarded as a wearing-out process, since it particu-larly attacked joints which had suffered undue strainfrom weight-bearing, deformity, or previous disease,there were cases whose evolution was different and which

presented a different pattern ; and these he classifiedas primary degenerative osteo-arthritis. Of 391 cases ofosteo-arthritis in Manchester in the last three years hehad made a special study of 196. Of these, 120 were ofprimary osteo-arthritis, nearly 80% of them being inwomen at or near the menopause. The characteristicfeatures of the disease included a tendency for certainjoints, particularly the distal interphalangeal and first

carpometacarpal joints, to be affected, although no

joint was immune. Each joint went through two stages- acute and chronic. In the acute phase there was

spontaneous joint pain, often in waves and especiallytroublesome at night ; this was described as a burning,bursting, or tingling pain. The affected fingers wereswollen and reddened, and though this disorder wasoften diagnosed as rheumatoid arthritis the peripheralvascular abnormalities and characteristic spindling ofthis disease were absent. The erythrocyte-sedimentationrate was often increased, but not to the great extentfound in rheumatoid arthritis. Small cystic swellingssometimes developed over the terminal interphalangealjoints ; these might even be opened by the patient inan attempt to relieve her pain, with the subsequentdischarge of a glairy colourless fluid. In other parts ofthe body pain was of a deep, aching nature and wasmade worse by cold, movement, or venous occlusion.After several months the acute phase subsided, leavinga deformed but painless hand with bony outgrowthsincluding Heberden’s nodes. Permanent crippling wasvery rare. Other features which differentiated thisarthritis from the rheumatoid variety were the absenceof constitutional symptoms and of soft-tissue lesions(as in bursae or tendon sheaths), nodules, rashes, andeye involvement. It did not respond to cortisone, andthe differential agglutination titre (Rose’s test) and otherserological tests usually positive in rheumatoid arthritiswere consistently negative.The meeting agreed that this concept of a specific

degenerative joint disease was less sterile for researchin osteo-arthritis than the old idea of " wearing out."

BIOCHEMICAL ABNORMALITIES OF RHEUMATOID

ARTHRITIS

Prof. N. F. MACLAGAN listed certain biochemicalabnormalities of rheumatoid arthritis. The serum-

albumin was reduced, but the globulin, :-globulin, andfibrinogen were increased. These changes were reflectedby the various flocculation tests, including colloidal goldand thymol turbidity. Liver function tests and endo-

genous steroid metabolism showed no constant changesor were normal. If rheumatoid arthritis and ankylosingspondylitis were compared by the frequency of abnor-mality of serum albumin and globulin and of theflocculation tests, it was found that significant differencesexisted between the two diseases which were not accountedfor by differences in age and sex of the patients.

Dr. E. G. L. BYWATERS noted that not enough caseshad yet been investigated as regards serum-fibrino-

gen and erythrocyte-sedimentation rate. He wonderedif differences in the activity of the disease process mightaccount for these other differences.

CLINICAL ASSAY OF A.C.T.H.

Dr. BARBARA ANSELL (Taplow) emphasised thatdifferent batches of A.C.T.H. differed widely in theirantirheumatic effects. No form of biological assay hadyet been systematically tested against the clinical effectsin rheumatoid arthritis. Furthermore, results of differentanimal assays were not mutually congruous. Therewas great need for a yardstick of antirheumatic actionagainst which other tests might be evaluated. Unfor-tunately, the difficulties of clinical assay were many.They had tried various systems.In one, consecutive seven-day courses of intramuscular

A.C.T.H. were given to a patient with disseminated lupuserythematosus. The effect on the rash, fever, and pulmonarycomplications was noted. By this means it was clearly shownthat some batches of A.c.T.H. were far less effective than abatch of known potency. It was not possible, however, tosay how much less effective, since after seven weeks it was

apparent that the patient’s response to even the potentbatch had decreased. Subsequently they had tried alter-

nating periods of treatment, with intervals of no treatment,in patients with rheumatoid arthritis. A fixed dose of hor-mone was given and the various preparations comparedaccording to the response, which was measured by clinicaltests such as pain on pressure, strength of grip, speed of

1165

walking, and range of joint movement. With this methodevaluation was not so easy as in other cases where a fixed

response was aimed at and the doses required to achieve it

compared. One difficulty always occurred. The patientand his disease did not remain the same over the period oftest. More promise was shown by intravenous infusion ofA.c.T.H. Here the response to small doses was rapid, andthe test could be repeated often. Unfortunately difficultieswere encountered with venous thrombosis. Whichever wayA.C.T.H. preparations were tested, the eosinopenic responsethey produced and the increase of 17-ketosteroid excretionthey caused did not reflect their clinical activity.Thus there was as yet no alternative to clinical assay,

which, however, was crude, tedious, and subject to

many variables.

PUNCH BIOPSY OF THE SYNOVIAL MEMBRANE

Dr. BRUCE CRUICKSHANK (Edinburgh) spoke of theneed for caution in interpreting the histology of synovialmembrane which had been obtained by punch biopsy.Some American writers had assumed that they couldattribute to the therapy in use at the time any histologicalevidence of improvement found in the synovial mem-brane obtained in serial punch biopsies. This was notnecessarily so.He had examined 35 diseased joints, and in only 16 of

them were the microscopic appearances, constant from onesite to another. In 10 cases there was considerable variationin adjacent parts of the synovial membrane, and sometimeseven in different parts of the same section. It was possibleto see in one piece of tissue all the changes of active rheumatoidarthritis with diffuse cellular infiltration and collagen necrosis,while a nearby piece of tissue showed only healing processesor inactive scars.

Similar variation could be found in the synovialmembranes in rheumatic fever, disseminated lupus, andgout.

A.<j. i .ti. ana cortisone

CORTISONE ANT) HEALING OF THE EYE

Dr. NORMAN AsH.roN pointed out that the rabbit’seye was satisfactory for the study of wound healing.Ten rabbits with a perforating wound of the cornea were

treated daily with subconjunctival injections of cortisone.

They were killed, along with paired controls, at 24-hourintervals and the eyes sectioned. The first change notedwas inhibition of migration of cells into the wounded corneaand of the fibrinous coagulum which should seal the perfora-tion. Subsequently there was inhibition both of fibroblasticrepair of the cornea and of regeneration of the endotheliallining of the anterior chamber. On the other hand, thecorneal epithelium proliferated and regenerated at a normalor increased rate. In other experiments he had producedopacity and vascularisation of the rabbit’s cornea by injectingalloxan into the anterior chamber, and had studied the effectof cortisone on the transfer of fluorescein across the blood-

aqueous barrier in these inflamed eyes.

It was clear that cortisone had no effect on the

permeability of normal capillaries but could reduce theincreased permeability of inflamed capillaries.

VARIATION IN INDIVIDUAL RESPONSE

Dr. J. H. KELLREN (Manchester) had used fourindices in the study of variation in individual responseto A.C.T.H. and to cortisone : (1) the patient’s ownassessment, (2) the results of daily clinical evaluationincluding measurements of pain and function, (3) therise of urinary steroid output, and (4) the degree of

relapse on hormone withdrawal.Patients were given a three-day course of A.C.T.H. followed,

after a sufficient rest period, by a standard three-day courseof cortisone. The response was of three types : (a) equallygood response to both hormones, (b) response to neither, and(c) response to one or the other (not necessarily in the sameway). Apart from this, the condition of some did not

respond to either treatment yet relapsed when treatmentwas withdrawn. This could be explained if the test dose

was within the patient’s physiological range and simplyreplaced and suppressed endogenous adrenal cortical secretion.

Dr. G. D. KERSLEY (Bath) said that he, too, hadhad patients refractory to A.C.T.H. Two cases of rheu-matoid arthritis had not responded to maximum stimu-lation with intravenous A.C.T.H. despite an eosinopenicresponse. One patient also resisted 500 mg. a day ofcortisone. Professor MACLAGAx had noted a similarvariation in responsiveness in haemolytic anaemia.

LONG-TERM TREATMENT OF RHEUMATOID ARTHRITIS

Dr. W. S. C. COPEMAN summarised his experience oftreating with cortisone 20 cases of rheumatoid arthritis.Each patient had been treated for several months,initially in hospital and latterly as an outpatient. Allhad responded to cortisone ; and 17 had been got backto work or to a comfortable life, sometimes after yearsof crippledom. Careful selection of patients was essentialsince one relied on them a good deal for assessment ofprogress. They must be cooperative, of stable personality,and good witnesses. In using cortisone he had abandonedthe " loading dose " and now started with a moderatedose, which was varied according to the clinical indica-tions. One patient went into clinical remission, whichpersisted without treatment. So far side-effects hadnot been serious. Painless cellulitis had occurred insome cases and might " flare up

"

severely when treat-ment was withdrawn. One patient had died from

apparently unrelated cerebral haemorrhage. Another,who had diabetes, found that joint symptoms were notrelieved unless sufficient cortisone was given to produceglycosuria.,." <

-

ANKYLOSING SPOXDYLITIS

Dr. H. F. VVEST (Sheffield) said that it was generallyagreed that cortisone could arrest the progress of

ankylosing spondylitis ; if given early enough it couldproduce striking clinical remissions with freedom frompain and stiffness. The great difference between anky-losing spondylitis and rheumatoid arthritis was that theformer was an ankylosing disease. If joint ankylosiswas delayed at the stage where unstable callus had

bridged the gap then neither solid bony union nor freemovement could occur and the joint remained painful.

This had been strikingly evident in one patient who hadhad fulminating ankylosing spondylitis which had involvedone hip-joint before the other. She had been relieved of

pain in the recently involved joint only. The other jointwas already in a state of unstable ankylosis and had remainedvery painful. He thought it would be necessary to reduceor interrupt treatment to allow this hip to become firmlyunited.

Dr. DUDLEY HART showed a series of comparisonsbetween A.C.T.H. and deep X-ray therapy. A similar

degree of remission was produced, but that from deepX-ray therapy lasted longer.

STILL’S DISEASE

Dr. BYWATERS pointed out that Still’s disease differedin no way from adult rheumatoid arthritis except in theage of the patient. Certain clinical features were,

however, more common in children. As in adults the

enlarged lymph-nodes and spleen and the arthritis,fever, and malaise rapidly responded, and the child

began to put on weight again ; but the typical rashand pericarditis might persist despite treatment. Remis-sions produced by cortisone sometimes lasted severalweeks, and he compared these with a remission producedby intercurrent measles ; both were followed by relapse.One patient with severe amyloidosis and rheumatoidarthritis recovered from arthritis during treatment, buther amyloidosis (judged by the size of liver and spleenand by renal function and Congo-red tests) was notimproved. In other cases, where symmetrical jointdeformities had needed manipulation, cortisone had

1166

been used to cover the operation on one side but noton the other. There was no objective difference betweenthe two joints in the immediate reaction to manipulation ;and the use of cortisone in this manner seemed to bewithout value.

GOUT

Dr. KERSLEY had confirmed that in gout there wasa low 17-ketosteroid excretion. Cortisone or A.C.T.11.

could produce an immediate remission in acute goutbut 5-6 days after withdrawal of cortisone there was asevere relapse. Attempts to provoke this relapse inthe chronic phase as a diagnostic test had given unreliableresults. The mechanism of cortisone-induced remissionswas still obscure. There was no reduction in the plasmauric acid. Tophi softened and became smaller, whilethose that had ulcerated discharged less. He concludedthat cortisone was of value firstly in the acute attackof gout provided that large doses of colchicine were

given to prevent the withdrawal relapse, and secondlyin the rare malignant tophaceous gout where large uratedeposits endangered joint function or possibly life.

RECENT TRENDS IN THE U.S.A.

Dr. DUTHIE said that in the U.S.A. cortisone wasnow most commonly given by mouth. Clinicians hadabandoned the initial loading dose, starting instead witha daily dose of 50-75 mg. which was gradually increasedif necessary. On this low dosage about one-third of allpatients could be controlled without side-effects ; theincidence of side-effects increased with the dose. Evenmild side-effects, if they persisted, might cause the

patient voluntarily to suspend treatment. Serious side-effects had been increasingly reported. These includedthe masking of intercurrent infections and of surgicalemergencies such as appendicitis. Latent tuberculosishad been fatally reactivated ; and peptic ulcers hadfirst appeared, had bled, or had perforated duringtreatment. In addition, fractures of long bones, collapseof vertebral bodies, thrombophlebitis with embolic com-plications, major psychoses, and coronary infarctionhad been reported. Cortisone was beginning to be

recognised as a drug of addiction ; indeed there was a

special "cortisone-withdrawal" syndrome. Patients

complained of profound weakness, exhaustion, anorexia,and generalised aching pains made worse by movementand not easily controlled by analgesics. Thest symptomspersisted when tests showed that adrenal function hadreturned to normal. Combined with a rheumatic relapse,the withdrawal syndrome produced great distress. A veryrare but perhaps significant complication of cortisonewithdrawal had been the first appearance in six casesof rheumatoid arthritis of the signs and symptoms ofdisseminated lupus, or of periarteritis nodosa.

Despite all research the fundamental site of action ofcortisone remained unknown. Clinicians now used itnot as a substitute for, but as an auxiliary to, othermethods ’of treatment. Complete suppression of symp-toms was no longer aimed at. There was no evidencethat cortisone altered the natural course of the disease.

Radiological progression had been noted in cases keptsymptom-free. The increased danger of secondaryosteo-arthritis, due to greater activity, should be recog-nised. Other methods of administration were beingexplored-in particular intravenous cortisone, intravenousA.C.T.H., intra-articular cortisone, and long-acting prepa-rations of A.c.T.H. Some promise was shown by intra-articular injections of compound F which, unlikecortisone acetate, was well tolerated in the inflamed

joint. Opinion as to the value of these substances couldbe summarised as follows :

Some believe that the benefits are so much greater thanthose from all other forms of treatment that their use isfully justified on outpatients and with the minimum of

laboratory control. At the other extreme are those who

think the risks of long-term administration are so great inmost patients that it should never be advised. The majorityof clinicians think that long-term therapy may be justifiable,combined with orthodox methods, in patients whose conditionis steadily deteriorating. Short-term administration for a

specific purpose, such as covering manipulation or operationor to facilitate correction of deformities by other methods,is regarded as of real value. Intra-articular injection hashad only a limited trial but justifies further study. Thefirst enthusiasm has been replaced by a more cautious andconservative attitude. A tremendous amount of researchinto the mode of action is going on, but with little successso far.

Reviews of Books

Tumours of the EyeALGERNON B. REESE, M.D., D.sc., F.A.c.s., attendingophthalmologist and pathologist, Institute of Ophthalmo-logy, Presbyterian Hospital, New York ; clinical pro-fessor of ophthalmology, College of Physicians and

Surgeons, Columbia University. London : Cassell.1951. Pp. 574. f.7 7s.

THE text of this elaborate work concerns "all tumoursand tumour like lesions, which directly and indirectlyaffect the eye " ; so tumours of the orbit and ocularadnexse are included. As pathologist to the Institute ofOphthalmology, New York, Dr. Reese has been able todraw on the stored knowledge and experience of severalgenerations, and his comprehensive volume shoulddelight all ophthalmologists. Tumours are arrangedaccording to the tissue that predominates in them-angiomatous, melanotic, epithelial, fibromatous, bony,lymphomatous, &c.-and in each category there isnot only a full account of the histology, signs,symptoms, differential diagnosis, and treatment, butalso case-histories illustrated by the appearance of thetumour in life and its microscopic appearance afterremoval. Finally, Dr. Reese deals with the varioussurgical approaches to the orbit and the indications foreach.In English money the price is "high, but in production

the book is a model. With its bibliography extendingover the past sixty years, it will long remain the standardauthority on its subject. It stands as a complete justifi-cation for the case-recording and filing of pathologicalmaterial which has been practised at the New YorkOphthalmological Institute and which is now becomingpossible also in this country.The Kidney

Medical and Surgical Diseases. ARTHUR C. ALLE, M.D.,pathologist, James Ewing Hospital, and assistant attend-ing pathologist, Memorial Cancer Center, New York.New York : Grune & Stratton. 1951. Pp. 583.$15.

ADVANCES in our understanding of renal pathologydemand not only that the clinician should appreciatethe histology of the renal lesions in his patients, but thatthe pathologist should attempt to explain the micro-scopical picture in terms of the functional upset definedby his clinical colleague. Both will welcome this book,for Dr. Allen has worked hard to correlate and combinethe clinical and pathological findings in kidney disease.This book is thus one of the most complete accounts ofrenal pathology now available, profusely illustrated byexcellent photographs and photomicrographs of all thecommon, and many rare, diseases of the kidney. Theclinical conditions are clearly described, with plenty ofreferences to the illustrations and to original papers.The sections on embryology and malformations are

particularly good, and the book is likely to become astandard work of reference on the histology of thekidney in various vascular, infective, and toxic conditions.Dr. Allen, being a pathologist, has been unable to resistan involved classification of glomerular lesions : the useof such terms as " chronic membranous glomerulo-nephritis " and " chronic lobular glomerulonephritis

"

for the lesions in type 11, or the nephrotic stage of

nephritis, will not find ready acceptance in this countryand can only make the existing confusion worse. Thisis, however, a minor objection which does not detractfrom the great value of the book.