frequencyofoccurrence, development, · frequencyofoccurrence, modeofdevelopment, andsignificance...

Annals of the Rheumatic Diseases, 1982, 41, 109-117

Frequency of occurrence, mode of development, andsignificance of rice bodies in rheumatoid jointsA. J. POPERT,1 D. L. SCOTT,2 A. C. WAINWRIGHT,2 K. W. WALTON,2N. WILLIAMSON,2* AND J. H. CHAPMAN1

From 'Highfield Hospital, Droitwich, Worcestershire, and the 2Department ofInvestigative Pathology,Rheumatism Research Wing, University ofBirmingham

SUMMARY The incidence of rice bodies (RB) in synovial effusions has been studied in 36 patientswith rheumatoid arthritis (RA) and in 12 patients with seronegative inflammatory arthritis (7 casesof Still's disease, 3 of psoriatic arthritis, and 2 of ankylosing spondylitis). In the RA group 50 jointswere aspirated before and after saline lavage with a specially designed wide-bore needle. RB werefound in 72% overall of the joints studied in this group, 14% on initial simple aspiration and anadditional 58% after lavage. In contrast no rice bodies were found in 31 aspirations with lavage byan identical technique in the 12 patients with seronegative synovitis. The RB in RA synovitisoccurred both early and late in the course of the disease and were not related to the severity ofclinical or radiological changes. However, removal of rice bodies was accompanied by clinicalimprovement and reduction of synovitis. Macroscopically RB varied in shape and size, some beingso large as to preclude effective removal by needles of the gauge customarily employed for jointaspirations. Microscopically the majority of RB were composed of coarsely reticular materialreacting immunologically with antifibrinogen and antifibronectin and containing mononuclearcells. Some showed vacuolation suggestive of fibrinolysis, but many showed organisation like thatseen in established connective tissues, with the formation of mature collagen, reticulin, and elastin.These findings are discussed in relation to the origin, development, and significance of rice bodiesin rheumatoid synovitis.

Intra-articular 'rice bodies' were first described inassociation with tuberculous arthritis' but are nowmore commonly encountered in other arthritides,including rheumatoid arthritis (RA). Their appella-tion derives from their alleged naked eye resemb-lance to grains of polished rice, but in fact theseparticles are markedly variable in size, shape, andconsistency.

Previous studies on their nature in RA2 3 have notdefined adequately their frequency, relation to clini-cal symptoms, or mode of origin, so that there is atendency to consider them to be uncommon and ofrelatively little significance. We present observationswhich might necessitate the revision of suchconclusions.

Accepted for publication 17 March 1981.*Present address: National Blood Transfusion Service, LancasterCentre, Lancaster LA1 3JP.Correspondence to Professor K. W. Walton, Department of Inves-tigative Pathology, Medical School, Rheumatism Research Wing,University of Birmingham, Birmingham B15 2JP.

Materials and methods

Fifty consecutive joint aspirations and lavage (per-formed as described below) were carried out in 36patients with classical or definite RA as judged by thecriteria of the American Rheumatism Association.4Details of the patients are summarised in Table 1.Five of these patients had additional diagnoses ofosteoarthrosis (3), chondrocalcinosis (1), and septicarthritis (1). Forty-nine of the aspirations were madefrom knee joints and 1 from a shoulder joint. Themean duration of symptoms was 6 9 years (range1-12 years). Plain radiographs of the affected jointwere made prior to aspiration. Details were recorded

Table 1 Details ofpatients with rheumatoid arthritis in thestudy.

Number Sex ratio Age, Disease duration, SCAT titre(M:F) yr (SD) yr (SD) 1/32

36 10:26 58-4 (12.1) 12 9 (11.4) 27 (75%)

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110 Popert, Scott, Wainwright, Walton, Williamson, Chapman

of the volume of the effusion, the temperature of thejoint, and the extent of synovial thickening. Arthro-grams were performed in several selected cases. Inaddition 31 aspirations and lavage were carried outby the same method in 12 patients with inflammatoryseronegative arthritis of the knee joint; 7 had Still's

disease, 3 psoriatic arthritis, and 2 ankylosing spon-dylitis. Six were male and 6 female, and they wereaged 9-52 years.Methods of aspiration and lavage. An 8-14 gauge

modified spinal needle with a short bevel was intro-duced medially or laterally into the knee joint, oranteriorly into the shoulder-joint, under local anaes-thesia (2% lignocaine) with aseptic technique. Inmost cases a 10 or 12 gauge needle was found to bemost suitable. Any fluid and any rice bodies aspiratedwere retained. Lavage was performed with 50-100ml of sterile 0-9% saline at 24°C. Any additional ricebodies removed were retained. The volumes of syno-vial fluid and of the rice bodies (by displacement)were measured and recorded.

Histological techniques. Particulate material fromjoints was examined after fixation in 10% formolsaline and embedding in paraffin wax. In some

instances material was also examined by conven-

tional histological techniques and immuno-histologically as frozen sections of fresh unfixedmaterial, or after fixation in cold ethanol by themethod of Saint-Marie.5 The immunohistologicalreagents and methods used have been previouslydescribed.6

Histological staining methods. Sections wereexamined after staining with haematoxylin and eosin(H and E); haematoxylin and van Gieson's fluid(HVG); Miller's modification7 of Weigert's elastic-tissue stain; Gordon and Sweet's method8 for reticu-lin; the Martius scarlet/blue (MSB) technique forfibrin of Lendrum et al. 9; the picropolychromemethod of Herovicit0; or with phosphotungstic acidhaematoxylin (PTAH). In selected instances, sec-tions were also examined after staining withhaematoxylin and oil red 0 for lipid; Congo red for

amyloid; and by the periodic acid Schiff method, withalcian blue, or by the dialysed iron method, forcarbohydrates.

Results

INCIDENCE OF RICE BODIES AND THEIRRELATION TO CLINICAL SYMPTOMSRice bodies were found to be common in rheumatoidsynovitis. The incidence found in our patients is given'in Table 2. It can be seen from this that lavage plusaspiration, as opposed to the initial simple aspirationalone, markedly increased the yield of rice bodies.Rice bodies were found both early and late in relationto the history of symptomatic involvement of joints.Both joints with normal radiographic appearancesand those with gross erosive changes and markedcartilage loss were found to contain rice bodies. Nosimple relation was found between the presence ofrice bodies and the radiographic or the clinical (sizeof effusion, temperature of joint, or extent of synovialthickening) assessment of the severity of joint dis-ease. Similarly no correlation was obtained withseropositivity (Rose-Waaler titre 1:32 or greater).On the other hand the removal of rice bodies

effected symptomatic relief and reduction ofsynovitis.1' This observation suggested that the per-sistence of rice bodies within the joint probably con-tributes directly to the chronicity of synovitis (also,see 'Discussion').

Rice bodies are occasionally detectable withouttheir physical removal from a joint in that they cansometimes be seen by arthrography. However, onlyrelatively large particles can thus be visualised, andthis procedure, we felt, could be justified ethicallyonly where there were other indications for its use, soit was not applied in all our cases.

In contrast to the patients with RA no rice bodieswere found in 31 aspirations and lavage of the kneejoints of the 12 patients with other inflammatoryarthropathies. The mean volume of synovial fluid

Table 2 Incidence ofrice bodies.

Rheumatoid arthritis (50 aspirations and lavage) Seronegative inflammatory arthritis(31 aspirates and lavage)

Synovial fluid containing rice bodies No rice bodies Synovial fluid No rice bodiescontaining ricebodies

In simple aspirate Additional recovery Totalwith lavage

Per cent cases 14% 58% 72% 28% 0 100%Mean vol. (ml) of rice

bodies and range 6.0 (3-9) 3 *0 (1-16) 3 6 (1-16) 0 0 0Mean vol (ml) of

synovial fluid andrange 23 0(6-70) 10-0(9-25) 12-5(6-70) 21-0(5-65) 0 18-0(1-110)



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Frequency ofoccurrence, mode ofdevelopment, and significance of rice bodies in rheumatoid joints 111

removed in these patients was 18 ml (range1-110 ml).

MACROSCOPIC APPEARANCESThe material aspirated showed marked variation inthe consistency, shape, and size of the particlespresent. The greatest diameter of the majority of theparticles exceeded 7 mm in 10/o of cases; rangedbetween 2 and 7 mm in 55% of cases; and was lessthan 2 mm in the remaining 35%. The particles weresometimes white and bore some resemblance to ricegrains but were also sometimes yellowish and irregu-lar in shape or thread-like in appearance. The varia-tion in size and shape of the particles is illustrated inFig. 1.

MICROSCOPIC APPEARANCESObservations previously made2 3 12 were confirmedand extended. The heterogeneity of the materialaspirated after lavage of joints was further revealedby microscopic examination in that occasional frag-ments easily identifiable as bone, cartilage, or shredsof synovial villi were seen in the aspirate (Fig. 2).Rounded structures composed of a vascularised col-lagenous core (presumptively derived fromsynovium) were also seen to be superficially coatedby fibrin (Fig. 3). However, the bulk of the specimensin aspirates made from acute and chronic synovialeffusions consisted simply of amorphous or coarselyreticular and condensed fibrin, as judged by conven-tional staining characteristics (Figs. 2 and 4). For

t l I -.T -j W. I -, I sV I - It I

m 10 2 30 40 50 60 70 SO

Fig. 1 Composite picture of rice bodies, photographed atthe same magnification, to show particles of3 different sizeranges.

example, the material was brightly eosinophilic insections stained with haematoxylin and eosin, stainedyellow with HVG or the picropolychrome method,brilliant scarlet with the MSB technique, and darkpurplish blue with PTAH.

i.M S : *W4-6;-0

Fig. 2 Depositfrom aspirate after lavage ofknee-joint. Twofragments ofsynovial membrane and irregularly shapedparticle composed ofcondensed fibrin (arrow) (MSB,x 125).

Fig. 3 Vascularised nodule (probably derived fromsynovium) with outer covering offibrinous deposit (Hand E,x 125).



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In fresh unfixed specimens, or in material fixed incold ethanol from the same patients as thosedescribed above, the nature of the material was con-firmed immunologically with antifibrinogen labelledwith fluorescein or with horse radish peroxidase(Figs. 5 and 7B). In addition, in sections made offresh or similarly fixed material from these subjectsafter treatment with similarly labelled antiserum tofibronectin (cold insoluble globulin) an abundance ofthis protein was also demonstrable (Fig. 7C). In adja-

cent sections, suitably stained conventionally for fib-rin and with antifibrinogen or antifibronectin, thedistribution of fibrin and of fibronectin was almostexactly similar (Figs. 7A-C). This was found despitethe fact that these 2 proteins are immunologicallyunrelated.6

Aspirates taken from effusions of many weeks' ormonths' duration still showed many rice bodies com-posed almost entirely of fibrin. Variable numbers ofmononuclear cells were seen on the surface and

Fig. 4 Rice bodies composed of/t ;g .;irregularcompacted fibrin admixed

with mononuclear cells. Note palerGulWw.. , area in large fibrinous rice body

where fibrosis is occurring (F). (HF: . and E, x 313).

Fig. 5 Unfixed rice bodies- ~~~examined in ultraviolet light after- ~~~~treatment with fluorescein-labelled

*.7 antihuman fibrinogen. Specificfluorescence (bright green inoriginal, white in picture) indicatespersistence offibrinogen-related

* s? antigens. But note inhomogeneityofreaction in places (arrows).(x 200).



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Frequency of occurrence, mode ofdevelopment, and significance ofrice bodies in rheumatoid joints 113

enmeshed within the interstices of such rice bodies(Fig. 4). Some rice bodies lacked much evidence ofcellular infiltration but showed irregular and diffusevacuolation, so that they appeared to be composed ofa loose and attenuated network of fibrin. Theappearance of these particles suggested the reductionof the rice body to a skeletal framework of its originalstructure, possibly by a fibrinolytic process (Fig. 5).

Other particles stained inhomogeneously, only aportion of the rice body showing the conventional

staining reactions or immunoreactivity for fibrin (seeFigs. 4, 5, 7A-C). In these instances the remainder ofthe particles was weakly eosinophilic, staining grey-ish blue with the MSB method and pink with PTAH.Mononuclear cells were still seen occasionally in suchareas. Otherareas of these particles showed the stain-ing reactions of mature collagen in being markedlyfuchsinophilic in sections stained with HVG or picro-polychrome, staining intensely blue with the MSBmethod and dark red with PTAH.

Fig. 6 Portion offibrinous ricebody showing delicate reticularstructure composed ofnetworkstaining as for fibrin surroundingvacuoles of varying size (? rice bodyundergoingfibrinolytic resorption).(PTAH, x 125).

WU. VFTVI w% _WO .: A. !ri 4L' 7%. W'V W-'Xi' .' Ai tA M 2,. ,1 -. W_AX7A %.

Fig. 7A Rice bodies showing varying stages offibrosis. Fig. 7B Same field in adjacent section from same material asNote formation ofmature collagen (dark grey in picture, in Fig. 7A. Section treated with peroxidase-labelled antihumanbright blue in original) as solid core in rice bodies X and Y fibrinogen. Dark reaction product (brown in original, grey inand as ring-like arrangement in centre of rice body Z. picture) denotes presence offibrinogen-related antigen. ButRemaining portions ofthese rice bodies stained greyish-blue note negative reaction ofcentral portions ofrice bodies X andin this section (MSB stain) in the original. ( x 110). Y and ofring-like arrangement in Z. ( x 110).



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Fig. 7C Samefield in anothersection from same material asin Figs. 7A and 7B. Section treated with peroxidase-labelledantihuman fibronectin. Note similarity of distribution ofpositively reacting areas to that seen in Fig. 7B. (x 110).

In some rice bodies this process of fibrosis was seento be occurring in the 'core' or deep within the sub-stance of the particle (Figs. 7A-C) while, in materialaspirated from the most chronically involved jointsthe particles were often rounded, with smooth mar-gins and a varying proportion of the rice body trans-formed into a collagenous mass. Some rice bodies ofthis kind, when suitably stained, showed the presencealso of a reticulin network and/or of elastic tissue.

In occasional instances in rice bodies undergoingfibrosis a portion of the rice body reacting as fibrin/fibronectin showed vacuolation of this at the 'bound-ary zone' demarcating it from the adjacent area,which gave the characteristic staining reactions ofcollagen. It is presumed that such regions of vacuola-tion again represented regions of fibrinolysis preced-ing fibrous tissue replacement. What was perhapseven more striking was how infrequently suchobvious areas of transition were seen. In mostinstances the junction between fibrin/fibronectin onthe one hand and collagen on the other was quitesharp, suggesting a smooth dovetailing of fibrinremoval and new fibrous tissue formation in the pro-cess of tissue remodelling.

Rice bodies showing early fibrotic change, with theformation of delicate fibres of immature collagen, onimmunohistological examination showed fibronectinto be present in such areas. On the other hand otherareas (often immediately adjacent) where denser andmore mature collagen was present failed to react forfibronectin. As previously reported,6 no relation was

found between the distribution of fibronectin andelastin, but a close similarity of distribution was notedbetween fibronectin and argyrophilic fibres iden-tified as 'histological reticulin'.No instance was encountered in the material

examined of amyloid deposits in rice bodies. Sectionsstained for lipid or for carbohydrates (with the PASmethod, alcian blue, or dialysed iron) did not showsignificant changes. Occasional deposits ofhaemosiderin and microscopic foci of calcium deposi-tion were encountered in a few instances.

Discussion

FREQUENCY OF OCCURRENCE OF RICE BODIESIN RAOur results suggest that rice bodies are a very com-mon accompaniment of rheumatoid synovitis, pro-vided they are sought by an adequate technique. Wefound them to be present in the effusions from 72% ofour patients. But rice bodies were detected in only14% of cases in which simple aspiration was per-formed, even when a wide-gauge needle was em-ployed. We found an additional 58% of our cases tohave rice bodies in the aspirate only when salinelavage preceded aspiration through a wide-boreneedle.

Since in many instances much of the particulatematerial recovered was quite large in particle size(Fig. 1), it seems probable that rice bodies wouldhave been detected in few if any of our cases if aspira-tion had been attempted, without preliminary lavage,through a fine-gauge needle in the manner widelyused for diagnostic aspiration of synovial fluid. Wefeel that the prevalent (but in our view mistaken)view about the relative rarity of occurrence of ricebodies in rheumatoid joints in fact derives from thisdifference in technique.

ORIGIN AND DEVELOPMENT OF RICE BODIESOur histological and immunohistological observa-tions supplement the scanty microscopic examina-tions previously published on rice bodies frompatients with RA, that is, the 2 cases studied byAlbrecht et al.2 and the 7 patients in the seriesreported by Berg et al.3 In agreement with theseauthors our findings suggest that there are progress-ive changes in the structure of rice bodies. However,access to patients seen over a wider range of thedisease process and to a much larger volume ofmaterial has allowed us to observe that rice bodiesmay progress to a degree of maturity resembling thatof established connective tissue in consisting ofcoarse collagenous fibres, reticulin, and elastin. Toour knowledge development to this degree of organ-isation has not previously been recorded in



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Frequency ofoccurrence, mode ofdevelopment, and significance ofrice bodies in rheumatoid joints 115

rheumatoid rice bodies-presumably because rela-tively so few specimens have been extensivelyexamined histologically.

It has been suggested that rice bodies originatefrom detached fragments of degenerating synovialvilli.'2 In synovial fluid from chronically involvedjoints we found occasional synovial fragments (Fig.1) along with other detritus derived from joint struc-ture, such as slivers of cartilage and minute spicules ofbone. In occasional instances rounded but well-vascularised structures (presumably thereforeoriginating from synovium) were seen, covered witha fibrin coat of variable thickness (Fig. 3). Neverthe-less, we consider that the earliest rice bodies arepredominantly fibrinous in nature and formed inde-pendently of synovial fragments, though whether theentrapped mononuclear cells are leucocytes derivedfrom the blood or synovial cells is difficult to deter-mine (also see below).

In fibrinous particles, free in rheumatoid synovialfluid, we have found fibronectin also to be present. Inthis respect such rice bodies resemble fibrinousdeposits ('fibrinoid') adherent to the synovium6 orplasma clots formed in vitro, in which fibronectinbinds to fibrin."2 Coprecipitation of fibronectin andfibrinogen also occurs in the presence of heparin andother glycosaminoglycans, especially at low tempera-tures."4 The possibility was considered that glyco-saminoglycans released into the synovial fluid fromeroded cartilage might play some part in precipitatingfibrin and fibronectin to form rice bodies. Conven-tional histochemical stains for glycosaminoglycans onrice bodies did not support this possibility.Our previous work has established that fibronectin

is locally synthesised by synovial cells and that thelevel in synovial fluid is often higher than that inplasma in RA." This intra-articular production offibronectin, which is markedly adhesive in its physicalproperties,"6 probably not only favours the initialformation of insoluble fibrin/fibronectin precipitatesbut also assists in effecting the aggregation of parti-cles and their increase in size, thus influencing ricebody formation.

PERSISTANCE OF RICE BODIES IN INFLAMED

JOINTSThere has been much interest and controversy as towhy fibrinous deposits persist in joints. On the onehand in inflamed joints in which large numbers ofphagocytic cells (both blood macrophages andphagocytic type A synovial cells) gain access to thesynovial fluid it can be envisaged that the cellularuptake of particulate fibrinous deposits and theireventual 'digestion' and disposal would occur. Anopsonic role for fibronectin in regard to this cellulardisposal mechanism has been proposed.17

On the other hand it is well established that notonly all the necessary blood coagulation componentsrequired to give rise to fibrinous deposits, but alsothose of the blood fibrinolytic system (concernedwith the resolution of such deposits), insude intosynovial fluid in active joint disease.'8 21 It would beexpected therefore that this humoral mechanismwould complement or reinforce the cellular removalmechanism referred to above. Since our results indi-cate that early rice bodies contain both fibrin-relatedand fibronectin-related antigens, it is interesting tonote that fibronectin is known to be as susceptible asfibrin to plasmin digestion22 and to the action ofneutral proteases from polymorphonuclearleucocytes.'While the appearance of some rice bodies was

consistent with the particle undergoing fibrinolysis(see Fig. 4), in other rice bodies abundant fibrinousmaterial was still present, and the majority of parti-cles showed condensation rather than attenuation oftheir structure. The occurrence and persistence offibrinous rice bodies probably depends on the bal-ance between the rate of production and maturationof these structures and the rate of their disposal byphagocytosis and/or fibrinolysis. With regard toplasmin activity, there is argument as to whetherfibrinous deposits persist because of reduction ofplasmin activators or increased amounts of anti-plasmins or antiactivators in rheumatoid synovialfluid.? 212426 It has been reported that urokinase iseffective in vitro in promoting the digestion of fibrin-ous rice bodies and also in vivo in suitable cases."

LATER STAGES IN THE EVOLUTION OF RICEBODIESEarlier reference has been made to the possible roleof the type A synovial cell in phagocytosing anddisposing of fibrinous deposits. It seems possible thatthe type B cells, which show many of the functionalcharacteristics of fibroblasts, may be concerned in theestablishment and development of rice bodies. This isbecause these cells synthesise both fibronectin andcollagen. It may be assumed that it is such cells,entrained in some of the rice bodies we haveexamined, which are responsible for the secretion offibronectin and immature collagen and for their laterreplacement by mature collagen. Particles under-going this sequence of changes would appear tocorrespond to the type II rice bodies described byBerg et al.'The codistribution of fibronectin with immature

collagen in the earlier stages of fibrosis of rice bodiesconfirms our earlier observations.6 It is presumablyaccounted for by the high binding affinity of fibro-nectin for certain varieties of collagen27 as well as forfibrin. However, in those areas of rice bodies com-



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116 Popert, Scott, Wainwright, Walton, Williamson,

posed predominantly of more mature, coarse col-lagen fibronectin could no longer be detected by theimmunohistological techniques used. The reason forthis loss of binding capacity for fibronectin by maturecollagen is not apparent.Some rice bodies, undergoing conversion to fibrous

nodules, resemble connective tissue elsewhere in thebody in containing argyrophilic reticulin fibres and/or elastic tissue. As observed in other situations,28the distribution of fibronectin in such rice bodies wasunrelated to that of elastin but closely similar to thatof histologically defined reticulin.

SIGNIFICANCE OF RICE BODIES

It has been shown that fibrin can serve as an irritantand a potent stimulus to fibrogenesis when implantedin serous cavities.a9 When instilled into joints,Dumonde and Glynn30 showed that even autologousfibrin can persist and evoke a persistent arthritis in a

small proportion of animals. In man Glynn3' has sug-gested that persistent fibrin deposits may provide a

continuous stimulus to antibody formation to otheraltered bodily constituents, possibly including pro-ducts of inflammation, in rheumatoid joints. Ricebodies may contribute in this manner to the chron-icity of synovitis in RA.

Indirect support for this proposition is provided byour observation that, conversely, effective removal ofrice bodies by lavage and aspiration in itself producesmarked clinical improvement in affected joints.Alternatively it may be argued that this result is nomore than can be expected from application of thewell-established surgical principle of ensuring effec-tive debridement of inflamed tissues to assist healing.However, where it is proposed to attempt to obtain

a similar result by the alternative procedure of pre-liminary instillation of fibrinolysis-promoting agentssuch as urokinase, our findings suggest that prelimi-nary lavage, aspiration, and histological examinationare advisable."1 This is because rice bodies whichhave undergone further maturation into partiallyfibrous structures will not respond to such treatment.For this reason, and also as a useful accessory meansof decreasing joint disability, we recommend lavage,aspiration, and microscopical examination of ricebodies in rheumatoid arthritis.

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3 Berg E, Wainwright R, Barton B, Puchtler H, McDonald T. Onthe nature of rheumatoid rice bodies. An immunologic, histo-chemical and electron microscope study. Arthritis Rheum 1977;20: 1343-49.

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Engvali E, Ruoslahti E. Binding of soluble forms of fibroblast atherosclerosis. In: Chalmers D G, Gresham G A. eds. Biologicalsurface protein, fibronectin, to collagen. Int J Cancer 1977; 20: Aspects of Occlusive Vascular Disease. Cambridge: Cambridge1-5. University Press, 1964: 76-83.

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