An aetiological diagnosis of reactive arthritis is based on the demonstration of recent or ongoing infection with the causative bacterium. This may be done by serological demonstration of antibacterial antibodies, demonstration of the causative microorganism at an extra-articular site or by identification of bacterial nucleic acids or antigens in joint material from patients with aseptic arthritis. The finding of elevated titres of bacteria-specific IgG- and IgA-class antibodies may indicate recent or persistent infection, but has some limitations due to the prevalence of such antibodies among apparently healthy individuals and the persistence of such antibodies after the infection. While Chlamydia can be demonstrated in urogenital specimens in at least one-third of patients with Chlamydia-induced arthritis, the triggering microorganisms are usually no longer detectable in post-dysenteric reactive arthritides. Assays involving molecular amplifications have been successfully used to demonstrate bacterial nucleic acids in joint specimens from patients with reactive arthritis. In addition, bacterial antigens have been detected by immunofluorescence tests. Even though examination of synovial fluid and synovial membrane specimens for bacterial DNA by the polymerase chain reaction is increasingly used to diagnose reactive arthritis, such assays have not been standardized and are not generally available. While some problems remain, these techniques will facilitate the exact diagnosis of reactive arthritides in the near future.

Among several animal models, HLA-B27 transgenic rodents proved useful for investigating the interplay between genetic factors and the bacterial environment in the aetiopathogenesis of the spondyloarthropathies (SpA). HLA-B27 transgenic rats spontaneously develop a multisystemic inflammatory disease resembling human SpA. This disease is dependent on the presence of a normal bacterial flora and implicates the immune system. The presence of both T cells and antigen-presenting cells expressing high levels of HLA-B27 seems of critical importance in its pathogenesis. HLA-B27 transgenic mice also develop arthritis, under the influence of the bacterial flora. In both types of model, CD8+ T cells seem not to be necessary, arguing against the 'arthritogenic peptide' hypothesis. In vitro models have been used to study the immune response against bacterial agents and the role of HLA-B27 in human SpA. It appears that an impaired immune response against bacteria could be involved in the triggering of human SpA. HLA-B27 could be implicated at the level of interaction between host cells and bacteria in the driving of a specific immune response against bacterial antigens or as a target of an autoimmune response.

Inflammatory joint disease can develop following an extra-articular infection. The term reactive arthritis was coined in order to differentiate this arthritis, which is often characterized by lack of culturable organisms in the joint, from septic arthritides. Bacteria known to trigger reactive arthritis include Campylobacter, Chlamydia, Salmonella, Shigella and Yersinia. Demonstration of bacteria or bacterial macromolecules in the joint has elicited the idea that reactive arthritis is a sterile process induced and maintained by antigenic material in the synovium. Continued synthesis of antigens to maintain synovial inflammation probably requires establishment of persistent bacterial infection in the joint, or at the primary site of infection. In the case of Chlamydia trachomatis, viable, metabolically-active organisms have been demonstrated to exist for extended periods in the joints of patients with reactive arthritis. In this chapter, we review the aetiological agents, and their molecular biology and phagocyte-host interactions, that are involved in reactive arthritis and spondylarthropathy.

In none of the rheumatic diseases has the genetic contribution to pathogenesis been so well characterized as in the seronegative spondyloarthropathies. Most important has been the elucidation of the structure and effect on disease expression of HLA-B27, where 11 subtypes have been distinguished to date. These vary in frequency in different ethnic groups and seem to show differential disease associations. The high frequency of this gene in patients with the seronegative spondyloarthropathies, especially ankylosing spondylitis (AS) and Reiter's syndrome (RS)/reactive arthritis (ReA), has emerged as probably the best example of a disease association with a hereditary marker. Other HLA genes, in addition to HLA-B27, have been implicated in psoriasis and psoriatic arthritis. These include those from the HLA-C locus and from HLA-DR. In addition, recent family studies have implicated other genes outside the MHC that further enhance the susceptibility to AS.

The present classification of a number of arthropathies linked to the B27 antigen under the term spondylarthropathy emphasises the frequent familial aggregation and clustering during follow-up of these diseases. This article is an attempt to review the progress elicited by the introduction of classification criteria for spondylarthropathy and the limitations of the concept. In particular, we address the continued need for better understanding of aetiology and pathogenesis. This makes it likely that we will need new classifications in the future and that this will evolve along with improvements in disease understanding. Working classifications that include the infectious triggers and features of the host response might be useful to guide new approaches.

The development of monoclonal antibodies and the emergence of recombinant DNA technology has made it possible to identify and selectively inhibit distinct cell subsets, surface molecules and secreted products that contribute to normal and pathological immune responses. These advances have helped to clarify the mechanisms that promote autoimmune diseases. As a result, it is now possible to contemplate rational strategies for the treatment of these diseases. Some of these strategies are designed to influence the cell surface interactions that determine whether potentially autoreactive T cells become activated or tolerant following antigen stimulation. Other strategies are designed to augment or inhibit distinct cytokines that regulate autoimmunity. All of these strategies have shown promise in animal models for systemic lupus erythematosus, and they may soon be translated into effective new therapies for people.

Over the past decade, cytotoxic drugs have come to assume an increasingly important role in the management of systemic lupus erythematosus. Intravenous cyclophosphamide has become the standard treatment for lupus affecting major organs, in particular lupus nephritis. Cytotoxics with less potential for adverse side effects such as azathioprine and methotrexate are widely used in the management of non-major organ lupus and as an adjunct to reduce corticosteroid requirements. Recent clinical experience in lupus with newer cytotoxic drugs such as cyclosporin A, adenosine analogues, and mycophenolate mofetil appear promising and may offer improvements in lupus management in the future.

Corticosteroid therapy has had a major impact on improvement in disease activity and long-term survival in patients with systemic lupus erythematosus (SLE). Unfortunately, the therapeutic advantages are accompanied by many manifestations of toxicity, some of which are short term and potentially reversible, while others cause chronic irreversible damage. Many of these features of toxicity have similar presentations to manifestations of SLE disease activity, and must be distinguished in the individual patient. The features of corticosteroid toxicity are reviewed in this chapter, and means of prevention and/or treatment are discussed.

The antiphospholipid syndrome, initially described in systemic lupus erythematosus (SLE), occurs in 20-35% of patients with this condition. Its clinical manifestations may precede, be concurrent with, or follow clinical features of SLE. There are no major differences between the primary antiphospholipid syndrome and the secondary form that associates with SLE. Several studies suggest that the presence of an antiphospholipid syndrome in patients with SLE conveys a worse prognosis. To prevent recurrence of thrombotic events (particularly arterial events), oral anticoagulation with an international normalized ratio (INR) close to 3 is recommended. Treatment of recurrent fetal loss is with aspirin, or with aspirin plus heparin. Controlled studies are underway to determine optimal treatment in patients with cerebral ischaemia as well as the optimal treatment in women with recurrent pregnancy loss.

The effect of pregnancy on disease activity in systemic lupus erythematosus remains controversial. Studies on lupus flares in pregnancy are discussed, including prospective data on severity of flares and organ involvement from the Hopkins Lupus Pregnancy Center. The major fetal concerns of miscarriage (due to the antiphospholipid antibody syndrome), pre-term birth (largely due to pre-eclampsia or premature rupture of membranes) and neonatal lupus, are reviewed.

All aspects of the role of renal biopsy in systemic lupus erythematosus may not be defined and accepted, but there is increasing agreement as to the information that can be obtained from biopsy. Awareness of the importance of clinical (non-biopsy) predictors has permitted a clearer understanding of the ability of renal biopsy to confirm and to add information to a determination of prognosis based on clinical data. New techniques for scoring the patterns of injury detectable on renal biopsy have provided important insights into prognosis, pathogenesis and treatment of lupus nephritis. Watchful waiting is often an unwise course for the management of lupus nephritis. Thus, renal biopsy is increasingly seen as an important tool in the timely determination of prognosis.

Patients with systemic lupus erythematosus (SLE) may present with a wide array of neuropsychiatric (NP) clinical features. This may either be a primary manifestation of SLE, the result of a complication of the disease or its therapy, or a concurrent disease process. As there is no single diagnostic gold standard for NP-SLE, the assessment of individual patients is heavily dependent upon clinical evaluation in addition to information from studies of autoantibodies, brain structure and function. Despite their lack of diagnostic sensitivity and specificity, these tests frequently provide information that can be used to support or refute the clinical impression. They may also provide a basis for the prospective evaluation of the efficacy of therapeutic interventions in individual patients with NP-SLE.

Criteria for the classification of systemic lupus erythematosus (SLE) are not sufficient to describe the degree of disease activity. Several instruments to assess disease activity have been developed. This chapter reviews the derivation, validation, and clinical application of current disease activity measures in SLE, as well as comparison among them. As patients with lupus survive longer, the sequelae of the disease activity and its therapy are becoming more common. The derivation and validation of the single, generally accepted SLICC/ACR damage index is also discussed.

Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease characterized by the deposition of autoantibodies and immune complexes, leading to tissue damage. The immunopathogenesis of SLE is like a jigsaw puzzle, some pieces of which are missing or have not fallen into place. In predisposed individuals, the initial stimulus is likely to be one or more of the environmental agents interacting with susceptibility genes. Once the critical threshold is breached there is a failure of the immune system to downregulate the ensuing abnormal immune response, involving polyclonal B cell activation and hyperactive T cell help. Key questions include, what are the processes behind the availability of autoantigens and the breakdown of tolerance that give rise to the pathogenic autoantibodies? Current areas of research also involve the roles played by cytokines, adhesion molecules, co-stimulatory molecules and apoptosis.

Idiopathic juvenile arthritis occurs throughout childhood; the young child needs a major paediatric input while the adolescent, at whatever age the disease started, will need help in achieving a satisfactory transfer to adulthood, perhaps using the 'young adult team'. Throughout, an appropriate team of paediatrician, rheumatologist, physiotherapists, occupational therapists and social workers is important in dealing with such young people and their families. They not only treat the disease but give information to parents and children that will aid the day-to-day management of the condition, and help maintain normal education (progressing to further and higher education) and training leading, hopefully, to an acceptable adult lifestyle.

Chronic childhood arthritis impairs joint function and may result in severe physical handicap. Joint pain and inflammation trigger a vicious cycle that often ends in joint damage and fixed deformities. A comprehensive rehabilitation programme must start early to restore loss of function and prevent permanent handicap. It is dominated by a physiotherapeutic regimen consisting of pain relief, movement expansion, training of muscular coordination and finally re-integration of a physiological movement pattern. The approaches of occupational therapy become integrated into the treatment programme, concentrating on joint protection and self-care training. Additional aids support the aim of joint restoration. They include individual splinting, adapted footwear and walking aids. Depending on the child's age and developmental status different aspects of rehabilitation dominate. Small children need adequate mobility to promote their psychosocial development. In later years integration into school life and the peer group becomes important. Adolescents require help for an adequate vocational training and self-care support. Last but not least, parental education and integration of the whole family into the rehabilitation programme markedly improve the patient's prognosis.

Rheumatoid paediatric diseases are a leading cause of uveitis in childhood. Juvenile chronic arthritis (JCA), juvenile onset spondyloarthropathies as well as sarcoidosis and other systemic diseases with arthritis may include ocular manifestations that can threaten vision, and especially so in juvenile chronic arthritis. Special risk factors concerning the eye have to be considered for JCA. The diagnosis, detection, follow-up studies and treatment in children may differ significantly from adult rheumatoid diseases because of the young age of the patients and the specific features and signs of ocular involvement. Medical and surgical treatment of such ocular manifestations may be challenging. Special attention to children's ophthalmic complications must be undertaken by paediatricians and ophthalmologists.

The concept of spondyloarthropathies in childhood is emerging. It should now be more easily recognized since more specific diagnostic criteria are available for young patients. It probably accounts for about 20% of the whole group of chronic arthritides seen in paediatric rheumatology clinics. Juvenile ankylosing spondylitis stricto sensu is very rare in childhood. Most children who present with peripheral arthritis at onset meet the diagnostic criteria of undifferentiated spondylo-arthropathies such as those of the SEA syndrome, or those of the ESSG or Amor criteria. At follow-up, quite a large proportion of children may develop axial involvement. Psoriatic arthritis differs from the other spondyloarthropathies with a different sex ratio, and an earlier onset. The role of immunogenetic, environmental and ethnic factors are important for a better understanding of these diseases.

Patients with oligoarticular onset of juvenile arthritis form a large group that is heterogeneous with regard to clinical presentation, further evolution and outcome. The three established subgroups do not cover the whole patient population and are not always easily distinguishable at onset. Therefore, the outcome of children with oligoarticular onset is still, on the whole, unpredictable. Treatment has been very conservative, but, as part of it, the use of intra-articular corticosteroids is increasing and should be encouraged. The question of whether to give slow-acting anti-rheumatic drugs is a difficult one, as these have neither been studied nor recommended for use in persistently oligoarticular patients.

Systemic onset juvenile rheumatoid arthritis (SoJRA) accounts for 10-20% of all JRA, affecting males and females equally and occurring most frequently under the age of 5 years. It is characterized by arthritis, daily spiking fever, an evanescent rash, serositis and a variety of other extra-articular features. Exclusion of systemic infections, malignancies and connective tissue diseases is most important in establishing the diagnosis. The disease has a wide range of severity from a short monocyclic course to a prolonged chronic course with severe destructive arthritis in approximately one third of patients. Destructive arthritis, secondary amyloidosis and treatment complications including infections, osteoporosis, growth retardation and the macrophage activation syndrome account for the significant morbidity and mortality associated with the disease. Pharmacological management includes non-steroidal anti-inflammatory drugs, corticosteroids, methotrexate and an emerging role for cyclosporine A and cytotoxic drug therapy. Elucidation of the immunopathogenetic mechanisms may lead to new targeted therapy.