Antirheumatic drugs: clinical pharmacological and therapeutic aspects.

There are many current concepts of the pathogenesis of rheumatic diseases which incorporate immunological, infectious and hereditary factors. Rheumatic diseases may sometimes become apparent after trauma, be associated with certain diseases and may be induced by nervedamage and serum sickness. Systemic lupus erythematosus may result from the use of a variety of drugs. At present the body of evidence tends to incriminate immunological factors as well as infectious agents as principal factors in the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus. Just as there is uncertainty regarding the pathogenesis of rheumatic diseases, knowledge of the mechanism of action of the various drugs used to treat these diseases is also incomplete. Recent progress indicates that inhibition of prostaglandin biosynthesis and possibly lysosomal membrane stabilisation are primary modes of action of the anti-inflammatory agents. Certain antirheumatic drugs have also been shown to exert some of their therapeutic effect by interfering with the kallikrein-kinin-kininase system. In the management of rheumatoid arthritis, a 5-level pyramidal plan of therapy is described which offers a realistic approach to the treatment of patients in various stages of this disease. The general basic medical treatment consisting of rest, psychological adjustment, pain relief, measures to combat anaemia, exercise and a well balanced diet and salicylate therapy, form the foundation of the pyramid. For many patients with low-grade disease and little disability, this level of therapy may give adequate control for long periods and no additional measures need be considered. In moderately severe disease affecting multiple joints with considerable constitutional disturbance and disability, when the basic medical treatment proves inadequate after several weeks of trial, additional measures are needed. These include the use of non-steroidal anti-inflammatory agents such as phenylbutazone, indomethacin and the phenylalkanoic acid derivatives, the antimalarials, and the anthranilic acid derivatives. Also included in this second level of therapy is the intra-articular administration of corticosteroids. Among the forms of drug treatment making up the third level of the pyramid are oral corticosteroid therapy and gold therapy. Of all the anti-inflammatory and long-acting agents commonly used in the treatment of rheumatoid arthritis, only gold salts may alter the clinical course or stop progression of the disease. Toxic reactions to gold are of the utmost importance, those involving the kidney or bone marrow being potentially the most serious. The corticosteroids are the most powerful anti-inflammatory compounds available, but their use in rheumatoid arthritis remains controversial. There is no convincing evidence that these drugs stop or significantly alter the natural course of the underlying disease. None of the newer steroid derivatives have any advantages over prednisone or prednisolone, and their greater potency makes dosage adjustment difficult. Treatment at level four involves hospitalisation. There is growing recognition of the value of 4 to 6 weeks of intensive hospital care for rheumatoid arthritic patients who do not respond to the measures already mentioned. Treatment which is still investigational is involved at level five and includes the use of new orthopaedic procedures and devices and drugs under clinical investigation that have been shown to be promising. Such drugs include immunosuppressive and cytotoxic drugs such as azathioprine and cyclophosphamide, and D-penicillamine. Use of immunosuppressive drugs in rheumatoid arthritis should be restricted to patients in whom all forms of conventional treatment have failed to curb rapidly progressive disease with life-threatening complications. D-penicillamine has been used particularly in the treatment of severe rheumatoid arthritis with vasculitis. Its use is limited by side-effects, some of which are hazardous. In juvenile rheumatoid arthritis salicylates are still the treatment of choice. Gold therapy is the second best choice and is the only treatment that may influence favourably the course of the disease. Treatment of ankylosing spondylitis differs from that of rheumatoid arthritis in that gold therapy is ineffective. There is no medication which will alter the natural course of the disease, but indomethacin or phenylbutazone elicit symptomatic improvement. The main concern in osteoarthrosis is to relieve pain and analgesics such as aspirin or paracetamol are useful. As there is little or no inflammation in affected joints in this disease the role of anti-inflammatory drugs is limited. Polymyalgia rheumatica is best treated with oral corticosteroids, and other anti-inflammatory agents are not indicated once corticosteroids have been started.