Biologic DMARDs

Rhenmatoid arthritis (RA) is a chronic systemic inflammatory arthritis that occurs in abont 1% of the population worldwide. Untreated, RA is associated with joint destruction, disability, and increased mortality (1). Early detection and therapy with disease-modifying antirheumatic drags (DMARDs) is critical in preventing these seqnelae of RA. With the recent advent of biologic DMARDs, which are effective bnt expensive therapies for RA, there has been a focns on developing methods that... 

This chapter highlights some of the recent major pubhcations in the field of pharmacogenomics in RA and describes the implications of this field for future research and cUnical care. The pharmacogenetics of three major DMARDs (methotrexate [MTX], azathioprine [AZA], and sulfasalazine [SSZ]) and one class of biologic DMARDs, the tumor necrosis factor (TNF) antagonists, in RA, are reviewed. 

With the advent of biological-DMARD combinations with Methotrexate (MTX) a new era of therapy in autoimmune disease is introduced. DMARD-refractory autoimmune diseases are treated with combinations of a biological with MTX with achievement of improvements of ACR 20 and ASAS 20 in the majority of patients. A small minority of around 20% obtains improvements of ACR 70 and ASAS 70. ACR responses are American College of Rheumatology response criteria and ASAS stands for Assessment in Ankylosing Spondylitis. ACR and ASAS 20, 50 or 70 scores are exactly defined improvements of respectively 20%, 50% or 70%. 

The introduction of intravenous DMARD combinations provides a less expensive alternative than the use of biologicals in DMARDs refractory autoimmune disease in developing countries. The regimen of Step-down Bridge Combination of 5 immunosuppressants (SBC-5-IMNs, see below) obtained better results than single biological DMARDs or biological DMARDs in combination with MTX. 

Outcome measurements used in the evaluation of the outcome of treatment of RA with sulfasalazine, parenteral gold salts, D-penicillamine, hydroxychloroquine, prednisolone, MTX, cyclophosphamide (CyC), and azathioprine in single drug therapy cannot be compared with endpoints used in SBC-5-lMNs and biological-DMARDs combined with MTX. 

Based on the bio-molecular pathogenesis, novel therapeutic agents have been developed since 1998 for the treatment of DMARDs refractory autoimmune diseases. These biological-DMARDs include infliximab, etanercept, adalimumab, rituximab and abatacept. The biological-DMARDs anti TNF-a were first approved for therapy of refractory RA, followed by Crohn s disease, AS, and PsA. Scores of other biological DMARDs in Phase I, II, and III clinical trials in autoimmune diseases indicate that the number of these biological agents may ultimately become equal to the number of NSAIDs introduced over the last 50 years. 

Biological DMARDs are indicated when autoimmune inflammatory diseases are refractory to therapy with single traditional DMARDs or with combinations of oral or IV traditional DMARDs. Improvements of ACR 20 and ASAS 20 in over 70% of patients with refractory RA and AS do not mean much to the patients in terms of pain relief, improvement of function and health-related quality of life. The present biological DMARDs combined with MTX still cannot fully address the problems of the majority of patients with DMARDs refractory chronic progressive autoimmune inflammatory diseases. Those who are refractory to MTX - - biological DMARDs respond well to SBC-5-IMNs in over 80% of cases. 

The application of the present biological DMARDs in RA in the Third World will not be feasible for reasons of treatment costs which range from 15,000 to 25,000 per patient per year. 

When SBC-5-IMNs is endangered 3 times by non-compliance to the execution of its 4 fixed schedule phases then the disease becomes refractory. Depending on the level of the ESR when patients drop out relapses occur after several months to several years. The majority of patients acquire remission in 2 months again with IVT - - PA and 100 mg infliximab at week 0-2-6 added to this. After tapering off IVT + PA guided by the ESR levels after induction of remission, oral IMNs will maintain remission and thus avoid the need for long-term use of biological DMARDs. 

The use of traditional DMARDs can be disappointing in moderate or severe SpA cases and also with biological DMARDs ASAS 70 was achieved in a minority (circa 20%) of patients with SpA. The majority, around 70% of the patients, reached an ASAS 20 response and less than 50% acquired ASAS 50. The high costs and long-term administration of biologic-DMARDs prohibit their use in the Third World. With inefficacy of traditional DMARDs and biologic-DMARDs being unaffordable, the SBC-5-IMNs approach is an attractive alternative. 

There is a slightly increased risk of infection (as with other biologic DMARDs), predominantly of the upper respiratory tract. Concomitant use with TNF-a antagonists is not recommended due to the increased incidence of serious infection with this combination. Infusion-related reactions and hypersensitivity reactions, including anaphylaxis, have been reported but are rare. Anti-abatacept antibody formation is infrequent (< 5%) and has no effect on clinical outcomes. The incidence of malignancies is similar to placebo with the exception of a possible increase in lymphomas. The role of abatacept in this increase is unknown. 

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