THE NODULES AND LYMPH-GLAND ENLARGEMENTIN RHEUMATOID ARTHRITIS

ALSO A SYNDROME OF RHEUMATOID ARTHRITIS COMBINED WITHMULTIPLE XANTHOMATOUS CONNECTIVE TISSUE INFILTRATIONS

BY

F. PARKES WEBER

In this paper I shall consider the nodules ofrheumatoid arthritis and some of the clinical featuresof cases in which they occur, including the occasionalmoderate painless enlargement of superficial lymphglands.

Collins (1937) and others have shown that thecharacteristic subcutaneous nodules consist of fociof fibrinoid degeneration and necrosis, surroundedby a border of tissue reaction, notably by a palisade-like radiate arrangement of fibroblasts. Obviouslysuch a microscopic appearance cannot be absolutelypathognomonic-showing as it does a primitive typeof reaction towards a central degenerative ornecrotic core of unknown causation, the whole pro-cess perhaps commencing as an acute focal exudativelesion. Indeed, similar appearances have beendescribed in granuloma annulare, * and Dr. W.Freudenthal has shown me microscopic sections inillustration, though granuloma annulare is clearly acondition of totally different nature. No exactaetiological explanation of the nodules will bepossible before the main causative agent of therheumatoid disease has been discovered.The identity of rheumatic fever with rheumatoid

arthritis cannot be proved by any histologicalresemblance between such primitive types of reactivelesions as Aschoff bodies and the relatively transitory"rheumatic nodules " in children suffering fromrheumatic fever and chorea on the one hand, andon the other the nodules of rheumatoid arthritis. Itis now universally acknowledged that various patho-genic agents (living or not-living) may produce thesame reactive or degenerative macroscopic or micro-scopic picture; also that a resulting lesion maylargely depend on, and morphologically vary accord-ing to, the reactive qualities of the " soil " on whichan identical agent works. It must be admitted onthe clinical side that there are subacute or chroniccases of rheumatic fever in adults, especially thoseaffecting mainly the small joints of the hands, which-for a time at least-very much recall the clinicalfeatures of rheumatoid arthritis and in which thedifferential diagnosis may be at first difficult. For

the matter of that it is not always so very easyclincally to differentiate osteo-arthritis (" degenera-tive arthritis ") from rheumatoid arthritis. Cer-tainly pathological changes of both categories mayoccur in the same patient, as would seem a prioriprobable. Indeed, one would think that a patientwith chronic rheumatoid arthritis is more likelythan others to develop some of the degenerativechanges of osteo-arthritis, and vice versa. I do notknow, however, of any case in which a patient withosteo-arthritis, unmixed with rheumatoid arthritis,has developed subcutaneous nodules (of therheumatoid arthritis type) or moderate painless en-largement of superficial lymphatic glands (of therheumatoid arthritis type-see further on). It issaid, indeed, that the very rare large type of " bone-cyst" above the acetabulum has been found inosteo-arthritis as well as in rheumatoid arthritis.Thus, Burt (1942) illustrates an example in rheu-matoid arthritis, whilst Alexis Thomson (1929)figured similar " cysts " as from a case of osteo-arthritis. Of great importance is the fact thatpatients with symptoms (for a time at least) more orless clinically like those of rheumatoid arthritis maypresent nodules and juxta-articular infiltrationswhich on microscopic examination are found not toconform to the rheumatoid arthritis type. But tothis subject I will return further on.

Some Case HistoriesI have mainly selected rather " exaggerated"

examples, in which in addition to ordinary changesof chronic rheumatoid arthritis there were sub-cutaneous nodules-in one case a smaller nodule,more cutaneous than subcutaneous, could beexamined by biopsy-enlarged synovial bursae withthickened walls, ganglia of the hands or wrists,juxta-articular thickenings of tendon insertions ortendon-sheaths, and moderate painless enlargementof superficial lymphatic glands.

CASE 1

Mrs. A. B. Aged 56 years. Has had rheumatoidarthritis for 25 years. The chief changes are in the handsand wrists. Large wrist ganglia. Lesser changes in thefeet, elbows, and knees. Subcutaneous nodules about

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* I understand that microscopically the so-called " lipoidnecrobiosis" (not confined to diabetics) is a somewhat analogousnecrotic lesion, but containing lipoids.

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ANNALS OF THE RHEUMATIC DISEASESaffected joints. Large lobulated ones at the elbows areconnected with the olecranon bursae. Small ones overknuckles of fingers and toes and over both patellae.These latter, which developed rapidly and almost pain-lessly within the last weeks, feel like tense cysts and arenot definitely attached either to the cutis or to theperiosteum. There is a large, fluctuating, ganglion-likeswelling at the back of the right wrist from which thereare hernia-like protrusions. Blood count: Hb. 58 percent.; erythrocytes 3,900,000 per c.mm.; C.I. =073;leucocytes 10,400 per c.mm. (polymorphonuclears 58 percent.; lymphocytes 31 per cent.; monocytes 5 per cent.;eosinophils 5 per cent.; basophils 1 per cent.). Blood-Wassermann reaction: negative. Urine: nothing special.Brachial blood pressure: 150,90 mm. Hg. Bloodcholesterol: 220 mg. per 100 c.cm. Blood urea: 30 5mg. per 100 c.cm. Blood uric acid: 41 mg. per 100c.cm. Basal metabolic rate: -10. There is moderatepainless enlargement of lymphatic glands in both axillae.No enlargement of liver or spleen. Some pyorrhoeaalveolaris. Nothing else of importance by ordinaryexamination. Recent dietetic treatment for gastric ulcerhas been successful.

early necrosis is taking place: here and there are manydegenerated neutrophil leucocytes as well as a smallernumber of coarsely granular eosinophils. Lymphocyteand plasma-cell infiltration is present in the lymphaticsof the dermis. No giant-cells seen." The photomicro-graphs (Fig. 1, A and B) show a necrotic centre withradiate reactive border of the " rheumatoid arthritistype."

CASE 2C. D. Aged 484 years. An office clerk (Weber, 1943;

Case 2). Rheumatoid arthritis of three years' duration.Large cutaneous-subcutaneous nodules about the joints,with juxta-articular infiltrations in the tendon sheaths andfibrous structures about the feet, ankles, hands, wrists,elbows, and knees. Most striking are the red shinynodules over the metacarpo-phalangeal articulations andabout the elbows-up to the size of large cherries (Fig. 2).The knees, ankles, and feet are similarly affected, but thenodules are less red. Very characteristic are the nodulesalong the ridge of the ulna of both forearms, from elbowto wrist. Moderate painless enlargement of the inguinal,axillary, and supracondylar lymphatic glands. Noobvious splenomegaly. None of the nodules are reallypainful or tender. The tendon sheaths at various partsare infiltrated, notably in the palms and at the heels

FIG. 1. Case 1 : Photomicrograph from a section of the left olecranon bursa, which has been transformed intoa lobulated massive nodule of the " rheumatoid arthritis type." It shows a necrotic centre with radiate reactiveborder. A. Under low power. B. Under high power.

Biops-.My colleague, Mr. H. Rast, kindly excisedthe whole of the subcutaneous, enlarged, lobulated leftolecranon bursal mass, in which there was only a minutesynovial cavity left. The bursa was transformed into amass of small hard nodules, one of which was so super-ficial as actually to be in the cutis. The mass waselongated, measuring 6-5 cm. (in length), 3 5 cm. (inwidth), and 2 cm. (in depth), and on incision presentedan anaemic, whitish, somewhat gelatinous appearance.Following is Dr. J. G. Greenfield's histological report(see Fig. 1 A and B): " The central core of the tissueconsists of a structureless unnucleated-i.e., necrotic-tissue which in Van Gieson sections shows a varyingamount of collagen. In some places it forms a loosenetwork, in others thicker strands. The outlines of oldobliterated blood vessels can also be recognized. Roundthis core there is a dense wall of viable collagen (i.e.nucleated connective tissue with thick collagen fibres),with a palisaded zone of radially arranged fibroblastsbetween the viable and necrotic tissue. In one place

(Achilles tendons). The distribution of the nodules andinfiltrations is markedly symmetrical. There is somestiffness at the back of the neck, and owing to the con-dition of the knees the patient cannot bend forwardproperly. The hands are stiff and show some sub-luxation of joints. The fingers are said to turn darkblue nearly every morning in cold weather. Ordinaryexamination of the thorax, abdomen, and urine showsnothing special. Erythrocyte sedimentation rate greatlyaccelerated. Blood-Wassermann and Kahn reactionsnegative. The blood cholesterol is rather on the lowside. The teeth were all removed at least twelve yearsago. About that time the patient was found to have aduodenal ulcer (confirmed by x-ray examination).

Biops'.-microscopic examination of one of thenodules (Fig. 3) shows connective-tissue reaction, withfoci of fibrinoid degeneration and necrosis, surroundedby palisade-like, radiate borders of fibroblasts, asdescribed by Collins (1937) in regard to the subcutaneousnodules of rheumatoid arthritis.

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FIG. 2. Case 2: Photograph of nodules on upper limbs, July, 1941.

CASE 3E. F. Aged 59 years. English. A stonemason,

working at present as a post-office packer. Rheumatoidarthritis of at least five years duration. On the whole,however, an active man, of " wiry" type. Hard sub-cutaneous nodules about the size of an olive over ulnarridge near either elbow, of about six months' duration,not painful, but slightly tender to pressure. Moderate,painless, symmetrical enlargement (the patient was un-aware of this) of lymphatic glands in axillae and groins.No enlargement of spleen or liver. Tense, cyst-like,

pea-sized, painless nodule over the proximal inter-phalangeal joint of the right fourth finger, which appearedabout twelve months ago, suddenly (as patients say suchsmall nodules of rheumatoid arthritis do). This was acutaneous rather than a subcutaneous nodule. He alsohas moderate flabby enlargement of the right olecranonbursa, which hurts slightly if he leans on it. Some stiff-ness and ulnar deviation of the fingers of the right hand.Slight stiffness in cervical spine. He had other symptomsformerly that disappeared under treatment. No historyof gonorrhoea or syphilis. Nothing special by ordinaryexamination of thorax, abdomen, nervous system, andurine. Slight anaemia. Blood sedimentation: slightlyaccelerated. Blood-Wassermann reaction: negative.Blood cholesterol: 345 mg. per 100 c.cm. Bloodcalcium: 9 mg. per 100 c.cm. Blood urea: 43 mg. per100 c.cm. Blood uric acid: 3-2 mg. per 100 c.cm.Biopsy.-My colleague, Mr. H. Rast, excised the above-

mentioned nodule from the knuckle of the right ring-finger, and it was carefully examined by Dr. W. Freu-denthal. It showed multiple foci of so-called " fibrinoiddegeneration" and necrosis (as described by Collins,1937), some of them surrounded by a palisaded borderof fibroblastic reaction; elastic fibres practically absentfrom the degenerative areas; no giant-cells seen.

RemarksEven if the histological features of the nodules of

rheumatoid arthritis were absolutely pathognomonicone would still be far from the discovery of theessential pathogenic agent of the disease. But, as Ihave already pointed out, the type of lesion inquestion cannot be regarded as really patho-gnomonic. Allison and Ghormley (1931) (comparealso Ghormley, 1938) made a great point of whatthey call " focal collections " of lymphocytes in thesynovial membrane of joints being almost patho-gnomonic of " proliferative arthritis of uncertainorigin "-that is to say, of rheumatoid arthritis.They write (p. 139): " Diagnosis made positive ondiscovery in the tissues of focal collections oflymphocytes." But if one looks at their illustra-

FIG. 3. Case 2 : Photomicrograph of a section from asubcutaneous nodule showing typical necrotic focuswith radiate fibroblastic border.

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ANNALS OF THE RHEUMATIC DISEASEStions (for instance, p. 147, Fig. 4; p. 169, Fig. 3;and Plate VIII) one recognizes the presence in these" focal collections " of so-called " germ-centres "of Flemming. Now, surely such lymphadenoid fociwith typical " germ centres " can hardly be con-sidered as pathognomonic of any special disease.Apart from their conspicuous presence in normallymphadenoid tissue (lymph glands, tonsils, thewalls of the vermiform appendix and intestines, theMalpighian corpuscles of the spleen), they form aspecial feature in so-called lymphadenoid goitres,and are also not rare in thyroids from patients withGraves's disease. I have seen them in abnormalsalivary glands. They constitute a conspicuousfeature of cutaneous lymphocytomata (Epstein,1935), and may be found in various other patho-logical conditions.

The Painless LymphadenopathyNeither is there anything absolutely patho-

gnomonic in the painless lymphadenopathy of thesuperficial lymph glands, which is present in manycases of rheumatoid arthritis, though seldom noticedby the patients themselves and often not looked forby the examining doctor. I myself have had abiopsy in only one of my cases, but I believe that thefinding is typical for other cases also-namely, anon-specific " follicular lymphadenopathy " of toxicor infective origin, with marked enlargement of the" germ-centres " of Flemming. This must of coursenot be confused with the early stages of " follicularreticulosis " or " follicular lymphoblastoma " ofnon-inflammatory (neoplastic) origin.

CASE 4Mrs. G. H. Aged 65 years. Of thin, wiry build, was

under treatment in 1941 and 1942 for rheumatoidarthritis. She had suffered from lobar pneumonia ofthe right upper lobe in the spring of 1939. In Sept.,1940, she began to suffer from rheumatoid arthritis,afterwards located notably in the hands, with some fusi-form swelling of the finger-joints. There was also con-siderable stiffness of the cervical spine. Some moderatediscrete painless enlargement of superficial lymphglands in neck, axillae, and groins, of which patientherself was unaware. No enlargement of spleen or liver.Brachial blood-pressure: 190/90 mm. Hg. Some hyper-trophy of the left ventricle of the heart, apparently fromhigh blood-pressure. Trace of albumin in the urine.Blood count (July 1, 1941): Hb. 65 per cent.; erythrocytes3,580,000 per c.mm.; C.I.=0-91; leucocytes 6,150 perc.mm. (polymorphonuclears 71 per cent.; lymphocytes21 per cent.; monocytes 6 per cent.; eosinophils 1 percent.; basophils 1 per cent.).Biopsy.-On Sept. 12, 1941, Mr. Rast excised one of

the enlarged lymph glands from the right axilla. Dr.J. G. Greenfield's microscopical report (Fig. 4) is: " Thesections show general proliferative activity, with manymitoses, in the lymphoid centres; and occasional col-lections of polymorphonuclear cells in relation to thesinusoidal systems. There is also a slight fibrosis of thegland. These are all evidences of toxic or bacterialstimulation of no specific type."When the patient left the hospital on Nov. 13, 1942,

she could walk almost normally, and no enlargement of

FIG. 4. Case 4: Photomicrograph of a section from anenlarged lymph gland showing toxic or infective" follicular lymphadenopathy " with large germ-centres.

any superficial lymph glands could be felt, excepting theinguinal glands, and that very slight and on the right sideonly.

A Syndrome of Rheumatoid Arthritis Combined withMultiple Xanthomatous Connective-Tissue In-filtrationsThere are other subcutaneous nodules and in-

filtrations which might in rare cases be confused withthose of rheumatoid arthritis (Weber, 1943), but Ishall here confine myself to a condition which seemsto be genuine rheumatoid arthritis associated withmultiple xanthomatous nodules and infiltrations,especially about the joints and in the subcutaneous(occasionally cutaneous) tissue.The special case that I shall fully record here has

been under observation for several years. Idescribed it originally with Dr. W. Freudenthal in1937 and later in 1943 (Weber and Freudenthal,1937; Weber, 1943), but can find no literature onthe subject excepting perhaps Layani's case of" Xanthomatous chronic deforming rheumatism "(Layani, 1939; Layani and others, 1939). Layani'scase was that of a woman, aged 46 years, who had adeforming rheumatoid disease of fifteen years'duration. In addition to the xanthomatous con-dition she had prolonged jaundice with hepato-megaly, and there were other remarkable featuresin the account.However, owing to the kindness of Dr. George

Graham and Dr. E. T. D. Fletcher, I have been ableto examine two other men in England apparentlysuffering from a somewhat similar syndrome. I

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hope that an account of these two cases will appearin due course. As I have been given kind per-mission to refer to these cases with my own one, Iwill here emphasize the point that hyperchole-sterolaemia seems not to be an essential, and iscertainly not a constant symptom. Another pointis that the infiltrations tend to be greatly in excessof those generally recognized as an occasionalfeature in typical rheumatoid arthritis. In allthree cases there was strong evidence that the appli-cation of heat made the xanthomatous infiltrationworse. This was pointed out to me by Dr. Grahamfrom various observations in his own case, and itmay be of some therapeutic significance. Dr.Fletcher's patient believes that radiant-heat therapy(which was given previously to seeing Dr. Fletcher)had made his trouble rather worse than better.Both my patient and Dr. Graham's patient developeda florid increase of the subcutaneous infiltrations-which tended to become actually confluent in partsover their shoulders and backs (the specially hotparts) after they had been lying for days on theirbacks in bed. Another remarkable feature in bothDr. Graham's patient and mine was the occurrence(in addition to the large and medium-sized nodules)of minute (miliary) superficial nodules (" droplets "),evidently arising in the outer part of the cutis; theseappeared for a time in great numbers on the nose,forehead, and other parts of the face, and then dis-appeared without leaving a trace. In my case theultimate atrophy or involution of the large nodularinfiltrations tended to be more complete than thatwhich occurs in acknowledged cases of rheumatoidarthritis. Finally, I cannot help thinking that thexanthomatous infiltrations in these little-known casesmay have a relation to the rheumatoid arthritisanalogous to that which gouty tophaceous depositssometimes appear to have to osteo-arthritis with

exaggerated Heberden's nodes. It may be re-membered, by the way, that Chauffard and others(1921 and 1923) found that tophaceous depositscontained a considerable admixture of cholesterol.In Dr. Graham's case a large sarcoma-like growthultimately developed. This reminds me of thepossible though doubtless exceedingly rare relationof sarcoma to benignant so-called " xantho-myelomaof tendon sheaths," and perhaps it might also becompared to the very rare supervention of frankspindle-celled sarcoma in " multiple idiopathichaemorrhagic sarcoma" of Kaposi (which isgenerally considered not to be a true sarcoma). Iwell remember this occurring in an old case ofSequeira's (Sequeira and Brain, 1926).

CASE 5This case was demonstrated by Parkes Weber and

Freudenthal at the Royal Society of Medicine in Dec.,1936 (Weber and Freudenthal, 1937), under the heading" Nodular non-diabetic cutaneous xanthomatosis withhypercholesterolaemia," but the presence of cholesterolin the lesions was not absolutely proved, and the hyper-cholesterolaemia was certainly not constant. Followingis the account of the case up to the time of the demonstra-tion in 1936.K. L. A man aged 35, general labourer, began six

months ago to suffer from pains and stiffness in variousjoints, which obliged him to give up work. Since thenhe has had varying swelling of the knee-joints and of thetendon sheaths at the back of the wrists, now hardlynoticeable. During the last six months cutaneous nodules(freely movable over the deeper parts) have been appear-ing on the hands, mostly on the back of the fingers andthumbs, especially near the joints; they are hard andreddish, averaging a small pea in size (Fig. 5). Duringthe same period similar nodules appeared over the ulnarridges, up to the size of a cherry over the right olecranon(Fig. 6); two pieces were excised for biopsy purposesfrom the left elbow, and one pea-sized nodule from over

FIG. 5 Case 5: Photograph of the right hand, Nov. 14, 1936.

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FIG. 6. Case 5: Photograph of the right elbow, Nov. 14, 1936.

the base of the left index finger. Numerous smallernodules are to be seen over the external ears, and stillsmaller ones (really miliary or minute) on the face,especially over the borders of the lips and nostrils. Someof the minute facial nodules have a yellowish-red colour.None of the nodules have been itching or painful ortender to pressure, except the large ones at the elbow.Recently, in December, fresh nodules, mostly red, haveappeared about the elbows, over the back of both greattrochanters, over the buttocks, and over the coccyx inthe intergluteal fold. There is now also a conglomerateor confluent nodular plaque over the back of bothacromial regions-more pronounced on the right side,on which the patient usually lies. It is highly probable,as I stated above, that this florid exacerbation of thesubcutaneous infiltrations was induced by local heat dueto the patient lying for days in bed. His body-weightis 53 2 kilogrammes, against (apparently) 60 kilogrammesearly in November.

There is nothing especial in the past history, exceptingdysentery in 1920 in India. The patient was kindlyhanded over by Dr. M. B. Ray, and he was in hospitalunder my observation from Nov. 14, 1936 to April 1937.

In the hospital there was occasional slight fever inNovember. By ordinary examination of the thoraxand abdomen and by x-ray examination of the thoraxand bones of the hands and feet, nothing abnormal isfound; nor is there anything special to be noted in regardto the nervous system and eyes (fundi normal) and internalparts of the ears, nose, and mouth (including pharynx).There is no thickening of the ulnar nerves at the elbows.The urine shows nothing abnormal (unless very slightexcess of urobilinogen), and no alimentary glycosuriafollows the ingestion of 50 g. glucose. Fasting bloodsugar: 0 07 per 100 c.cm. Blood-sugar curve normal.Blood-serum cholesterol on the first occasion was 230mg. per 100 c.cm., and on the second 350 mg. per 100c.cm. Fractional examination of the gastric contentsshows complete absence of free hydrochloric acid evenafter a subcutaneous injection of histamine; pepsin

present. The blood serum, which is clear but somewhatover-coloured, gives a negative direct, but positiveindirect, Van den Bergh reaction. Wassermann andMeinicke reactions: negative in the blood. Pirquet cuti-reaction: negative. Blood sedimentation: not decidedlyaccelerated. Blood urea: 365 mg. per lOOc.cm. Blooduric acid: 3 7 mg. per 100 c.cm. Non-protein nitrogenin the blood: 30 5 mg. per 100 c.cm. Blood-serumcalcium: 8 5 mg. per 100 c.cm. Blood count (Nov. 24):Hb. 84 per cent; erythrocytes 4,500,000; leucocytes3,500 per c.mm. (eosinophils 7 per cent.; polymorpho-nuclear neutrophils 45 per cent.; lymphocytes 45 percent.: monocytes 3 per cent,).

BiopsY. Histological report by Dr. W. Freudenthal(Figs. 7, 8): The main change seen in the sections is thepresence of large masses of cells, which form round, oroval more or less, defined areas, and are scatteredirregularly between the bundles of the collagen tissue inall parts of the cutis. The cells are so numerous thattheir mass exceeds that of the collagen tissue, the bundlesof which are pressed aside rather than destroyed. Thesecells are conspicuous by their size, which is up to fourtimes that of an epithelial cell. Most of them are multi-nucleated and have three to five or more bright nuclei(with definite nucleoli), frequently aggregated. Theyhave a well-stained, well-defined, abundant, round,oval or polygonal cytoplasm. Most of the cells areclearly defined; sometimes neighbouring cells are con-nected by cytoplasmic threads giving them a certainresemblance to prickle cells. The cytoplasm is homo-geneous: even by oil-immersion magnification it does notshow a foamy structure.When the sections are stained for fat with Sudan III,

these cells in some areas show no fat or lipoid at all; inother areas the cytoplasm is stained a faint red, whichis in some places more distinct. No double refraction.Even in the areas in which the cells are stained moredistinctly the colour is paler than the bright red of thefat cells of the subcutaneous tissue; the colour of thesupposed xanthoma cells has the slightest tinge of brown.

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FIG. 7. Case 5: Photomicrograph of a section from anexcised nodule. The epidermis is seen in the upperpart of the figure, and the large size of the " pre-xanthoma cells " is obvious by comparison with thesize of the epidermis cells.

In fact, it is a question whether the cells ought to becalled xanthoma cells at all, for by the term " xanthomacell" one usually understands a cell the cytoplasm ofwhich is loaded with lipoid droplets (" foam cells ").In our sections the cells show either no lipoid (visible byour imperfect histo-chemical method) or lipoid in a

diffuse form. Merely to call these cells giant-cells wouldscarcely help us. One could perhaps call them " pre-xanthoma cells" to mark their connexion with typicalxanthoma cells. It must be admitted that we have noproof that these cells actually become xanthoma cells.A possible explanation is, then, that these cells representan intermediate stage in the development towards typicalfoam cells (cf. Arzt, 1919). Yet it is possible that theyare not an intermediate stage, but are at the height oftheir development, and that their peculiar appearance isdue to some special lipoid they contain. Microscopically,it must be admitted, they show a marked resemblance to"Gaucher cells."

Progress of the Case after Dec., 1936.-Under a fat-poor diet the blood-serum cholesterol fell to 110 mg.per 100 c.cm. (Feb. 19, 1937), and the nodules decreased,notably the patches over the back of the acromial regions.The patient finally left the hospital in April, 1937. Whenhe was seen again in April, 1941, at the age of 40I years,there were only remnants of the nodules on the handsand about the elbows. The process of involution hadleft a little shrivelling of the skin about the left elbow.Rheumatoid troubles were in the foreground, but evenin regard to these he thought he was improving. Hecould get about, but owing to stiffness in the hips hecould not stoop sufficiently to pick up anything on thefloor. His fingers were rather stiff and slightly deformed.There was some limitation of movement in the leftshoulder and a little crackling on movement could befelt over the joint and left scapula. Both knee-jointsmanifested considerable crackling on movement. Theappetite was good. The patient said he was treated atthe Middlesex Hospital about 1938-39, where he hadall his teeth removed, a fat-poor diet, orange juice withglucose, massage, and injections of some kind.On Nov. 6, 1943, I was able again to examine the

patient, K. L., who said that he was able to walk aboutwell and do night watching (without any medical treat-ment). In short he had functionally almost recovered,although he could not yet flex his right hip normally.He still had " knotty " rheumatoid hands, with nodulesat the knuckles and over the elbows. There was also agood deal of crackling when he flexed and extended hisknee-joints.

FIG. 8. Case 5: Photomicrograph of a section from an excised nodule. Hair follicle on the left.

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CASE 6In June, 1941, a married sister of the patient was seen,

Mrs. M. N., aged 43, who was said to be suffering froma chronic rheumatoid disease. She is a well-built womanof about 10 st. 4 lb. in weight. There is chronic thicken-ing of both wrists with limitation of movement. Bothelbow-joints cannot be properly extended. The rightknee is somewhat flexed and there is crackling on move-

ment. The left knee seems normal. There is thickeningaround the proximal interphalangeal joint of the leftlittle finger and apparently some infiltration of its flexor-tendon sheath. No other joints are affected, and thereare, and have been, no cutaneous or subcutaneousnodules. She has had twelve children, of whom ten are

living and well. Her rheumatoid troubles commencedin both hands eighteen months after the birth of herthird child, that is to say, about sixteen and a half years

ago. She has never had pain in connexion with themshe says, except a little aching in rainy weather, and shehas never really been laid up. It is possible that hercondition is similar to that of her brother, but a very

incomplete form of the disease.

SummaryIn this paper the nodules, infiltrations, and pain-

less adenopathy of rheumatoid arthritis, and theirpathological significance, are considered.

Attention is also drawn to the existence of a little-known syndrome in which clinical features ofrheumatoid arthritis are associated with nodulesand infiltrations, apparently of xanthomatous nature,though hypercholesterolaemia seems to be of notnecessary (at least, not constant) occurrence. I

have described only one case fully (which was first

observed many years ago), but I know of the exist-ence of other cases probably of the same category,two of which will, I hope, be fully described in duecourse. The interest of this syndrome does not liein its extreme rarity, but rather in the light which,when more completely studied, it is likely to throwon the pathology and nature of various other groups

of cases.

My thanks are due to Dr. George Graham, Dr. M. B.Ray, and Dr. Ernest T. D. Fletcher for enabling me tosee and helping me to examine some of the patients, .toMr. H. Rast for carrying out the biopsy excisions, toDr. W. Freudenthal and Dr. J. G. Greenfield for theirmicroscopic reports and to Dr. Greenfield for photo-micrographs, and to the Editors of the British Journal ofDermatology and the Proceedings of the RoYal Society ofMedicine for allowing me to use previous papers of mineand blocks for illustration.

REFERENCESAllison, N., and Ghormley, R. K. (1931). Diagtiosis in Joilit Dise(ase.Arzt, L. (1919). Arch. Derni. Syph.. Wien, 126, 809.Burt, J. B. (1942). Proc. Rot'. Soc. Med.. 35. 85, Fig. 2.

Chauffard, A., and Troisier, J. (1921). Ann. mnMd., 9, 149.-, and Wolf, M. (1923). Presse mned., 31, 1013.Collins, D. H. (1937). J. Path. Bact.,45, 97.

(1939). .4Anni. Rheum. Dis., 1. 38.Epstein, S. (1935). Arch. Derin. Srph. 173. 181.Ghormley, R. K. (1938). "The Pathology of Non-specific Arthritis,"

in A Suruel of Chrotnic Rheumatic Diseases, p. 73. OxfordUniversity Press.

Layani, F. (1939). Bull. Soc. Med. HcJp. Paris, 3rd series, 55, 343.Laudat, and Astruc, P. (1939). Ibid., 55. 355.

Sequeira, J. H., and Brain, R. T. (1926). Brit. J. Dern., 38. 501.See also the discussion. Proc. Roy . Soc. Med., 1939, 32. 1023.

Thomson, J. Alexis (1929). Proc. Rot. Soc. Med., 20, 1,119, Fig. 4.Weber, F. Parkes (1924). Cutaneous Xanthoma and Xanthornatosis of

other Parts of the Bodc London (Lewis).-, (1943). Cutaneous and Subcutaneous Nodules with

Juxta-articular Infiltrations and Rheumatoid Symptoms,"Brit. J. Dermti., 55. 1.

and Freudenthal. W. (1937). Ibid., 30. 522.

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