Specific Therapy for Rheumatoid Arthritis

THE term 'specific' is used to describe the effects of drugs like gold and penicillamine in rheumatoid arthritis. This type of action is to be distinguished from the effects of 'nonspecific' or symptomatic therapy, for example with analgesic and anti-inflammatory drugs. In rheumatoid arthritis, specific drugs act not only on pain and inflammatory manifestations like swelling and stiffness, but also on extra-articular features of the disease such as nodules. Their action is slow, taking several months to reach a maximum, and is accompanied by reduction in ESR, rheumatoid factor and immunoglobulins. There is evidence that some of these drugs alter the outcome of the disease: for example cyclophosphamide has been shown to slow the rate of radiological deterioration (Cooperating Clinics Committee of the American Rheumatism Association, 1970). By contrast, non-specific therapy will relieve pain and manifestations of inflammation but does not alter extra-articular features of the disease, ESR, rheumatoid factor, immunoglobulins or the outcome of the disease. The action of non-specific drugs is not dependent on the nature of the underlying disease—anti-inflammatory drugs are likely to be effective in any inflammatory arthropathy but 'specific' therapy implies an action dependent on the underlying disease. Penicillamine is effective in rheumatoid arthritis but not in inflammatory arthritis as a whole. Unfortunately formal trials of many specific drugs have not been carried out in conditions other than rheumatoid arthritis. Certainly some are effective in other conditions, for example, immunosuppressives may be useful in psoriatic arthropathy. For this reason, the term specific can be criticized. More appropriate nomenclature may become available when there is greater understanding of the mode of action of the drugs. One problem, which has delayed studies of the mode of action, has been the lack of animal models. Many of these compounds are not active in conventional models of inflammation such as carrageenan oedema and adjuvant arthritis. Perhaps the most promising model to demonstrate their effects is pertussis vaccine oedema (ArrigoniMartelli et al., 1976) or pertussis vaccine pleurisy (Dieppe et al., 1976). This model, mediated by delayed hypersensitivity, distinguishes at least certain of the specific agents from anti-inflammatory drugs; the former enhance the inflammatory reaction and the latter suppress it. Not all of the specific agents have this effect, and it is unlikely that they all act in the same way. The mode of action of the drugs in man cannot easily be deduced. These compounds have been shown to exert many different actions, some of which must be irrelevant. The actions of penicillamine, for example, include chelation of copper, inhibition of polio virus and a lathyritic effect which does not appear to be important (Lovell et al., 1976). The importance of one of these mechanisms might be inferred from finding a correlation between it and changes in the disease. Such a correlation does not necessarily imply a causal relationship: changes in laboratory parameters such as immunoglobulins may be secondary to changes in the disease and show a correlation for this reason. Support for a mechanism of action would also come from the finding of a common action of two or more drugs which were known to have the same effect on the disease. It is therefore of interest that levamisole has been shown to have a specific action in rheumatoid arthritis similar to that of r>penicillamine (Huskisson et al., 1976) and that both these compounds have in common the ability to enhance a cell-