Autoimmune inflammatory diseases

Deficiency of thiopurine S-methyl transferase (TPMT) is another phenotype that exhibits inter-ethnic differences in frequency. TPMT is an enzyme that catalyzes methylation of therapeutic agents used in the treatment of acute lymphoblastic leukemia, rheumatoid arthritis, and autoimmune/inflammatory diseases, as well as in organ transplantation. Patients who have TPMT deficiency experience less efficient methylation and are at greater risk of fatal toxicity when treated with standard doses of fhiopurines. TPMT phenotype is defined by erythrocyte 6-mercapto-purine methylation. African American populations exhibit a 20% lower erythrocyte TPMT than Caucasian Americans, and persons of Chinese descent tend to exhibit greater activity than either of these other American subpopulations. 

The etiologies of the autoimmune inflammatory diseases, OA, osteoporosis and crystal-deposition disease are still not known in exact details. This is in contrast with impressive molecular insights gained recently. However, there is consensus that manifestations of autoimmune diseases are precipitated by either acute and/or chronic interactions of genetic and environmental risk factors. 

Unfortunately, a substantial proportion of patients with autoimmune inflammatory diseases have become refractory to NSAIDs, and/or oral or intravenous Disease Modifying Anti Rheumatic Drugs (DMARDs). However, oral combinations of DMARDs generate better outcomes compared to single drug therapy in autoimmune disease. Even autoimmune diseases can become refractory to oral DMARD combinations. 

In terms of molecular biology, the attachment of Antigen Presenting Cells (APC) to T-cells can at this moment not be prevented. So a cure for chronic progressive autoimmune inflammatory disease is not feasible yet. Sooner or later disease in remission relapses when APC attach to T-cells with induction of Co-stimulatory pathways. The current therapeutic principles are to stop or slow down disease progression. This is achieved by elimination or at least a reduction of the pool of existing autoantibodies and of cytokines in the upstream systemic and downstream local interleukin independent and dependent pathways. 

The most important prognostic factors in autoimmune inflammatory disease are, disease duration, the degree of disease activity-dependent radiological erosion, previous drug therapy and previous exposure to immunosuppressants (IMN), i.e. IMN naivety. Early autoimmune inflammation can be totally eradicated, irreversible disability and damages can be prevented when adequate treatment has been initiated. 

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 current trend is to treat OA as a low-grade autoimmune inflammatory disease as indicated by activated cytokine dependent pathways with the presence of IL-6jS, IL-lo , TNF-jS, abnormal ESR and CRP. ESR (<40 mm) and CRP are mildly elevated and suppression to normal can be achieved with a few weekly IVT and PA sessions from SBC-5-IMNs. Early diagnosis of relapses and suppression of inflammation is the key to prevent radiological stage III and IV knee OA. 

A. L. Parke, C. loannides, D. F. V. Lewis, and D. V. Parke, Inflammopharmacology, 1, 3 (1991). Molecular Pathology of Drug—Disease Interactions in Chronic Autoimmune Inflammatory Diseases. 

E. M. Sternberg, Neuroendocrine regulation of autoimmune/inflammatory disease, Journal of Endocrinology, 169, 2001, 429-35. 

CQ and HCQ have been found useful in the suppressive treatment of autoimmune inflammatory diseases such as rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) (see Chapter 5). The higher dosages required increase retinopathy as a complicating toxicity. 

A chronic autoimmune inflammatory disease involving multiple organ systems and marked by periods of exacerbation and remission. 

The drug exerts its action exclusively in the suppressive treatment of autoimmune inflammatory diseases, for instance rheumatoid arthritis (RA) and systemic lupus erythromatosus (SLS). Just like chloroquine (CQ), this drug (HCQ) is found to remain in the body for over a month and the prophylactic dosage is once-a-week only. It is somewhat less toxic than CQ. 

Rheumatoid arthritis is an autoimmune inflammatory disease, and various proinflammatory cytokines are thought to be involved in the pathogenesis of this disease. Possible roles of lymphotactin (Blaschke et al., 2003a) and fractalkine (Blaschke et al., 2003b) in rheumatoid arthritis have also been suggested. 

Parke, A.L., loannides, C., Lewis, D.E.V., and Parke, D.V. 1991. Molecular pathology of drug-disease interactions in chronic autoimmune inflammatory diseases. Infiammopharmacology, 1(1), 3-36. 

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