Modern high-speed aviation and space flight are fraught with many problems and require a high standard of health and fitness. Those responsible for the health of pilots must appreciate the importance of early diagnosis even before symptoms appear. This is particularly true in terms of preventing spinal injuries where even a single Schmorl's node may make a pilot unfit for high-speed flying. Spinal fractures are frequent during emergency ejection and landing. Helicopter crews are particularly prone to spinal disc degeneration due to vibration. By effective lowering of vibration by changes in the seats, a reduction in such lesions is possible. The osteoporosis and muscle atrophy occurring among astronauts subjected to prolonged weightlessness can be prevented by regular physical exercises.

Dysbaric osteonecrosis is a serious complication for those exposed to a hyperbaric environment, with prevalence of 17% amongst compressed air workers and 4.2% amongst divers. Bone lesions are characteristically multiple and bilateral, occurring frequently in the shafts of the femora or tibiae and the heads of the humeri or femora. A proportion of the lesions will lie next to the joint surface, the so called juxta-articular lesion, and these may progress to a structural failure and secondary osteoarthritis. These lesions can be severely disabling, especially in a young adult male. When related to the occupational history the prevalence of bone lesions, both in compressed air workers and divers, increases with age, experience and with greater pressures of air or at greater depths. Moreover, acute attacks of decompression sickness, the bends, are more liable to be associated with subsequent bone lesions. Current decompression schedules certainly reduce the bends rate but, no matter how strictly adhered to, will not prevent the development of dysbaric osteonecrosis. It is possible that bone necrosis could result solely from exposure to a high pressure of air, either from work in compressed air or diving. Those men with positive bone lesions should be advised to seek expert medical opinion and probably advised to discontinue work in compressed air or diving if a juxta-articular lesion is present. Detection of bone necrosis depends on good quality radiographs with reliable interpretation, preferably by double observation, especially in the early stages. Lesions, especially when early or doubtful, can be confirmed by CT or bone scintigraphy. MRI promises to detect osteonecrosis in the very early stages but is not yet readily available. To detect dysbaric osteonecrosis at an early stage it is important to monitor both compressed air workers and divers with regular radiological skeletal surveys or bone scintigraphy. In 1987, the Bone Necrosis Working Group of the Decompression Sickness Panel recommended that all divers should have a radiological survey on completion of their initial diving training and that bone scintigraphy should be used for subsequent surveillance for certain groups, including those diving deeper than 30 metres, where the time at depth exceeds 4 hours, when experimental decompression is used and in other situations.

SLE is a syndrome defined by clinical criteria and by the presence of autoantibodies reactive with nucleic acids and proteins concerned with transcription and translation. Breeding experiments in mice have illustrated the enormous genetic heterogeneity of this syndrome, of which the final common pathway is a widespread immune complex disease. The causes of SLE in humans are likely to be equally multifactorial. Family studies have demonstrated that genetic factors exist, but each factor appears to be a relatively weak disease-susceptibility gene. The major exceptions to this are the very rare complete deficiencies of classical pathway complement components, which are almost invariably accompanied by the development of SLE. Observations of these patients have led to the formulation of hypotheses relating complement and its receptor, CR1, to the defective removal of immune complexes from the circulation.

The results of family and twin studies suggest that RA may result from an interaction between an oligogenic susceptibility and unknown environmental factors. Part of this genetic predisposition is accounted for by genes within the MHC where there is a well-documented association with HLA-DR4. Studies of DR and other MHC variants have shown different associations with particular subgroups. One subgroup is Felty's syndrome where there is a strong association with DR4, as well as associations with DQ-beta and C4B null variants when DR4-matched Felty's and RA subjects are analysed. These DQ-beta and C4B null variants may characterize a single haplotype which is associated with extra-articular disease. A further rheumatoid subgroup characterized by circulating antibodies to native type II collagen, shows an association with HLA-DR3 and 7. Genes on chromosome 14 may also influence susceptibility to RA, probably by interaction with MHC genes and there are different Gm associations for DR4-positive and collagen-antibody-positive rheumatoid subgroups. HLA and Gm markers so far identified only account for a small part of the total genetic predisposition to RA and a third or further loci may also be involved. Possible candidates include T-cell alpha- and beta-chain genes and immunoglobulin light chain genes. One present concept of the genetic predisposition to RA is of several independent immunogenetic pathways each including interactions at two or more loci.

Rapid progress has been made recently on the elucidation of the structural components of the complement system by the application of recombinant DNA techniques. The derived amino acid sequences of most of the complement proteins are now available through cDNA cloning, and significant progress has been made in the discovery of the genetic organization of the corresponding genes. The linkage of some of the complement component genes has been established through the study of phenotypic genetics. Of particular interest has been the mapping of two clusters of genes which encode proteins involved in the activation of C3. C2, C4 and factor B, three of the structural components of the classical and alternative pathway C3 convertases, are encoded by genes which map to the MHC on human chromosome 6. The linkage of the genes with each other in a 100 kb segment of DNA has been established through the isolation of overlapping cosmid clones of genomic DNA, and PFGE has defined the molecular map position of these genes within the class III region of the MHC. The regulatory proteins factor H, C4BP, CR1 and DAF, which are involved in the control of C3 convertase activity, are encoded by closely-linked genes (termed the regulators of complement activation or RCA linkage group) that have been mapped to human chromosome 1. PFGE has defined the linkage of the CR1, C4BP and DAF genes, together with the CR2 gene in an 800 kb segment of DNA, and it is clear that this technique will eventually be applied to the molecular mapping of other complement genes in relation to their flanking loci. Polymorphism is a feature of many of the complement proteins, especially those encoded by genes in the MHC class III region. Of these, C4 is by far the most polymorphic, and differences in gene size and gene number, in addition to the functional and antigenic differences in the gene products, have been recognized. Null alleles at either of the C4 loci are rather common and may be important susceptibility factors in some HLA-associated diseases, particularly SLE. The molecular basis of complement deficiency states has begun to be elucidated. In many cases, the deficiency is not caused by a major gene deletion or rearrangement, and techniques which detect single point mutations in DNA (Cotton et al, 1988) will have to be applied to fully characterize the nature of the defect.

Rheumatic diseases are generally non-mendelian, depending on an interaction between genetic susceptibility and environmental factors. The overall role of genetic factors can be estimated from family resemblances and twin studies, while the role of individual susceptibility genes is studied by lod score analysis, haplotype sharing and population associations. Linkage analysis allows a long-range search of chromosomes for susceptibility loci, while population associations depend on much shorter-range effects. It is often very hard to tell whether an association of a disease with a marker is because the marker confers susceptibility or because it is in linkage disequilibrium with a separate susceptibility gene. When searching for individual susceptibility genes, it is important to avoid postulating models which would require an unrealistically high degree of genetic determination of the disease.

Recent immunogenetic studies of JRA patients have both helped to clarify subdivision into distinctive subtypes and identified those subtypes which may be related to adult rheumatic disease. Despite the variability of HLA associations from different geographic sources, a consensus appears to be emerging as to the most important associations. In addition to the HLA-DR locus, distinct associations with the HLA-DP and HLA-DQ loci have been described. Family studies have suggested an increased risk with certain haplotypes, particularly in the EOPA JRA population. Although inheritance patterns remain to be defined, recent studies with monoclonal antibodies, alloreactive T cell clones, and DNA have identified the existence of specific epitopes encoded by a variety of Ia molecules which may be more directly related to disease susceptibility. The concept of an epitope dose effect is put forward to account for the variable HLA association with disease, particularly with regard to EOPA JRA. Further developments in the definition of micropolymorphisms of Ia molecules at the genomic level as well as the possible involvement of other genetic loci, in particular T cell receptor variable gene products, should help clarify our understanding of the role of genetic factors in the aetiology of JRA. The studies of the last two decades indicate that inferences made by Carter (1969) on the 'polygenic, weakly penetrant genetic effect' in autoimmune disease are indeed applicable to JRA.

The structure of major histocompatibility complex class I (HLA-A, B and Cw) and class II (HLA-DP, DQ and DR) genes and their products is now well understood. Knowledge of the high degree of polymorphism which occurs at all MHC gene loci, primarily derived from serological studies, has largely been confirmed and extended by the application of functional, biochemical and molecular techniques. The frequencies of class I and class II antigenic products are variable between ethnic groups and also between many diseased and healthy populations. In many cases the occurrence together of two or more MHC gene products (allelic association) provides haplotypic markers specific for diseases. The function of MHC products is widely speculated upon but little is known of the precise mechanisms whereby class I and class II molecules mediate their prescribed functions of co-ordinating cell-cell interactions, their involvement in susceptibility to disease or their established role in the artificial situation of organ allografting.

Recent investigation of the possible role of bacteria in the pathogenesis of AS has provided very interesting data. What is at present lacking is a clear demonstration that the findings point to the actual mechanisms involved in the initiation of the disorder. Rapid progress in three related areas of research gives hope that, in the relatively near future, the genetic basis for susceptibility to AS will be elucidated. These are the demonstration of the detailed structure of an HLA class I molecule, of the primary amino acid structure of B27 heavy chain with its subtypes, and of the nature of the interaction between foreign proteins and MHC molecules which leads to antibody and cytotoxic cell responses. It is just possible that the B27 molecules have a disease-promoting capability because of some structural characteristic independent of their antigen binding site. However, it may perhaps be considered more likely that it is the propensity of the specific antigen-binding site itself to bind to a particular group of antigenic peptides that will explain the susceptibility of B27-positive individuals to several clinical disorders. The ability to study the properties of antigenic epitopes which preferentially bind to the very variable binding site of different MHC molecules raises the possibility of revealing the antigenic structures which bind to B27 molecules in patients with AS. This could in turn lead to the source of these antigens in the environment. There has been a tendency to assume that one simple model will explain all the B27-associated disorders but it may be preferable to keep an open mind about the possibility that the mechanisms involved in AS, in the bacteria-induced acute arthropathies and in acute anterior uveitis may not be identical. At the same time, there is a need to continue further direct investigation of the role of microbiological agents in AS both in vitro and in vivo, as ultimately it is most likely that, by blocking the effects of such agents as may be shown to be involved, progress in our ability to influence the progress of the disease in a fundamental way will be achieved. There is still little information as to how the tissues involved in AS come to be the particular targets of the pathological process and currently proposed theories of pathogenesis have not yet provided very satisfactory answers to this problem.

As NSAIDs are commonly used in patients receiving concomitant drug therapy, there is a risk of clinically significant drug interactions. Important interactions with NSAIDs involve one or both of two major mechanisms: pharmacokinetic (e.g. lithium, phenytoin and barbiturates) and pharmacodynamic (e.g. antihypertensive agents, diuretics). Prescription of a NSAID should be preceded by a careful evaluation of any coexisting pathology (such as renal dysfunction or hypertension) or concurrent drug therapy (such as anticonvulsant or anticoagulant agents) which may predispose a patient to the development of an interaction with potentially severe effects.

Despite a continuing lack of good quality epidemiological studies, our knowledge of the side-effects of NSAIDs has advanced in recent years. The most important reactions are those which are related predictably to the pharmacology of the drugs and these need to be considered whenever a NSAID is prescribed, particularly for patients who can be identified as belonging to high-risk groups. The important reactions are: 1. Gastrointestinal damage, which is now known to extend to some degree from the oesophagus to the rectum, although the acid contact areas of the stomach and duodenum are the most important. Although the studies have produced heterogeneous results, NSAIDs probably double or triple the risk of an individual developing serious gastrointestinal haemorrhage or perforation. The risk increases with age and previous history of ulceration, and, in communities with particularly high use of NSAIDs, the drugs may account for up to 30% of all cases of ulcer complications. 2. Renal syndromes, of which functional renal impairment is the most important. This may precipitate cardiac failure, and hyperkalaemia is an additional hazard. Antagonism of the action of diuretics may contribute to the fluid retention, and antagonism of antihypertensive therapy is probably quite common and may result in additional unnecessary therapy. Patients at risk of functional renal impairment from NSAIDs can be identified readily and in these subjects the drugs have to be used with great care and with appropriate monitoring. 3. Respiratory effects, in particular acute bronchospasm in subjects with a history of aspirin sensitivity. NSAIDs should be used with caution in asthmatics, and patients purchasing NSAIDs without prescriptions need to be warned of these effects. Other uncommon serious reactions include hepatocellular damage, acute interstitial nephritis, agranulocytosis and aplastic anaemia, Stevens-Johnson syndrome and toxic epidermal necrolysis. These are unpredictable reactions which generally need not be considered before prescribing. However, in patients who present with any of these conditions, NSAIDs, because of their wide use, should always be considered as a possible cause.

The reasons for variability of response to anti-rheumatic drugs are myriad. All the factors that contribute to kinetic variability, for example, contribute to differences in response between individuals. Thus, differences in drug formulation, protein binding, drug metabolism and excretion, all contribute to variable responses. Further, factors which contribute to differential clinical response/toxicity must be considered. Here, age, gender, genetic background, weight, concomitant diseases and numerous environmental factors come into play. Among the environmental factors are such diverse elements as smoking, activity and diet. Finally our ability to measure change, be it in response or toxicity, is limited, introducing apparent variability (as much as real variability) into the equation. While we cannot, at present, delineate the contribution of each factor to individual variability, it is hoped that systematic, persistent effort will help us understand and then control these elements, leading to improved ability to individualize therapy and decrease the variability of response to anti-rheumatic drugs.