Extraarticular manifestations of rheumatoid arthritis

Seminars in Arthritis and Rheumatism VOL. VI[IL NO. 3 Extraarticutar

FEBRUARSi 1979 Manifestations

of Rheumatoid

Arthritis

By Eric R. Hurd

I L E in the majority of patients with W Hadult-onset rheumatoid arthritis (RA) the arthritis is the most prominent feature, many patients have cxtraarticular manifestations. These manifestations can be severe, leading sometimes to blindness or death. Death due solely to RA is rare. When it occurs it is usually due to the extraarticular manifestations. The extraarticutar manifestations tend to be associated with those patients who have positive rheumatoid factor, and lhey generally occur more frequently in those patients with a higher rheumatoid factor liter. Because rheumatoid nodules are usually present with high liters. extraarticular manifestations usually occur in these patients. Several studies have suggested that the presence of e x t r a a r t i c u t a r features varies directly with the severity and duration of rheumatoid disease. ~-4 Some studies have shown that extraartieular features appear when rheumatoid articular disease activity subsides; ~'~ others have shown that extraartieular fealures may be a consequence of eorticosteroid therapy} "~ A recent study found no relationship between the p r e ~ n c e of extraarticutar features and use of eortic~steroids or duration of disease. |° The extraarticular manifestations did correlate with evidence of persistent articular inflammatory activity, roentgenologic .stages of more severe disease, and the presence of soluble i m m u n e complexes and high liters o f rheumatofd factor. There was also an increased mortality in patients with extraarticular features. MANIFESTATIONS

Rheumatoid Nodules Rheumatoid nodules are one of the characteristie findings in RA. Histologically ~ (Fig. 1) they are composed of three zones. The central Seminars in Arthritis and Rheumatism. VoL 8, No. 3 (Febru~t'), 1979

zone consists of necrotic connective tissue fibers and is surrounded by the middle layer oF histiocytes, fibroblasts and monocyte~, which are radially arranged to form a palisade. The outer layer is composed primarily of chronic inflammatory granulation tissue, which is comprised of fibroblasts, plasma cells, and [ymphoeytes. Rheumatoid nodules of the patmar surfaces of the hands and fingers often immediately follow the devetopment of l - 2 - m m slightly raised areas of cutaneous vasculitis}' These lesions persist for 2-3 wk and are then followed by development of typical subcutaneous nodules. Both arteritis ~3"~s and vcnulitis ~6 have been noted early in the development of a nodule. Heterologous and homologous fibrin implants in experimental animals produced nodule formation. Approximately onedhird of patients have nodulesfl 7 The most commonly recognized sites for rheumatoid nodules are the extensor surfaces of the arms and elbows, especially the olecranon process; however, they may be found anywhere in the subcutaneous tissue but particularly on contact or pressure points over tendons and bone and on feet and knces, knuckles, buttocks, scalp, or baekJ 2 They may also be fourtd in the abdominal wall, ~s heart, ~9-~t larynx, z| lungs and pleura, ~sm'~2 splenic capsule, peritoneum, eye, bridge o f the nose3324 pinna of the ear, ~4 and over the ischiat tuberosity and Achilles tendon. From the Department o f lnternal-itIedlcine, Rheuenatology Unit. The University o f Texas Health Science Center a¢ Dallas. Dallas, Texa,~. Dr. Hard is an Associate Professor of lnreroal Medicine, Uni,~rsity o f Texas Health Science Center at Dallas, and a Clinical Scholar of the Arthritis Foundation. Address for reprint requests: Eric R. tfurd, M.D., Oept, of fnternal Medicine, Rheumutolo&v Unit, The ttn¢~rslt)' o f Texo.r Health Science Center at Dallas. Texas 7J235. 1979 b)" Grt~ne & Strattoa, Inc. 004 9-017 2179/080 3-000 25 05.0010 151

52

ERIC R. HURD

i m~nocyle~ {pol~Oe]

Fig. 1. Htsto|oglc appaara~¢e of a sul~¢utane~t= l~=luIe in rhetsmatold 8rthttt|s, f r o ~ Boyle and Buchana~-~fl~

An uncommon complication is breakdown of the overlying skin with discharge of the contents. This may result in "~stulous rheumatism" and may r~quire excision. A nmnber of n ~ u l a r l~ions may be confused with rheumatoid nodules. Over the olecranon process, these include gouty tophi and amyloid nodules. Other lesions thai might be mistakenincfude ganglions of the hand or wrist, sebaceous cysts, xanthomatous tendon nodule.%'" ba:sa] cell ~rcmoma," and nodules of multicentric retieuMhistiocylosis or granuloma annutare, z* In patients with small rheumatoid nodides on the bridge of the nose, _the nodules may have been ~ndueed in this location by pressure from spectacle frame, z* Some of these patients also have small rheumatoid nodules on the antihelix of the ear. Both the location and appearance of these lesions suggested basal cell carcinoma of the skin. Lipoid nodule~ are unusual lesions occurring in patients with chronic RA, :7 These masses arc large, cystic, and contain yellow fatlike material containing calcium, lipids, and cholesterol. Thus

these lesions are not really rheumatoid nodules. The rapid developmenl of a large cystic mass in a patient with chronic rheunmtoid arthritis should be suspected of being a lipoid nodule. These are usuaBy in the vicinity of a joint and are frequently in the groin. Draining the mass satisfactorily eradicates the lesion. Perhaps the most unusual form of rheumatoid granuloma reported in a few patients is the linear subcutaneous band. 2s These bands were manifested as elevated and elongated ¢ordlike sa~cutaneot~s lesions that histologically were compatible with rheumatoid nodules. They were associated with numerous subcutaneous nodules~ Trea/mem o f nodules. Trc;ttment with oral corticosteroJds or injection directly into the nodule with corzicosteroids can decrease the size of the nodule.'~ However, older and larger nodules may be unaffected. Treatment is usually unnecessary, but if the nodule becomes extremely large or infected surgical excision may bc necessary.

Ocular }m,oh,ement Disease-assbciated lesions. The major types of eye involvemem are episcleritis, scleritis, scleromalacia perforans, marginal furrows of the cornea, retinopathy, ~md the sicca ~'ndromc of ~ g r c n . The most common ophtha|mologie symptoms of RA are associated with the sieca syndrome of SjOgren, i.e, keratoconjunctivitis sick3, if one does not include ~Sgren syndrome. tl~e most frequem~ty~ of eye involvement is Table ~, A~so¢iation o f Scbacit~s ~ t h Rheurc~told Arthrltls in 147 Pat;s~ts W~th Sc~r~q~s

W~thc~t ~S¢~er~t~s

10 4

34 99

p < O.O1+

Yes No

1:2 2

1 | 32

p < 0.05

ArreSt, s: Yes No

t0 4

16 ! 17

p < 0.0Ot

Systemic ~mplicStion s: Yes No

1 '1 3

18 115

p < 0.001

Rheumatoid nodules" Yes NO

~n~ cat~ce

Pe,;icaxd~|tsJpleurisy:

Adapted f~0m tel. 3 ~.

EXT~RTICULAR

RI-I~J~,TO|D

ARTHRITI~

inflammation of the deeper layer, the setera. The inflammation can be .~o severe or recurrent-that severe seleraI thinning may result,' with possible eventual perforation. Such" weak, nine of the sciera is most noticeable ir/'the ~uperior scler~l segmer~ts. Seteritis is usually related to the severity of the rheumatoid disease, 'particularly with the presence of systemic manifestations J°J~ (Table I). When the scleritis is severe, a rheumatoid granuloma may form in the sclerat tissue. These lesions grossly and microscopically resemble rheumatoid nodules. When such lesions are present. the sciera is markedly thinned and seleromalacia perforans may result. Van der Hoeve ~'- was one of the first to describe seleromalacia perforans. By t938, 14 cases .had been rep2Jrted and some of them had been studied microscopicatlyY Verhoeff and King first noted the pathologic similarities between the subcutaneous nodules of RA and the nodules of scteromatacia perforans. Hearever, t'hese nodules are also different in certain respects; e.g, lrauma undoubtedly is an important ~nlributory cause of the subcutaneous but apparently not of the scleral nodules. In addition, the scleral n ~ u l e s tend to become densely infiltrated with pus ceils and cause marked chronic inflammatory reaction, while s u ~ u t a neous nodules tend to remain relatively free from infiltration. The scleral n ~ u l e s consist of a sharply defined area of necrotic scleral tissue surrounded by a wall of epithelial cells that b~zcornes infiltrated with pus ceils. This process results in a sequestrum, ~'hich ~ c o m e s disintegrated and densely infiltrated with necrotic pus cells. These a form ~vities in the selera. In a few nodules there may he infiltrates of lympho--cytcs and plasma cells. Replacement of the damaged sclem and urea by fibrous tissue takes place, and new epithelium forms an external covering) a Because the selera is a fibrous and almost avascular structure, pathologic pr~e~ses affecting it are chronic in character and resistant to therapy. Js w h e n the sclera becomes involved, the adjacent .tissues take over the role of a vascular system, but often they are too far away from the damaged scleral "fibers, which then

1,:53

rapidly become n¢crotic, with no chance for organization or repam If the legion is near the episcloni'or urea the chances for replacement by fibroblastic tissue arc correspondingly greater. In some cases the episetera is rich in lymphocytes, forming follicle-like structures. ~ ]~n severe eases,-perforation of the sclera with resultant collapse of the globe occurs. Scleritis and episcleritis can be, but are not necessarily, exclusively precursors of selerofi~alacia?7 A necrotizing nodular seteritis proceeding to scleromalacia perforans may be seen in systemic lupus erythematosus, periarteritis nodosa, Wegener granulomatosis, porphyria, herpes zoster, 3s and Crohn diseasefl ~ Thus seleromalacia is not specific for RA. This complication is diJficutt to treat, and perforation with an cndoph~halmitis with rapid :loss of vision may occur. Treatment of scteromalacia. Unlcss topical or systemic corticosleroids or surgery (e.g., fascia lain grafting) is helpful, perforation will occur and enacleation may be necessary. Treatment of the underlying disease to suppress the inflammatory p r e c i s is mandatory prior to~ surgical intervention. Fascia tata autografts are preferable to donor homografts in t h e ~ cases, since homografts have generally produced poor results?O 42 A Nirly characteristic corneal lesion of RA has also been describcdfl -~ Such lesions are marginal furrows at ~he edge of the cornea that can become thin to the l~3int of ~rforation or le~kage, in such patients, corneai grafts have been helpful. A similar IesiorJ consisting of partial opacity of the peripheral areas of the ~cornea involving all or part of its circumferenc-c has been described. ~4 |t has been called lhe *~contact lens" cornea because the cornea may be thinned and slightly opaque "and~the appearance is that of an eye wearing a_conlact lens. I m p a i r meat o f the arteriolar vascular supply at the corneal timbic areas may be the cause of this l~ion. Uveitis and iritis arc seen in patients wilh RA, but the incidence is probably no higher than in the genei~al population/-%46 ~ t h e r s have reported a variety of retinal l~ions found in patients with RA not treated with chloroquine.~ H o w m a n y of-lhese lesions were related to the disease, the patient's age, or other lypes of treatment (e.g., gold salts) is not known~

Ocular side effects c f drugs used for treat-

'ERIC R, HURO

154

Tabls 2. M i~jor "rypes of'Cardiac tmtolvement P,ericarditis Rheumatoid granulomas ~picardial f~t Epicardium Myocardlum Interventricular sep¢om Chordae ~ndineae Aorta Valws Arteritis Myocarditis

menI of R A . Corticosteroids, gold salts, and antimalarial drugs can all produce eye lesions. Corticosteroids can increase intraocular pressure, ~ precipitate glaucoma, 4~ and with chronic use can cause posterior subcapsular cataracts. 49-s2 They may progress to the point that visual acuity is impaired, necessitating surgical removal. Gold may be deposited in the cornea or conjunctivae alter prolonged use and rarely may produce a pseudomembraaous conjunctivitis.5~ Antimalarial drugs may cause.retinopathy or keratopathy? 7 Cardiac Involvement Cardiac Iesi(~ns occu7 in RA but are noted more frequently at necropsy than on clinical examination and study. The major types of cardiac involvement are shown in Table 2. Chror~ic pericarditis is probabl.~, the most common rheumatoid lesion or the heart, ~t least at time of autopsy. ~ A receni-eehocardiographic study o f 30 patients with classic RA showed pericardiat effusion, thickening, or both in 14 patients (46.6%) and mitral valve abnormalities in 9 patients (30%). 5~ Another echoeardiographic study ~6 found that 44% of patients had evidence of posterigr.perieardial effusion that could not be detected by.electrocardiogram and chest x-ray sludy. A reduced E to F slope 9f the anterior leaflet of the mitra! valve_was present in 25% of patients. All of these 9atients were free of "~cardi~c symptoms[A third study "~7 showed a pericardial effusioh:-in 34% of 44 RA patients and 50% of the subgrot~p with subcutaneous "h--odules find also showed sl_o,,~,ingof mhral valve movement, which tt/e authors sti-ggested was caused by granulomata involving ~he mitrai valve-.-The most recent_echoeardiographic study, ~ however, claimed that eehoe_ardi0: graphic abnormafities of the anterior mitFal

waive leaflet rarely, if ever, occur in palients with RA. AI] of this study's 31 patients showed normal valve motion and a normal E to F slope. The authors believed that the earlier studies were not meticulously carried out. Pericarditis has been observed since i881, when Cheroot ~ found evidence of previo~ts pericardial inflammation in 4 of 9 rheumatoid patients at autopsy. Since then the incidence has ranged between 30% and 50% in several autopsy series. ~4"e~)-6`-While the postmortem incidence of pericarditis is approxhnately 40%, 6-' the clinical incidence is much lower. In a study of 1130 consecutive patients with arthritis of severity sufficient to require hospitalization for articular probl6ms, 6"~ 10 pati~:nts (10%) had some clinical evidence of pericarditis. While all 10 patients had pericardial friction rubs, only I had chest pain, and 7 w e r e entirely asymptomatic. in a recent study of 17 patients with rheuma~.oid pericarditis, 6~ all had definite or classical RA. Rheumatoid factor was present in 14 (93%) of the 15 patients tested, and subcutaneous nodules were presem in 8 (47%). The presenting complaints were left-sided-chest pain__ in 10 (59%) and symptoms of congestive heart failure in 3 (18%). A pericardial friction rub was detecte_d in 14 (65%). All 17 patients had eardiomegaly by-x-ray, and 14 (65%) had-an accomp~iiaying pteural effusion. In the pericardial fluid the diagnoslic triad of markedly reduced pericardial fluid sugar, ir~creased gamma gt~buiins, and increased concentration of LDH may help to establish RA as the cause for the effusion. Ttii~'-most c~_.mmon findings in rheumatoid peri~ardiat..effusions a r e shown in Table 3. The WBC counts were-950, 2000, 2600, and 28,000 per mm a "in four patients recently reported. 64 Protein levels averaged at-6.4 g/dl. The levels of gamma globulin were increased, and co_mplement levels were decreased. Glucose

Table 3. Rheun3~to~d Pefir-.a~'dial Effusion

WBC. 9 5 0 - 2 8 " . ~ ( m m t Protein, 6.4 g/di (range 5,1-9,7} Increased concentration of gamma globulin Decreased C=HSO Decreased glucose Rheumatoid factor=maTbe &cesent Immune complexes pcesent in some Lymphoklnes predominate i~ others

EXT~AJ~RTtCULA'R RI,~Ek~MATOIO ARTHR~,TIS

levels in t h e e patients were 17.6%, 26.5%, and 65.6% of the serum glucose values; in a fourth patient the pericardial fluid gluc~e was only 2 mg/dl, Low glucose levels are believed to be due to decreased glucose transport across the pericardNt membrane. Cholesterol may be increased ~s to ~ c h a.n extent that the crystals produce a ~'~ld pare appearance, A re~nt study~ of a patient with cardiac tamponade due to ~ricarditis reported lgG-lgG immune o-~-nplexes of 19S size in the ultracentrifuge. T h e e complexes diss~iated into 7S lgG melece~les in acidic buffers. However, we~s recently studied the perieardial fluid in one patient and found no evidence of immune complexes. In this fluid we found evidence of MIF (~migration-inhibitory factor), which is a-manifeslation of cellular immunity. While most elDasions are transient and disappear s~-ontaneously with 'rest and aft increase in analgesics, ~rticosteroid treatment or pe~eardie-contests ~.~rpericardiectomy may ~ necc~sary in a few cases. According to Fraffco et al.,~ corticosteroids in a"dosage of 30-40 mg prednisone daily frill predictabl~t-reverse signs and symptoms of rheumatoid pericarditis in a mean period of 3 wk ( 2 ~ wk). Pericardi~entesis should ~ performed for diagnostic purpo~s and (promptly) as a lherapeuti9 measure if early tampon:ado is s~s~cted. P~ticardieetomy should be done if the ~ricardi~t effusion reaceumulates or signs of constriction appear. In the£3eri~ by F~n¢o et al.,~ 34% of the ~lients with perieardifis eventually required pericardiectomy, or died of their disease. Cardiac t a ~ p p n a d e was reported in 20 casLcsof RA. ~'~The male twfemale ratio iffthe cases in whict~ sex was recorded was 11:8, which is~similar to~that found in the RA ~pulation. The age rangelqas 4-62~yr. In the cases in which dLease seventy was recorded, th6 majority of-patients (15 of t8, 83%)'~had moderate or severe~RA. Rhfumatoid factor was positiy~z in t2 of t ~ 13 pdtien~ ~ h e r e it--w~ obtainS, and there were-subcutaneous nc-dul~s in 9.~A'pericardial type of pain or ~ricardiat friction xub preceded the cardiac tamponade in 12 of ~ (63%) of the ~tients in which the information was available. The pericardiaI e~ffi~sions-inthe patienlts wi~h t a m , n o d e was_bloodstain~ or ser~anguin~us in 13, turbid in 4, and straw colored in ruin 2 cases th~ information was_.not recorded, The

15,5

glucose level was

either very low or absent in the

5 patients in which it was obtained. Treatment with corticosteroids is of little benefit for cardiac tamponadc. 69~ Occasionally as~ration of the pericardial fluid may ~ beaefic ai, but this may be di~cult to perform because the fluid is thick and loculated~69 Once the di~}gnQsis of cardiac tamponade has bee'n established, perieardiai resection usually is neeessary. All I0 pati~Is who underwent resection ~rvived, but 9 of the l0 patients who were not operated on died39 Constrictive ~ricarditis is more common than tamponade; more than 42 cases have been recorded, 'As with pericardial tamponade~- treatment of cdnstrietive p~ic~rditis with corticosteroids is not beneficial. The only effective~treatment is surglcai?9 Of a total of 3g perieardicctomie~, only 2 paticnts died postoperatively. Of 2t .of these patients who were follow~ for 3 mo~o l0 yr, j 9 remaine~ ~'elt. In most cases the tissue histology is nonspecific. I n a few cases tfpical granuiomatous iesians hwve been observed; ~'~ Calcium deposits7~;~ and cholesterolcrystats~'7~'7~:n~are sometimes seen. In a controllfid autopsy study of 47 RA patlents a n d 47 a g e - a n d seK-matehed cor~trds, ~. it°v.,as apparent that the incidence of pericardhis was significantly~higher in the rheumatoid group, but the difference ~as not statistically significant. It is of intercst that ad~er-oselcrpsis~.vas significantly less comlnaon in the RA- patientsThe eh~ical three-layered .fibrinoid_granutome is ~nsfdered to be specificfor rheumatoid disease, The~e granulom-as have been reported in nit parts of the heart: lhe pericardium, epieardial fat ahd epi.cardium,.7x myo~trdium, ~ airium, s° inte~emri~'ular septum,,st eadcS,z~rdium, s~ a~rto,~ and chordae tendinease and all valve c u s ~ anT.t d n ~ (predomifantly mitral and ao(tic)fls'~s°'s~a 7n addition/nodules in the conduction system have produced lethal arrhythmias3 ~-~ The reported inc'ideace of granulo'mas in thc~heart is3% (see Table 4). s~'s~ The nodules, wlien wcsent in a-cardiac valve, are Ioeat~ ~in the "core" or c'entral ~rlions of the leaflets and may cause thdm lo be ineom~tent;~ IrivolvemenL~of the conduction system appardftly e~*ri be pxc.du~d by the granuloma itsci'f, or by-extension of the granulomatous inflammation from the base of the aortic or mitrai valves,u In some-~reported cases, ~ no

! 5R

ERIC~R. HaRD Table4. Rheumatoid Heart Disease

,Rheumatoid granulomas |3%) Valve lrin~lsand valve'~eat1,~,!S

Table 5, Rheumatoid PleufM Effusion +Glu~0so < 40 mg/dl in most <~10 mg/di in many

Mpocarc~ium

Protein~-< 3 ~/Ol

Veotticul~t septum

Cells. 1 O 0 0 - 3 0 0 0 / m m a lmosily T Lymp~ocytes| Complement decreased (CHSO~:C4,and C3)

~/~,~ complete heart block

"--'~"2=~"left bundle branch block Periear~i~Jm Nonspec~fic {nflammat¢~ lesions Pedca~'di6s H0%)--,f~brouS Myoea~ditis (Z0%) _Co~:;3na~ydrteri¢ls (20~) Acute a~d chronic Va|~itis (5%} Peieenta~es fmm ¢~s. 85 an~ 87~

active granulomas-were present in the conduction system, but fibrotic patches were present i~ the spot where active granutomas had presum* ably been present. Coronary arteritis in patients wit;~RA-has b~_-en found at autopsy in el\many as 2 0 % o f cases~ ~ howe~L',::r, this complication is rarely diagnosed during life. Weirdraub andZv,~ifler ~°~ reported a group of patients with widespread rheumatoid~ranu~lo mas. either-scleromalacia perforans or nodular episcleritis,-rheurfi~ttoid het~rt disease;: iind, in two instances, aorthis-with dilatation of~. the aortic r~;ot:.A murmur of aoi'tic insutticieacy was pi=csent in fiye patients: At autopsy, systenoie vascuiii-is, pcriciL"ditis...and-cardiomyoptnhy were noted. In.~.,ldditionr dilatatlon-of the aortic root with aortitis, chronic inflammatory periva]g; d~tlar culling in the a:.~rtic vasa vasorum, and rheumatoid granulomas in the advent]tin ,~fthe aortic root were observed, Pit lnlomtr)~-lil re/remetit While the 7overall incidence of pulmonary involvement 'in RA-pat]enid is small, certain types of royal emcnt are generally accepted as i~eing p~trt of the rheum, told process; these arc pleurnI effusion, nod~iles, cavitary, lesions, Caplan syndrome, and dittq.tse interstitial fibnrsis. Pleural involvement is probably the m o s t common pulmonary complication of- RA. At postmortem examination, more i#,ih 40% of pat ictus with RA had chronic pleural adhesions, some of which were extensive. "' Pleural effu. tar.6 tend to c~cur in men more than'women ~ and mostly in males over 45 yr of age, ~- While tll(i:it patients with pleuritis have had severe,

Adaotodlt~rel.

~2.

Jongstaading arthritis, pleura/ effusion- may d~velop early in the-discascJ <95 The~pleural invol~,enlentis ~asu~ly asymptomatic. The effusion is-~Js~!y~modcrate in sizc.-and may be bilateraE-'In a scales of 516 patients with RA, 21% gave a history o~pleurisy, as ~ m p a r e d with l ~ of__<301 control patients with degene_rative joint disease. " ~* P|e~rat effusions~,~'ere pr~ent in 17 rheumaloid p a l l e t s (3.3%.). but in only 1 of the'301 °Fat]eats in the control series. The most common ~ndin~ in the plcural fluid a r c shown in Tabi~iS.'~ The most°}m~rCant feature of the rheumatoid pleurai effusion "is that the glucose level is e~4S fl'equently low, sometimes zero. In one study low glucose c-oneentrations were observed in the p'Ieural effusions of 6 patients'\~,'ith RA. In a more recent study thes~meinvestigators 97 found that in all but 3 of 18 patientswith rheumatoid pleural effusions the glucose concentration was !ass than 37 mg/dl. However, the glucose is not invariably low and ~casionalty will be normal. About 17% of patients had glucose concentrations of more than 50 mg/._ml,?7 In one study,'? only 2 of 8 patients had glucose concentrations of tess than.30 mg/dh~Glucose levels may also be low in malig~qant or tuberculous serous effusions, but in these conditlons-bacteriologic_pr cytologic ~diagnosis can be re,adv.- Thus some feel that a low glucose level i-n-pleura-I fluid that is nonpurulent, negative for bacteria on smear and culture, and negat!ve for maligmtiitcetts on cytologic examination almost invariably indicates that the effusion is due to rhetrmatoid pteuritis unless pleural biopsy shows tubcrcidosis. .7 Studies of patients with pteural effusions hard-concluded that the glucose levels are decreased because of.m paired t r a n s ~ r t of g l u ~ e into the pleural fluid from the b i ~ ? "~ In these studies intravenous glucose infusion failed to raise intrapleural glucose ~ncemration, but glucose injected diP=ctly into the pleural effusion was not utilized rapidly. In addt ton to tow giueose values, low complement valu~ in the pleu~l fluid may ~ helpful in

E)(TRAAIB'~ICULAR RHEUMATO|O A~THRITIS

distinguishing rheumatoid pleurat effusions from those due to malignancy, congestive heart failure. and other causes. In-a study by Hunder et aL,~ levels of whol~ hemolytic complement'and two~ebha~nents (C4 and C3) were found to be significantly decreased in pleural effusions from both rheumatoid and lupus patients. Other findings reported in .some pleural effusions include positive tests for rheumatoid factor, ~ ~cL'zvated lipid lcvcls~~°~'Z°-' elevated lactic dehydrogenas~ levds,~ and presence of RA cellsI°°'~°~ (phagocytic teukocytes containing ihdusion bodies). Cholesterol crystals'are also ~casionalty seen. The presence of rheumatoid factor in the fluid is not of diagnostic value, since it may be absent in rhefimatoid effusions and may be present in effusions of nonrheumatoid patientsJ ~ The predominant cell type pr~ent usually is the lymphc~:yie, ahhough p-olyt~o~r#~ nuclear leukocytes may predominate)~ Oceasionat|y large numbers of eosinophils may be presentJ e~ Williams et all n~ showed that the majority of these pleura! fluid lymphocytes are T lymphocytcs using either anti-T cell antiscra or the sheep cell rosette technique. Bio~y of the pleura usually shows only nonspecific granulomatous or fibrotie changes. Only rarely are rheumatoid nodules present. The pleurat effusions usually resolve spontaneously within 3 too: however, some require re~ated aspiration if symptoms are present. Conicosteroids may be of value if the effusion is associated with early aedve RA) ~ Decortication of the lung may be ary infrequently if gross thickening of the pteura causes disability. One of the most common pulmonary manifestation~ of RA is the subpteural or intraparenchyreal rheumatoid nodule. It has been suggested that movement of the pleura may favor their predilection for a sub&rural toeatlonJ ~ The pulmonary nodules usually occur in patients with severe disease with subcutaneous nodules and high tilers of rheumatoid factor. The tung nodul~ arc usually round and discrete, subpleural, and sometimes slightly lobulated)°s They vary in size from several millimeters to a few centimeters. The)' may eavitate, and spontaneous pneumothorax may rarely occur. As with su~utaneous n~ules, pulmonary nodules may regress s~ntaneously. Although nodules may solitary, they tend to be multiple)~ ' ~ The nodule may ~ associated with a pleutal effusion

1 57

and may thus suggest the possibility of carcinoma. The distinction from carcinoma should be established on biopsy. in one reportod ~ s e "° of a young woman with RA, a solitary pulmonary lesion was composed ofan alveolar cell carcinoma in intimate association with a rheumatoid n ~ u | e . There are several reports of lung carcinoma and c~xisting rheumatoid nodulesJ ~ According to these investigators, the finding of a solitary puhnonary nodule, particularly a recent or enlarging one, in a ~tient with RA carries no assurance that the process is benign, They recommend that such nodules be excised for diagnosis. Cavitation of nodules occurs when they shell out or erode their centers. These may be very difficult to differentiate from tuberculous, mycotic or tumor lesions. In two unusual spontaneous pneumothorax, and peripheral eosinophiiia w~s secn. tn 1953, Caplan ~3 rcported a close association between nodular tung disease and RA in Welsh coal miners. The lung disease often preceded the devefopmenlof active arlhrhis. In fact. systemic RA is absent in 40% of patients with typical Caplan n~ules~ although these patients usually have rheumatoid factors present in their serum. "'t The characteristic roentgcnographic appearance consists of multiple well-defined nodular opacities 0.3-5 cm in diameter distrib. uted throughout both lungfields but predominantly in the periphery)~a ~ There is a tendency for calcification and cavitation of the opaciti~ to occur. The lesions may becon'te confluent and may be indistinguishable radio.graphically from progressive massive fibrosis, ~" henc~ the term nodular fibrosis. The smaller nodules may be few in number and confined to the upper zones or may present a "'snowstorm" appearance widely scattered throughout the chest. "~ The~ n ~ u | e s have a l ~ been reported in workers exposed to other types of dust, e.g., carbon e l e c t r i c workers,"n boiler sealers, "~ asbestos workers, ~° gold miners,j~ chalk workers, m~2and foundry workers) z~ The majority of reports of this syndrome have come from Europe, and this syndrome appears to be rare in the U n i t ~ States. Of IC~ bituminous coal re[tiers in the U.S. who had RA, two met the roentgenographic criteria of Caplan syndromeJ z" Benedek~24 suggested that these

158

ERIC R. HURD

pulmonary lesions are a manifestation of rheumatoid disuse and that their devel~pment is facilitated by the presence of silica rather than that these patients hencecoincidental silicosis and RA. He also suggested that both tuberculop_rotein and rheumatoid factor increase the granulomatous reaction to silica in the lungs+ Neither the prevalence nor tiler of rheumatoid factor is increased in persons with RA who have a history of exposure to silica) 2+ A~t the Mayo Clinic ~:5 16 patients with pneumoconiosis, consisting of nodular fibrosis of the lungs associated with RA, were seen between I955 and 1964:12 of these patients were foundry workers; the remainder included a coal miner, a granite polisher, a textile mill worker, and a rubber factory worker who had experienced prolonged exposure to rubber dust. The characteristic lesion consists of fibrosing pneumonitis with necrobiotie foci and closely resembles the subcutaneous nodules of RAJ 26Thus the Caplan nodules have features similar to rheumatoid nodules, while pneumoconiotic nodul~ do not. It has been suggestedt2s that the pulmonary nodules develop in the lung parenchyma because of antecedent damage from the irritating dust particles. Noonan et at. +27 described coarsely nodular pulmonary fibrosis in patients with RA who had no history of exposure to silica or other toxic inhalants. Careful examination of the lung tissue failed to show silica in the lesion. On this basis the classification shown in Table 6 has been suggested}:+ The production of the rheumatoid factor may result from an immune res~nse .that results from antigenic stimulation of the respiratory mucosal system. That such a meehafiism is ~ssible is supported by the fact that high titers of rheumatoid factor developed in the sera of several patients who developod chronic hypersensitivity pneumonitis due to mold contamination in an air conditioner,n9 The rheumatoid Table 8, Pathology of LUng In Rheumlltot¢t ArlhriUs Pleuritis |nterstitial pnaumonitis Fibrosis Oiffuse Coatse|y nodule) Pneumoeoniosis(Caplan) W~thout pneumoeem=osis{Noonan et al ) A~tedtls

Adapted from ref, 128+

factor disappeared after inhalation exposure was st~ped.. Diffuse interstitial fibrosis of the lungs is +an unusual type of pulmonary involvement in patients with RA. X-rays usually show a diffuse bilateral reticular or reticulonodular pattern. Inter~sed areas of translucency may give a "honeycomb" appearance. +3°There is some disagreement as to whether or not interstitial fibrosis is a specific manifestation of the rheumatoid procesS;92 however, most workers (including this observer) seem to accept i~)~HJ+ One study re~rted that of l l6 cases in which pulmonary interstitial +fibrosis was an isolated finding, 25% were associated with joint disease. +3s In a review of 702 pat~,ents with RA, 8 instances of moderate or severe diffuse pulmonary Hbrosis were found. )2g In a controlled study, Walker and Wright )3+ found an incidence of 1.6% of diffuse interstitial lung disease in patients with RA. However, this incidence was no higher than that of the control group of osteoarthritis patients. Thus unless pathognomonic rheumatoid n~ules are found in association, if'may be di~eult to make the diagnosis of rheumatoid interstitial fibrosis. The pathology is similar to that seen in Hamman-Rich syndrome, with proliferation of the interstitial fibrous tissue around the small bronehioles and within the alveolar walls, which become thickened. An infiltrate of lymphocytes and plasma cells may be present in the interstitial spacesJ )+The fibrosis may be so intelase that it distorts the bronchi. Because of t h e e changes there is diminished vital capacity and impairment in the efficiency of alveolar-capillary gas transfer) ~7The progn~is is poor, with death due to respiratory failure and hypoxemia. if pulmonary function tests are utilized in addition to radiology, 47% of patients with RA have pulmonary involvement}Js A recent study ~3+ selected 85 patients with RA and normal chest x-rays. Tests porformed included spirometry lung volumes and gas transfer (DLCO). Significantly lower values of DLCO were found in patients with RA compared with a control group. Although the exact ~thogenetie mechanism of rheumatoid lung disease is unknown, rheumatoid factors and/or intermediate complexes of 8-I IS size may play an im~rtant role) ~9"~" Immunofluorescent studies were done on lung tissu~ from patients with RA and pulmona~ involvement.++~Striking immuno-

EXTRAARTICULAR FIHEUMA3"O}D ART~RFI'IS

fluorescence was noted with ami-lgM and heataggregated 7 in to l ~ l i z e tissue depo,~ition of IgM rheumatoid fa,~or. Pa4chy nee of lgG was also pr~ent. Positive lupus er2¢thematosus (LE) ~ 1 preparations a ~ serum'levels of intermediate IgG co~nplcx~ (1~-15S) were found in a large pror~rtion of the ~tients, although no correlation with the clinic| or ~tho]osic could be established. The same investigators~4~ showed in animal lungs that intravenously injected lgM rheumatoid factors could accelerate or aggravate hemorrhagic or vasculitic lesions near or adjacent to established granulomata. These small parenchymatous pulmonary granulomata had been induced by prior intravenous inoculation of complete Freund adjuvant. This work confirms and extends that reported by Baum et at. TM in which the effec| of rheumatoid factors on antig e n - a n t i ~ y complexes in the capillaries of living rat mesentery was studied. Thus the above studies suggest that lgM rheumatoid factor m,~y enhan~ p~tential~y harmful immune reactions. Diffuse interstitial pulmonary fibrosis may therefore result from occlusion or damage to pulmonary v~seIs. Such damage may be caused by intermediate complexes that may cause either vascular damage (vaseu|itis) or occlusion.

Felt), S),ndrome

1 59

ulin (Ig) complexes that will react with purified tgM rheumatoid factor (RF) was first shown by Hannestad ~ in 1967. Winchester et al. nat confirmed this finding and in addition described the presence of IgG RF in certain RA syJaovia! fluids. The presence of 22S complexes in the sera of certain RA patients, including some w~th Felly syndrome, was described by Franklin et ak in 1958."s An association of the presence of lgG RF and tow molecular weight lgM with vascuIitis has been reported by several groups. Norberg '49 recently observed~thzt 54% of RA sera contained lgG complexes by using a platelet agglutination technique. We recently described the presence of intermediate-sized complexes (11-15S) in 100% or our patients with Felly syndrome as compared with RA patients without feukopenia or splenomegaly.~-~° Weisman and Zvaifler TM showed the presence of cryoglobulins in the majority of FS sofa. Thus the presence of immune complexes in RA and FS is well established.

C h e r o o t s of* neutrophils by imm~tne comp&,xes aml phagocyto~s of immune complexes. It has been shown that both aggregated lgG and IgG-lgM RF complexes are ehemotactic for neutrophils?5~ Parker and Schmid |~'~ in 1962 showed thal complexes consisting of aggregated IgG and lgM RF were phagocylosed by neutrophiis. We have shown that normal neutrophils can phagocytose immune complexes from IgM RF-posilive RA fluids after incubation for 90 rain at 37°C in vitroJ ~ in contrasl, IgM RF-negative fluids produced phagocytosable inclusions only if purified lgM RF was added to the synovial fluid prior 1o incubation. Added Waldenstr6m IgM did nol produce such an effect. Cats et al. ~s~ produced formation of intracytoplasmic incluslopes in normal neutrophils incubated in RA sera. The presence of such intracytoplasmic inclusions or "RA cells" in synovial tlu~d neutrophils was fi~t observed by Hollander et all ~ A number of investigalors confirmed these observations and also .reported the presen~ of the inclusions in circulating peripheral b l ~ d neutrophils~ and in synovial lining cells from RA iratientsJ ~

In 1924 Felty summarized his cases as follows: "'Five cases, strikingly similar in their essential features, are described, presenting an unusual, but unmistakable clinical picture, characterized by arthritis, splenomegaty, and leukopenia. The etiology is entirely obscure, though the various findings seem best accounted for as manifestations of a single disease process. ""~ The major components of Felly syndrome as originally described are RA, splenomegaly, and leukopenia, e~pecialty granulocytopenia. Such patients have a high incidence of rheumatoid nc~lules, infections, and systemic extraartieular manifestations of the disease procxzsssuch as vasculitis and ~ripheral neuropathy and serologic abnorma|itJes such as positive LE cell tests, positive antinuclear antibody tests, both organ nonsr,eei~e and granulocyte reactive, high titers of IgM rheumatoid faclor, and an increased incidence of eryoglobulinemia,

Effects of ingestion of immune complexes by neut,"ophils. The release of tysosomaI enzymes

Immune complexes in RA and Felly syndronte (FS). The presence of immunoglob-

from neulrophils exposed to immune complexes has been shownJ ~'u~ Increased nitroblue tetra-

160

zolium dye reduction after exposure to IgG-lgM RF complexes has ~lso ~ e n shown. ~6~Increased dye reduction in RA synovial fluid (SF) ~tls and ~n normal calls incubat~ in RA SF has been shown. Similarly, d ed phagocytic ability ~62 in these cells as well as decreased e h e ~ t a x i s ~$2 in both SF and peripheral blood neutrophils has been found in RA and Felly patiems. In patients with Felty syndrome ~there ix an increased incidence of bacterial infection, vasculitis, peripheral neuropathy, and other manifestations of systemic disease. Serologically, there is a high incidence of positive LE cell preps, aminuclear antibodies (ANAL hypc~complementemia, cryoglobulinemia, high liters of rheumatoid factor, and granu|~cyte reactive ANA. ~ * ' r Some of the patients have granuloeyte-s~cific ANA that have been shown ~o be complement fixingJ ~ The ieukopenia appears to be primarily peripheral, since the bone ma~rrows are usually hyperplastieJ ~ Mostly granulocytes are involved. I t was recently shown that there is increased margination of the granulocytes in Felly palients, i~e., the circulating granulocyte pool is decreased but the total body granuloeyte number is normal? ~ A high incMence of 22S complexes in Felly sera has ~ e n shown. We recently found, in addition to 22S complexes, intermediate-sized (II-15S) complexes in the sera of 100% on" patiems with Felty syndrome. ~ We also showed that normal leukocytes can phagocytose large intracytoplasmic inclusions from the majority of Felly patients' sera as compared with sera from RA patients without Fetty syndrome. |~' There is also goed correlation between presence of intermediate complexes and phagocytosable inclusions, It is s ted that the explanation for ttve above findings is that the granulocytes ph tose immune complexes and are immediately removed from circulation by marginafion or trapping by the spleen or other |ym#oid organs. This would ex#ain the fact that the majority of circulating neutrophils do not have large intracytoplasm~ inelusions. One could explain the existence of the granulocyte ANA as a secondary event that takes place as a result of the continual breakdown and release of granulocvte nuclear material against which the ~ y then devel6ps an antibody. An alternative explanation for the

ERfC R. HURD

ANA is that the ANA is produced nonspecifitally by the immune ~mplexes sticking to the damaged .neutrophiI nucleus. It was recently shown by Weisman and Zvaifler *~ that most of the granul~yte ANA activity is concentrated in the cryoglobulin portion of a Felty serum. It seems unlikely'that the granut~yte ANA is Of etiologic importance, since its presen~ does not correlate with total numbers of circulating nentroph! s. Suggested mechanism for development, It is suggestedthat a plausible explanation l:or the various features comprh;ing Felty syndrome is as follows: These patients have a high incidence of large (22S) and intermediat~ ( l l - I 5S) circulating immune complexes thai arc phagocytosed by the patient's neulrophits, which because of deformation of the cell (and ~ssibly because of complexes slicking to the cot! surface) are immediately marinated and/or sequestered in the~ spleen and perhaps in other sites. This or~uees enlargement of the spleen. The chronic intermittent peripheral margination and sequestration of neutrophils is res~nsible for the hyperplastic bone marrow res~nse. Follow~ng enlargement of the spleen, a hy~rsplenic state may also contribute lo further sequestration of gmnulocy vs. While the increased incidence of ifif\eetion may resuh primarily from the neutropenia, an additional factor may t:~ important, i.e., a defective neutrophiI may result from phag~yt~is of the immune complexes. The half-life of the cell may ire decreased; in addition, such cells may be degranulated. Decreas~ ability to kill bacteria may ~eur. thus contributing to the problem of infection. This would perhaps explain why Felty patients may have m~ et~ons and neutro~nia after splenectomy. It is also sugg~ted that the immune complexes are also re-s~nsible for the vasculitis that may ~ e u r in +these patients. Speculation concerning 'therapy, Gowans and Salami ~7~re~rted an increase in humors of blood neutrophils in gold salt-treated Fdty patients. We ~ n t l y o b ~ c d not onty ~n increase in blood neut~phils but a l ~ dec spleen size after gold ~ ! t therapy. ~T' ~here is evid..'nee that gold treatment decr~ses phag~ytosis) 7~ It is ~ssible that one ~n¢ficial effe~ of gold treatment is due to im~irment of the uptake of the immune complexes by the neutrophil. It ia also po~sibie that gold treatment may

EXTRAART~CUL~,=R RHEUMATOID ARTHRiTiS

decrease the amount of circulating immune compiex~. Lithium has also recently been reported beneficial in Felly syndrome. ~74 While the exact mechanism of action is unknown, lithium does cause enlargement of the total circulating neutrophil mass and accelerates neutrophit production without impairin/g neutrophii migration ~nto skin lesions, ~ The increased granulocyte production may }esuit from stimulation of granulocyte colony proliferation) v~ I t is suggested that agents that inhibit phagocytosis of immune complexes or that decrease their amount in the -blood should, help reverse the pathogenetie process at work in patients with Felly syndrome.

Lymphadenopathy L~,m~hadenopathy is generally accepted as part of the rheumatoid process, in one of the earlies! studies, ~7 of 293 patients with RA, 86 (~9.4%) had significant lymp]~ node enlargement compared with 26 (8.9%)' of 293 control subjects.' There was ~ a higher incidence in males, but there was no correlation between amount, or degree of Iym phadenopathy and disease activity, course of disease, or type ~of onset. In a controlled s~udy by Robertson et al., ~7~ 100 patierits with active RA were compared with 100 patients with a variety of other conditions. They found that lymph node enlargement was significantly more common and more marked in rheumatoid patients in axillary, epitrochlear, a n d inguinal regions but not above the clavicles. Although in a few cases there was a generalized lymph nod~ enlargement, the majority of patients had lymphadenopathy near actively inflammed joints. They also noted that lymph node enlargement was significantly greater in males than in females in both the rheumatoid and control groups of patiaats. The amount of lymph node enlargemeht was greater in rheumatoid faczor-positive patients and in those with active disease with erythrocyte sedimentation ~ates above 30 mm/hr, By lymphangiography, only nonspecifie inflammatory changes were noted, with no evidence of lymphangiectasis or lymphatic blockage. A coarse granular appearance was noted. Generalized lymph node enlargement should raise the possibility of a retieulosis that upper-

161

ently occurs slightly more often in patients with RA than in the general population) 19 Generalized lymph node enlargement may also raise the possibility of a malignant lymphoma. Rheumatoid follicular hyperplasia may simulate malignant nodular (follicular) lymphoma? ~°'=SzInvestigators ls°'ls~ pointed out that the presence of discrete follicles with active germinal centers surrounded by a welt-demarcated cuff of lymphocytes and the presence of numerous plasma cells in the interfollicular areas, and proliferation of vascular ;endothelium, are features of a benign rather than a malignant process.

Neurologic invoh,entent The major ~ypes of nervous system involvement include nodules in CNS, cerebral vasculitis, cervical myelopathy due to atlantoaxial subluxation, entrapment or compression neuropathy (carpal tunnel syndrome, tarsal tunnel syndrome, ulnar nerve entrapment, and posterior intei'osseous nerve entrapment), and neuropathy due to arteritis. A more complete tabulation is shown in Table 7, ~: As with other organ systems, the CNS can be involved with rheumatoid nodules, as infrequently reporlcd) We4 Table 7, Neurologic ManiJestatlons of Rheurnato|d Artt~rlzis AT~icu|ar.ce|vic.e,~ ~pi~e dise~sQ CerVIcal sublgxstions (four types) C1 moves anteriorty or~ C2 C1 moves posteriorly on C2 VertieeI subluxation of odontoid "'Staircase- ot multipre lower leve~subluxatioP,s Radiologic findings, often with clinical symptoms "'lDotlble crush" syndrome Na~'rowed disc spaces above C5 Radio|ogic findings withouz cfinicsl symptoms Vertebral plate erosion Apophyseal joint erosion Basi~ar impression of the skull Extraarticular Peripheral neurop~thiss Compression reading to entrapment Mild sensory neutopathy with e good prognosis Diffg~ sensc~¢imotorneuropa¢hy Fufnninant sensorimotor neuropathy Vasculifis Mononeu~tis complex Cewebra! vascghfis Dural rheumatoid nodules causing brain ar~t ~pina] cord compression

~u~apT~ from ref 182,

162

ERIC R, HURD

A~

I~ome~

OfC,h of otk~s(C))

Pos)~

A~nte~ I~joment

hgamen~

|++oment of

Synov~o! +}Ore)

o)~s

o+ olios {C I )

An!errOr o1!on~O0~io)

/

hgomen!

{C 3)

process

/ Fig+ 2+ Anatomic telatlon of the odonto)d arocess of C2 w~th synovia! | o | n t s a n d

Body of o~,s(C2)

wllh t h e Z n t e a o r n)¢h a n d l t a n s Y e r ~ | | g ~ {£:31

Recently, several cases compatible with cerebral vasculitis wen reported+ 's~ Postmortem examination of one patient sh~owed lgM d e . s i t with rheumatoid factor activity in the ehoroid plex. US IS~

+

Vertebral bodies may be affected by presence of nodules with" eventual erosion and collapseJS+ ,s,+ Three other types of cervical spine involvement have been reported. One is rheumatoid discitis. '~ In this condition the annulus fibrosus and normal intervertel~ral disc substance are replaced by rheumatoid pannus, which arises directly in the middle of the neur~,~entral joints. The second is spinal cord i~ury and myelopathic disease resulting from thickening and fibrosis of the dura without ~ n e compressionJ ~' The third and most common type of cervical spine involvement is atlantoaxial sub!uxation with secondary cervical myelopathy. The odontoid p forms two synovial joints, one anteriorly with the atlas and one ~steriorly with the transverse ligament of the atlas (Fig. 2)++02Thus both the ~ontoid proc~Ls itself and the transverse ligament are subject to erosion because of their proximity to synovial tissue. Laxity of the transverse ligament also may occur, allowing slippage of the ~ontoid process lZmsteriorty, causing pressure on the

merit o! the ;;tlas (C), f+om Boyle aria 8uchatmSn+ +*

spinal cord. In addition, vertebrobasilar insul~eieney +may result from torsion of the vertebral arteries caused by the sublaxation+ By x-ray of the cervical spine using lateral tomography in flexion, subluxation is probably present if the distance between the ~sterior as~=ct of the anterior arch of the atlas and the anterior part of the ~ontoid process is greater than 2+5 mm in females and 3+0 mm in males. Subluxation can be detected clinically by gently rocking the head. Using the 3-ram x+ray criterion, atlantoaxial subluxation was found in 36 of tO0 successive rheumatoid patients+ 'gs Other studies found subluxation in 25% of 76 outpa+ tieats studied, '0+ 19% of hospitalized patients, '9~ and 71% of rheumatoid patients with neck symptoms+,% Nakano +s~ described four types of ~c¢ical subluxation (Table 7): (1) C t moves anteriorly on C2. which as described above is the most common form; (2) CI moves ~ t e r i o r l y on C2, resulting from severe erosion or fracture of the odontoid; (3) vertical subluxation of the orlontold and M y of C2, which is rare and results from destruction of the lateral atlantoaxial joints or of the ~ n e around the foramen magnum; and (4) "staircase" subluxation or subluxation of one vertebra on another, often being multiple and

EXTRAARTtCULAR nHEUMATOtD ARTHRITIS

caused by destruction of the apophyseaf joints. It occurs l~low the level of C2 ~and is the second most common type of cervical sublt~xation. The combination of degenerative disease of the cervical spine wkh variable degrees of spondytosis and the carpal tunnel syndrome occurring in a patient with RA has been termed the "'double crush" syndrome. Neuro~ogic involvement consists primarily of cervical cord myeiopathy with a pathologic increase in deep tendon reflexes or positive plantar responses. In one study, ~*~24 of 36 patients with atlamoaxial subluxation by x-ray had symptoms of cervical cord myelopathy. These symploms may increase in se~'erity, and death may result from severe compression of the cord, obstruction of the vertebral arteries, or snapping of the weakened odontoid process, which impinges into the foremen magnum, t~7'~9~ Surgical fixation is necessary when there is gross vertebral displacement,v~9However, conserv~ttive treatment such as attempting to immobilize the neck with a cervical collar is probably tile best therapy, z92 In f,~ct, surgical therapy has not been ideal, since neurologie complaints frequently return. ~°° Studies of x-rays of t30 patients showed that over a 5-14-yr folIowup period 46 patients died: 4 developed spinal cord involvement and 6 acquired symptoms of verlebral ischemia. In the 84 survivors, approximately 25% increased their degree of subluxation, less than 50% remained the same, and 25% either improved or recovered completely.TM Neck trauma should be avoided if at all possible in these patients. Automobile accidents with whiplash injury, intubation, and extreme head positions under anesthesia or even at the hairdresser should all be avoided. However, in spite of the above considerations and precautions, the experience of the author suggests that the majority of patients with significant subtuxalton by x-ray do not have cord symptoms. Entrapment or compression neuropathies may occur in patients with RA (Table 8). =~2 These include the carpal tunnel and tarsal t~nnel syndromes, ulnar nerve entrapment syndrome, and entrapment of the posterior interosseous branch of the radial nerve. M e d i a n nerve. The carpal tunnel syndrome is the most common of these entrapment syndromes in RA. In a study of 29 patients2°z and 23 normal control individuals over the age of

163 Tsbto 8. Entrapment Syndromes of Rheumatoid Arthritis Media~ nerve Carpal tunnel syndrome "Doubte Crush" Syndrome of the median nerve Utt'~r rtewe Cubilsl canal s y n d r ~ r n e ~ l elbow C 8 ~ | Of Guyon s y ~ d r o m e ~ a t wrist "Double crush" syndrome of u~nar n~rve Radial nerve Posterior interosseous syndrome Sci~6c neme Tibial or common pe[onea! entrapment by a Baker (pop|iteal) cyst Common p~ronea| nerve Pressure palsy Posterior tibiel nerve Tarsal tunnel syndrome Med~at' placater syr~ome Lateral plantar syndrome Adapted from ref. ~82.

40 yr, the symptoms of numbness, tingling, and burning in the median nerve distribution were .found to be significantly increased in the patients. There was no relationship between symptoms and sex, duration of RA, erythrocyte sedimentation rate, rheumatoid factor, functional class, x-ray stage, limitation of wrist motion, swelling, or wrist tenderness. Symptoms were related to a positive Tinel test. By electromyography, symptomatic rheumatoid patients had significantly slower conduction across tbe carpal tunnel than the remaining rheumatoid patients. This study concluded that complaints of numbness, tingling, and burning in the median nerve distribution plus a positive Tinel (tapping over median nerve) or Phalen (flexion of wrist to compress median nerve) test suggests the diagnosis of carpal tunnel syndrome. The diagnosis can be substantiated by electromyography. Approximately two-thirds of patients with verified carpal tunnel syndrome will have prolonged median motor la!eneies when the nerve is stimulated at the wrist. "~2c" About 85%--95% of affecled hands will have prolongation of median distal sensory latencies (beyond 3.5 msee),z°'~In a group of 36 patients with early RA, the incidence of eleetrodiagnostic abnormalities was 5.5%. The incidence of patients with clinically diagnosed carpal tunnel syndrome who underwent electrical tests was 17%, and the overall incidence was 23%:'~ Sprinting the wrist in slight extension or injecting a cortieosteroid preparation into the carpal tunnelprovides

prompt shortqerm relief in the majority of c a s ~ 2°s However, patients with thenar atrophy or ~progressionof numbness and weakness should have surge.,'y,2°~Sectioning the ttansvers.e c a r o l ligament will usually relieve the patient's symptoms. The "double crush" syndrome is the combination of cervieat spondylosis and carpal tunnel syndrome in a patient with RA. Ulnar nerve. Ulnar nerve neuropalhy secondary to compression at the cubita! fo~a occurs uncommonly in the rheumatoid patient. Compression is due to synovitis extending extraarticularlyJs= A large olecranon bursa may also compress the dnar nerve. D~mpression and excision of the synovial mass results in alleviation of symptoms. Elbow entrapment causes weakness of the flexor carpi ulnads, flexor digiforum profundus of the fourth and fifth fingers, and intrinsic muscles. Sensory loss involves the dorsum of the ulnar aspect of the hand. Rarely the synovham within the carpal tunnel can bulge and compress the ulnar nerve proximal to Guyon's canal, resulting in symptoras that simulate ulnar nerve neuropathy at the etbow. If uh~ar nerve entrapment and lower cervical spine disease {C8, T1) occur coneomitanlIy, as wiIh the median nerve, it is known as the "double crush" syndrome of the ulnar nerve. hernia. A few patients have been reported with ~sterior interosseous ne~e paralysis secondary to RA. :~s'2~°ClinicaIly there is an inability to extend the fingers and thumb. The condition is a co~npression neuritis of the posterior inter<~seous nerve ~eeondary to elbow synovitis bulging anteriorly against the overlying supinator muscle. In many patients the diagnosis of extensor tendon rupture has erroneously been made.:°s Treatment by injection of corticosteroids may help. Synoveetomy with radial he~d resection may also be of value, Sciatic ~rvd. ~-Oeeas[ona! patients with RA and synovitis of a knee will develop poptiteal (Baker) e~ts. These may dissect into the calf and sometim~ rupture. When i~flamed they may elose'|y simulate thrombophlebitis, inbAud. ing a positive Hereon sign. If anticoagulants such as heparin are given, hemorrhage into the cyst may ~eur. Such a cyst may involve the peroneal or tibial nerves or both. t~z If the common peroneal nerve is involved, one will see paresis of the peroneal muscles, tibialis anterior,

~extensor hal|ucis longs, extensor digitor-um Iongus, and extensor digitorum brevis. Sensory I~s will occur over the latcraI leg and dorsum of the foot. When the tibiat nerve is involved, there will be weakness of the gastrocnemius, soleus, tibialis posterior, flexor digitorum longus, flexor hallueis longus, and the intrinsic muscles of the foot, including the heel and the posterolateral aspect of the calf. Aspiration of synoviat fluid from the knee joint ftllowed by, instillation of ca3rticosteroids may improve symptoms when popliteai or posterior calf cyst~ communicate with the k n ~ joint. If the cyst continues to be a problem symptomatleally, synoveetomy of the knee may be necessary in order to decrease syriovial fluid form.ation.'lf improvemefit is not permanent, then capful dissection and ligation of the pediele of the cyst may be required. Peroneat nerve. Pressure palsy of the common deep or superficial peroneat nerve is apparently due more to immobility and a pressurevulnerable area rather than a true complication of the rheumatoid processJ 82 Posterior tibiat nerve. The tarsal tunnd syndromem results from compression of the posterior lib-~al nerve beneath the flexor retinacufum along the m~ial malleolus in the foot. It caused by rheumatoid tea~ynovitis affecting the tendon sheaths of the tibialis posterior long foot flexor tendons. Ctini~Ily there are paresth~ias over the first three to:s, and patients may complain of "burning feet," especially at night, and may have di~culty with the intrinsic toe muscles. As with the carpal tunnel syndrome, l~at cortieosteroid injection may be b~e|pfuL A partial ~arsa| tunnel syndrome involving only the medial or lateral plantar nerces may also seen. Complaints include weakne~ or burning or the feet. Peripheral neuropathy is a well-recognized ~mplicalion of RA. ~2"-'~3A mild distal sensory neuropathy and a severe sensorimotor neuropathy (monoaeuritis m~ltiplex) are the two predominant clinical patterns) In ~ e h , the major etiologic factor is art occlusive arteriopathy."~ " ~ Ae~rding to one study,z~s segmental dern-yetination is the fundamental nerve abnormality i~ RA. In a study by Dyck etal., z~7nerve fi~r degeneration was found to be related to sites of vessels occluded due to arteritis. With the

EXTRAARTtCULAR RHEUMATOID ARTHRITIS

distal sensory neuropathy, patients may c o r n plain, of paresthesias, dysesthesias, o r `• burn in g feeC' Examination may show decreased touch and pin sensation distally in the toes and feet and decreased vibratory senlsation. With the.more severe sensorimotor nearopathy, the pafie,n~t may have symme_trie_distal weakness of the limbs in addition to diminished totich and: vibratory sensations. In ,a ~tudy of five patierfts with rheumatoid neuropathy of vascular etiology, n ~ e fibers showed axonal degeneration,z~s One patient wi~h acule n~ropathy had acute necroti~ng arteritis in vessels of the surat ne~e with depo:dts of lgG, IgM, and B~C pr~ent. Mu&%te l~,rvolveme~

In the majority of patients with RA, there is some degree of chronic muscle w~kness and wasting. This is usually attributed to muscle atrophy resulting from lack of use of the joints, i.e., a disuse atrophy. Thus primary muscle involvement clinically is not a prominent feature 6f RA. However,.musele biopsies have shown a vasculhis in 10% of patients, z*~ In addition, nodular cellular infiltrates of I-2 mm in size composed mainly of iymphocytes (lymphorrhages) and plasn4a cells was believed to be specific for RA.~° Muscle fiber degeneration was present and most apparent nearest the cellular infiltrate. In a similar study nodular myositis was noted in 13 of l6 muscle b~opsms. " " '~ The cellular accumulatloas appear to be benign, however, s~nce muscle necrosis and elevation of muscle enzymes such as ereatine phosphokiuasc and aldolase are not seen in rheumatoid patients?-'~ Williams~ suggested that the rapid onset of myopathy and wasting of muscles that is (rccasionally seen in "rheumatoid patients over a 2~3-mo period might possibly ~ due to rapid dissolution of muscle mass brought about by re, ease of a lymphokine-likesubstance from the lymphocyte clusters. Such a mechanism is probably responsible for the muscle damage seen in patients with polymyositis. ~z~ Skin Skin involvement in RA ~.s nonspeei~c. Involvement can be s e r r a t e d into three major entities: vasculitis, subcutaneous n~ules, and Raynaud phenomenon (Table 9).

t65 Tetble 9, Skin IIgvolverr~ent in Rthoumatoid Arthlitis "~ VesselsInvo~eUI Vascufifis Oigital infarcts Peripheral gangrene Hemorrhagic b u a a e and ~Urpu~J¢ p.apulos Subcutageo~s n o d u l e s

Small muscular arledes Srnai! muscular arteries Po~ copilla~ venu~es Small and ~ed~um muscular •3rt~'iss t~r V6~S

{;veao ~etictll~fis ~

Subcutaneous ~heurnato~d n~¢es Ray~U~ pho~omeno~

"¢asculhis may invob~e sinai! muscular arteries, arteriol~, venu|es, and capiltadesY ~ The

l ~ o n s typically involve isolated segments of arterioles and small muscular arteries. R~ctive changes range I~om proliferative to neerotizing and include intramural deposition of fibrinoid material and a mixed cellular infiltrate consisting primarily of lymphocytes. In the more fulminant forms of rheumatoid disease large numbers of neutrophils or eosinophils, massive necrosis, thrombosis, or aneurysm formation may be present, but these findings are uncommonf25 When thcsQ_ghang~ are present, ischemia or hemorrhage may occur, producing myaigias, peripheral neuropathy, localized purpura, and cutaneous ulceration. However, such changes may also be due to venular-capillary derangernent, z~s The histologic features of venulitis and capiltaritis are similar to those seen in the arteries. It has been suggested that the initial histologic defect in rheumatoid disease is rapid plasma leakage from dilated terminal venules and capillaries?~ The resulting interstitial accumulation of protein-rich exudate correlates with proliferation of connective tissue with resultant connective tissue necrosis. " 224 According to Gdham (Table 9), digital infarcts and penph ral gang cue are probably due to vaseulitis of sinai! muscular arteries, hemorrhagic bullae, and purpur~c papules are produced by damage Io postc~apil~ary venules and su~utaneous nodules, ulcer, and livedo reticularis are due to involvement of small and medium m~cular arteries and veins, Unusual plaques and papules resembling granuloma annutare226 and lesions resembling pyoderma gangren~um have also been described.227Biopsy

EmC R.

t~,~

of the lesions-in these cases showed necrotizing vasculitis or rheumatoid granulom~is. Williams t2 reported the occurrence of nodules on (he p~lmar surfaces of the hands and fingers immediately following the development of I-2-mm slightly raised areas of cutaneous wascutitis:~ Initially, these areas are the size of a pencil point. They persist for 2-3;wk and are then followed by the development of a 2L3-mm painful ~ubcutancous nodule. In some patients with extensive vasculitis, cropsof as many as t0-20 such lesions may be seen within a 7-10-day period. The incidence of clinical digital arteritis in ,RA has been reported as 34%-36.-5% in males and 18%-32.4% in females, aS'n9 Both studies showed that the incidence of arteritis varies in proportion to the number of times the patients are examiJted. The incidence rose from 4.2% at the first-examination to 33.9% at the fourth examination. One study "-:9also'pointed out that distinction should be made between nail-fold lesions and splinter hemorrfiages, since splinter hemorrhages occur in other diseases and in the normal popul',tlion, zJ~'2~ Nail-fold lesions, however, occurred only in adult RA patients and not in the normal controls in this study, n° q'he incidence of nail-fold lesions was t4.6% in males and 4,6% in females, with an overall incidence of 7.9%. Rheumatoid vasculitis tends to occur in patients w~th high titetrs of IgM rheumatoid factor and seldom occurs in seronegative RA, 23'-'34 It is associaled with a decreased complement level in the b l o o d , z3J Recently it "~vas shown that IgG rheumatoid factor and low molecular weight (75) IgM are present in the blood in a large nttmber of patients, z~*':'~6 For example, IgG rheumatoid factor was found in 67% of patients with rheumatoid vasculitis and only 18% of patients without vaseulitLs, z~ Although they are probably of no clinical significa..ncc, dermoepidermal immunogiobulin deposits staining primarily for [gM, C3, and fibrinogen have been noted in patients with RA. :37''~s The presence of the deposits correlated with presence of serum cryoglobulins.

Circulating Immune Complexes and Serum ttype~'viscosity Syndrome The presence of immune complexes during the course of RA has been shown by studies of synovial tissue, synovial fluid, and serum

HUF~O

samples. 2~249 The complexes of intermediate. size (t l - t S S ) are presumably produced by the combination of lgG with .lgG-rheumatoid factor (RF). According to Winchester et al., ~5° some tgG complexes will fix complement although isolated IgG directs will not. TM These complexes apparently c_an react with lgM RF to form igG-IgM-C" complexes? ~4 Clinical features seen in patients with the rheumatoid hyperviscosity syndrome include, in addition to serum hyperviscosity, nodular RA, a high tiler of rheumatoid factor, bleeding diathesis, dyspnea, and weakness and palmar erythema. ~sz Crygiobulinemia may aiso result from the precipitation of thesc rheumatoid fa'ctor-lgG. complexes. -'*J.z~4 Recent studies have described the use of a sensitive test for determination of both circulating and intraarticu}ar immune o,~mplexes. This test involves a measure of immune complexes that bind to ~"'~l-Clq.'5~ Results showed that the serum C Iq binding activity (Ctq BA) in patients with RA and extraarticular disease manifestations (40% ± 34% in those with IgM RF, 32% ± 29%' in those who were factor negative) was significantly increased as compared to the serum Clq BA in patients with joint disease al_one {24% ± 30% in those with ;heumatoid factor, I0% .-+ 13% in those without). Other t~ts that have been used for detection of immune complexes include use of monoclonal rheumatoid factor) 4~ Kaji cell assay," -'~ platelet agglutination, '4~ and histamine release method 257 The presence cf circulating immune complexes correlates with many extraarticular nmnifestations of RA. ~OJt~S

There are no specific bone lesions associated with RA. However. the features of osteopenia, rib erosions, granulomatous lesions, and geodes

have been described in these patients. Ostcopcnia in rheumatoid patients is by far the most common type of bone involvement. It occurs in patients who have never received corticosteroids as well as in those who have. 2~ The causes are Probably multiplc, with contributions from generalized malnutrition, immobilization due to the disease, loss of anabolie effects of androgens and estrogens in patients of older age

EXTAAARTICULAR RHEU~4",/~'I-~Ot~) ARTHRITIS

groups, and possibly, excessive generalized protein catabolism brought about by the disease process. -'5~ The major elinic~:t manifestation ofosteopcnia is fractu_re, occurring either spontaneously or in association with minimal irauma. Most of these fractures involve the co!!apse of the dorsal or lumbar verlebrae. Other, less common ~ites are th~ ribs, hips, femurs, libia; and humeri. The pain of such fractures may simulate a flare-up of the RA or an acute gouty attaclc ~9 An interesting and unusual manifestation of RA is chat of rib erosions. They consist of a localized notch or a more diffuse erosion involving the outer aspects of the second to the sixth ribs, at or just beyond the angle of the rib. :6~'~'~1 The erosions were more easily seen on x-rays of the shoulder than by routine chest film. Clinically, the patients were disabled, with stiff shoulders and a dorsal kyphosis. It is believed that ~he erosions resuhed from pressure from the fixed scapulae and'frequently were associated with an overlying acquired bursa. Subchondral granuiomatous lesions that appear as cystic or ,lytic areas on roentgenograms are frequent findings in r h e u m a t o i d pat ients.-%-',-'6~ The geologists" term geode' has been used to describe the radio~ogic appearance of cavities in the bone ends in patients with various forms of arthritis. They have beet= reported in patients with RA. -'~ Jayson and co-workers :~4"2~-~showed that use of a swollen joint produces a high ihtraarticular pressure that in patients whose articular surfaces have been eroded and weakened by disease could lead to extrusion of the joint contents into the bone ends. At some subsequent time the communication between the knee and geode then closes and is obliterated by the dense fibrous tissue. Occasionally, as the geode contents become static, calcium aggregates within its center, producing a Iarge co~tral radioopaque mass. In one particular case 2~~'6~ calcified geodes were present in the upper end of the left tibia and in the right lateral femoral condyle, This topic has been extensively reviewed.:~

Hematologic Abnormalities The most common hematologic abnormalities seen in patients with R.A are anemia, eosinophitin, and Felty syrtdrome {see separate section on

]67

i--city syndrome, abbve). The types of anemia that may be seen-are normocytic, hypoehromic, megialoblastic, and sideroblastie. The most important type of anemia ,is the normoeytic hypochromie form. Approximately 65% of women and 45% of, men with R A have this type of ane~ia. ~r The l~emoglobu~in concentration correlates well with activity of the disease and the erythro.cyte sedimentation rate (ESR), although there is no correlation with duration of the arthritis. 2~ The plasma-iron level is low, and there is no increase in plasma iron binding capacity, z~'9 In one series the m ~ n hemoglobin concentration was 11.7 g/all i n patients as compared with 14.9 g/,d| ~in controls, The mean hematocrit level was 38.2% for patients and 43.t % for controls. ~-7°The mechanisms involved in the pathogenesis of this type-of anemia have been extensively studied, Some of the demonstrated abnormalities are shown in Table 10. In one study of rheumatoid patients the bone marrow iron content was moderately.decreased as compared with ~aormal controls} ~ In a histologie study by Muirden ~72 of I00 .synovial membranes, iron deposits were seen in 96, and some were extensive. Electron microscopic cxan.tination showed ferrhin within synovial cell cytoplasm and concentrated into [ysosomes irt t6 of 20 biopsies. Muirdert suggested that the iron deposits arose from continued .oozing of blood l'rom the vascular granulation tissue into the synoviai cavity. In. fact, the sequcnce.from .erythrophagocytosis to ferritin formation could be followed with the electron microscope. He also showed data suggesting that iron given as parenteral therapy found its way into synovial macrophages. A highly significant relationship was found between the presence of anemia due to RA and the extent of iron deposits in the synoviuni. He also found a relationship between the duration of disease in the joint, the grade of x-ray change, and tJ~e iron deposits. He concluded that the synovial membrane is an Table 10. Pathogene~is of Norrnocytic A~qemia in RA i~on absorption normal or slightly decreased Bone marrow iron deposits variable but mosdy normal Synovia[ iron deposits markedty increased Small increase" in plasma relume and hemodilution (primar=~ • in Ferry syndromet Blood loss from salicyla|es and other an6inttarnmatoxy ag0nts Fa~Jure of f~::~nem a r r o w tO increase e~throcyte producl=o~

!,68

important source of iron sequestration and that a delay in release of iron from this and the rcticul~endotheliat storage sites could explain many of the features of the anemia of RA° A small increase in plasma volume with hemodilution ocqurs in a small number of patients, particularly in those with Felty syndrome with a large spleen, zTJ''74 The average" spleen in rheumatoid patients has been found to be increased twofold in size and weight.2~'s Blood t o s s o f up to 4 rot/day may occur in patients taking sa[ieylates?~6 However, this is enough blood loss to produce anemia only in menstruating women with margina| iron stores. ~7 Thefts is no evidence to suggest that continued salieylate therapy enhances the degree of anemia in patients with RA in the absence ot" gastrointestinal mucosal ulceration. '77 Only slightly increased levels of erythropoietin have been found ~in rheumatoida~patientsPK Why erythropoieti~ production is n~i more strikingly increased is not known. Another possible mechanism is that rheumatoid patients commonly have low serum albumin levels; ~ tow gerum albumin contributes to a diminb~hed production of erythroeytes and prevents correction of anemia even in the presence of adequate iron. ~7~ Megaloblastic anemia has been reported" in rheumatoid patients, but the incidence may be increased only with folate defieieney.~ Eosinophifia ranging from 20% to 89% has ~ e n re~rtofl in patients with severe deforming articular disease and a high prevalence of rheumatoid vasculitis, pleuritis, and subcutaneous nodules}~''~s~ The cause of the eosinophilia is unknown. The incidence of eosinophilia in rheumatoid patients is low.

Gastrointestinal and Liver ~eolventem No specific gastrointestinal lesions associated wilh the rheumat~d process have ~ e n d~¢ribed except possibly arteritis of the l>awel and of other intraabdominat structures. Involvement of small arteries can cause multiple ischemic ulcers of the intestine, which usually cause severe hemorrhage and may pcrrorate. 's~ Involvement of larger arteries may cause segmental or extensive bowel gangrene or intraperitoaeal hemorrhage. :~" Acute arteritis may occur in hepatic, cystic, pancreatic, and renal arteries and in vessels of the peritoneum}s~ Perisplenitis and splenic infarcts may cause left hypochondrial

~RIC R. HURO

pain in rheumatoid patients? s~ Thus necrotizing arteritis should be considered in any rheumatoid patient with an acute abdomen. In a few reports malabsorption syndrome has been documented.2~7'25s In these ~ s e s there was very little histologic eviderice of villous atrophy of the small bowel. In some patients, primary amyloid involvement within the gastrointestinal tract resulted in infarction and pe|'foration.2s9 Most ,gastrointestinal disease in patients with RA is related to the various antiinflammatory or immunosappressive agents used for treatment. In one instance* chronic ulceration of the as~nding colon occurred in a 57-yr-old female treated with eorticosteroids for her RA. It was \ suggested thai both the eortieosteroids and vasculitis-induced isehemia may have been etiologically important. Liver involvement is rarely seen in patients with pure RA. Most liver involvement is assoc i a t ~ with either Felty or Sj6gren syndrome or some type of overlap syndrome and includes a few isolated cases of primary biliary cirrhosis or chronic aggressive hepatitis5m

A no'loidosis Secondary amyloidosis may be seen infrequently in patients with RA. z~z The incidence of amylo[d in rheumatoid patients varies considerably in various studies, a~ shown in Table ! 1. Thus it is dil~icult to determine the true incidence. In this author's experience, it is extremely uncommon from a clinical standpoint. Although there is much individual variation, clinical evidence of amyloidosis usually appears several years after the onset of RA. and the diagnosis is seldom made during the first 2 yr of the disease."'97 In one study it occurred at age 1-41 yr (mean 16) after the onset of arthritis:~" Man~, organs can be involved. Ren. i invoh'emeat causes the most common as well as the most serious symptoms. One of the most Tab|e 11. lnc{den©m ot Amy{oiclosls | . Rheumato|d Arlhritis No of RA Paben~s

~81" ~ 28 289 ; tSf

Pe~r~nta~ W~lh A m v ~

~ef

14 6t 29 5

293 294 295 2~

* Postmortem ser{@S t O~agno~s mode by metal i~olmsy.

E~RAARTICULAR RHEUMATOID ARTHRITIS

t6~

frequent clinical findings is proteinuria, which may b e severe ertough to cause the nephrotic syndrome. Gastrointestinal amyloidosis m a y cause bleeding or malabsorptionfl ~s-zc~ Enlargement of the liver or spleen m a y also occur. O t h e r sites that may contain amyloid include the gingiva, rectum, lymph nodes, bone marrow, skin, endometrium, adrenals, thyroid, parathyroids, pituitary, heart, lungs, and urinary bladderJ ~ The survival time after diagnosis of'amytoid in rheumatoid patients has been as long as 8 yr in one s t u d y J °~ The diagnosis is .best m a d e by bioosy. Sites well recognized as suitable for the biopsy diagnosis include the gingiva, liver, kidney, and rectum. O f these, the rectum is the preferred site. In one study, ~°~ 70%-75% of rectal biopsies were positive in known cases of amyloidosis. Rectal biopsy is a simple procedure causing little discomfort to the patient and almost devoid o f d a n g e r J °~ In a study by Blum and Sohar, ~°~ 2t of 24 renal biopsies (87.5%) in proven cases of amyloidosis contained amyloid. In contrast, in the same studies only 13 of 27 (48%) liver biopsies and 6 of 32 (19%) gingivai biopsies were positive for amyloid. One ~ s s i b l e reason for the decreased yield by liver biopsy is that the amyloid deposits in the liver are commonly restricted to the periportat vessels, and these regions may not be presented in small needle biopsy specimens. ~°~ It should be pointed oul that there m a y be an increased risk of bleeding associated with kidney

and liver biopsies in this condition. These sites, of course, are inaecessable for hemostasis. The pathologic diagnosis is made by use o f congo red staining or methyl violet metaehromasia. in addition, amyloid fluoresces when stained with Thioflavine T. By examination of congo red-stained sections with the polarizing microscope, one can observe green birefringent material. Finally, amyloid fibrils are characteristic in electron microscopy. In recent years it has been shown that some preparations o f amyloid appear to be identical with the sequences of aminoterminal portions of h a m a n light chains, ~°~-~°~ although some amyloid material does not originate from immunoglobutin moleculesJ °s,~°9

Laryngeal Involvement Cridoarytenoid joint disease due to the rheumatoid process may cause pain or dimculty with swallowing, hoarseness, dyspnea, and a feeling o f fullne~ in the throat. Stridor m a y also lye present. If the joints e immobilized the vocal cords m a y be addncted to the midline, producing a marked impairment in an airway diameter. Superimposed respiratory infection can cause life-threatening airway '' obstruction d u e to laryngeal and cord edema. 3~° The possible presence of ~ m p r o m i s e d ¢ricoarytenoid motion should be borne in mind when intubation is needed in a patient with RA. Arytenoideetonly m a y rarely be necessary for treatment o f this condition.

REFERENCES

I. Schmld FR, Cooper NS. Ziff M. eta|: Attcrifis in rheumatoid arthritis, Am J Mcd 30:56, 196~ 2. Thomp-~n M: The clinical features of rhcuma~old disea,~, in Dixon AStJ (ed): Progress in Clinical Rheuma~olog~. London, Churchill, [965 3. Kellgren It J: Epidemiologyof rheumatoid arthritis, in Dulk©r J JR. Alexander WRM (eds): Rheumatic Diseases. Baltimore. Williams & Wilkins, 1968 4. Hart FD: Rh~umaloid arthritis: Extra-articular manifestatlong Br Mud J 3:i3i. 1969 5. ~ r n ~ CG. Turnhul! At.. Vernon-Roberts 8: Fctty:s syndrome: A clinical aM ~dmtogical survey of 21 patients and their t~.I~as~ to l~:atmgaL Ann Rheum Dis 30:359. 197l

6. Ogryz[o MA: Difft~s¢ syslemic rhcumato/d disease. A ~ Rheum Dis 12:323, ;953 7~ ltart F|L Guiding JR, MacKen;,ieD||: Nearopathy in rhcutnatoid disease. Arm Rheum Dis I6:471, 1957 8. Bywalers EGL, Scott JT; The ~atural history of va~ular lesions in rheumatoidarlhrilis. J Chron Dis t6:905, 1963

9. HoIJingsworthJW, Saykaly: Symp~ium on ~heum~tie dls~ascs. Mcd Clio North Am 6]:217, I977 tO. Gordon DA, Stein .]L, Brodcr 1: Extra-articular fea|urcs of rheumatoid arthritis: A system'~lic~ma|ysi~or 12"/cas=. Am J Mud 54;445, 1973 |[, Boy|c JA, Buchanan WW: Clinica] Rheumatology. Philadelphia, Davis, t971, p 89 12. Williams RC: Rheumaloid arthritis as a systemic disgase, in: Major Problems in Internal Medicine IV. PhiIadclphia, Saunders, 1974 13. Sokoluff L: The Fathophysi~logyof peripheral blood v©~els in collagen discuses, in Otbi,~n M., Smilh D (~s): Tb~ Peripheral B l ~ Vessels. Baltimore, Williams & Wflkins, 1963 14~ ~koloff L. McC|uskcy RT, 8uaim JJ~:Va~ul~arityof the early subcutar~zousaod~|¢ of rheumatoid arthrith. Arch Palbo! 55:475. ig53 ~15. Sokotoff L. Wilens SL, Bunim JJ: Ancritis of striated muscle in rheumatoid arthritis. Am J Palhol 27:157, 1953 I6. Kulka JP: The va~ular lesionsassociated with rheumatoid nrthrilis. Bull Rheum Dis 10:20l, 1959

170

17. Keilgren J H , Bait J: Clini~l significance of the rheumatoid serum factor. Br Med J 1:523, 1959 18. Grucnwa|d P: Viscera| lesions ~na case of rheurra~toid arthritis. Arch I~thol 46:59, 1948 19, Baggenstoss At|, Rosenberg EF: Vis~ral: I ~ i o ~ associated with chrome infectiot~s (rheumatoid) arthritis. Arch Pathol 35:503, 1943 20. Baggenstoss A}I, Rosenberg El": Unusual cardiac lesions associated with chronic maltipM rheumatoid arthritis, Arch Pathol 37:54, 1944 21. Raven RW, Weber FP, Price LW: The neerobiotie nodules of rheumatoid arthritis: Case in which the scalp, abdominal wall (involving striped muscle), larynx, pericardium (involving myocardium), pleurae (involving lungs), and peritoneum were affected. Ann Rheum Dis 7:63, 1948 22. Robertson JL, Brinkman GL: Nodular rheumatoid lung disease. Am J Med 31:483, 1961 23. Bunim J J, Sokoluff L, Williams RR, et ah Rheuma. reid arthritis: A review of recent advances in our knowledge concerning pathology, diagnosis and treatment. J Chron Dis 1:168, |955 24. Healey LA. Wilske KR, Sagebiet RW: Rheumatoid nodules simttlating basal-cell carcinoma. N Er~gl J Med 277:7. 1967 25. Kellgrcn JH. Bal| J: Tendon le:.~ions in rheumatoid atthritL~: A clinico-pathologicat study. Ann Rheum Dis 9:48. 1950 26. Keil tl: The rheumatic sulrmutaneous n~ules and sima|ating lesions. Medicine (Baltimore) |7:261-389. |938 27. Mitta| A, Block MA, Wylie Jt4: Lipoid n~atu|es of chronic rhettmatnid arthriils presenting in the groin. Am J Surg 34:309. 1968 2g, I)ykmatt C J, Gaiens GJ. Go,.x:l AE: Linear su~ntaaeuus bands in rheumatoid arthritis: An unusual feral of rheumatoid granuloma. Ann Intern Med 63:134, 1965 29. Bu~im JJ. Ziff M, McF.wen C: Evaluation of prolonged cortlsoae therapy in theumaloM arthritis: A four year study. Am J Med |8:27. 1955 30. Jay,on M|V. Joncs DEP: ~ k d t i s and rheumatoid atthrilis. Ann R ~ u m Dis 30:343, 1971 31..lone; P. 2ayson MIV: Rheumatoid arthritis o~ t ~ eye. l)r<~: g ~ M ~ 6b:t t61, 197.3 32. Van der }Inert J: ~leron~aL~cLa pcrfora~s. Arch Ophtha|mol I l:| I 1. 1934 33, Verho¢ff |:tl, King MJ: ~:|erumalacla ~rforans: Rel~3rt c,f a ¢;~se in which ~he ¢y¢ w~asexamined micr~copi¢al|y. Arch Ophthalmo~ 20:10[3. 1938 34. |:.gger~ I1: Necro~clerltis nodosa a~.oclated with chronic rhe|tmatoid polyarthritis: Report of case. Arch Ophthahntfl 23:50t, |949 35, SmoleroffJW: E~cMratdivease in rhcumatoM arthritis: Report of three cases in one of which both eyes were st~di~ p~x~tmorten~. Arch Ophthaimol 29:9,~. t943 36. Gc~tr El.. Smith LS: Rheumatoid nodules of the eye, JAMA 14~:889. 1952 37. Anderson IL Margotis G: S¢leromalacia, Clinical and pathological study of a case with consideration of differential diagnosis, rclati~mship of collagen disease ,tad elTecl of AC~fil and cortisone therapy, Am J Ophthalmol 35;917, 1952 38, Duke-Elder,S, Leigh AG: System of Ophthalmology (cd 8, pt 2), London, Kimpton, 1965~ p 1098

ERIC R. HURD

39 Evans PJ, Eust~cc P: Sderoma|acia pcrforans associat~ with Crohn\~ d/scas~: Treated with ~ i u m versenate EDTA~ Br J Ophthalmo! 57:330, 1973 4{L Armstrong K, McGovern VJ: Sclcromalacia perforans with repair g~ftiag, Trans Ophthalmol Soe A~st 15:t10, |955 41, Rosenthal JW, Williams GT: Scleromalacia perleruns: As a complication of rheumatoid arthritis. Am J Ophthalmol 54:862, 1962 42. Torchh RT, Duan RE, Pease PJ: Fascia lata grafting in scleromaheia perforans, Am J Ophthatmol 66:705, 1968 43, Brown SI, Gray~n M: Marginal furrows: A characteristic corneal lesion of rheumatoid arthritis. Arch Ophthal, mot 79:563, 1968 44. Lyne A J: "Contact lens" cornea in rheumatoid arthritis. Br J Ophthalmoi 54;410, 1970 45. Kimura SJ, }logan MJ. O'Connor GR, Epstein WV: Uveitls and joint dlscase~. Clinical findings in 191 cases. Arch Ophthalmol 71:309, 1967 46, Stanworth A. Sharp 2~: Uveitis and rheumatic diseases. Ann Rheum Dis IS:ld,O, t956 47. Scherbct AL, MacKenzie AlL Nousek JE, et al: Ocular lesions in rheumatoid arthritis and related disorders with particular reference to retinopathy: A study of 741 patients treated with and without chloroquine drugs. N Engl J Med 273:360, 1965 48. Bc-ckerB, Miilc.'sDW: Cortieosteroids and intraocutar pressure. Arch Ophthalmol 70:5C4.1. 1963 49. Black RL, Og|esby RB. yon Sallrnan L, et ah Posterior ,~u~psuklr cataracts induced by corticosteroids in patlgnts with rheumatoid arthritis, -lAMA 174:166. 1960 50. Giles CL, Mason GL. Duff IF, et at: The association of cataract fofma~ion and systemic corticosteruid theral~v. JAMA |82:719~ 1962 51, Ogt~by RB, Black RL. yon SaBman L, el a|: Catatact~ in ~ t ~ n t s with rheumatlc disease treated with cortic~.~t¢toids Arch OphthatmM 66:625, 196| 52. Hart FD~ Casey TzS,, O'Riordan MD: Cataract and steroids, Br Med J t:1680. ! % i 53. Her&irM P: Ocularcomptications~drug t ~ t m e n t o f rheumatic dP.ocde~s~ Ann Physical Mod 7:...58. 1963 54. ~nfiglio T, Atwater EC: tleart disease in ~tients with .~crop¢~itiv¢ rheumatoid arthritis. Arch Intern M ~ I24:714. |969 55. Nomler AM+ Tarrier R+ Watts E, ¢t at: Ca~ia'c i at in rheumatoid arthritis. Ann Intern Med 79:800. 1973 56. Prakash R, Atassi A. Poske R, e t a | : Preealence of pcricardiat effusio,t and mit~bvalve involvement in patiet~ts with rheumatoid arthritis without cardiac symptor~s: An echocardtograph~c ct-aluation. N Engi J Med 289:5q7. t973 57. ~ n PA, Gibe,on DG: Cardiac invo|vement in rheumatoid arthritis: An ech~ardiographic study. Ann Rheum Dis 33:20, t974 58, Davia SE, Chitlin MD, de Castro CM, el al: Absence of ~hocardlographi¢ abnormalities of the anterior mitral valve leaflet in rheumatoid arthritis. Ann Intern Mcd g3:500, t975 59. Charo.~t JL: Clinical Lectures on Senile and Chronic Disca~. London~Syndenha m ~ i e t y , lgg i, p 172

EXTRAARTICULAR RHEUMATOID ARTHRITIS

60. BaylesTB: Rheumatoid arthritis and rheumatic heart disuse in autopsied cases, Am J Med Set 205:42, 1943 61. Egclius N, Grhle O, Jonsson E, et al: Cardiac changes in rheumatoid arthritis.-Ann Rheum Dis 14:1 l, 1955 62. Catheart ES, S ~ i e k DH: Rheumatoid heart disease: A study of the incidence and nature of cardiac l~ions in rheumatoid arthritis. N Engl J Mt:d 266:959, 1962 63. Kirk J, Cosh J: The ~riearditis of rheumatoid arthrit i s . Q J Med 38:397, 1969 64. ,Fr~nco AE. Levine HD, Hall AP: Rheumatoid ~rit:arditls: Report of 17 eases diagn~ed clinically. Ann Intern Med 77:837, 01972 65. Kindred LH, Heilbrunn A, Dunn M: Cholesterol ~ricarditis as.s~iated with rheumatoid arthritis: Treatment of pericardioctomy, A m J Cardiol 23:464, 1969 66. Alexander JS: A wzricardial effusion of "gold-paint'" appearance due to the presence of cholesterin. Br Mcd 3 2:463, t919 67. Ball GW. Schrohenloher R, Hester R: Gamma globulin complexes in rheumatoid pericardial fluid. Am J Med 58:123, 1975 68~ Andreis M. Hurd E: Macrophage migration inhibitory factor in rheumatoid ~riearditis, Arthritis Rheum 20:969. 1977 69. Thadani U, lveson JMI, Wright V: Cardiac tamt~nade, constrictive perlearditis and pericardial resection in rheumatoid arthritis. Medicine (Baltimore) 54:261, 1975 70. Walker WC, Wright V: Rheumatoid pleuritis. Ann Rheum Dis 26:467, 1967 71. K~nnedy WPU. Partridge REIL Matthews MB: Rheumatoid periearditis with cardiac failure treated by pericardiectomy. Br Heart J 28:602, 1966 72. Granirer LW: Pericardial effusion in rheumatoid arthritis. Mcd Clin North Am 30:562. 1946 73. Baggcnst~ AlL R~enberg EF: Visceral lesions as~.ciated with chronic infectious (rheumatoid) arthritis, Arch Pathol 35:503, 1943 74. Baggenstoss AH, Ro~cn~rg EF: Unusual cardiac l~sions associated with chronic multiple rheumatoid arthritis. Arch Pathol 37:54, 1944 75~ Barley W J, Uddin J, Kelly ItG: Rheumatoid arthritis complicated by constrictive pericarditis: Report of a case treated snec~sfully by pericardieetomy. Can Med Assoc J 1~:863, 1969 76. Szatkowski J, Inoue T: Chol~terol pericarditis: An unusual case of probable tubercular origin in a patient with rheumatoid arthritis. Am J Cardiol 12:730. 1963 77. Tubbs OS. Slade PRH, Turner-Warwick M: Constrictive pericarditis in as~.~ciation with rheumatoid arthritis. Thorax 19:555, 1964 78. Goehrs ItR, Bagge~toss Att, Slocumb CH: Cardiac lesions in rheumatoid arthritis. Arthritis Rheum 3:298, 1960 79. Crulckshank B: Heart l~ions in rheumatoid disca~. J Pathol Baeteriol 76:223, 1958 80. Lebowitz WB: The heart in rheumatoid ~rthritis (rheumatoid disease): A clinical and ~thologieal study of 62 cas~. Ann Intern Med 58:102, 1963 81. Gowans JDC: Complete h~rt block with StokesAdams syndrome due to rheumatoid heart d i s ~ : Reporl of a ease with autopsy findings. N Engl J Med 262:1012, 1960

t7'1

82. Sehoenc RH, Risse GB: Rheumatoid heart disease: A case study with illustrations. Ohio State Med 3 60:377, I964 83. Baggenstoss AH, Rosenberg EF: Unusual cardiac I~ions associated with chronic multiple rheumatoid arthritis. Arch Pathol 37:54, 1944 84. Lassiter GS, Tassy FT."Malignant rheumatoid disease with aortic stenosis. Arch Intern Med 116:930, 1965 85. Carpenter DF, Gdden A, Roberts WC: Quadrivalvular rheumatoid heart disease associated with left bundle branch block. Am J Med 43:922. 1967 86. Roberts WC, Kehoe JA, Carpenter DF, et ah Cardiac valvular l~ions in rheumatoid arthritis. Art:h Intern MOd 122:141. 1968 87, Sokoloff L: The ht:art in rheumatoid arthritis. Am Heart 3 45:635, 1953 88. Lev M, Bharati S, Hoffman FG. et ah The conduction system in rheumatoid arthritis with complete atrioventricular block. Am Heart J 90:78, 1975 89. Weintraub AM, Zvaifler N J: Rht:umatoid heart disease: A clinical as well as pathologic entity. Arthritis Rheum 5:327, 1962 90, Zvaifler N J, Weintraub AM: Aortitis and aortic insufficiency in the chronic rheumatic disorders: A reappraisaL Arthritis Rheum 6:241, 1963 91. Weintraub AM, Zvaifler N J: The occurrence of valvular and myocardial disease in patients with chronic joint deformity. Am J M~.~d35:145, 1963 92. Aronoff A, Bywaters EGL, Fearnley GR: Lung Icsions in rheumatoid arthrltis~ Br Med J 2:228, 1955 93. Cruickshank B: Rheumatoid arthritis and rheumatoid disease. Proc R Soc Med 50:462, 1957 94. Walker WC, Wright V: Rheumatoid pleuritis. Ann Rheum Dis 26:467, 1967 95. llorler AR. Thompson M: The pleural and pulmonary t:omplications of rheumatoid arthritis. Ann Intern Med 51:1179, 1959 96. Cart DT. Power Mtt: Pleural fluid glucose with special reference to its concentration in rheumatoid pleurisy with effusion. Chest 37:321, 1960 97. Lillir.gton GA, Cart DT, Mayne JG: Rheumatoid pleurisy with effusion. Arch Intern Med 128:764, 1971 98. Dodson Wit, Hollirgsworth JW: Pleural effusion in rheumatoid arthritis: Impaired transport of glucc~e, N Engl J MOd 275:1337, 1966 99. Itunder GG, McDuflie FC, Ilcpper NGG: Pleural fluid complement in systemic lupus erythematosus and rheumatoid arthritis, Ann Intern Med 76:357. 1972 I ~ . Berger ltW, Seckler SG: Pleural and pericardial effusion in rheumatoid disease. Ann Intern Med 64:1291, 1966 I01. Stengel B|:, Watson RR, Darling RJ: Pulmonary rheumatoid nodule with t:avitation and chronic lipid effusion. .IAMA 198:1263, 1966 IOZ Bower,GC: Chyliform pleural effusion in rheumatoid arthritis. Am Rev Rcspir Dis 97:455, 1968 103, Carmichael DS, Golding DN: Rheumatoid pleural effusion with "RA cells'" in the pleural fluid. Br Med 3 2:814, 1967 104. Levine H, STanto M, Grieble l IG, ct ah Rheumatoid factor in nonrheumatoid pleural effusions. Ann Intern Med 69:487, 1968

~72

f05. Dieppe PA: Empyema in rheumatoid arthritis. Ann Rheum Dis 34:lgI, 1975 106. Campbell GD, Webb WR: E~inophi|ie pleuraI effusion: A review with the presentation of seven new cases.' Am Rev gespir Dis 90:I94, 1964 10~. Williams RC Jr, DeBord JR) Mellby¢ O J, ¢t al: Studies of T- and B-lymph~yt~ in patients with connective tissue diseases.J Clin Invest 52:28~ ~973 10g. Martel W, Ahe~l iv/R, Mikkelsen WM, et at: Abstracts MOd Mud 18:99, 1968 109. Schneider PJ, Ehrlich GE: ~lmonary lesions in rheumatoid arthritis, Chest 62:747, 1972 l I0. BIodgett Re, Cera PJ Jr, Jon~ FL: Alveolar cell carcinoma associated with rheumatoid nodule. Chest 62:625, 1972 111. Stack BHR, Grant IWB: Rheumatoid inte~titial lung diseases. Br J Dis Chest 59:202, 1965 112. Portner MM, Gracle WA: Rheumatoid lung disease with cavitary nodules, pneumothorax and eosinophilia. N Engl J Mud 275:697, 1966 l 13. Capt~n A: Certain unusual ~diologieal appearances in the chest of coal-miners suffering from rheumatoid arthritis. Thorax 8:29, 1953 114. Morgan WKC. Wolfel DA: The lungs and pleura in rheumatoid arthritis. Am J Rocntgenol Radium Ther Nucl Mud 9g:334, 1966 I I5, Caplan A, Payne RB, Withey JL: A broader concept of Caplan~s syndrome related to rheumatoid factors, Thorax 17:205, 1967 116. Boyle JA, Buchanan WW: Clinical Rheumatology, Chap 6. Philadelphia, Davis, 1971 117. Decker J: in Hdlander JL, McCarty DJ (eds): Arthritis and Allied Conditions~ Philadelphia, Lea & Febig. er. 1972~ p 349 / 18, Watch AJ, Black J. Eh3igAT, ¢t al: Pneumo¢oniosis in carbon elect~:le makcrs~ Br J Ind Mud 16:274, 1959 119. Campbell JA: A case of Caplan's syndrome in a boiler-sealer. Thorax 13:177, t 958 120. Richards AG, Barnett GM: Rheumatoid lung changes associated with asbest~ Thorax 13:185, 1958 121. Chatgidakis CB. Theron CP: Rheumatoid pneumoeoniosis (Capla#s syndrome): A discussionof the disuse and a report of a ease in a Eurog~an Wit~'atersrand gold miner. Arch Environ Health 2:397, t96l i 22. Lamvik J: Rheumatoid pneumoconiosis: A case of Ca#an's syndrome in a chalk-mine worker. Acta Pathol Microbiol Stand 57:169, 1963 123. Caplan A, Cowen EDH, Gough J: Rheumatoid pneurc~.~coniosisin a foundry worker, Thorax 13:181, 1958 124. Ben~ek TG: Rheumatoid pneumoconiosls: Documentationof onset and pathogenic considerations. Am J M ~ 55:515, 1973 125. Dines DE, Ward LE: Caplan~s synd~me. Minn Mud 50:I707. 1967 126. Gough J, Rivers D, Seal RME: Pathological audies of m ~ i f i ~ pneumoeoniosis in coal-miners with rh~matoid arthritis (Caplan's syndrome), Thorax 10.'9, I955 127. Noonan CD, Ta)'lor I~B Jr, Engleman EP: Nodular rheumatoid disease ~of the I~ng with cavitation. Arthritis Rheum 6:23L 1963 128. Eatterson CD, tiara'tile WE. Piercx:JA: Rheumatoid lung disease. Ann Intern M ~ 62:685, 1965

ERIC R. HURD

|29. Banasza~ EF, Thiede WH, Fink iN: Hy~ensitiv* ity pneumonltis duc to ~ncaminatirn of an air~oonditioner. N Engl J M ~ 283:27I, I970 130. Dixon AStJ, Ball J: H b lung atnd chronic rheumato~ arthritis: A case report.. An~ Rheum Dis 16:24 I, 1957 13l, Sinciair RJG, Cruickshank B: A clinical and pathological stud)" of sixteen cases of rheumatoid arthritis with extensive visceral involvement ('rheumatoid d!sease'). Q J Med 25:313, 1956 132. El|man P, Ball RE: "Rheumatoid d!sr.ase7 with joint and p~monary manifestations~ Br Mcd J 2:816. 1948 [33. Rubin EH: Pulmonary lesions in "rheumatoid disease" with remarks on diffuse interstitial pulmonary fibrosis. Am J M ~ I9:569, 1955 134. Martel W, ~Abeil MR, Mikkelsen WMI ¢t al: Pulmonary and pleural l~ions in rheumatoid disease. Radiol~y 90:641, 1968 135. Doctor L, Snider GL: Diffuse interstitial pulmonary fibrosis associated with arthritis~ With comments ot~ the definition of rheumatoid lung disuse. Am Rev Respir Dis 85:413, 1962 136. Walker WC, Wrght V: Diffuse interstitial pulmonary fibrosis and rheumatoid arthritis. Ann Rheum Dis 28:252, 1969 13% Stack BHR, Grant IWB: Rheumatoid interstitial lung disease. Br J Dis Chest 59:202, 1965 138. Frank ST, Weg JG, Harkleroad LE, et al: Pulmonary dysfunction in rheumatoid disease. Ch~t 63:27. 1973 ~/39. Franklin EC, Holman HR, MLtller-E~rhard H J, et ah An unusual protein com~nent of high molecular weight in the serum of certain patients with rheumatoid arthritis. J Exp Mud 105:425, I ~ 7 140. Tomasi TB Jr, Fudenborg HH, Finby N: Possible rdationship of rheumatoid factors and pulmonary disease. Am J Mcd 33:243, 1962 141. Sievers K. Ale K. Schakir R~ et al: Studi~ of rheumatoid pulmonary disease. IL "Intermediate" protein componenls in the ~ r a of potients with rheumatoid arthritis With simultaneous plcuropulmonary l~ions. Aeta Tu~rc Scand 46:101, 1965 142 Dettoratius R J, Abmzzo JL, Williams RC: Immunofluoresc~entand immunologic studi~ of rheumatoid lung. Arch Intern Mud 129:441, 1972 I43. ~Horatius R J, Williams RC Jr: Rheumatoid factor accentuation of pulmonary lesions associated with ex~fi. mental diffuse prolife~tive lung disease. ArG~tritis Rheum 15:293, 1972 144. Baum J, Stastny P. Ziff M: Effects of the rheumatoid factor and antigen u n t i d y ¢om#ex~ on the v ~ e l s of the rat ~-sentery. J Immunol 93:985, 1964 145. Fehy AR: Arthritis in the adult associated with splenomegaly and lcuko~nia. Johns Hopkins M ~ J 35:16, 1924 146. Hannestad K: Presence of aggregated ~ globulin in ~rtain rheumatoid synovial effusions. Clin Exp lmmunol 2:51 I, I967 147, Winchester RJ, Agndlo V. Kunkel HG: Gamma globulin ~mplexes in synovial fluids of ~tients with rheumatoid arthritis: Partial characterizat~n and relationship to lowered ~m#ement levels. Clin Exp lmmunol 6:689, 1970 148~ Franklin EC. Kunkd HG, Ward JR: Clinical studies

EXTRAAR~CULAR RHEUMATOID ARTHR|TIS of seven ~tients with rheumatoid arthritis and uniquely large amounts of rheumatoid factor. Arthritis Rheum 1:400, 1958 149. Nor~-erg R: lgG ~mplexes in serum of rheumatoid arthritis patient. Sc~nd J tmmunol 3:229, 1974 150. Andreis M, Hard ER, Ziff M: Com~rison of the presence of immune complexes in F ltys syndrome and rheumatoid arthritis (RA). Arthrais Rheum 18:383, 1975 I51. Welsman M, Zvaifler ~-,tJ: Cryoimmuaoglobull. hernia in Felty's syndrome, Arthritis Rheum 19:103, 1976 152. Mowat AG, Baum J: Chemotaxis of poiymorphonuclear leakocytes from patients with rheumatoid arthritis. J Clin Invest 50:254I, 1971 153. Parker RL, Sehmid FR: Phagocytosis of particulate complexes of "r-globulin and rheumatoid favor. J lmmunol 88:519, 1962 154. Hard ER, LoSpalluto J, Ziff M: Formation of leukocyte inclusions in normal polymorphonaclear cells incubated with synovia! fluid. Arthritis Rheum 13:724, 1970 155. Cats A, Lafeber GJM, Klein F: tmmunoglobulin phagocytosis by gtanulocytes from sera and synovlal fluids in various rheumatoid and nonrheamatoid diseases. Ann Rheum Dis 34:146, 1975 15& Hollander JL, McCarty DJ, Astorga G, ct ah Studies on the pathogenesis of rheumatoid joint inflammation. L The "RA cell" and a working hypothesis. Ann Intern Mud 62:271, I965 157. Vaughan JH, Barnett EV, Sobel MV, et ah Intracyt~lasmic inclusions of immunoglobulins in rheumatoid arthritis and other diseases. Arthritis Rheum I 1:125, 1968 158, Kinsella TD, Baum J, Ziff M: lmmunofluorescent demonstration of an IgG-#~ complex in synovial lining ceils of rheumatoid synoviaI men'ft,,rane.Clan Exp lmmunol 4:265, 1969 159. Weissmann G, Zurier RB, Spieler PJ, et ah Mechanisms of I ~ o m a l enzyme reline from leukocytes exposed to immune complexes and other particles. J Exp MOd 134:149s, 1971 160. Taichman NS, Pryzanski W, Ranadive NS: Release of intracellular constituents from rabbit polymorphonuclear leakocytes exposed to soluble and insoluble immune complexes. Int Arch Allergy Appl Immunol 43:182, 1972 161. Paekman LM, Jayanetra P, Rothberg RM: Rheumatoid sera and soluble complexes: Nitroblue tet~zolium dye test and hexose monoph~phate shunt activation. Pediatrics 52:823, 1973 162. Turner RA, Sehumacher HR, Myers AR: Phag~ cycle function of polymorphonucl~r leukocytes in rheumatic diseases. 3 Clin Invest 52:1632, 1973 163. ~ e l PT, Hollingsworth JW: Com~rative morphology, respiration, and phagocytic function of leukocytes from blood and joint fluid in rheumatoid arthritis. 3 Clin Invest 45:580, 1966 I64. DeGruehy GC, Langley GR: Felty's syndrome. Australasian Ann MOd !0:292, 1961 165. Barnes GG, Turnbill AL, Vernon-Roberts B: Felty's syndrome: A c|ini~l zl~d pa'tholog[eal survey of 21 patien~ and their response to treatmenL Ann Rheum Dis 30:359, 1971 166, Denko CW, Zumpft CW: Chronic arthritis with splenomegaly and leukoponia, Arthritis Rheum 5:478, 1962

173 167. Ruderman M, Miller LM, pinaIs RS: Clinical and serologic observationson 27 patients with Fclty's syndrome, ArthritisRheum 11:377, 1968 168, Fabcr V, Eiling P: Leucocyte-specific antinuclear factors in ~tlents with Fc|ty½ syndrome, rheumatoid arthritis, s~temic lupus ¢rythematosus and oth¢~ diseases. Acta MOd Scand 179:257, 1966 169. Vincent PC, Levi JA, Maequeen A: The mechanism of neutropaenla in Felty's syndrome. Br J Haematol 27:463, 1974 t70. Hard ER, Andrels M, Ziff M: Phagocytosis of immune complexes by polymorphonuelear leukecytes in patients with Fehy's syndrome. Clin Exp lmmunol 28:413 1977 171. Gowans JDC, Salami M: Response of rheumatoid arthritis with leukopon~a to gold salts. N Engl J Mud 288:1~7, 1973 172. Hurd ER, Cheatum DE: Decreased spleen size and increased neut~phils in patients with Felty's syndrome: Effects ofgotd sodium thiomalate therapy..lAMA 235:2215, 1976 173. Jessop JD, Vernon-Roberts B, Harris J: Effects of gold ~lts and prednisolone on inflammatory mils. L Ph~gocytle exudates studiod by a 'skin-wlndow" technique in rheumatoid and control patients, Ann Rheum Dis 32:294, 1973 174~ Gupta RC, Robinson WA, Smyth CJ: Efficacy of lithium in rheumatoid arthritis with granul~ytoponia (Felty's syndrome)~ Arthritis Rheum 18:I79, 1975 175. Rothstein G, Clark.son DR, Larsen W, el al: Effect of lithium on neutrophil ma~ and prodaetion, N Engl J Mcd 298:I78, 1978 176. Gupta R, Robinson WA, Albrecht D: Granulopoietie activity in Felty's syndrome. Ann Rheum Dis 34:156, 1975 177. Short CL, Bauer W, Reynolds WE: Rheumatoid Arthritis. Cambridge, Mass., Harvard Unlv, 1957, p 31 I 178. Robertson MDJ, Hart FD, White WF, et al: Rheumatoid lymphadenopathy. Ann Rheum Dis 27:253, 1968 179. Lea A J: An association between the rheumatic dlseas~ and the reticuloses. Ann Rheum Dis 23:480, 1964 180. Nasanchuk JS, Schnitzer B: Follicular hyperplasia in lymph nodes from patients with rheumatoid arthritis. Cancer 24:343, 1969 I81, Motulsky AG, Wei~rg S~ Saphir O, et ah Lymph nodes in rheumatoid arthritis. Arch Intern Mud 90:660, I952 |82. N a k a ~ KK: Neuro|ogic complications of rheumatoid arthritis, Orthop Clin North Am 6:862, 1975 183. Maher JA: Dural nodules in rheumatoid arthritis: Report of a case. Arch Pathoi 58:354, 1954 184. Steiner JW, Gelbl~m AJ: Intracrania! manifestations in two ~ses of systemic rheumatoid disease, Arthritis Rheum 2:537, 1959 185. Skowronski T, Gaiter RA: Cerebral vasculitis associatod with rheumatoid disease--s ~ s e report. J Rheumatoi 1:473, 1974 18& Gupta VP, Ehrlieh GE: Organic brain syndrome in rheumatoid a~hritis following corti~steroid withdrawal. Arthritis Rheum 19:!333, 1976 187, Baggenstoss AH, Biek¢l WH, Ward LE: Rheums-

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told granulomatous nodules as destructive lesions of vertebrae. J ~ n c Joint Surf 34A:601, 1952 188, Luther A, Pearson CM, Rene RM: Ostcoly.tie vertebr~ai I~Aons as a manifestation of rheumaloid arthritis and related disorder. Arthritis Rheum 4:514, 1961 189~ Glay A, Runs G: Nodular rheumatoid vertebral lesions versus ankylosing spondylitis. Am J Roentgenot Radium Ther Nuel Med 94:631, 1965 190. Bland JH: Rheumatoid arthritis of the cervical spine. Bull Rheum Dis 18:471, 1967 191. Hopkins JS: Lower cervi~l rheumatoid subluxation with tetraplegia. J Bone Joint Surg 49B:46, 1967 192, Boyle JA, Buchanan WW: Clinical Rheumatology. Philadelphia, Davis, 197 I 193. Stevens JC, Cartlidge NEF, Saunders M, el ah Atlanto-axial subluxation and cervical myelol~mthyin rheumatoid arlhrltis. Q J Med 40:391, 1971 I94. Matthe~s JA: At|auto-axial sabluxatioa in rheumatoid arthritis, Ann Rheum Dis 28:260, 1969 t95. Sharp J. Purser DW: Spontancx)us atlanlo-axial dislocation in ankylosing spondylitis and rheumatoid arthritis. Ann Rheum Dis 20:47, 1961 196. Martel W: The occipito-atlanzo-axial joints in rheumatoid arthritis and ankylosing s~ndylitis. Am J R~nlgenol Radium Ther Nucl Med 86:223, I961 197. Davis FW Jr, Markley HE: Rheumatoid arthritis with death from medullary compression. Ann Intern Med 35:451, 1951 t98. Ford FR: Syncope, vertigo and dlsturbanees of vision resulting from inlermiltent obstruction of the ~'ertebral arteries due to defect in the odontoid process and excessive mobility of the second cervical vertebra. Bull Johns Hol~¢Kins Ilosp 91:168, 1952 199. Cregan JCF: Internal fixation of the unstable rheumatoid cert'ical spine. Ann Rheum Dis 25:242, 1966 200, Meljers KAE, Van Beusekom GT, Duyfjes F, et ah Treatment of dislocations in the cervical spine in rheumatoid arthritis and ankyl~ing spondylitis complicated by signs of cord compres,gion: A follow-up study. Ann Rheum Dis 32:88, 1973 201. Smith Pll, Benn RT, Sharp J: Natural history of rheumatoid cervical luxurious. Ann Rheum Dis 31:431, 1972 202. Hcrbison G J, Teng C, Martin Jlt, et al: Carpal tunnel syndrome in rheumatoid arthritis. Arc~ J Phys Med 52:68, 1973 203, Kopell HP, Goodgold J: Clini~l and e|eetrodiagnostie features of carpal tunnel syndrome. Arch Ph)'s Med Rehabii 49:371, 1968 204, Thomas JE, Lambert, Cseuz KA: Eleetrodiagn~tic aspects of the e a r ~ l tunnel syndrome. Arch Neurol 16:635, 1967 205. lloffman DE: C a r ~ i tunnel syndrome: Im~rtance of sensory nerve conduction studies in diagnosis, JAMA 233:983, 1975 206, Chamberlain MA, Corbett M: Carpal tunnel syndrome in ~ r l y rheumatoid arthritis. Ann Rheum Dis 29:149, 1970 207. Phalen GS: The carrel,tunnel syndrome: Sixteen yea~" experience in diagn~is and treatment of fix hundred fiftyffour hands. J Bone Joint Surf 48A:211, 1966 208, Millender Ltt, Nalebuff EA, Holdsworth DE: Poste-

ERIC R. HURt::) r i o r interosseous.necve syndrome secondary to rheumatoid synovitis. J Bone Joint Surg 55A:753, 1973 209. Murmur L, Lawrence JF. Dabois EL: Posterior intcrosseous nerve t~lsy due to rheumatoid arthritis. J 8one Joint Surf 49A:381, 1967 21~0. Popelka S. Vainio K: Entrapment of the ~ t e r i o r interosseous branch of the radial nerve in rheumatoid arthritis, Acts Octhop Scaod 45:370, 1974 211. Lloyd K, Agarwal A: Tarsal-tunnel syndrome, a presenting feature of rheumatoid arthritis, Br Med J 3:32, 1970 212, ~art FD, Guiding JR: Rheumatoid neuropathy. Br Med J I:1594, 1960 213. Pallis CA, Scott .IT: Peripheral neuropathy in rheumatoid arthritis. Br Med J 1:!141, 1965 214. Weller OR, Bruckner FE, Chamberlain MA: Rheumatoid neuropathy: A histological and electrophysiologi~l study. J Neurol Neur~urg Psychiatry 33:592. 1970 215, Iiaslock DI, Wright V. Harriman DGF: Neuromuscular disorders in rheumatoid arthritis: A motor*point muscle biopsy study. Q J Med 39:335, 1970 216. Beekett 3L, Dinn J J: Segmental demyelination in rheumatoid arthritis. Q J Med 16:71, 1972 217. Dyck PJ, Corm DI., Okazaki H: Neerotizing angic~ pathie neuropathy: Three-dimensional morphology of fiber degeneration related to sites of occluded vessels. Mayo Clin Proc 47:46t, 1972 218, Corm DL, MeDume FC, Dyck PJ: !mmunopathologic study of sural nerves in rheumatoid arthritis, Arthritis Rheum 15:!35. 1972 219. ~koloff L, Wilen~ SL, Bunim J J: Arteritis of striated muscle in rheumatoid arthritis. Am J Pathol 27:157, 195t 220. Stcincr G. Freund I~IA,Leichtentritt B, et at: Lesions of skeletal muscles in rheumatoid arthritis nodular polymyosiris. Am J Pathol 22:103, I946 221, DeForest GK. Bunting 1t, Kenney WE: Rheumatoid arthritis: Diagnostic significance of focal cellular accumulations in skeletal muscles. Au~ J Med 2:40, 1947 222. Hendriek F, Kuthan F. Tovarek J, et ah The eP.zymatie I~attern in the ~rum of rheumatoid Ixltients related to muscular w~sting. Scripts Med 39:63, 1966 223. Johann RL, Fink CW. Ziff M: Lympholoxin formation by lymphocytes and muscle in polymy~itis. J Clin lnv~t 51:2435, 1972 224. Git!iam IN: P e ~ n a l ~mmunic~tion 225. gulka JP: Vascular derangement in rheumaloid arthritis, in: M~crn Trends in Rheumatology, Chap 4. London, Butterworths, 1966 226. ~ k e r RJ. Johnson WC. Buffoon CF: Unusual skin l~ions of rheumatoid arthritis, ~rntatologica 143:300, 1971 227. Staiman LP, Rosenthal D. Yaworsky R, et ah Pyodcrma gangrenosum and rheumatoid arthritis. Arch ~ r m a t o l I I 1:1020, 1975 228, Guiding JR, Hamilton MG, Gill RS: Artefitis of rheumatoid arthritis. Br J Dermatol 77:207, 1965 229, Dequeker J, gocsberg G: Digital ~pillaritis in rheumatoid arthritis. Acts Rheum ~ a n d 13:299, 1967 230. Dowling RH: Sub-unguat splinter haemorrhages. Pe~stgrad M ~ J 40:595, 1964 231, Kitl-gtlrick ZM, Greenh,~rg PA, Sanford JP: Splint~

E

U~R RHEUMATOID A~THRffIS

hemorrhag~their clinical signifi~n¢,. Arch Intern Med I ~5:730, 1965 232. ~hmld FR, C o o e r NS, Ziff M. ~ a|: Arteritis Jn rheumatoid arthritis. Am.J Med 30:56, 196I 233. Mongan ~S, C a ~ RM, ~ta-eoxRF, ct al: A study of the relation of seronegative and seroposltive r~umatoid arthritis to ~eh other and to n~rotizlng va~ulitis. Am 3 Med 47:23~ 1969 234. Elx~teln WV, Engleman EP:" The relation of the rheumatoid factor contcm of serum to clinical neurovaseular m~nlfcstadons Of rheumatoid arthrhis~ Arthritis Rheum 2:250, 1959 235. Thiofilopou|os AN, Burtonboy G. L~Sf~al|uto J J, el al: IgG *rheumatoid factor and low molecular weight lgM~ an a ~ i a t i o n with vascn/itis~ Arthritis Rheum 17:272. 1974 236. Stage DE. Mannik M: 7SyM-globu|in in rheumatoid arthritis: Evaluation of its clinical significance. Arthritis Rheum 14:440. 1971 237. Donde R: Orthopa~ie Review IV (Eighth European Rheumatology Congrcss~ Helsinki, ["inland, 1975)~ 1975, p 50 (~npublishcxt) 23g. B~ldassare A, Wi~s T. T ~ i C, e t a | : Immune complexes in the skin of patients with rheumatoid arthfitls~ Arthritis Rkecum 19:788 {al~tr) 239. Munthe E. Natvig JB: Charactefzation of IgG ¢omp~ex.~, in eiuat~ from rheumatoid tissue Clio Exp Imm~o! 8:249, 1971 240. Kinsella TD, Baum J. ZilF M: Immunofluore.scent demonstration of an IgG43t, complex in synovia| lining of rheumatoid synovial membrane C|in Exp Immanol 4:265, 1969 241. Hannestad K: Presencx:of aggregated y-globulin in certMn rheumatoid synovlal effuslons~ Clin Exp Immunol 2:51 I, 1967 242~ Winch~ter R& Agnel|o V. K~nkel HG: Gamma globulin complexes in synovlal ~uids of patients with rheumatoid arthritis: Partial characterlzatMn and relationship to lowered corn#creche levels. Clio Exp Immuno| 6:689~ 1970 243~ Winchester R J. Kunkc| HG~ Agaello V: Occurrcno= of *r-globulin com#exes in serum and joint fluid of rheumatoid arthritis patients: Use of mon~lonal rheumatoid factors as r~gcnts for their demonstration. J Exp M ~ 134:286s~ t971 244~ Franklin EC. Holman HR, M~ller-EIv2rhard IIJ~ et al: An unusual protei~ cx~m~nent of h i # mo|ccuMr weight in the ~rum of certain ~atien~ with rheumatoid arthritis. J ~ p Med |05:425. 1957 245. Kunke| ||G, Mflller-Ebcrhard HJ. Fudenberg l{tl, et al: Gamma globulin complex~ in rheumatoid arthritis and certain other conditions. J Clio Invest 40:! 1L 1961 246. Ch~irker WB, Tomasi TB: Low*molecular-weight rheumatoid factor. J Clio Inv~t a2:876, 1963 247. ~hrohenMher RE: Characteriz~tMn ofthc ~-gbalvalin com#ex~ present in certain ,.era having high tilers of anti-*r-globulin activity. J C|in Invest 45:50L 1966 248. Hann~tad K: Rheumatoid t'actors r~cting with auto~ogous r~tive*rG-glrb~lin and joint f~uid"~ aggregates. Clio Exp lmmtmol 3:671, 1968 249~ ~ RM, Mannik M. Gitliland Be, et al: Th¢ hypendsc~ity sy~rome in ~heutr'~atoid arthritis due to i n t e ~ i a t e ~mplexes form~ by ~lf-as~iation of IgG~ rhettmatoid factor. Aflhritis Rheum 18:9L I975

t75 250. Winch~ter RJ. Agnello V. Kunkel fIG: Gamma globulin complexes in synoviat fluids of paticms with rheumatoid arthritis: ~rtial characterization and relationship to lowered complcmem levels. Clin Exp Immuno} 6:689, 1970 251, Pop: RM, Teller DC, Mannik M: Intermediate comp|exc~ formed by self-association of lgG-rhcumatoid factors.Ann NY Acad ~ i ?~6:82. 1975 2S2, 3asin HE. LCSpaffuto 3~ Ziff M: Rheumatoid hypev visc~ity syndrome. Am J Med 49:484. 1970 253~ Capra 3D, Kunket HG: Amino acid sequence similarities in t~'o h~man ami gamma globulin antlb~ies. Proc Natl A~td Sci 67:87. 1970 254. Mcltzcr M. Franklin EC: Cryoglobu|incmia--A study of twenty-aloe paticnts. L lgG and IgM cryoglobalins and factors affecting cryopreciNtaMlhy~ Am 3 Med 40:828, 1966 255, Zublcr RI'L Nydcggcr U. Portia L|I. et al: Circulating and intra.artlcular immune ¢omMcxes in paticms with rheumatoid arthritis. Correlation of ~t-C Iq binding activily with clinical and bio~ogi~l features of the disease J CEn |nvcst 57:1308, 1976 256. Theofi|opoul~ AN, Wilson CB. Dixon F J: The R~ji ceil radioimmum assay for deleting immune eom#excs ia human sera.J Clio |nv¢~t 57:|69, 1976 257. Baumal R. BreWer I: Studi~ into the ~eurrence of so~uble antlgcn-amibcMy ,eom#cxe:~i~ dis~sc. L A b~otogV ~al assay for ..'~luble eom#excs. Ciin EXD lmmuno| 3:525r t968 258. Bjelle AO, Nilsson 81:.: ~teoF~rcrls in rheumatoid arthritis. Caleif Tissue Res 5:327. 1970 259. IlarI O|:: Complicaled rheumatoid disease. Br Med J 1:|3|. 196fi 260. Park W. Ward D. Ball J. ctal: Rheumatoid disuse and fib defects. Ann Rheum Dis 30:466, 1971 261. Anderson IF. Corrigan AB. Champion GD: Rib erosions in rheumatoid artltritiso Ann Rheum Dis 31:16. 1972 * 26Z Baggenstc~s AlL Biekd W|L Ward I.E: Rheumatoid granutomatous nodules as d~tructivc le~ions of vcrtcbrae. 3 Bone Joint Surg 34A:601, 1952 263. Cruick~;hank B, Madeod 3G. Shearer WS: Suharticular f~seudocysts in rheumatoid arthritis. 3 I:ae Radio| 5:218, 1954 264. 3ay~n MIV, Dixon ASI& Yeoman P: Unusual genes ('~ne cysts') in rhenmAltoid arthritis. Ann Rheum Dis 31:174. 1972 265. July,on MIV, Ru~nsteln D. Dixon AStJ: Imraarticuhr pressure and rheematoid geod~ {~ne "cysts'). Ann Rheum Dis 29:496, 1970 266. Gerber N J, Dixon ASIJ: Synovial cysts and juxtaarticular bc~ae cysts (g~es)~ Semin Arthritis Rheum 3:323. 1974 267. Mowat AG: tlematologic abnormaliti~ in rheumatoid arthritis. S~min Arthritis Rheum 1:195. 1971 268. Engst~t L, Strand~rg O: ttaematologi~l data and clini~! aetivity Of the rheumatoid disca~. Aeta Med Stand 180:13. 1966 269. Roy LMtt, Alexander WRM, Duthie J JR: Nature of anaemia in rheumatoid arthritis. L Metabolism of iron~ Ann Rheum Dis I4".¢,3, 1955 270. FreircMh EJ, R~'~ Ji:. Bayl¢~TB. et al: Radioactive iron metabolism and ©rythrocyte survival studies of t ~

176 meet~nism of the anemia asscbfated with rheumatokt arthritis. J Clio Invest 36:10,3, 1957 271. Kerr LMH: A n ~ t ~ for the deter.~r~natton of nan-harm iron in bone marrow. Bioehem J 67:627, 1,957 272. M~lirden KD: The anemia of rheunmtoid arthritis: The signi~can~ of iron deposits in the sYnovial membrane. Australasian Ann Med t9:97, 1970 273. Read HC, Woodbury JFL, Slaplcton JE~ ct ah Anemia in rheumatoid arthritis. IL Blood volume studies. Can Med Assoc J 87:7P,1, I962 274. Strandberg O: Blood, plasma and ~ed-ceil volumes in patients with rheumatoid arthritis or iron deficiency and in controls. Aeta Med Sound 454:73. t966 275, Gardner DL~ Roy .LMH: Tissue iron and the reticu* Ioendothdiat system in rheumatoid arthritis, Ann Rheum Dis 20:258, 1961 276. Beckon WL: Effect of five salicyl~te-Contairling compounds upon loss of ~lehrom~um-labelied ¢rythrocytes from t~e gastrointestinal tract of normal man, Gut 9:475, 1968 277. Baragar FD, Duthi= J JR: Imporlance of aspirin as a cause o1"anaemia and peptic ulcer in rheumatoid arthritis, Br Med J 1:] 106. t960 278. Ward HP, Gordon B, Pickett JC: Serum levels of erythropoietin in rheumatoid arthritis. J Lab Clin Med 74:93~ 1969 279. Adams EB: Anemia associated with protein deficiency. Semin Hematof 7:55, 1970 281). Ma~ibbon BH, MolIin DL: Siderohlastlc anaemia in man: Obsarvations in seventy cases. Br J Haematol 11:59¢ 1965 281. Panush RS, Franco AE, Schur PH: Rheumatoid arthritis ass~iated with eosinophilia, Ann Intern Med 75:199, 1971 282. Portner MM. Graeie WA: Rheumatoid l~r~gdis~se with c~vitary aodul~, pneumothorax arm ~{nophilia. N Eng| J Med 275:697. 1966 283. Sylvester RA. Pinals RS: Eosinophilia in rheumatoid arthritis~ Ann Allergy 28:565, 1970 28¢. Lindsay MK. Tavadia HB~ Whyte AS, et ah Acute abdomen in rheumatoid a~thrit~ due to necrotising arterltis. Br Med J 2:592. 19"/3 285, Adler RH, Norcross BM, Lockie M: Arteritis and infarction of the intestine in rheumatoid anhrhis. JAMA 180:922. i962 286, Sinclair RJG, Cruickshank B: A clini~l and pathological study of sixteen cases of rheumatoi~ ar~hrltis with extensive visceral involvement ('rheumatoid disease'). Q J Med 25:313, I956 287. Pettetsson T~ Wegelius D, Skrifvars B: Gastro* intestinal disturbances in patients with severe rheumatoid arthritis. Aeta Med Sound 188:139, 1970 288. Dyer NH) Kendall M J, Hawkins CF: Mala.bsol~tloa in rheumatoid disease. Ann Rheum Dis 30:626, 197I 289. Akbarian M, Fenton J: Perforation of small bowel in amyloidosis. Arch intern MUd 114:815, 1964 290. MeMahon MJ, Horse J: Ulcemtlorl of the colon

ERIC R. HURl3

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