Isotretinoin and etretinate are synthetic derivatives of vitamin A widely used in the treatment of dermatological diseases, mainly those affecting keratinization. They have numerous side-effects, among which the rheumatic symptoms are not the most common or the most severe. The main skeletal adverse reaction of retinoids is hyperostosis. It mainly occurs with protracted treatments and high dosages, and its incidence may exceed 80% after a few years of administration. Hyperostosis is axial, located in the cervical and thoracic spine, and may be responsible for limitation of movement; in the appendicular bone, enthesopathies occur at the foot, pelvis, hip, and less commonly the shoulder and elbow. They are usually mild and asymptomatic. The radiological appearance is very similar to diffuse idiopathic skeletal hyperostosis. Isotretinoin tends to be responsible for axial involvement, etretinate for peripheral locations. The other skeletal side-effects are uncommon and include periosteal proliferation, calcification of the interosseous membrane of the forearm and diffuse radiological bone hyperlucency. In children, premature epiphyseal closure is very rare. About 20% of patients complain of musculoskeletal pain and arthralgias. A few cases of true arthritis have been reported. Retinoids may be responsible for muscular damage and an abnormality of muscular tone resembling the stiff-man syndrome. Some cases of necrotizing vasculitis and three cases of Wegener's granulomatosis have been observed in patients treated with retinoids. Except for these latter arguable cases, rheumatoid syndromes due to retinoids are rather benign, and should not be an obstacle to the future development of their therapeutic utilization.

Fluoride stimulates bone formation and is used in the treatment of vertebral osteoporosis. Epidemiological and experimental studies have shown that fluoride bone is denser but not always stronger than normal bone, and the main side-effects attributed to this drug involve bone tissue. True fractures, with cortical rupture, are few (near 5%); their rate seems to correspond to that generally found in osteoporotic patients without treatment. On the other hand, stress fractures and arthralgia of the lower limbs are much more frequent (near 30%), but they often follow a benign course. Digestive tolerance of fluoride is now good, improved by the introduction of gastro-resistant industrial galenicals. However, the question of whether the risk/benefit ratio is positive is always under discussion.

A number of pharmacological agents can induce hyperuricaemia, and sometimes gout, usually by interfering with the renal tubular excretion of urate but also in some instances by increasing the formation of uric acid. Alcohol is well known to have this property and in recent years diuretic-induced hyperuricaemia has become a global phenomenon. Other drugs which can cause hyperuricaemia are salicylates, pyrazinamide, ethambutol, nicotinic acid, cyclosporin, 2-ethylamino-1,3,4-thiadiazole, fructose and cytotoxic agents. A special type of 'drug-induced gout' can follow the rapid lowering of serum uric acid by allopurinol or uricosuric drugs.

Myopathies are not an unusual complication of drug therapy. The major symptoms in drug-induced myopathies are proximal muscle weakness, increased muscle enzyme levels, electromyographic changes and histological lesions. Some drug-induced myopathies are associated with neuropathy. Drug-induced myopathies can be classified according to the presence or absence of muscular pain and associated neuropathy. Among painless myopathies, we can distinguish myopathies without neuropathy (corticosteroids), myopathies with neuropathy (colchicine, chloroquine and hydroxychloroquine) and myasthenic syndromes (D-penicillamine, antibiotics, beta-blockers). Among painful myopathies, the classification is similar: painful myopathies may or may not be associated with neuropathies. Painful myopathies include polymyositis (D-penicillamine, cimetidine, zidovudine) and other myopathies without polymyositis (clofibrate, statines, cyclosporin). Among the painful neuromyopathies, eosinophilia-myalgia syndrome is a recently described disorder associated with the use of L-tryptophan. Combinations of drugs (for example, a fibrate and a statine or cyclosporin and colchicine) can induce severe myopathies. If such drugs are used together a vigorous surveillance to detect any sign of myopathy is warranted. Instead of classifying drug-induced myopathies according to clinical features, a histological classification can be proposed. Many drugs can induce vacuolar myopathy (colchicine, chloroquine, amiodarone, cyclosporin, drugs causing hypokalaemia and lipid-lowering agents), some others cause a mitochondrial myopathy (zidovudine) or a necrotizing myopathy as seen with vincristine. Overall, several criteria for reporting drug-induced myopathy can be recommended: lack of pre-existent muscular symptoms, a free period between the beginning of the treatment and the appearance of symptoms, lack of another cause accounting for the myopathy, and complete or incomplete resolution after withdrawal of the treatment. Rechallenge of the treatment is not advisable because of the risk of a serious relapse. The exact mechanisms by which drugs cause myopathies are unknown. Some cases may be due to metabolic changes, whereas others may be immune mediated. Nevertheless, the aspect these conditions have in common is the regression of the myopathy with the discontinuation of the drug.

New approaches for antirheumatic therapy are firmly based on current knowledge of immunopathogenic processes. Specific immunotherapy is directed at the treatment of the disease per se and not the production of generalized immunosuppression with its unwanted side-effects. The three targets against which specific immunotherapy is directed are the T cell receptor, the HLA antigen linked to the disease and the antigenic peptide involved in the initiation and/or persistence of the disease. Therapies directed against lymphokines, monokines and cytokines produced during the chronic immune-mediated inflammation are also being developed but they may be unsuccessful not only because of the great redundancy inbuilt into the inflammatory response but also because they would produce too general a response with possibilities of harmful side-effects. Specific immunotherapy at present is largely through the use of monoclonal antibodies directed against a variety of T cell membrane antigens such as CD4, CD7 and the interleukin 2 receptor. A possible therapy is monoclonal antibodies, directed against the HLA molecule involved in the aetiopathogenesis of disease. The use of disease-causing T cell lines or clones as vaccines or therapeutic agents has solid experimental support and studies are in progress in patients with rheumatoid arthritis using T cell lines grown from synovial fluid aspirates. If successful, such therapy could be modified to the use of short peptide fragments from the relevant T cell receptor. T cells recognize antigenic peptides presented on the surface of antigen-presenting cells within a groove formed by the HLA molecule. Displacement of disease-inducing antigenic peptides by engineered 'neutral' peptides could offer a very precise form of immunotherapy. Many of these approaches are based on the hypothesis that transient but effective switching-off of the disease process may allow immunoregulatory circuits, as yet poorly defined, to come into play to permanently cure the disease. Many such therapies are in the offing. It may be that they have to be used in various combinations in order to achieve cure. For this complex and time-consuming task to attain that desired consummation, co-operative interaction between many clinicians, basic scientists and patients will be required. It is to that cooperation that we dedicate this chapter on new approaches for antirheumatic therapy.

Immunosuppressive agents serve a major role in the management of once-fatal conditions such as the systemic necrotizing vasculitides, but they are also being used in more common, chronic inflammatory disorders such as rheumatoid arthritis. The drugs are all capable of reducing cell division but they differ in their modes of action. This is in keeping with their differing rates of action, and different indications. Azathioprine is a valuable alternative to slow-acting antirheumatic drugs in older patients with rheumatoid arthritis. Cyclophosphamide has transformed the outlook of many forms of vasculitis. Chlorambucil is particularly useful in improving the prognosis for children with amyloidosis secondary to juvenile chronic arthritis. We have tried to highlight the role of these drugs in a number of rheumatic diseases. We have emphasized their clinical applications, with some laboratory evidence for their effects. The major side-effects are reviewed. Finally, we have discussed their possible mechanisms of action.

D-Pen represents an effective treatment for a proportion of patients with RA and PSS. Its status in the treatment of juvenile RA is uncertain. The best results will be obtained by a skillful, careful physician maintaining careful surveillance for toxicity. Neither the mode of action nor the mechanisms of toxicity are well understood in RA. Consequently, safer and more effective analogues of D-pen have not been produced.

The antimalarials hydroxychloroquine and chloroquine remain established and effective agents for the treatment of rheumatoid arthritis and systemic lupus erythematosus. Although the mechanisms of action remain uncertain, evidence is accumulating that the antirheumatic and immunological effects of the antimalarials are related to their massive distribution into the cellular acid-vesicle system. These drugs are attracting new interest because their relative safety recommends their use in early rheumatoid arthritis and as a component of second-line antirheumatic drug combinations. The absence of data examining the effect of antimalarials upon radiological progression of rheumatoid arthritis needs to be rectified. Recent understanding of the pharmacokinetics of these drugs reveals that steady-state concentrations are not achieved for at least 3-4 months. Preliminary information also suggests a relationship between blood concentrations and effect. Taken together, these data suggest that more effective dosage regimens will be possible when therapeutic concentration ranges are properly established.