From the studies which are reviewed above, it is generally apparent that in terms of the acute phase response, the initial findings in early inflammatory arthritis (particularly rheumatoid arthritis, with which the majority of such studies are concerned) have little predictive value for either the functional outcome or mortality. The wide interindividual variability in these measurements is also likely to limit their clinical usefulness as predictors of disease outcome. The trend in certain acute phase reactants may be more useful in indicating disease activity, although the number of satisfactory studies in this area is very limited.

The role of cytokines in inflammatory joint diseases is well documented, especially with regard to tissue destruction and remodelling. In these processes, IL-1 and TNF alpha play a prominent part by stimulating protease production. The regulation of their production, their release and their effects on target cells (e.g. synovial cells, chondrocytes and bone-derived cells) has therefore been the subject of intensive investigations. In this context a new dimension has emerged recently due to the observation of the existence of natural specific cytokine inhibitors. IL-1-ra and the soluble fragments of both TNF receptors--inhibitory by binding to TNF alpha--are natural products. These appear to be the molecules best suited for controlling the imbalance between pro- and anti-inflammatory processes. The use of the recombinant forms of these inhibitors may open new perspectives for therapeutic intervention. The fact that the respective mechanisms of action of receptor antagonists and inhibitory binding proteins differ does not rule out their complementarity. Preliminary experiments with animal models have yielded promising results which should be followed up by clinical trials.

Cytokines are soluble molecules which control communication between cells of the immune and non-immune systems. Studies on their role in the pathogenesis of inflammatory arthritis have been increased with the discovery of new cytokines and the development of assays for their detection. Conditions such as rheumatoid arthritis are characterized by increased production of proinflammatory cytokines in association with reduced control by regulatory cytokines produced by T lymphocytes. The inadequate inhibition of proinflammatory cytokines by anti-inflammatory cytokines and other regulatory mechanisms contributes to this cytokine imbalance. This situation is responsible for the enhanced degradation, without sufficient repair activity. These results have provided the rationale for the use of cytokines as well as for drug targeting of the cytokine network in rheumatoid arthritis. This also includes the modulation of the cytokine network by targeting the level of the receptors as well as the effects and/or the responding cells.

Disease patterns in RA vary between the sexes; the condition is more commonly seen in women, who exhibit a more aggressive disease and a poorer long-term outcome. Men, however, are more likely than women to die from extra-articular complications of rheumatoid disease. This chapter discusses the outcome and mortality studies that substantiate these conclusions and then examines the possible mechanisms that may account for them, including the HLA system, seropositivity, compliance, response to therapy and pain threshold. In particular, sex and sex hormones emerge as independent risk factors in rheumatoid disease. The epidemiological evidence points towards a peak age of onset of RA at the time of the menopause in women and towards later in life in men. Premenopausal women may fare better than postmenopausal women with RA. The possible protective effects of the oral contraceptive pill and the dramatic amelioration with pregnancy are well documented. In vivo and in vitro studies have demonstrated that sex hormones interfere with a number of the putative processes involved in the pathogenesis of RA, including immunoregulation, interaction with inflammatory mediators and the cytokine system, and direct effects on cartilage itself. All these observations point towards the importance of gonadal hormones. However, trials on the potential therapeutic use of sex hormones in RA are limited and, as yet, disappointing. Further work is necessary to determine whether the roles of sex hormones are as central protagonists or just supporting cast in the complex arena of rheumatoid disease.

The use of quantitative measures to analyse the long-term course of RA appears to have provided new insights into the severe morbidity and increased mortality rates of this disease. Quantitative assessment of RA may be viewed as an expression of clinical rheumatology as a quantitative science designed to assess accurately the long-term course of disease. The description of the joint count, radiographic scores, laboratory tests, questionnaire measures and physical measures of functional status, as well as the importance of socio-economic status, may provide new insights into the pathogenesis, prevalence, morbidity and mortality of RA.

A large number of laboratory tests have been developed within the past decade to measure factors involved in the immune inflammation of RA. These can be divided into genetic markers, general measures of inflammation, autoantibodies and tissue-specific markers. In general, it is simpler to prove the power of a certain test to measure the disease process than to predict outcome. Apart from RF positivity and CRP/ESR, few, if any, tests have proven to be of importance in independent studies from different centres. Among the promising candidates for future work are detailed analysis of the HLA-D region genes, sulphoxidation status, the autoantibody against RA33 nuclear antigen, soluble IL-2 receptor measuring lymphocyte activity, hyaluronate/hyaluronan or PIIINP from synovial tissue, the combined use of COMP and proteoglycan epitope tests for cartilage matrix, and pyrodinoline cross-linking for collagen from bone and cartilage. The ideal setting for testing such markers are prospective cohort studies starting early in the disease, and since many such studies have been initiated recently, one can expect much new information in coming years. Attention needs to be devoted to the kinetics of marker metabolism, since many are degraded or removed at very fast rates from the circulation, making serum assays less informative.

Polymyalgia rheumatica and giant cell arteritis are amongst the most satisfying conditions for clinicians to diagnose and treat because the unpleasant effects and serious consequences of these conditions can be almost entirely prevented by corticosteroid treatment; the fact that the side-effects of this treatment sometimes seem to be more serious than the complications of the disease is an indication of its effectiveness. Unfortunately, there is no objective way of determining the prognosis in the individual, and decisions concerning duration of treatment remain empirical.

Corticosteroids control arteritis in GCA and suppress polymyalgic symptoms within days of starting treatment. PMR patients can be treated with approximately 15 mg prednisolone/day, reducing the dose to 7.5-10 mg by 8 weeks. GCA is normally controlled on 40 mg prednisolone/day, although patients with persistent visual symptoms may need 60-80 mg. Slow reduction to about 20 mg by 8 weeks should minimize relapses. For both PMR and GCA a maintenance dose of 7.5 mg after 6-9 months should be enough. Steroid withdrawal is possible within 2 years of starting treatment, although some will need 4 years or more. Relapse should be defined clinically; the ESR is the most useful laboratory parameter. Steroid side-effects can be minimized by using low doses of prednisolone whenever possible and azathioprine may be used as a steroid-sparing agent.

The most useful investigation in supporting the clinical diagnosis of PMR/GCA is elevation of the ESR or viscosity. Acute phase proteins, particularly C-reactive protein, are also elevated but in most cases are not more helpful than the ESR in either diagnosis or follow-up. The definitive investigation is the demonstration of giant cell arteritis histologically, usually from temporal artery biopsy. The classical changes are internal elastic lamina fragmentation and destruction, with marked intimal thickening and an inflammatory infiltrate in the vessel wall with giant cells. Changes of healed arteritis can be distinguished from ageing changes and can therefore confirm the diagnosis. Positive biopsies are found in about 70% of patients with clinical GCA but are unlikely to be helpful in pure PMR. Elevation of alkaline phosphatase of liver origin is seen in one-third to half of patients with both PMR and GCA. Abnormal tracer uptake has been reported in radionuclide scans with a variety of non-specific abnormalities on liver biopsy. Promising developments include measurement of CD8+ lymphocytes and interleukins.

Giant cell arteritis (GCA) is an ophthalmic emergency because, if undetected or managed inadequately, there is a high risk of developing a painless, permanent blindness in one or both eyes; however, if it is quickly identified and treated urgently and aggressively, blindness is almost entirely preventable. The ocular manifestations of GCA are essentially ischaemic in nature, with blindness as the most dreaded complication. Blindness is usually due to anterior ischaemic optic neuropathy (AION) and occasionally to other causes, e.g. posterior ischaemic optic neuropathy or central retinal or cilioretinal artery occlusion, although extremely rarely it may be cortical in origin. Diplopia and other types of ophthalmoplegias are seen in some cases but are usually transient in nature. Ischaemic lesions of the anterior segment of the eye are also seen in a few cases. Diagnosis of arteritic AION is discussed at length. Finally, management of GCA from the point of view of visual loss is discussed in detail.

The clinical features of GCA can be classified into: (1) the systemic manifestations of malaise, weight loss, fever, night sweats and depression; (2) the proximal muscle pain and stiffness of polymyalgia rheumatica; (3) arteritic manifestations of pain or tenderness due to local inflammation; and (4) arteritic manifestations of ischaemia due to narrowing or occlusion of vessels. These may occur singly or in any combination and may come and go with the passage of time. Thus GCA can result in many different clinical signs and symptoms. The feared ocular and cerebrovascular complications of the condition can be prevented by the early institution of corticosteroid treatment. Early diagnosis is therefore vital. This is a simple matter when GCA presents in the classical textbook manner, but in atypical cases diagnosis can be exceedingly difficult. The absence of a reliable way of excluding the disease means that diagnosis is often a clinical exercise. A sound knowledge of the many and varied clinical manifestations of GCA is therefore required if the physician is going to prevent the ocular and cerebrovascular complications of GCA by early diagnosis and treatment.

The results of investigations on the humoral immunological mechanisms are conflicting in giant cell arteritis (GCA) and have not been able to explain the pathological findings in the inflamed arterial wall. Altogether, immunological studies suggest that a cell-mediated immune reaction, possibly against an autologous antigen, occurs locally in the arteritic lesions of GCA. The excellent effect of treatment with glucocorticosteroids on the inflammation in GCA can also be explained by this model. The glucocorticosteroids inhibit the synthesis of interleukin-1 (IL-1) by the macrophages and suppress the IL-2 production from the T cells (Palacios, 1982). The observed HLA-DR expression in the arterial wall can be accounted for by the sum of macrophages and activated T cells, the macrophages being the most probable antigen-presenting cells. The interdigitating reticulum cells observed in some of the GCA patients may also be involved in antigen presentation. What the antigen(s) may be is, however, still unknown, as are the factors initiating the inflammatory process. It has recently been possible to extract T lymphocytes from the inflamed tissue and to culture these cells in vitro. After culture, it is possible to study the gene for the T-cell receptor, and probably even the antigenic specificity of the T cells. I hope that this approach may lead to a better understanding of the pathogenic mechanisms in GCA.

In both clinical and histological terms cranial arteritis is one of the most distinctive of all vascular disorders. The dense granulomatous inflammatory infiltrates which characterize the acute stages of the disease resemble those of Takayasu's arteritis or granulomatous angiitis of the central nervous system, but the clinicopathological features in patients with positive temporal artery biopsies are diagnostic. Well over a third of patients with classical signs and symptoms of cranial arteritis have negative temporal artery biopsies, and focal involvement of arteries of the head and neck is the probable explanation for this. Pathologists should be aware of the wide spectrum of histological changes that occur in muscular arteries as part of normal ageing and must not interpret these as evidence of healed arteritis. The histological changes of healed arteritis include medial chronic inflammation with ingrowth of new blood vessels, focal medial scarring and a bizarre pattern of intimal fibrosis. Although ultrastructural and immunohistochemical studies have provided some insight into the underlying pathological changes, they have not contributed directly to the diagnosis of cranial arteritis. Between 15 and 55% of patients with polymyalgia rheumatica have positive temporal artery biopsies, but apart from an elevated ESR there are no other laboratory investigations or biopsy procedures that contribute to diagnosis.

Polymyalgia rheumatica and temporal arteritis appear to be separate syndromes rather than two manifestations of an underlying giant cell arteritis. Polymyalgia rheumatica is a synovitis that may be persistent or recurrent, while temporal arteritis is almost always a single episode; documented recurrences are rare. The two syndromes frequently occur in the same patient although not necessarily at the same time and they may be separated by a long interval. In some patients with polymyalgia rheumatica, giant cell arteritis is found on biopsy of an asymptomatic temporal artery. The frequency of this concurrence is variable in different populations. It is high in Scandinavia, low in Israel and intermediate between these extremes in other populations that have been studied.