MRI is a tool of unprecedented capabilities for evaluating arthritis and its progression. Not only can it non-invasively delineate the anatomy of all components of a joint with unparalleled clarity, MRI is also capable of probing important functional and compositional parameters of disease in these tissues. Particularly intriguing is MRI's potential for identifying very early changes of joint disease when clinical symptoms may be minimal or absent. Early detection of patients who are at risk for developing progressive disease may allow appropriate treatment to be initiated earlier, when there may be a greater chance of favourable outcome. MRI can, furthermore, provide objective and quantitative measures of disease progression and treatment response. Certain parameters, such as articular cartilage volume, have been validated cross-sectionally; however, their longitudinal performance has yet to be established. Further work is, therefore, necessary to thoroughly validate and optimize some of these measures so that they can begin to be used in more powerful ways to explore the pathophysiology and potential therapies of arthritic disorders.

The study of the cartilage is relatively easy with modern imaging. If the interpretation of MRI cartilage remains difficult arthro-CT images are easy to obtain. Arthro-CT is much preferable to simple arthrography. These two steps are in fact complementary: the global study of the joint is made with arthrography while the accurate assessment of cartilage is obtained with thin CT native slices acquired in an adapted plane and completed with reformatted images. The detection of small lesions, such as a faint thinning of the cartilage, or a focal fissure is only possible with a long and meticulous examination. The pathological value of the images still depends on the clinical examination, because of the high incidence of asymptomatic chondromalacia in elderly patients. The assessment of the cartilage overlying osteochondritis or osteochondral fractures is of particular clinical interest. The detection of post-traumatic cartilaginous lesions may also be valuable in medicolegal problems.

Patients with a wide variety of rheumatological conditions can be usefully investigated by nuclear medicine techniques and particularly by bone scintigraphy. This aspect of nuclear medicine work is increasing and the trend can be expected to continue. The principal conditions that can be imaged are sports medicine injuries, osteomyelitis, avascular necrosis, reflex sympathetic dystrophy syndrome, enthesopathies and bio-mechanical stress lesions, inflammatory arthropathies, metabolic bone disease and miscellaneous bone conditions such as costo-chondritis. Single photon emission tomography (SPECT) has provided new indications for bone scintigraphy such as the evaluation of spondylolysis and facet syndrome in the spine and of meniscal tears and ligamental lesions.

Ultrasound is an extremely useful and versatile method of assessing soft tissue abnormality in rheumatological conditions. It is best performed as an extension of clinical examination. Ultrasound has the advantage of not only being able to demonstrate abnormalities but also allows transducer compression of those abnormalities to see if it reproduces the patient's characteristic symptoms. It is likely to find even greater use in the clinical setting over future years. In the near future skeletal ultrasound should develop into an essential tool for the extension of physical examination in rheumatology practise. It hopefully will become as vital to a rheumatologist as echocardiography is to a cardiologist. This will however require clinicians to be prepared to undergo sufficient training in order to avoid diagnostic errors. Probably it will only be at that time, when skeletal ultrasound has become a fundamental part of rheumatological diagnosis, that its full potential will be realized.

Percutaneous needle biopsies of synovium are successfully used for diagnosis and investigation of joint disease by an increasing number of groups around the world. This procedure can be done in the office with little morbidity; a large number of samples can minimize the potential limitation of sampling error. Clinical indications for 'imaging the joint' by looking at morphological and other features of the actual tissue include undiagnosed acute or chronic mono- or oligoarthritis, haemarthrosis, suspected deposition diseases, new developments in previous stable disease and less often unexplained polyarthritis. Research into any joint disease can be helped by study of synovium especially using newer immunohistochemical, EM and molecular techniques. This report has reviewed other methods used for obtaining synovium, described the different percutaneous biopsy needles, detailed the methods used for biopsy with the Parker-Pearson needle and described how our group handles tissue so as to obtain maximal impact. The very few side effects of needle biopsy include haemarthrosis and, rarely, needle breakage. Finally, we have provided a brief overview of normal synovium and some aspects of synovium in a variety of joint diseases.

Arthrocentesis has to be considered as a part of the clinical examination. A reasonable amount of aspirated synovial fluid is the best argument in favour of an objective articular disorder. Moreover some very simple evaluations are very helpful to make a diagnosis and to distinguish some particularities of rheumatic diseases. Such evaluations have to include both bacterial and synovial fluid analysis. Moreover, when performing synovial fluid analysis, a search for microcrystals is also performed. Haemarthrosis can easily be distinguished from a traumatic tap if the investigator is observing carefully the synovial fluid entering in the syringe. The diseases responsible for haemarthrosis differ with the age of patients: chondrocalcinosis, together with osteoarthrosis, is the most frequent aetiology in the elderly; disorders of haemostasis and synovial tumours are mostly observed in children and young adults. Paucicellular (< 1000 cells/mm3) synovial fluid is observed in different 'mechanical' disorders. In the case of purulent synovial fluid the primary diagnosis is septic arthritis. However, the most common aetiology is probably crystal-induced acute arthritis. Differential cell count analysis performed in case of 'inflammatory' (> 1000 or 2000 cells/mm3) synovial fluid usually shows a predominance of polymorphonuclear cells. However, high cellularity may sometimes be associated with a predominance of other cells, i.e. lymphocytes, monocytes, eosinophils. In this situation, such a simple evaluation (differential cell count analysis) is very helpful in making a diagnosis, e.g. eosinophilic arthritis, or to distinguish some particularities of rheumatic diseases, e.g. absence of cartilage breakdown in case of lymphocytic arthritis.

Arthroscopy has served a diagnostic role for most of this century, but found widespread popularity only when operative interventions were coupled with the procedure. The untapped potential inherent in directly observing the pathoanatomy underlying various rheumatologic disorders is being unlocked by developments on several fronts that have taken arthroscopy away from the operating room environment. Information from arthroscopy can influence diagnosis and treatment in certain non-traumatic knee disorders, particularly when the cause of synovitis is not evident from other clinical features and when knee symptoms are accompanied by bland synovial fluid and X-rays that are normal or show only minimal changes of osteoarthritis. Other joints can now be arthroscoped, which may prove useful for rheumatological diagnosis and evaluation, particularly for the smaller joints of the upper extremity commonly affected in 'early' disease states.

Arthroscopy still remains the 'gold standard' for the assessment of articular cartilage and synovium because it provides direct and magnified evaluation of these anatomical structures. Thus, alongside the use of arthroscopy as a diagnostic or therapeutic procedure in knee disorders, a further function of knee arthroscopy, performed under local anaesthesia on an outpatient basis, has been proposed: the monitoring and follow-up of knee chondropathy and synovitis conducted for research purposes on patients suffering from knee osteoarthritis or chronic synovitis. This function is used in order (1) to evaluate the natural history of these diseases, (2) to assess 'de visu' the effect on chondral or synovial lesions of medical treatments or surgical interventions, and (3) to validate non-invasive imaging techniques such as plain radiographs or magnetic resonance imaging. The development of this arthroscopic outcome measurement of chondropathy and synovitis required the establishment and validation of systems for scoring the severity of chondral and synovial lesions. The author reviews both earlier and newer arthroscopic classifications and underlines the need for a quantitative description of cartilage and synovial abnormalities, either global and based on the investigator's overall assessment by using a visual analogue scale of severity, or, more analytically, taking into account the baseline parameters of the lesions, i.e. depth/intensity, extent and location.

Radiographs are characteristically required to define the nature of the disease process in spondylarthritis. They need rarely be repeated, except for complications or unusual manifestations of the underlying disease. To date, new techniques of radio-imaging have provided only minimal advantages, if any. (Berkowitz et al, 1991; Docherty et al, 1992; Gibbon, 1992; Ralston et al, 1992; Deyo, 1994; Jensen et al, 1994). The plain radiograph is still pivotal to our understanding of the disease.

Radiographs are a suitable outcome measure in patients with rheumatoid arthritis. They reflect the history of the joint pathology and provide a permanent record necessary for serial evaluation of the disease. Great care should be taken to overcome technical problems with radiographs to ensure that good quality films are available to score. Many scoring methods have been described ranging from a global score for the whole patient to the more sophisticated methods of scoring erosions and joint space narrowing in a selected number of joints. These latter abnormalities give additive information and are the most important features in scoring radiographs in rheumatoid arthritis. An overview of the most important methods is given with an emphasis on four selected methods: the Larsen method, a modification of this by Rau and Herborn, the Sharp method and a modification of this by van der Heijde. All four methods produce sufficient intra- and inter-observer reliability. Although data are scarce, the Sharp method and its modifications seem the most sensitive methods for detecting changes over time. However, these are more time-consuming than the Larsen method or its modifications. Depending on the type of study a choice can be made between the two types of methods. For clinical trials where small differences are important, the (modified) Sharp method seems the most appropriate. In working with large data sets, time might be a more crucial factor and, therefore, the (modified) Larsen method could be chosen.

Radiographic joint space narrowing is the hallmark of progression in osteoarthritis (OA). An accurate measure of progression for OA requires a precise quantitative method. New techniques have been designed to quantitatively assess knee and hip joint space using computer analysis of digitally stored radiographs. The interobserver coefficient of variation of the technique ranges from 1% to 3.3% and is clearly better than that obtained by the use of dividers and rule. A precise standardization of the radiological procedure as well as use of films of good quality are required for a good reproducibility of the method. The computerized measurement of joint space size from standard radiographs is applicable to monitor progression of hip and knee OA, and appears to be of value in the evaluation of disease-modifying therapies for OA.

This article has reviewed the use of semiquantitative individual feature scales based on standard photographs in published atlases, and quantitative techniques, including chondrometry, high-definition microfocal radiography, and computerized digital image analysis, and commented on their use in longitudinal studies of osteoarthritis where data are obtained from the reading of serial radiographs. For investigators planning future studies involving the reading of already available radiographs, the use of computerized digital image analysis, if available, is recommended for measurement of joint space because of its superior reliability; if this is not available, then chondrometry should be used. Other individual features should be scored using a standard atlas. For investigators planning new studies, especially therapeutic trials, recent guidelines recommended by a World Health Organization Satellite Workshop on 'The standardization of methods for the assessment of articular cartilage changes in osteoarthritis of the knee and hip joint' should be followed (Dieppe, 1995).

Quantitative macroradiography of patients with hand and knee OA, employing standardized radiographic and mensural procedures, permit: accurate and reproducible measurements of all radiographic features. significant changes in JSW and osteophyte number and size to be detected within as short a period as 18 months. therapeutic effects upon articular cartilage to be determined from changes in JSW. a better understanding of the disease process from an evaluation of the relative changes in the different radiographic features of OA.

Radiological assessment of joint space width on plain radiographs is the most frequently used primary outcome criterion in clinical trials of disease modifying drugs. Changes in measurement over time are slow. Therefore, in order to improve the capacity of measurement to detect changes, the sources of variability (i.e. radiographic procedure, joint positioning, process of measurements, etc.) must be limited. Precise guidelines concerning radiographic procedure, joint positioning and methods of reading are required to achieve this goal.

In the light of more modern techniques such as sonography and magnetic resonance imaging, the reader may well ask if plain radiography has still a role in the diagnostic work-up of rheumatoid arthritis. However, in daily routine, the value of diagnostic radiography in support of the clinical and laboratory diagnosis of rheumatoid arthritis is unrivaled. It allows differentiation from other joint diseases, such as osteoarthritis or crystal arthropathies, when the ARA criteria are not conclusive for the diagnosis of rheumatoid arthritis. Further, plain radiography is part of the basic documentation of the disease in measuring disease progression. Therapeutic decisions, such as systemic versus local therapy, and selection of drugs, as well as the form of local therapy, are heavily dependent on radiographs. However, the limitations of radiography in evaluating disease progression have to be recognized. Ultrasonography, as a 'bedside method', and MRI are indispensable adjuncts to radiography, because they are superior in detecting synovitis, early forms of cartilage damage as well as bone reaction such as erosions and cysts. A superior assessment of the degree of synovial changes is also possible with MRI.

Modulation of the immune network through the hormonal system is an exciting emerging concept. It results from a decade of experimental research obtained on rodents. Unfortunately, the therapeutic response on NZB/NZW F1 mice with murine lupus or in adjuvant induced arthritis are not transferable to man. This new field opens new therapeutic perspectives with well known and relatively safe drugs (hormone agonists, antagonists or inhibitors of hormonal secretion). Today we lack controlled, randomized clinical studies, with long-term follow-up. We also need to identify the subgroup of patients who could benefit from hormonal immunomodulation (sex, basal hormonal status, menopausal status for women, disease activity).

Fibromyalgia (FM) falls into the spectrum of what might be termed 'stress-associated syndromes' by virtue of frequent onset after acute or chronic stressors and apparent exacerbation of symptoms during periods of physical or emotional stress. Patients with FM exhibit disturbances of the major stress-response systems, the HPA axis and the sympathetic nervous system. Integrated basal cortisol levels measured by 24-hour urine-free cortisol are low. FM patients display a unique pattern of HPA axis perturbation characterized by exaggerated ACTH response to exogenous CRH or to endogenous activators of CRH such as insulin-induced hypoglycaemia. The cortisol response to increased ACTH in these stress paradigms is blunted, as is the the cortisol response to exercise. Functional analysis suggests that FM patients may also exhibit disturbed autonomic system activity. For example, plasma NPY, a peptide co-localized with norepinephrine in the sympathetic nervous system, is low in patients with FM. Abnormalities of related neuronal systems, particularly decreased serotonergic activity, may contribute to the observed neuroendocrine perturbations in FM. Finally, other neuroendocrine systems, including the growth hormone axis, are also abnormal in FM patients. Many clinical features of FM and related disorders, such as widespread pain and fatigue, could be related to the observed neuroendocrine perturbations. This hypothesis is supported by the observation that many useful treatments for FM affect the function of these central nervous system centres. Further clarification of the role of neuroendocrine abnormalities in patients with FM, and the relationship of these disturbances with particular symptoms, may lead to improved therapeutic strategies.

Compared to the now numerous studies on the endocrinology of rheumatic diseases in adults, only a small number of studies has been published on children with rheumatic diseases. Prolactin has been most extensively investigated, showing interesting parallels with the findings in adults with rheumatological diseases. Thus, analogous to adult RA most forms of JRA or JCA (with the exception of ANA-positive JRA with uveitis) appear to show, if anything, low to normal levels of prolactin. Since the prolactin levels in adult RA depend on the inflammatory activity, and the physiological prolactin secretion decreases in chronic stress (especially sleep disorders), these results are most likely to be explained as reactive non-specific mechanisms in the stress of the disease. However, specific mechanisms are also being discussed to explain the low prolactin levels in adult RA. The results of prolactin measurements in juvenile SLE, juvenile ankylosing spondylitis and ANA-positive JRA with a raised incidence of uveitis, contrast with this. These conditions sometimes show significantly higher prolactin levels compared to healthy controls. A correlation of the increase of prolactin concentration with the inflammatory activity has been described for juvenile ankylosing spondylitis. These results correlate well with those of adult forms such as diseases of the seronegative spondyloarthropathies type, SLE and iridocyclitis. Raised prolactin concentrations are also found in these diseases. The inflammation promoting and immunostimulatory effects of prolactin found especially in animal experiments are confirmed clinically in these diseases by reports of successful treatments with the prolactin inhibitor, bromocriptine. The results available up to now for human growth hormone in JRA and JCA tend to be comparable with the results for prolactin in these form of paediatric rheumatological diseases. Besides normal values above, all lowered concentrations are measured for this hormone. Apart from other non-specific factors, its diminished secretion is mainly determined by the inflammatory activity of the disease. Low levels of growth hormone are likely to be a significant factor in the growth retardation in children with inflammatory rheumatological diseases. Up to now, the small number of investigations on gonadotrophins and the sex hormones in juvenile SLE and various forms of JRA published have not as yet yielded unequivocal results. The endocrine aspects of paediatric rheumatological diseases are thus still incompletely elucidated. However, there are many promising avenues for further fruitful research in this field.

It has become clear that the neuroendocrine and immune systems are closely linked and interdependent. The exact mechanisms of this interaction are only beginning to be unravelled. The complexity of these connections may partly explain why the aetiopathogenesis of autoimmune diseases remains obscure and why genetic, hormonal, microbial, environmental, as well as a host of other factors, have all been put forward as explanations. What has become clear is that a number of neuroendocrine and hormonal factors have important immunomodulatory roles in health and disease.

The available evidence reviewed does not allow definitive response to the question of a primary versus secondary role of sex hormone perturbations in RA. However, this conclusion should not be discouraging in view of the relatively recent focus upon this facet of the physiopathogenesis of RA and the enormous complexities of sex hormone biology and this disease. Specifically, data on the incidence of RA as well as life cycle changes in serum androgenic-anabolic (A-A) and sex hormone levels suggest important risk correlations. Furthermore, HLA-susceptibility markers for RA, gender, menopause and older age are all factors which significantly relate to the risk of developing RA and each has been shown to associate with sex hormone status. Whether or not HPG-AA hormonal status may modulate RA risk (or its course) primarily and independently or merely be predictive markers of other biological mechanisms was critically considered and requires further study. Sex hormone influences on cellular and humoral immunological reactivity and vascular pathogenetic mechanisms in RA were summarized. Androgens generally suppress immunoreactivity and cartilage responses to inflammation-mediated injury processes and may enhance synovial macrophage-like lining cell apoptosis. Oestrogens generally enhance immunoreactivity, offer some protection to inflammation-mediated cartilage damage (but less than androgens) and may inhibit apoptosis in certain in vitro cell models. Scant information is available on the balance of sex hormones (and glucocorticoids) in RA or its presumed pathogenetic mechanisms. Data were reviewed which support the concept of a spectrum of androgenicity in the normal population, particularly among women. A simplified schema of trophic and tropic steroidogenic mechanisms was proposed which could influence androgenic-anabolic (A-A) status and might relate to RA. Serum concentrations of DHAS (mumol/l), T (nmol/l) and O2 (pmol/l) span several orders of magnitude in normal physiology. The effects of alterations in the individual levels of these sex hormones and deviations from their normal physiological balance are not well understood. Critical attention to their biological functions is needed in RA as well as in health and disease generally. Such focused clinical and experimental investigations of HPG-AA functions promise to clarify the complex physiopathology of RA and contribute to its improved long-term management.