synovialmembrane cellularity and vascularity

Annals of the Rheumatic Diseases 1995; 54: 511-515

Synovial membrane cellularity and vascularity

Oliver FitzGerald, Barry Bresnihan

Studies of the synovial membrane in jointinflammation, over many years, have proven ofmixed benefit: while it is rarely of diagnosticvalue, clues to understanding the mechanismsinvolved both in the initiation and main-tenance of the inflammatory response havebeen uncovered. While the path to under-standing is fraught with difficulty, progress isslowly being made and, it is hoped, will leadin turn to novel and better treatmentapproaches. This review of synovial membranecellularity and vascularity will describe ourcurrent understanding of the pathways to jointdamage.

vascularity is seen, depending on the type ofmembrane surface.The cartilage-pannus junction, important in

the development of joint erosion, has also beenstudied carefully in normal samples. Allardet al analysed the cellular composition both ofthe cells adjacent to bone and of the cellscontained in the layer of tissue which extendsover and merges with the cartilage, lining thejoint cavity.7 Adjacent to bone, the cells stainpredominantly with the monocyte/macrophagemarker 63D3; in contrast, those cells lining thejoint cavity express the monoclonal antibody67, thought to be a marker for materialsurrounding type B synoviocytes.8

Normal celiularity and vascularityNormal synovial tissue is characterised by asurface layer of cells, or intima, below which isa loose connective tissue which contains fibro-blasts, macrophages, adipocytes, mast cells,nerve fibres, vascular endothelial cells, andoccasional polymorphs and lymphocytes.' Theintima contains two or possibly three cell types.Type A cells are of bone marrow origin andconform to the ultrastructural criteria formonocyte derived macrophages. They expressmacrophage markers including CD68 andCD 14 and also stain with non-specificesterase.2 Type B cells are fibroblastic in typeand can be distinguished cytochemically andimmunochemically from fibroblasts deeper inthe tissues. Being involved in collagensynthesis, they express the ,B subunit of theenzyme prolyl hydroxylase.3 They are distinctin terms of their ability to express uridinediphosphoglucose dehydrogenase (UDPGD)which is an important enzyme involved inhyaluronan synthesis-a specialised synovialmembrane function.3 The constitutiveexpression of vascular cell adhesion molecule(VCAM)-1 by type B synoviocytes is also animportant distinguishing feature not shared byfibroblastic cells elsewhere in the synovialmembrane.4 The exact function of thisVCAM- 1 expression remains a matter ofspeculation, but it suggests a role in trappingcells within the lining layer. The third type ofintimal cell is dendritic in type, accounts for< 1% of the total, is CD68 negative butexpresses the class II related marker, RFDIL.

Studies on synovial vascularity date back to1743, when Hunter described the plexus ofvessels which supplied the synovial membraneand which he called the circulus articulivasculosus. A more recent detailed study ofnormal synovial membrane has highlighted thehigh frequency of capillaries, with a peakdensity just below the lining layer between 6and 11 ,um deep.6 Considerable variation in

Synovial membrane in early rheumatoidarthritisMost of the studies of rheumatoid arthritis(RA) synovial membrane have been performedon samples obtained from patients with longestablished disease, largely at arthroplasty.There have only been a few studies in earlydisease, when samples are more likely to reflectfactors important in disease initiation ratherthan those contributing to chronicity.Schumacher and Kitridou described 24patients with synovitis of recent onset, six ofwhom developed RA.9 They described variable(< 10 cells in depth) lining cell proliferationwith largely a perivascular lymphocyticinfiltration. There were prominent vascularchanges, but no lymphoid follicles and onlyoccasional polymorphs were observed. Theintensity of the inflammation did not appear tocorrelate with the disease duration. Lindbladet al also studied arthroscopic biopsies from asmall number of RA patients with diseaseduration between nine months and five years.'0Again, lining layer thickening was observed,with cells positive for both OKM1 and OKT9,suggestive ofmacrophage infiltration and acuteproliferation. The sublining cells were largelyof the helper T lymphocyte phenotype andfocal aggregates of B cells were also seen.More recent studies from our own group of

11 RA patients with a mean disease durationof 22 months have quantified the cellularinfiltrate." Again, variable lining layer thick-ening was seen (mean 4 cells in depth;range 2-32). In the sublining, 10 of the 11patients had a diffuse mononuclear infiltratecomprising predominantly CD 14 macro-phages and CD5 T lymphocytes, with roughlyequal numbers of CD4 and CD8 cells. Smallnumbers of B cells and plasma cells were alsoseen. Thus lining layer thickening, vascularproliferation and a diffuse sublining infiltratemade up of macrophages, T lymphocytes,

Department ofRheumatology,St Vincent's Hospitaland UniversityCollege,Dublin0 FitzGeraldB BresnihanCorrespondence to:Dr 0 FitzGerald,Department ofRheumatology,St Vincent's Hospital,Elm Park,Dublin 4, Ireland.

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more CD4 than CD8, and a small number ofB cells, appear to be typical features of theinvolved synovial membrane in early RA.The examination of synovial membrane

obtained from clinically uninvolved joints isanother approach to exploring changes early inthe disease. The clinically uninvolved joint ishistologically involved, though there is lesslining layer hyperplasia and fewer mononuclearcells infiltrate the sublining compared with theinvolved joint.'2 In a further study, a vascularproliferation index and a high endothelialvenule (HEV)-index were calculated both inthe clinically involved and clinically uninvolvedRA samples, in addition to postmortemcontrols.'3 Of interest, vascular proliferationwas not a feature of the uninvolved joint, andHEV-type vessels, readily seen in activelyinflamed joints, were also not observed. Thissuggests that vascular changes, which maydetermine the rate of mononuclear trafficking,are important in the clinical expression of jointinflammation in early RA.

Adhesion molecule expression in RAThe receptor-ligand pairs important in thecontrol of mononuclear trafficking into thesynovial membrane have been the subject of anumber of recent studies.'1'6 The importantadhesion molecules expressed on the endo-thelium include E-selectin, which plays arole in the initial margination and rolling ofleucocytes, and both intracellular adhesionmolecule-i (ICAM-1) and VCAM-1, whichare involved in leucocyte adhesion andpenetration through the endothelial junctions.Studies ofRA synovial membrane by our groupand others have shown E-selectin expression tobe vessel specific, the majority of vesselsstaining positive, particularly in the superficialsynovial membrane.'7 ICAM-1 expressionis not vessel specific, cells in the lining andwithin the mononuclear infiltrates alsostaining positive. Perhaps surprisingly, vascularVCAM- 1 expression is either minimal orabsent, depending on the monoclonal antibodyused. VCAM-1 is found in the lining, as it isin normal individuals, and occasional dendritictype cells within the infiltrates also stainpositive.

In a recent study of biopsies taken frompatients with actively inflamed joints (nineseropositive RA, three psoriatic arthritis, oneankylosing spondylitis), correlations weresought between the expression of adhesionmolecules in the synovial membrane, measuresof disease activity, and concentrations ofsoluble adhesion molecules in both sera andsynovial fluid.'8 19 A consistent positivecorrelation was identified between ICAM- 1concentrations in serum, synovial fluid,synovial membrane, and measures of diseaseactivity (Ritchie articular index, erythrocytesedimentation rate (ESR)), but this wasnot seen with VCAM-1 or E-selectin.'8 How-ever, a consistent negative relationship wasidentified between ICAM-1 and E-selectinexpression in these patients.'9 As serum levelsof soluble E-selectin were greater in patients

with a shorter duration of disease, it may bethat E-selectin expression is more upregulatedin early disease, ICAM-1 then correlating withthe intensity of the inflammatory response.

Synovial membrane in established RAMost studies of RA synovial membrane havebeen performed on samples obtained at jointarthroplasty. While the immunohistologicalfindings in established disease are not dis-similar from those seen earlier on, the mono-nuclear infiltrate is focal in about 70%,compared with about 10% ofbiopsy samples.20Duke et al described four different patterns ofinfiltrate: scattered/diffuse, perivascular, lym-phoid follicles and germinal centres.2'Kurosaka and Ziff went on to study the infil-trates in more detail, and described lympho-cyte rich areas where most cells stained positivefor OKT4, and more peripheral transitionalareas containing plasma cells, macrophages,and both OKT4 positive and OKT8 positivelymphocytes.22 More recently, Yanni et alanalysed lymphoid infiltrates of different sizesand found that the composition of each aggre-gate depended on the total number of mono-nuclear cells it contained:23 large aggregatescontained a substantial number of B cells andcells bearing the CD45RA phenotype; incontrast, small aggregates contained few B cellsand relatively larger numbers ofT cells bearingCD8 and CD45RO.

Lining layer thickening is also a prominentfeature of established RA. Considerablecontroversy exists as to whether this thickeningis a result of macrophage recruitment or ofsynoviocyte proliferation. In favour of recruit-ment, mitotic cells are rarely seen, and stainingfor the proliferation marker Ki-67 is notobserved in RA synovial membrane.24 Inaddition, lining layer cells express a wide rangeof macrophage antigens, and after lethalirradiation and heterologous bone marrowtransplantation, the synovial macrophages arereplaced by cells of bone marrow donor

2 25strain. In favour of proliferation, some3H-thymidine incorporation of synovial liningcells in RA is seen, and lining layer thickeningwithout mononuclear infiltration occasionallyobserved.26 In a recent study, Qu et al furtheraddressed this question by examining synovialmembrane samples for three markers ofcell proliferation: proliferating cell nuclearantigen, C-myc proto-oncogene, and nucleolarorganiser regions.26 All three markers indicatedthat there was active proliferation in thesynovial lining ofRA patients. Double labellingexperiments indicated that the proliferatingcells were fibroblastic in type, as they weretype I procollagen positive and CD68 negative.Thus lining layer thickening is likely to be theresult of a combination of macrophagerecruitment and fibroblast like synoviocyteproliferation.The central role of the T cell in the initiation

and maintenance of the inflammatory responsein RA has often been stressed.2" It is of interest,though, that T cell products such as interferongamma and interleukin-2 (IL-2) are difficult to

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find in RA synovial fluid and membrane, andthat gene expression for these lymphokines isalso sparse. In contrast, monocyte/macrophagederived products are plentiful in RA synovialmembrane with cells, mostly of macrophageorigin, staining positive with antibodies againstIL-la, tumour necrosis factor (TNF) a,TNF,B, and IL-6, in addition to both the type1 IL-1 receptor (IL-iRI) and the TNF recep-tors (p55TNF-R and p75TNF-R).2"32 WhileIL-1 receptor antagonist (IL-Ira) expression isalso seen, it has been suggested that insufficientamounts are produced by RA synovialmembrane to neutralise IL-I activity.3" Finally,in vitro production ofcytokines IL- 1 [ and IL-6by RA synovial membrane explants wascompared in two groups of arthroplastysamples, those with focal and those with diffuseinfiltrates.20 Focal infiltrates occur morefrequently in arthroplasty samples, and bothIL-i1[ and IL-6 production was significantlyenhanced in those with focal disease. Thissuggests that lymphoid follicle formation isassociated with enhanced IL- 1 [ and IL-6production, which in turn leads to greatersynthesis of the proteases involved in jointdestruction.

Cartilage-pannus junction in establishedRATwo main histological patterns at the cartilage-pannus junction have been recognised inestablished RA.33 These patterns are based onthe presence or absence of a transitional fibro-blastic zone overlying the cartilage andseparating the cartilage from pannus whichcontains macrophages, fibroblasts, and endo-thelial cells. This transitional fibroblastic zonestains positively for keratin sulphate and typeII collagen, suggesting that it is of chondrocyticorigin. In a further study, Allard et al examinedthe association between cartilage-pannusjunction pattern, joint involved, cartilagedegradation (proteoglycan depletion and chon-drocyte necrosis), and radiological appear-ance.34 The transitional zone occurred morecommonly in the hip and knee compared withthe metatarsophalangeal joint. When the zonewas absent and a distinct, well definedcartilage-pannus junction was present,cartilage degradation appeared to be enhancedand joint erosion more common. Thus it wassuggested that these different cartilage-pannusjunction patterns may explain the predomi-nance of erosive change in small joints,compared with joint space narrowing found inlarge joints in RA.The cytokine profile of the cartilage-pannus

junction has also been studied in these twohistological patterns.35 In those samples inwhich a distinct junction was seen, there wasplentiful IL-ia, IL-1,[, TNFa, and IL-6, inaddition to both IL-iR1, p55TNF-R andp75TNF-R.3' 32 3 In contrast, these cytokinesand receptors were not seen in samples whichcontained the transitional fibroblastic zone.Transforming growth factor [3, which isthought to inhibit the immune response and topromote tissue repair, is also found at the

cartilage-pannus junction and elsewhere in thesynovial membrane, and it appears to be thedominant cytokine in samples containing atransitional fibroblastic zone. Finally, IL-ira,seen in 35% of lining cells in RA, is seen in< 10% of cells at the cartilage-pannusjunction.3' Particularly in samples of invasivecartilage-pannus junction, there appears to bea predominance of proinflammatory cytokinescapable of promoting release of factorsinvolved in joint destruction.

Follow up studies ofRA synovialmembrane and effects oftreatmentIt has long been recognised that certain jointsmay deteriorate radiologically even in theabsence of clinical inflammation. Follow upstudies in RA have confirmed that radiologicaldeterioration occurs despite significantimprovement in parameters of disease

36activity. In a study of patients for 40 monthsafter total lymphoid irradiation, a significantand sustained decrease in peripheral blood Tcell numbers was observed, accompanied by acontinued, gradual radiological deterioration.37Rooney et al compared synovial membraneimmunohistological features with the clinicaloutcome of disease over a one year period.38 Inthose patients in whom there was a measurableclinical improvement, there was a reduction inspontaneous in vitro IgM rheumatoid factorproduction, a decrease in the intensity of theT cell infiltrate, and reductions in the T helpercell to T suppressor cell ratio and the numberof samples that contained B cells. These obser-vations were consistent with the suggestionthat some of the immunopathogenic events inRA may be arrested or reversed by treatment.A more recent study has sought correlations

between clinical and radiological outcome overone year and synovial membrane featuresobtained before treatment in RA patients.'2While a significant correlation was observedbetween the number of macrophages and thedegree of joint erosion, there was none withinfiltrating T or B lymphocyte populations. Inaddition, the number of synovial tissue macro-phages correlated with lining layer cellularity,which in turn correlated with synovial fluidconcentrations of IL-6. These findings suggestthat synovial tissue macrophages are critical inthe pathogenesis of joint erosion, which isperhaps mediated through release of cytokinessuch as IL-6.Mulherin et al have examined the same

question in a prospective study of 58 RApatients followed over a mean of 6- 1years.36 39 40 In that study, all clinical measuresof disease activity improved, while the meanLarsen score deteriorated significantly. Syno-vial membrane was obtained at review from 28patients and analysis showed that sublininglayer CD14 counts and lining layer thicknesscorrelated with both the percentage changeand the final Larsen scores. Additionalcorrelations were seen between lining layerCD68 count and final Larsen score, subliningCD 14 count and both lining layer thicknessand lining layer CD14 counts, and between

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lining CD68 count and both sublining CD68count and lining layer CD14 count. While nocorrelation was found between T cells or T cellsubsets and radiological outcome, these con-sistent positive correlations underscore theimportant role of the macrophage in articulardamage.

Current treatment strategies in RA involvethe use of a number of drugs which areconsidered to modify the course of the disease.These drugs do appear to modify indices ofdisease activity, but support for their ability toalter the radiological outcome has not beenconvincing. In addition, only a few studies haveexamined the effects of these agents on thesynovial membrane. Corkill et al examinedsynovial membrane biopsy samples after twoand 12 weeks of treatment with intramusculargold.4' Interestingly, the number of vesselsexpressing E-selectin was significantly reducedafter two and 12 weeks. As IL- 1,B expressionwas also shown to decrease, the reduction inE-selectin expression could have been due tothis decrease in IL-13p.42The mechanism of action of methotrexate

was also examined in a recent serial synovialmembrane biopsy study of eight patients whowere beginning oral therapy.43 All patientsnoted a clinical improvement, with a reductionin ESR and a variable though slight reductionin synovial membrane inflammation. Given theimportance of macrophages and metallo-proteinases in joint destruction, collagenasegene expression was significantly decreasedafter methotrexate therapy. Tissue inhibitor ofmetalloproteinase- 1 and stromelysin geneexpression were not changed. As methotrexatedid not alter the in vitro collagenase geneexpression by IL- 1,8 stimulated fibroblast likesynoviocytes, it was suggested that its effectsin vivo are probably the result of an alterationin synovial membrane cytokine profiles.

Synovial membrane in psoriatic ardritisCertain clinical features in patients withpsoriatic arthritis (PsA) are helpful in diag-nosis: the presence of psoriasis, an asymmetricjoint distribution, nail dystrophy, distalinterphalangeal joint involvement and dactyl-itis. Radiological features are also different andhelp distinguish the disease from RA; inparticular the presence of bone proliferation iscommon in PsA.44 The immunohistologicalfeatures of PsA synovial membrane haverecently been described and quantified.'7Compared with RA controls, there wassignificantly less lining layer hyperplasia, fewermacrophages and a greater number of bloodvessels in PsA synovial membrane. In addition,E-selectin expression was less intense in PsAsynovial membrane, while there was no differ-ence in expression of ICAM-1 and VCAM-1.Numbers ofT cells, T cell subsets and B cellswere similar in both groups. With thesefindings, it is tempting to suggest that with thereduction in E-selectin, fewer macrophagestraffic into the synovial membrane and out tothe lining layer. It may also be suggested thatthe reduction in macrophage numbers and

lining layer thickness in PsA explains thedifferent radiographic features observed.

SunmnaryBoth inflammation and destruction of the jointare the hallmarks of RA. While the con-ventional model of RA suggests that synovialinflammation is T cell mediated and that thisin turn stimulates lining layer thickening andpannus formation leading to joint damage,Zvaifler and Firestein have recently postulatedan alternative model of joint destruction.45 Inthis model they suggest that synoviocyteproliferation, pannus formation and inflam-mation comprise an autonomous processindependent of T cell derived factors. Insupport of their suggestion, they point out thatthe RA synoviocyte expresses features of atransformed phenotype: evidence of activeproliferation, ability to invade cartilage, theexpression of oncogenes, and the secretionof metalloproteinases. In addition, T cellproducts and lymphokine gene expression arenot a prominent feature in RA, animal modelsof arthritis have shown that joint damage canoccur in the absence of lymphocytic infil-tration, and T cell targetted therapies havelargely been disappointing.

Studies reported in this review lend supportto the suggestion that mechanisms of jointinflammation and destruction operate at leastin a semi-autonomous fashion. With the treat-ments currently available, clinical features ofjoint inflammation in RA improve and yet jointdamage worsens. A consistent relationship isseen between radiological deterioration andsynovial membrane macrophage infiltrationand lining layer thickening. In PsA, a diseasewith different radiological features comparedwith RA, there is a reduction in macrophagenumbers and in lining layer thickening. Themacrophage, lining layer cells and theirproducts clearly play a role in joint destruction,and current treatment strategies do not appearto affect this process. The treatments domodify inflammation which is mediated bothby cells in the lining and by the sublininginfiltrate, but new approaches are neededwhich are aimed at altering the moredestructive potential of the disease.

1 Henderson B, Edwards J C W, eds. Structure of synoviallining. In: The synovial lining in health and disease.Cambridge: Chapman and Hall Medical, 1987; 17-40.

2 Athanasou N A, Quinn J. Immunocytochemical analysis ofhuman synovial lining cells: phenotypic relation to othermarrow derived cells. Ann Rheum Dis 1991; 50: 311-5.

3 Wilkinson L S, Pitsillides A A, Worrall J G, Edwards J C W.Light microscopic characterization of the fibroblast-likesynovial intimal cell (synoviocyte). Arthitis Rheum 1992;35: 1179-84.

4 Wikinson L S, Edwards J C W, Ponston R N,Haskard D 0. Expression of vascular cell adhesionmolecule-1 in normal and inflamed synovium. Lab Invest1993; 68: 82-8.

5 Wllkinson L S, Worrall J G, Sinclair H S, Edwards J C W.Immunohistochemical reassessment of accessory cellpopulations in normal and diseased human synovium. BrJRheumatol 1990; 29: 259-63.

6 Knight A D, Levick J R. The density and distribution ofcapillaries around a synovial cavity. QJ'Exp Physiol 1983;68: 629-44.

7 Allard S A, Bayliss M T, Maini R N. The synovium-cartilage junction ofthe normal human knee. Implicationsfor joint destruction and repair. Arthrtis Rheum 1990; 33:1170-9.

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8 Stevens C R, Mapp P I, Revell P A. A monoclonal antibody(Mab 67) marks type B synoviocytes. Rheumatol Int 1990;10: 103-6.

9 Schumacher H R, Kitridou R D. Synovitis of recent onset.A clinicopathologic study during the first month ofdisease. Arthritis Rheum 1972; 15: 465-85.

10 Lindblad S, Klareskog L, Hedfors E, Forsum U,Sundstrom C. Phenotypic characterization of synovialtissue cells in situ in different types of synovitis. ArthritisRheum 1983; 26: 1321-32.

11 Yanni G, Whelan A, Feighery C, Bresnihan B. Synovialtissue macrophages and joint erosion in rheumatoidarthritis. Ann Rheum Dis 1994; 53: 39-44.

12 Soden M, Rooney M, Cullen A, Whelan A, Feighery C,Bresnihan B. Immunohistochemical features in thesynovium obtained from clinically uninvolved knee jointsof patients with rheumatoid arthritis. Br Jf Rheumatol1989; 28: 287-92.

13 FitzGerald 0, Soden M, Yanni G, Robinson R,Bresnihan B. Morphometric analysis of blood vessels insynovial membranes obtained from clinically affected andunaffected knee joints of patients with rheumatoidarthritis. Ann Rheum Dis 1991; 50: 792-6.

14 Koch A E, Burrows J C, Haines G K, Carlos T M,Harlan J M, Leibovich S J. Immunolocalization ofendothelial and leukocyte adhesion molecules in humanrheumatoid and osteoarthritic synovial tissues. Lab Invest1991; 64: 313-20.

15 Gerritsen M E, Kelley K A, Ligon G, et al. Regulation ofthe expression of intercellular adhesion molecule 1 incultured human endothelial cells derived from rheuma-toid synovium. Arthritis Rheum 1993; 36: 593-602.

16 Szekanecz Z, Haines G K, Lin T R, et al. Differentialdistribution of intercellular adhesion molecules (ICAM-1,ICAM-2, and ICAM-3) and the MS-I antigen in normaland diseased human synovia. Arthritis Rheum 1994; 37:221-31.

17 Veale D, Yanni G, Rogers S, Barnes L, Bresnihan B,FitzGerald 0. Reduced synovial membrane macrophagenumbers, ELAM-1 expression, and lining layer hyper-plasia in psoriatic arthritis as compared with rheumatoidarthritis. Arthritis Rheum 1993; 36: 893-900.

18 Mulherin D, Veale D J, Belch J J F, Bresnihan B,FitzGerald 0. Adhesion molecule expression in matchedsynovial membrane, synovial fluid and serum in inflam-matory arthritis. IrJMedSci 1995; 164. In press.

19 Mulherin D, Bresnihan B, FitzGerald 0, Veale D, Belch J.Relationship of ICAM-1 with E-selectin in synovialmembrane, fluid and serum in inflammatory arthritis.Arthritis Rheum 1994; 37 (suppl 2): S189.

20 Yanni G, Whelan A, Feighery C, et al. Contrasting levels ofin vitro cytokine production by rheumatoid synovialtissues demonstrating different patterns of mononuclearcell infiltration. Clin Exp Immunol 1993; 93: 387-95.

21 Duke 0, Panayi G S, Janossy G, Poulter L W. Animmunohistological analysis of lymphocyte sub-populations and their microenvironment in the synovialmembranes of patients with rheumatoid arthritis usingmonoclonal antibodies. Clin Exp Immunol 1982; 49:22-30.

22 Kurosaka M, ZiffM. Immunoelectron microscopic study ofthe distribution of T cell subsets in rheumatoid synovium.JExp Med 1983; 158: 1191-210.

23 Yanni G, Whelan A, Feighery C, Bresnihan B. Analysis ofcell populations in rheumatoid arthritis synovial tissues.SeminArthritisRheum 1992; 21: 393-9.

24 Lalor P A, Mapp P I, Hall P A, Ravell P A. Proliferativeactivity of cells in the synovium as demonstrated bymonoclonal antibody Ki-67. Rheumatol Int 1987; 7:183-6.

25 Edwards J C, Wllloughby D A. Demonstration of bone-marrow-derived cells in synovial lining by means of giantintracellular granules as genetic markers. Ann Rheum Dis1991; 41: 177-82.

26 Qu Z, Garcia C H, O'Rourke L M, Planck S R, Kohli M,Rosenbaum J T. Local proliferation of fibroblast-like

synoviocytes contributes to synovial hyperplasia. ArthritisRheum 1994; 37: 212-20.

27 Sewell K L, Trentham D E. Pathogenesis of rheumatoidarthritis. Lancet 1993; 341: 283-6.

28 Field M, Chu C, Feldman M, Maini R N. Interleukin-6localisation in the synovial membrane in rheumatoidarthritis. RheumatolInt 1991; 11: 45-50.

29 Chu C Q, Field M, Abney E, et al. Transforming growthfactor-P 1 in rheumatoid synovial membrane andcartilage/pannus junction. Clin Exp Immunol 1991; 86:380-6.

30 Chu C Q, Field M, Feldman M, Maini R N. Localizationof tumor necrosis factor a in synovial tissues and at thecartilage-pannus junction in patients with rheumatoidarthritis. Arthritis Rheum 1991; 34: 1125-32.

31 Deleuran B W, Chu C Q, Field M, et al. Localization ofinterleukin-lt, type 1 interleukin-I receptor and inter-leukin-1 receptor antagonist in the synovial membraneand cartilage/cannus junction in rheumatoid arthritis. BrJ Rheumatol 1992; 31: 801-9.

32 Deleuran B W, Chu C Q, Field M, et al. Localization oftumor necrosis factor receptors in the synovial tissue andcartilage-pannus junction in patients with rheumatoidarthritis. Arthritis Rheum 1992; 35: 1170-8.

33 Allard S A, Muirden K D, Camplejohn K L, Maini R N.Chondrocyte-derived cells and matrix at the rheumatoidcartilage-pannus junction identified with monoclonalantibodies. RheumatolInt 1987; 7: 153-9.

34 Allard S A, Muirden K D, Maini R N. Correlation ofhistopathological features of pannus with patterns ofdamage in different joints in rheumatoid arthritis. AnnRheumDis 1991; 50: 278-83.

35 Chu C Q, Field M, Allard S, Abney E, Feldman M,Maini R N. Detection of cytokines at the cartilage/pannus junction in patients with rheumatoid arthritis:implications for the role of cytokines in cartilagedestruction and repair. BrJRheumatol 1992; 31: 653-61.

36 Mulherin D, FitzGerald 0, Bresnihan B. Radiologicprogression of rheumatoid arthritis over six yearscorrelates with macrophage numbers in the synovium.Arthritis Rheum 1993; 36 (suppl): S86.

37 Soden M, Hassan J, Scott D L, et al. Lymphoid irradiationin intractable rheumatoid arthritis: long-term follow-up ofpatients treated with 2000 rad and 750 rad. ArthritisRheum 1989; 32: 523-30.

38 Rooney M, Whelan A, Feighery C, Bresnihan B. Changesin lymphocyte infiltration of the synovial membrane andthe clinical course of rheumatoid arthritis. Arthritis Rheum1989; 32: 361-9.

39 Mulherin D, FitzGerald 0, Bresnihan B. An analysis of thediscrepency between the clinical and radiologic course inrheumatoid arthritis. Arthritis Rheum 1994; 37 (suppl):S251.

40 Mulherin D, FitzGerald 0, Bresnihan B. The relationshipbetween macrophage populations in the synovium andarticular damage in rheumatoid arthritis. Arthritis Rheum1994; 37 (suppl): S222.

41 Corkill M M, Kirkham B W, Haskard D 0, Barbatis C,Gibson T, Panayi G S. Gold treatment of rheumatoidarthritis decreases synovial expression of the endothelialleukocyte adhesion receptor ELAM-1. J Rheumatol 1991;18: 1453-60.

42 Kirkham B W, Navarro F, Corkill M M, Gibson T,Panayi G S. Change in interleukin 1 beta expression inrheumatoid synovial membrane after treatment with goldand glucocorticoid. Clin Rheumatol 1990; 9:118-9.

43 Firestein G, Paine M M, Boyle D L. Mechanisms ofmethotrexate action in rheumatoid arthritis. Selectivedecrease in synovial collagenase gene expression. ArthritisRheum 1994; 37: 193-200.

44 Brewer A C. The radiographic features of psoriatic arthritis.In: Gerber L H, Espinoza L R, eds. Psoriatic arthritis.Orlando: Grune and Stratton, 1985: 125-46.

45 Zvaifler N J, Firestein G S. Pannus and pannocytes.Alternative models of joint destruction in rheumatoidarthritis. Arthritis Rheum 1994; 37: 783-9.

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