Ann. rheum. Dis. (1975), 34, 7

Lack of correlation of synovial histologywith joint damage in rheumatoid arthritis

D. R. F. HENDERSON, M. I. V. JAYSON, AND C. R. TRIBEFrom the Department ofMedicine, University ofBristol; the Royal National Hospitalfor RheumaticDiseases, Bath; and the Department ofPathology, Southmead Hospital, Bristol

Henderson, D. R. F., Jayson, M. I. V., and Tribe, C. R. (1975). Annals of the RheumaticDiseases, 34, 7. Lack of correlation of synovial histology with joint damage in rheumatoidarthritis. Twenty-two patients with rheumatoid arthritis (RA) involving the knee were

studied. The systemic features of the disease were graded and the extent of knee involve-ment was quantified in terms of the clinical, radiological, and arthroscopic appearances.Adequate synovial biopsies were obtained from 21 patients. In these patients no correla-tion could be found between the severity of any of the features on histological examina-tion nor between any of these features and the extent of local joint damage, inflammation,or the severity of the systemic disease.

It has been thought that the histological features ofRA do not reliably indicate the degree of activityor prognosis of the disease and that they are notspecific for that condition (Hamerman, Sandson,and Schubert, 1963). Indeed, Waxman and Sledge(1973) were unable to distinguish histologicallybetween rheumatoid and osteoarthritic synovia.

Recently, however, Muirden and Mills (1971)found in rheumatoid joints submitted for syno-vectomy a direct correlation between the degree ofsynovial lining cell hyperplasia and joint damageand an inverse correlation between the degree oflymphocytic infiltration and joint damage. Lympho-cytes might play a helpful role in protecting therheumatoid joint. Muirden (1970) has also reporteda significant relationship between histological esti-mates of the extent of the iron deposits with thegrades of x-ray changes in biopsied joints.

These findings are obviously of importance andsuggest that methods of determining the prognosisof RA and the choice of appropriate therapy couldbe based on the histological appearances of synovialbiopsies.

Precise quantification of the degree of synovialinflammation and the amount of articular damagein the joints of patients with RA is difficult. Physicalexamination and radiology provide informationwhich is useful but indirect. For example, the degreeofdamage to articulating surfaces seen at arthrotomymay far exceed that suggested by x-rays. Arthroscopyof the knee allows direct inspection of much ofthe synovium and articulating surfaces. It alsoenables direct biopsy of selected sites without

recourse to arthrotomy (Jayson and Henderson,1973).The present study was directed towards confirming

the findings of Muirden and Mills (1971). Clinicalparameters, arthroscopic findings, and x-ray changeswere quantified and used to determine the activityof the inflammatory process and the degree of jointdamage. These have been compared with the gradedhistological changes in synovial biopsies.

Materials and methods

Studies were performed on patients with definite orclassical RA (Ropes, Bennett, Cobb, Jacox, and Jessar,1959) and significant involvement of at least one knee.The clinical assessments were performed by one of us(D.H.) before arthroscopy, and the following data werenoted: age, sex, duration of disease, treatment with goldor corticosteroids, duration of morning stiffness, presenceof nodules, grip strength, haemoglobin, ESR, rheumatoidfactor, functional capacity (Steinbroker, Traeger, andBatterman, 1949).The involved knees were assessed for the extent of

inflammatory changes and the degree ofjoint damage, andthe following clinical features were noted: duration ofknee involvement, synovial thickening, effusion, tender-ness or pain on movement, range of movement, fixedflexion deformity (measured in degrees with a gonio-meter). When appropriate the information was graded0 = normal; 1 = doubtful or minimal abnormality;2 = definite abnormality; 3 = gross abnormality.

X-rays of the knees were coded and read simultaneouslyby two of us (M.I.V.J. and D.H.) without knowledge ofthe clinical and arthroscopic findings, and these featuresexamined: osteoporosis, surface erosions, geodes (bone

Accepted for publication May 12, 1974.Reprint requests to: Dr. M. I. V. Jayson, Department of Medicine, Bristol Royal Infirmary, Bristol BS2 8HW.

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8 Annals ofthe Rheumatic Diseases

cysts), osteophytes, loss of joint space in (a) patello-femoral, (b) medial tibiofemoral, (c) lateral tibiofemoralcompartments.The observations were scored 0 = normal; 1 = possible

change; 2 = definite change; 3 = gross change. The totalof these scores was calculated by adding up the variousscores. The maximum and worst possible radiologicalscore was, therefore, 21.

Arthroscopy of the knee was performed under localanaesthesia using the Stortz Arthroscope (Jayson andHenderson, 1973). Particular attention was paid todegree of synovial erythema, extent of synovial prolifera-tion, contact bleeding, fibrin, and cartilage damage.Each of these observations was again graded on a 0 to 3scale.

Multiple synovial biopsies were obtained under directvision. These were mainly taken from the medial tibio-femoral compartment where synovial proliferation isusually most obvious, but also were obtained from thesuprapatellar pouch.The biopsies were fixed in formol saline and sections

were stained with haematoxylin and eosin and by Perls'sPrussian Blue reaction for iron. On occasions, stepsections were taken to obtain adequate amounts of tissuefor histological examination.The sections were coded and assessed without knowl-

edge of their identity by all three authors. Standardsections were kindly provided by Dr. K. D. Muirden andthe biopsies were graded with frequent reference to thosesections. Features quantified were synovial lining-cellproliferation and lymphocytic infiltration, and gradingswere established between 1 = normal or slight change to4= gross change, in a similar fashion to that used byMuirden and Mills (1971).

In addition, the following features were noted andgraded on the same scale: total mononuclear cell infiltra-tion, degree of plasma cell infiltration, synovial surfacecell pleomorphism, vascular proliferation, thickening ofvessel walls, iron deposition.

Results

The general characteristics of the patients are shownin Table I and the clinical, radiological, and arthro-scopic changes in the involved knees in Table II.No correlations could be found between the severityof any of the clinical parameters for general diseaseand the severity of the process within the knee.Of 22 patients, adequate biopsies for histological

grading were obtained from 21, and the data pre-sented are restricted to these patients.

Table I Systemic features of 21 patients

Age 57-0 yrs (21-74 yrs)Sex Male 10, female 11

Duration ofRA 7-5 yrs (0-15-25 yrs)Duration ofmorning stiffness 2-4 h (0-12 h)Nodules Present 5, absent 16Functional capacity I 1. II 11. III 9. IV 0Blood sedimentation rate 62 mm/h (10-108 mm/h)Haemoglobin 12-4 g/dl (9-8-17-1 g/dl)RA latex test Positive 20, negative 1

Table II Data on 21 knees examined

Assessments

ClinicalDuration of knee involvement

(yrs)Synovial thickening (yrs)Effusion (yrs)Tenderness or pain onmovement (yrs)

Fixed flexion deformity (degree)

RadiologicalX-ray score

Arthroscopic scoreErythemaSynovial proliferationContact bleedingFibrinCartilage damage

Mean Range

5.7 (0-15-22)

2-1 1- 31-6 0- 31-6 0- 3

6 70 0°-200

8 7 0-17

1-6 1- 32-2 1- 31-2 0- 32-1 0- 31-7 0- 3

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44 .

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FIG. 1 Synovial biopsy from a patient showing severesynovial lining-cell proliferation with some pallisadingassociated with a marked mixed cellular infiltration in theunderlying tissue consisting of both lymphocytes andplasma cells. This illustrates that high grades in the twohistological criteria studied by Muirden and Mills (1971)can, andfrequently do, occur in the same biopsy. H. & E.x264

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Lack of correlation ofsynovial histology with joint damage 9

Histological grading often proved extremelydifficult because of marked variation in the degreeof cellular reaction within any specimen and betweendifferent specimens. Two photomicrographs ofsynovial biopsies (Figs 1 and 2) are included toillustrate the difficulties in histological assessment.The specimens were considered as a whole, however,and an attempt was made to assess the best overallgrading with the proviso that the features of thespecimens from the tibiofemoral compartmentswere weighted more heavily than those from thesuprapatellar pouch.

Fig. 3 shows the comparison between lymphocytic

-4

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0

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4

3

2

1

2 1

1 3 4 3

1 5 1

1 2 3 4Synovial lining cell hyperplasia (grade)

FIG. 3 Comparison of lymphocytic infiltration andsynovial lining cell hyperplasia

infiltration and synovial lining-cell hyperplasia.Although there was a tendency for synovial lining-cell hyperplasia to be worse in the patients with theleast lymphocytic infiltration, this change did notreach statistical significance. None of the pathologicalspecimens showed grade 4 lymphocytic infiltration asshown by Muirden and Mills (1971). Table III liststhe comparisons between histological features whichwere undertaken. No significant correlations emerged.

Table IV lists the comparisons made betweenthe degrees of lymphocytic infiltration (a) and theclinical, radiological, and arthroscopic evidenceof synovial inflammation and joint damage. No

FIG. 2 Synovial biopsy from a

patient showing two contrastingsynovial villi. On the left, thevillus shows marked synoviallining-cell hyperplasia with some

pallisading and only a scantyunderlying cellular infiltration.In contrast, the villus on the rightjhas a thinner, more indistinct

synovial lining with an intense

underlying lymphocytic and

plasma cell infiltration. This

illustrates the difficulties ofgrading histological featureswithin different areas of onebiopsy. H. & E. x436

Table III Comparisons between histologicalfeatures

Lymphocytic Synovial surface cell hyperplasiainfiltration Iron deposition

Lining cell pleomorphismGiant cells

Synovial surface cell Lymphocytic infiltrationhyperplasia Total mononuclear cell infiltration

Plasma cell infiltrationIron depositionPleomorphismGiant cells

Iron deposition Lymphocytic infiltrationTotal mononuclear cell infiltrationPlasma cell infiltrationSynovial surface cell hyperplasiaLining cell pleomorphismGiant cellsVascular proliferationVessel wall thickness

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10 Annals of the Rheumatic Diseases

Table IV List offeatures compared with (a) lympho-cytic infiltration, (b) synovial lining cell proliferation

Systemic AgeDuration of RADuration of morning stiffnessBlood sedimentation rateTreatment with gold or

corticosteroids

Knee-clinical Duration of knee involvementSynovial thickeningEffusionTenderness or pain on movementFixed flexion deformity

Knee-radiological X-ray score

Knee-arthroscopic ErythemaSynovial proliferationContact bleedingFibrinCartilage damage

significant correlations were found. Figs 4 and 5illustrate comparisons of lymphocytic infiltrationwith the arthroscopic evidence of cartilage damageand with the x-ray score.

Table IV also lists the comparisons between lining-cell proliferation (b) with the grades for inflammationand articular damage. Again, there were no significantcorrelations. Figs 6 and 7 illustrate comparisons ofsynovial lining-cell proliferation with the arthro-scopic evidence of cartilage damage and with thex-ray score. Comparisons were drawn between theother histological features, including the extent ofiron deposition and the degrees of synovial inflam-mation and joint damage. No significant correla-tions were found.

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Lymiiphocytic infiltrationi (grade)

FIG. 5 Comparison of lymphocytic infiltration and kneex-ray score

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1 2 3 4Synovial lining cell hyperplasia (grade)

FIG. 6 Comparison of synovial lining cell hyperplasiawith arthroscopic estimate ofcartilage damage

Discussion

This study failed to confirm any relationship betweenthe histological pattern of rheumatoid synovitis

I I Iand the extent of disease activity or joint damage.This failure may be interpreted in different ways.

1 2 3 4 Quantification of clinical parameters of a diseaseis exceedingly difficult and most of the conventional

rmphocytic infiltration (grade) methods of assessment which were used in thiscarison of lymphocytic infiltration with the study are more useful for assessing the status of atimate of articular cartilage damage single patient when seen on a number of occasions

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Lack of correlation ofsynovial histology with joint damage 11

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Synovial liningi cell hyperplasia (grade)FIG. 7 Comparison of synovial lining cell hyperplasia andknee x-ray score

than for making comparisons between groups ofpatients. The variation of reporting between differentobservers is well recognized and, indeed, the sameobserver may report the same material in a differentfashion on separate occasions. In particular, theappearances at arthroscopy can be altered consider-ably by varying the physical conditions such as the

intensity of lighting, the pressure and temperatureof the irrigating fluid, and the distance from thetelescope tip to the observed surface. Despite theseprovisos, in experienced hands, arthroscopy providesconsiderable additional information, and in particularmakes direct vision biopsies of involved areasavailable.The biopsies were small and not comparable with

the large amounts of synovium obtained at syno-vectomy. However, whenever possible multiplespecimens were obtained from different parts of thejoint so as to obtain representative samples. Thechanges of the synovium in RA are many and varied(Gardner, 1972) and it was disappointing that nocorrelations were found between the various featuresnor between the histological changes and the extentof the disease. It is still possible that with a largerseries and perhaps with the use of more sophisticatedtechniques, such as electron microscopy and immuno-fluorescence, useful correlations giving some guidanceto the likely prognosis of the disease may emerge.

It is also possible that there was some selection inthe cases documented by Muirden and Mills (1971)in that the histological specimens were obtained atsynovectomy so that only those patients suitablefor this procedure were examined. In contrast,a broad spectrum of disease activity was includedin the present study.

We wish to thank Mr. B. Amer and his fellow techniciansfor their meticulous histological assistance, and Mrs. 0.Cumliffe who assisted with the arthroscopies. The studywas performed with the aid of grants from the Arthritisand Rheumatism Council, the Association of Friends ofthe Royal National Hospital for Rheumatic Diseases inBath, and the Boots Company Limited.

References

GARDNER, D. L. (1972) in 'The Pathology of Rheumatoid Arthritis.' Arnold, LondonHAMERMAN, D., SANDSON, J., AND SCHUBERT, M. (1963) J. chron. Dis., 16, 835 (Biochemical events in joint disease)JAYSON, M. I. V., AND HENDERSON, D. R. F. (1973) Rheum. and Rehab., 12, 195 (Arthroscopy in the diagnosis of

inflammatory joint disease)MUIRDEN, K. D. (1970) Aust. Ann. Med., 19, 97 (The anaemia of rheumatoid arthritis: the significance of iron

deposits in synovial membrane)MUIRDEN, K. D., AND MILLS, K. W. (1971) Brit. Med. J., 4, 219 (Do lymphocytes protect the rheumatoid joint?)RoPEs, M. W., BENNETr, G. A., COBB, S., JACOX, R., AND JESSAR, R. A. (1959) Ann. rheum. Dis., 18, 49 (Diagnostic

criteria for rheumatoid arthritis. 1958 revision)STEINBROCKER, O., TRAEGER, C. H., AND BATTERMAN, R. C. (1949) J. Amer. Med. Ass., 140, 659 (Therapeutic criteria

in rheumatoid arthritis)WAXMAN, B. A., AND SLEDGE, C. B. (1973) Arthr. and Rheum., 16, 376 (Correlation of histochemical, histologic and

biochemical evaluations of human synovium with clinical activity)

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