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.

SASP is a useful DMARD in RA and is probably useful in early ankylosing spondylitis, psoriatic arthropathy and reactive arthritis. It shares many of the characteristics of other DMARDs such as gold and penicillamine. It produces improvement in clinical and laboratory parameters of disease activity, with a slow onset of action--8-12 weeks elapse before beneficial effect is noted. SASP probably slows radiological progression of RA but definitive proof is difficult to obtain. Although side-effects are common, these are often managed by a reduction in dose, and serious adverse events requiring cessation of therapy are uncommon. Serious side-effects do occur however, and regular monitoring with full blood counts is recommended. The mechanism of action of SASP is unknown and this remains one of the principal areas of research interest.

Since systemic lupus erythematosus most frequently affects women of childbearing years, the management of patients during pregnancy is an important and common problem facing the clinician. This review concerns the effects of pregnancy on the course of maternal disease and fetal well-being. On the maternal side are the problems of renal disease which may exacerbate and be difficult to differentiate from pre-eclampsia especially when occurring in the third trimester. An active urinary sediment, falling C3 and CH50 and elevated complement split products of the alternative pathway and terminal attack complex may serve as useful parameters of lupus activity. In general, maternal disease is not an imposing threat and prospective studies suggest that the exacerbation rate is not significantly greater in the pregnant lupus patient than in the non-pregnant patient. On the fetal side are the problems of placental insufficiency and in utero attack on developing organs. Maternal antibodies such as those reactive with negatively charged phospholipids are associated with second trimester miscarriages and suggested, but not firmly established, thrombosis of placental vessels. The placental transfer of maternal antibodies against components of the rapidly expanding group of SSA/Ro-SSB/La ribonucleoproteins is strongly implicated in the transient and permanent manifestations of neonatal lupus. Using various techniques for defining the specificity of the antibody response most associated with heart block, the data suggest that mothers whose sera contain antibodies which recognize antigens of SSA/Ro-SSB/La on SDS-immunoblot are at greatest risk. In the absence of antibodies to SSB/La, mothers whose sera contain antibodies reactive only to bovine SSA/Ro by ELISA do not appear to be at high risk. A rational approach to in utero treatment of autoantibody mediated fetal myocarditis includes plasmapheresis and the use of dexamethasone. Finally, the safety of the commonly used medications for the treatment of lupus such as the nonsteroidal anti-inflammatory agents, glucocorticoids and anti-malarials during gestation and breast feeding, is addressed.

NLE is manifested most typically as transient subacute cutaneous lupus lesions or isolated complete congenital heart block. Babies with NLE have maternal anti-Ro/SSA, anti-La/SSB, or anti-U1RNP autoantibodies. It is presumed, but not proven, that transmission of these autoantibodies through the placenta to the baby has resulted in disease. However, other factors such as inflammatory cells or complement activation may be necessary for disease to be expressed. About half of babies reported with NLE have had heart disease and about half have had skin disease. There have been a few reports of liver disease and a few of thrombocytopenia. Any combination of these findings is possible in a given infant. Possibly, other haematologic abnormalities, pneumonitis or neurological disease could occur, but the evidence that these other abnormalities are part of NLE is scant. Mortality in NLE has occurred in babies with severe cardiac disease. It is estimated that 10% or more of babies with cardiac NLE die in infancy. Of the remainder, perhaps half will require permanent pacemaker implantation. Thus, there is substantial morbidity and mortality with cardiac NLE. The skin disease, by contrast, is not serious and typically leaves little or no residua. Individuals who have had NLE may develop connective tissue disease in adulthood. Whether this is a common or an unusual occurrence is not yet known, since a large cohort of individuals with NLE has not yet been followed into adulthood. Mothers of babies with NLE are often initially asymptomatic. With time, they frequently develop connective tissue disease symptoms. In our experience, these have been largely symptoms of Sjögren's syndrome and have generally not been debilitating. Most babies of mothers with anti-Ro/SSA, anti-La/SSB, or anti-U1RNP autoantibodies do not develop NLE. There is no way to determine prospectively which fetus or infant will be affected and which of those affected will have life-threatening disease. Systemic therapies should be reserved for those infants who have life-threatening manifestations of NLE. It is not yet known whether treatment of the mother during gestation will be beneficial or harmful to fetuses with severe NLE cardiac disease.

Systemic alterations of the maternal inflammatory and immune system occur during pregnancy. These changes alone are unlikely to be responsible for the acceptance of the fetal semiallograft. Numerous local events at the maternal-fetal interface appear to be more important. The alterations of the maternal inflammatory and immune systems are subtle enough for no significant increase of infections or malignancy to be apparent. However, 75% of women with rheumatoid arthritis are clinically improved during pregnancy. The effects of pregnancy on polymorphonuclear cells are not likely to be responsible because cell function actually appears enhanced in vivo, despite the fact that pregnancy serum is suppressive in vitro. There is no clear evidence for reduction of monocyte/macrophage function during pregnancy, either in vivo or in vitro. It is unlikely that modulation of B cell phenotype or function is responsible because no suppression is noted, either in vivo or in vitro. Selected products of B cells, immune complexes, appear to be reduced during pregnancy. In patients, the reduction in the concentration of complexes may be due to adsorption by the placenta. The importance of this reduction as a causative factor in the improvement of women with rheumatoid arthritis during pregnancy remains to be determined. Natural killer cell cytotoxicity is decreased during pregnancy. This may in part be due to the release of progesterone induced blocking factor. It is also possible that circulating factors, capable of inhibiting IL-2 release or IL-2 function in vivo, might be responsible. Natural killer cytotoxicity can be normalized by incubation with IL-2. It is unclear how the reduction of natural killer cell activity might systematically affect inflammation or immunity in vivo during pregnancy. In vivo delayed type hypersensitivity appears somewhat reduced during pregnancy. This observation appears consistent with the improvement of rheumatoid synovitis, which is also thought to be T cell mediated. T cell function, measured in vitro, generally appears normal. However, most recent studies have employed mitogens, such as PHA, which is not physiological. Subtle defects involving antigen processing or antigen presentation might be missed in this system. These observations suggest that circulating factors might be important in modulating the cell mediated immune system, in vivo, during pregnancy. While anti-HLA-DR antibodies eluted from the human placenta may be effective therapy in patients with rheumatoid arthritis, their occurrence is too infrequent to account for the improvement seen in afflicted patients.(ABSTRACT TRUNCATED AT 400 WORDS)

The natural inclination of patients with rheumatic diseases wishing to become pregnant or to breast feed will be to take as few medications as possible. The guidelines outlined above can be used to balance the risk of drug effect on the fetus or neonate with the risk of inducing a flare in disease activity by stopping the drug. Although there are situations where no information on drug behaviour during pregnancy or lactation exists, some guidelines can be developed from a knowledge of the drug's inherent metabolism. In the majority of the rheumatic diseases, disease activity can be reduced to a minimum using the smallest possible dose of drugs known to be safe in pregnancy and lactation, thus providing minimum risk to mother, fetus and neonate.