The basis of susceptibility to rheumatoid arthritis (RA) is complex, comprising genetic and environmental susceptibility factors. We have reviewed the available approaches to the investigation of the genetic basis of complex diseases and how these are being applied to RA. Affected-sibling-pair methods for nonparametric linkage analysis, linkage-disequilibrium-based approaches, transmission disequilibrium testing, and disease-association studies are discussed. The pros, cons, and limitations of the approaches are considered and are illustrated by examples from the literature about rheumatoid arthritis.

Systemic lupus erythematosus is the prototype multisystem autoimmune disease. A strong genetic component of susceptibility to the disease is well established. Studies of murine models of systemic lupus erythematosus have shown complex genetic interactions that influence both susceptibility and phenotypic expression. These models strongly suggest that several defects in similar pathways, e.g. clearance of immune complexes and/or apoptotic cell debris, can all result in disease expression. Studies in humans have found linkage to several overlapping regions on chromosome 1q, although the precise susceptibility gene or genes in these regions have yet to be identified. Recent studies of candidate genes, including Fcγ receptors, IL-6, and tumour necrosis factor-α, suggest that in human disease, genetic factors do play a role in disease susceptibility and clinical phenotype. The precise gene or genes involved and the strength of their influence do, however, appear to differ considerably in different populations.

A study was done to determine if the differentiation and activation phenotype of T cells in synovial fluid (SF) from patients with juvenile idiopathic arthritis (JIA) is associated with T-cell proliferation in situ. Mononuclear cells were isolated from 44 paired samples of peripheral blood and SF. Differentiation and activation markers were determined on CD4 and CD8 T cells by flow cytometry. Cell-cycle analysis was performed by propidium iodide staining, and surface-marker expression was also assessed after culture of the T cells under conditions similar to those found in the synovial compartment. The majority of the T cells in the SF were CD45RO+CD45RBdull. There was greater expression of the activation markers CD69, HLA-DR, CD25 and CD71 on T cells from SF than on those from peripheral blood. Actively dividing cells accounted for less than 1% of the total T-cell population in SF. The presence or absence of IL-16 in T-cell cultures with SF or in a hypoxic environment did not affect the expression of markers of T-cell activation. T cells from the SF of patients with JIA were highly differentiated and expressed early and late markers of activation with little evidence of in situ proliferation. This observation refines and extends previous reports of the SF T-cell phenotype in JIA and may have important implications for our understanding of chronic inflammation.

The genetic basis for rheumatoid arthritis (RA) is likely to be extremely complex. Even the role of MHC genes remains to be fully defined, and may involve interactive genetic effects. The difficulty of precisely defining the clinical phenotype, as well as underlying genetic heterogeneity, complicates the problem. In addition, stochastic genetic or physiologic events may contribute to the low penetrance of susceptibility genes. This situation parallels developing paradigms for other autoimmune disorders, in which many different genes each appear to contribute a small amount to overall risk for disease, and where severity and specific phenotypic subtypes are subject to genetic effects. The completion of the human genome project, along with advances in informatics, will be required to reach a deeper understanding of RA. It is likely that this will involve an iterative and interactive process between several different scientific disciplines.

To determine whether IL-4 is therapeutic in treating established experimental arthritis, a recombinant adenovirus carrying the gene that encodes murine IL-4 (Ad-mIL-4) was used for periarticular injection into the ankle joints into mice with established collagen-induced arthritis (CIA). Periarticular injection of Ad-mIL-4 resulted in a reduction in the severity of arthritis and joint swelling compared with saline- and adenoviral control groups. Local expression of IL-4 also reduced macroscopic signs of joint inflammation and bone erosion. Moreover, injection of Ad-mIL-4 into the hind ankle joints resulted in a decrease in disease severity in the untreated front paws. Systemic delivery of murine IL-4 by intravenous injection of Ad-mIL-4 resulted in a significant reduction in the severity of early-stage arthritis.

The availability of a draft sequence for the human genome will revolutionise research into airway disease. This review deals with two of the most important areas impinging on the treatment of patients: pharmacogenetics and pharmacogenomics. Considerable inter-individual variation exists at the DNA level in targets for medication, and variability in response to treatment may, in part, be determined by this genetic variation. Increased knowledge about the human genome might also permit the identification of novel therapeutic targets by expression profiling at the RNA (genomics) or protein (proteomics) level. This review describes recent advances in pharmacogenetics and pharmacogenomics with regard to airway disease.

Recombinant adenoviruses are straightforward to produce at high titres, have a promiscuous host-range, and, because of their ability to infect nondividing cells, lend themselves to in vivo gene delivery. Such advantages have led to their widespread and successful use in preclinical studies of arthritis gene therapy. While adenoviral vectors are well suited to 'proof of principle' experiments in laboratory animals, there are several barriers to their use in human studies at this time. Transient transgene expression limits their application to strategies, such as synovial ablation, which do not require extended periods of gene expression. Moreover, there are strong immunological barriers to repeat dosing. In addition, safety concerns predicate local, rather than systemic, delivery of the virus. Continued engineering of the adenoviral genome is producing vectors with improved properties, which may eventually overcome these issues. Promising avenues include the development of 'gutted' vectors encoding no endogenous viral genes and of adenovirus–AAV chimeras. Whether these will offer advantages over existing vectors, which may already provide safe, long-term gene expression following in vivo delivery, remains to be seen.

Gene therapy in rheumatoid arthritis: how to target joint destruction?

The challenge of early synovitis: multiple pathways to a common clinical syndrome

A chance observation has led to the development of a new murine model for inflammatory arthritis. Arthritis is induced, and transferred, by T-cell-dependent antibodies to glucose-6-phosphate isomerase. This enzyme is expressed in all cells, and is detectable in serum. There are several similarities to rheumatoid arthritis (RA) in the murine disease. This elegant model raises several questions as to how and why a systemic response focuses inflammation so strongly on synovial joints. The model also re-introduces the possibility that antibodies to widely expressed self-proteins may play a role in the pathogenesis of RA.