INFLAMMATION IN OSTEOARTHRITIS

Transcription

1 INFLAMMATION IN OSTEOARTHRITIS BY PAUL DIEPPE SUMMARY Osteoarthritis is usually regarded as a non-inflammatory disease. However, several authors have stressed the importance of an inflammatory phase early in the development of the condition, and specific inflammatory types of osteoarthritis have been described. Comparative trials of pure analgesic and anti-inflammatory drugs in a small sub-group of these patients showed a similar reduction of pain with both types of agent. However, a significantly greater improvement in joint tenderness and stiffness was found during treatment with anti-inflammatory drugs. INTRODUCTION IN 1829 Cruveilhier suggested that inflammatory synovitis was the cause of the cartilage destruction of osteoarthritis. However, osteoarthritis was only clearly distinguished from rheumatoid disease at the end of the 19th century, and since then attention has centred largely on the cartilage itself, and the contribution of mechanical and other physical factors to its destruction, rather than on the synovium, and the inflammatory component. As Wood (1977) has observed, the terms used to describe the disease have not helped (degenerative joint disease, arthrosis, etc), implying the aetiology, even though the causes remain unknown, and focusing work on the cartilage alone. There is much work in support of those who believe that mechanical factors are of overriding importance in osteoarthritis, particularly when only small numbers of weight bearing joints such as the hips are involved (Solomon, 1976). However, in this paper, only evidence of a contrary nature will be reviewed. Many authors have found a high incidence of polyarticular involvement associated with systemic and inflammatory features. The possible causes and the therapeutic consequences of these findings will be discussed. POPULATION SURVEYS Using radiological criteria to define osteoarthritis Kellgren and Lawrence carried out a number of large population surveys in the 1950s (Kellgren and Lawrence, 1957, 1958). They found that a striking pattern of polyarticular involvement in middle-aged women was common. This correlated with obesity and the presence of Heberden's nodes; and obesity also correlated with Heberden's nodes in men, suggesting constitutional factors in the aetiology. Kellgren (1961) noted that a preceding inflammatory arthropathy was often diagnosed clinically, although radiological signs of osteoarthritis and rheumatoid arthritis are negatively correlated (Miall, Ball and Kellgren, 1958). The findings of the New Haven study of joint disease also led its authors to conclude that constitutional factors, and perhaps inflammation, were important in the development of osteoarthritis (Acheson and Collart, 1975). OSTEOARTHRITIS IN RHEUMATOLOGY CLINICS In 1926 Cecil and Archer reviewed 182 cases seen in an out-patient clinic; 145 had polyarticular involvement with Heberden's nodes, the disease often came on suddenly, 59

2 60 DRUG TREATMENT OF RHEUMATIC DISEASES and was chiefly in middle-aged women ("menopausal arthritis"). Kellgren and Moore (1952) studied 196 cases, and found monoarticular involvement in only 20; the majority of their patients were defined as having "primary generalized osteoarthritis", a disease with an early inflammatory phase followed by the development of the typical clinical and radiological features of osteoarthritis. Wardle (1953) made similar observations and Crain (1961) described 23 cases, mainly middle-aged women, with "interphalangeal osteoarthritis", a very inflammatory condition resulting in the formation of typical Heberden's and Bouchard's nodes. Peter, Pearson and Marmor (1966) investigated 6 similar cases, and described extensive inflammatory changes in the synovium. Ehrlich (1972, 1975) documented all patients attending a rheumatology clinic over a four-year period. From a total of 1446, 337 were diagnosed as having rheumatoid disease, and 170 were labelled "erosive osteoarthritis"; a disease of women with a mean age of 50.5 years at the onset, starting abruptly, and after an inflammatory phase settling into the typical pattern of osteoarthritis. The studies mentioned suggest that a common type of osteoarthritis is a disease of women beginning with inflammation. However, even in later cases, and cases of a different type, a number of clinical features suggesting an inflammatory component may be seen (Table I). Pathological studies have also highlighted inflammatory features. Cruickshank (1952) found overlap in synovial histology between osteoarthritis and rheumatoid and other diseases, and Fassbender (1975) has described a variety of changes in the synovium in osteoarthritis. Arthroscopy has revealed a vascular, hypertrophied synovium in some cases of osteoarthritis (Moll, 1977). TABLE I CLINICAL FEATURES OF OSTEOARTHRITIS SUGGESTING AN INFLAMMATORY COMPONENT Acute polyarticular onset Variable nature of the disease Short-lasting exacerbations of pain and swelling Early morning stiffness Inactivity stiffness Hot, red, Heberden's nodes Effusions, that are often warm Baker's cysts, which may rupture Response to anti-inflammatory drugs ONE HUNDRED PATIENTS WITH OSTEOARTHRITIS One hundred consecutive patients attending a rheumatology clinic with a clinical and radiological diagnosis of osteoarthritis have been studied (Dieppe, 1978; Huskisson et ah, 1978). Most of the patients had involvement of several joints, and inflammatory features were common. Morning stiffness, although of shorter duration than in rheumatoid arthritis, was usually present. Ten had tender Heberden's nodes, and others gave a history suggesting an inflammatory phase in their development. Of the 74 with involvement of the knees, 54 had effusions, 31 Baker's cysts, and warmth was noted in 19. The synovial fluid was examined in 34 cases, the mean cell count was 3.45xlO 9 /L (range ) and the cells were predominantly mononuclear (mean 79.6%). There were 70 women and 30 men, the mean age was 60.2 years, but the mean

3 P. DIEPPE 61 age at onset of symptoms was 50.5 years; if the previously mentioned studies are relevant, an even higher incidence of inflammatory features might have been seen if the patients had presented earlier on. POSSIBLE CAUSES OF INFLAMMATION IN OSTEOARTHRITIS There are several possible causes of inflammation in osteoarthritis (Table II). Traumatic synovitis is one of the most popular explanations, although what this means is not always clear. Patients are encouraged to believe that the "knock" received a little while before, explains the flare-up of the disease, as well it may, but the mechanism is not apparent. Small fragments of cartilage, and sometimes bone, are characteristic of the synovial fluid of patients with osteoarthritis (Hollander, 1960); these cartilage fragments may be seen sequestered in the synovium, and are a potential cause of inflammation. However, the fragments are rarely phagocytosed, and in experimental studies they have little inflammatory potential. TABLE H POSSIBLE CAUSES OF THE INFLAMMATION IN OSTEOARTHRITIS Traumatic synovitis Foreign body reaction to fragments of cartilage and bone Reaction to chemical constituents of cartilage Immunological reaction to cartilage products Crystal-induced synovitis Chemical factors extracted from the cartilage have been implicated by Chrissman, who was able to produce a synovitis in dogs by injecting sterile autogenous homogenates into the knee joint (Fessel and Chrissman, 1964; Chrissman, Fessel and Southwick, 1965; George and Chrissman, 1968). Cartilage components may also be antigenic (Herman and Carpenter, 1975), and an alternative explanation is that altered or newlyreleased cartilage components set up a secondary low-grade immunological reaction in the synovium. Another possibility is raised by the recent finding of crystals in the synovial fluid of patients with osteoarthritis. A proportion of patients with osteoarthritis have deposition of calcium pyrophosphate dihydrate crystals within the affected joints (Currey et ah, 1966). Recently hydroxyapatites have also been described in the synovial fluid in osteoarthritis (Dieppe et al., 1976; Schumacher et ah, 1977). Ali (1977) has described minute aggregates of hydroxyapatite forming around the chondrocytes in osteoarthritic hyaline cartilage, and the crystals have been shown to have inflammatory properties (Dieppe, 1977). In the series of 100 patients described above, hydroxyapatite crystals were found in 9 of the 34 synovial fluids examined. All of the explanations offered so far assume a primary role for cartilage changes, resulting in a secondary inflammatory component. And yet, the clinical studies highlight the early nature of the inflammatory features of osteoarthritis. Perhaps osteoarthritis is primarily a disease of the synovium (Cruveilhier, 1829; Glynn, 1977), or perhaps a metabolic condition leading to changes in the cells within both the cartilage and the soft tissues of synovial joints. THERAPY: ANALGESIC OR ANTI-INFLAMMATORY DRUGS Osteoarthritis is usually a mild but variable disease, and it is difficult to assess. In practice anti-inflammatory drugs have often been found to be more effective than

4 62 DRUG TREATMENT OF RHEUMATIC DISEASES analgesics (Lee et al., 1974), although there have been few comparative trials. Shah and Wright (1967) found that intra-articular steroids were no more effective than normal saline, although others have noted great but temporary improvement using this technique (Peter, Pearson and Marmor, 1966; Haslock, 1977). Pure analgesics, such as "Distalgesic" (dextropropoxyphene and paracetamol; Dista Pharmaceuticals) are widely prescribed for osteoarthritis. In a recent trial "Distalgesic" and ketoprofen were compared in a double-blind cross-over study in osteoarthritis (Doyle, Huskisson and Dieppe, 1978). The amount of pain relief was similar in the two treatment periods, but stiffness and tenderness of the joints was significantly less while patients were on the anti-inflammatory drug. More trials of this sort are necessary to help rationalize the treatment of osteoarthritis. At present the evidence for an inflammatory component, and the experience of the use of different drugs would seem to justify using the milder, non-toxic anti-inflammatory drugs as first-line therapy in osteoarthritis. REFERENCES ACHESON, R. M. and COLLART, A. B. (1975) "New Haven survey of joint disease XVII. Relationship between some systemic characteristics and osteoarthrosis in a general population." Ann. rheum. Dis. 34, 379. Au, S. Y. (1977) "Matrix vesicles and apatite nodules in arthritic cartilage". In: Perspectives in Inflammation. Ed: WHAOUGHBY, D. A., GROUD, J. P. and VELO, G. P. Manchester: M.T.P. Press. CECIL, R. J. and ARCHER, B. H. (1926) "Menopausal arthritis". /. Amer. med. Ass. 87, 741. CHRISSMAN, O. D., FESSEL, J. M. and SOUTHWICK, W. O. (1965) "Experimental production of synovitis and marginal exostoses in the knee joints of dogs". Yale J. Biol. Med. 37, 409. CRATN, D. C. (1961) "Interphalangeal osteoarthritis". /. Amer. med. Ass. 175, CRUICKSHANK, B. (1952) "Interpretation of multiple biopsies of synovia] tissues in rheumatic diseases". Ann. Rheum. Dis. 11, 137. CRUVEUJDER, J. (1829) "Anatomic Pathologique du Corps Humain". Vol. 1. Part 9, p. 10. Paris, France: J. B. Bailliere. CURREY, H. L., KEY, J. J., MASON, R. M. and SWEETENHAM, J. (1966) "Significance of radiological calcification of joint cartilage". Ann. rheum. Dis. 25, 295. DIEPPE, P. A. (1977) "Crystal induced inflammation and osteoarthritis". In: Perspectives in Inflammation, Ed.: WILLOUGHBY, D. A., GIROUD, J. P. and VELO, G. P. Manchester: M.T.P. Press. (1978) "Crystal deposition in osteoarthritis". Europ. J. Rheumatl. Inflam. 1, 125. HUSKISSON, E. C, CROCKER, P. R. and WILLOUQHBY, D. A. (1976) "Apatite deposition disease, a new arthropathy". Lancet i, 266. DOYLE, D. V., HUSKISSON, E. C. and DIEPPE, P. A. (1978) In preparation. EHRLICH, G. E. (1972) "Inflammatory osteoarthritis. I. The clinical syndrome". /. chron. Dis. 25, 317. (1975) "Osteoarthritis beginning with inflammation. Definitions and co-relations". /. Amer. med. Ass. 232, 157. FASSBENDER, H. G. (1975) Pathology of Rheumatic Diseases. Translated by G. LOEWL Berlin: Springer. FESSEL, J. M. and CHRISSMAN, O. D. (1964) "Enzymatic degradation of chondromucoprotein by cell free extracts of human cartilage". Arthr. Rheum. 7, 398. GEORGE, R. C. and CHRISSMAN, O. D. (1968) "The role of polysaccharides in osteoarthritis". Clin. Orthopaedics 57, 259. GLYNN, L. E. (1977) "Primary lesion in Osteoarthritis". Lancet i, 574. HASLOCK, I. (1977) "Medical treatment of osteoarthrosis". Clin. Rheum. Dis. 2, 615. HERMAN, J. H. and CARPENTER, B. A. (1975) "Immunology of cartilage". Seminars Arthr. Rheum. 5, 1. HOLLANDER, J. L. (1960) 'Treatment of osteoarthritis of the knees". Arthr. Rheum. 3, 564.

5 P. DIEPPE 63 HUSKISSON, E. C, DIEPPE, P. A., TUCKER, A. K. and CANNELL, L. B. (1978) "Another look at osteoarthritis". Ann. rheum. Dis. In press. KELLGREN, J. H. (1961) "Osteoarthrosis in patients and populations". Brit. med. J. 2, 1. and LAWRENCE, J. S. (1957) "Radiological assessment of Osteoarthritis". Ann. rheum. Dis. 16, 494. (1958) "Osteoarthrosis and disc degeneration in an urban population". Ann. rheum. Dis. 17, 388. and MOORE, R. (1952) "Generalised osteoarthritis and Heberden's nodes". Brit. med. J. 1,181. LEE, P., ROONEY, P. J., STURROCK, R.D., KENNEDY, A. C. and DICK.W. C. (1974) "The aetiology and pathogenesis of osteoarthrosis: a review". Seminars Arthr. Rheum. 3, 189. MIALL, W. E., BALL, J. and KELLGREN, J. H. (1958) "Prevalence of rheumatoid arthritis in urban and rural populations in South Wales". Ann. Rheum. Dis. 17, 263. MOLL, J. H. M. (1977) "Investigation of osteoarthritis". Clin. Rheum. Dis. 2, 587. PETER, J. B., PEARSON, C. M. and MARMOR, L. (1966) "Erosive osteoarthritis of the hands". Arthr. Rheum. 9, 365. SCHUMACHER, H. R., SMOLYO, A. P., TSE, R. L. and MAURER, K. (1977) "Arthritis associated with apatite crystals". Ann. intern. Med. 87, 411. SHAH, K. D. and WRIGHT, V. (1967) "Intra-articular hydrocortisone in osteoarthrosis". Ann. rheum. Dis. 26, 316. SOLOMON, L. (1976) "Patterns of osteoarthritis of the hip". /. Bone Joint Surg. 58 (5), 176. WARDLE, E. N. (1953) Primary generalised chronic arthritis. Trans. G. LOEWI. Berlin: Springer. WOOD, P. H. N. (1977) "Osteoarthritis in the community". Clin. Rheum. Dis. 2, 495. DISCUSSION Questioner: Could I ask what analgesics you use in this treatment? Dieppe: Yes. The case I put up was the mixture of dextropropoxyphene and paracetamol but there are certainly a few drugs which have a pure analgesic action as opposed to anti-inflammatory action and I think codeine, dihydrocodeine, paracetamol and dextropropoxyphene would fit into that category. Grahame: If the "hot Heberden's node" is not due to hydroxyapatite-induced synovitis what is it due to? Dieppe: I really don't know, but there have been very few studies of this. There have been some studies which have looked at a small number of patients to analyse what the "hot Heberden's node" is composed of and all that has been found is hyaluronic acid. Questioner: In the patients you mentioned with osteoarthritis in the shoulder, was it in the shoulder itself or in the acromio-clavicular joints? Dieppe: Mostly in the shoulder joint itself. I know it is said that this is a very rare joint to be involved but that is not our experience. Interestingly, if you go back to the paper by Cecil and Archer (1926) they say it is a commonly involved joint. Husby: Have you tried colchicine in any of your patients? Dieppe: No, not on the patients. We have, however, tried it on ourselves. We took twelve voluntary subjects and induced inflammatory reactions in the skin whilst taking either colchicine or placebo in a crossover study involving three types of crystal. We found that with colchicine one can reduce the inflammatory reaction, in this model at any rate, to all three types of the crystals. But we haven't seen fit to give it to the patients yet.