Rheumatoid arthritis patients have defective neuroendocrine-immune responses to the stress of inflammation, and currently available data shows that this contributes to the pathophysiology of the disease. The advances in neuroendocrine immunology have improved our understanding of the pathophysiological mechanisms involved in RA. These observations raise important therapeutic questions which are certainly worth further investigation as they may open up novel avenues for the management of the disease.

Hormones, particularly those involved in the hypothalamic-pituitary-gonadal and -adrenal axes (HPG and HPA), play important roles in various animal models of autoimmunity such as systemic lupus erythematosus in mice and collagen-induced arthritis (CIA) in mice and rats, and the streptococcal cell wall, adjuvant and avridine arthritis models in rats. Intimately linked to the subject of hormones and autoimmunity are gender, sex chromosomes and age. The importance of these factors in the various animal models is emphasized in this chapter. Several major themes are apparent. First, oestrogens promote B-cell dependent immune-complex mediated disease (e.g. lupus nephritis) but suppress T-cell dependent pathology (CIA in mice and rats), and vice versa. Second, testosterone's effects are complicated and depend on species and disease model. In rats, testosterone suppresses both T-cell and B-cell immunity. In mice, the effects are complex and difficult to interpret, e.g. they tend to enhance CIA arthritis and suppress lupus. Sex chromosome/sex hormone interactions are clearly involved in generating these complicated effects. Third, studies in Lewis and Fischer F344 rats exemplify the importance of corticosteroids, corticotrophin releasing hormone and the HPA axis in the regulation of inflammation and the predisposition to autoimmune diseases. Fourth, the HPA axis is intimately linked to the HPG axis and is sexually dimorphic. Oestrogens stimulate higher corticosteroid responses in females. The animal model data have major implications for understanding autoimmunity in humans. In particular, adrenal and gonadal hormone deficiency is likely to facilitate T-cell dependent diseases like rheumatoid arthritis, while high oestrogen levels or effects, relative to testosterone, are likely to promote B-cell dependent immune-complex-mediated diseases such as lupus nephritis.

Current evidence indicates that the neuroendocrine system is the highest regulator of immune/inflammatory reactions. Prolactin and growth hormone stimulate the production of leukocytes, including lymphocytes, and maintain immunocompetence. The hypothalamus-pituitary-adrenal axis constitutes the most powerful circuit regulating the immune system. The neuropeptides constituting this axis, namely corticotrophin releasing factor, adrenocorticotrophic hormone, alpha-melanocyte stimulating hormone, and beta-endorphin are powerful immunoregulators, which have a direct regulatory effect on lymphoid cells, regulating immune reactions by the stimulation of immunoregulatory hormones (glucocorticoids) and also by acting on the central nervous system which in turn generates immunoregulatory nerve impulses. Peptidergic nerves are major regulators of the inflammatory response. Substance P and calcitonin gene-related peptide are pro-inflammatory mediators and somatostatin is anti-inflammatory. The neuroendocrine regulation of the inflammatory response is of major significance from the point of view of immune homeostasis. Malfunction of this circuit leads to disease and often is life-threatening. The immune system emits signals towards the neuroendocrine system by cytokine mediators which reach significant blood levels (cytokine-hormones) during systemic immune/inflammatory reactions. Interleukin-1, -6, and TNF-alpha are the major cytokine hormones mediating the acute phase response. These cytokines induce profound neuroendocrine and metabolic changes by interacting with the central nervous system and with many other organs and tissues in the body. Corticotrophin releasing factor functions under these conditions as a major co-ordinator of the response and is responsible for activating the ACTH-adrenal axis for regulating fever and for other CNS effects leading to a sympathetic outflow. Increased ACTH secretion leads to glucocorticoid production. alpha-melanocyte stimulating hormone functions under these conditions as a cytokine antagonist and an anti-pyretic hormone. The sympathetic outflow, in conjunction with increased adrenal activity. leads to the elevation of catecholamines in the bloodstream and in tissues. Current evidence suggests that neuroimmune mechanisms are essential in normal physiology, such as tissue turnover, involution, atrophy, intestinal function, and reproduction. Host defence against infection, trauma and shock relies heavily on the neuroimmunoregulatory network. Moreover, abnormalities of neuroimmunoregulation contribute to the aetiology of autoimmune disease, chronic inflammatory disease, immunodeficiency, allergy, and asthma. Finally, neuroimmune mechanisms play an important role in regeneration and healing.

The neuroendocrine and immune responses to inflammatory stress represents an integrated circuit whose basis is reviewed in this chapter. Pro-inflammatory cytokines such as IL-1 beta, TNF-alpha and IL-6 released from inflammatory foci initiate local anti-inflammatory mechanisms and travel via the blood stream to the brain where they trigger a variety of neuroendocrine counter-regulatory mechanisms. There is therefore an important neuroendocrine-immune loop in which stimulatory signals are received by the neural systems from inflammatory foci. These signals are transduced by the hypothalamus which initiates a complex hormonal cascade reaction aimed at modulating inflammation and returning the organism to normal physiological homeostasis once the trigger has been neutralized. Abnormalities in this cross-talk can profoundly influence the susceptibility to developing chronic inflammatory disease. Thus, in conclusion, the neuroendocrine-immune loop has important pathophysiological implications for disease processes.

The stress system is controlled by brain nuclei at the hypothalamus and brainstem. These nuclei interact with each other and control the HPA axis and sympathetic nervous systems, respectively. Major inputs to the stress system arise from the cerebral cortex and subcortical systems, the sensory organs and nerves, and the endocrine and immune systems. The major peripheral effectors of the stress system are glucocorticoids and the catecholamines. Pathological hypoactivity of the stress system has been associated with atypical depression, the chronic fatigue/fibromyalgia syndromes and autoimmune inflammatory disease; hyperactivity with melancholic depression and anxiety disorders. The stress system responds in a quantitatively and qualitatively specific fashion to different stressors. A major role of the HPA axis is to restrain the immune system and prevent tissue damage. Reciprocal interactions between the HPA axis and immune system constitutes a new endocrine feedback loop that has given rise to the field of neuroendocrine immunology. Gonadal axis hormones directly, and indirectly via the HPA axis, alter the tone of the immune system and the quality and quantity of the inflammatory responses. Effects of the HPA axis on the gonadal axis are consistent with conservation and redirection of valuable resources towards homeostasis during times of stress. These complex interactions between the HPA axis, immune and the gonadal systems may prove to be fundamental in the genesis and perpetuation of autoimmune disease.

Recent rodent models have been exploited to explore mechanisms of intestinal and joint inflammation. HLA-B27 transgenic rats develop colitis, gastritis, and arthritis when raised in a conventional environment, but have no evidence of inflammation under germfree (sterile) conditions. Metronidazole treatment attenuates gastrointestinal inflammation, suggesting that anaerobic bacteria are important. Experimental bacterial over-growth of predominantly anaerobic bacteria reactivates arthritis in Lewis rats which have been previously injected intra-articularly with bacterial cell wall polymers. Reactivation arthritis is mediated by interleukin-1, tumour necrosis factor-alpha, and can be blocked by metronidazole. Intramural injection of the bacterial cell wall polymer, peptidoglycan-polysaccharide, leads to biphasic, chronic granulomatous enterocolitis and peripheral arthritis in Lewis rats, but only transient intestinal inflammation and no arthritis in Buffalo or MHC-matched Fischer rats. Chronic granulomatous inflammation is mediated by T lymphocytes and interleukin-1 and is dependent on persistent antigenic stimulation by poorly biodegradable bacterial polymers. Results in these models firmly incriminate resident normal enteric flora (especially anaerobes), bacterial products, and host genetic susceptibility in the pathogenesis of spondyloarthropathies. We suggest that increased uptake of luminal bacterial components across the inflamed mucosa leads to systemic distribution of these arthropathic products. The genetically susceptible host develops reactive arthritis due to defective downregulation of inflammation in response to immunologically active bacterial components.

Decreased systemic immune responsiveness to a specific antigen following exposure to that antigen by the enteric route is termed 'oral tolerance.' Oral tolerance is revealed when attempts are made to parenterally immunize the host to the same antigen that was previously administered orally or intragastrically. A similar phenomenon is also seen following antigen exposure via the nasal mucosa and a related phenomenon is seen following antigen exposure in the upper respiratory tract. There has been a marked renewal of interest in the mechanisms that underlie oral tolerance because of its potential role for preventing and treating autoimmune and inflammatory diseases and IgE-mediated allergic disorders. The specific factors that determine whether or not the host develops mucosal tolerance to an antigen administered by the mucosal route are also of substantial importance for those involved in mucosal vaccine development. Furthermore, putative abnormalities in the ability of the host to develop mucosal tolerance may play a pathogenetic role in certain autoimmune and allergic diseases and disorders. Several well-defined immunological mechanisms mediate oral tolerance. These include the induction, following mucosal antigen exposure, of regulatory populations of T-cells that can down-regulate specific immune responses (e.g. DTH) via the production of specific cytokines (e.g. TGF-beta 1, IL-10 and IL-4). In addition, clonal anergy, clonal deletion and antibody-mediated suppression can be shown to play a role in the induction and maintenance of mucosal tolerance in several experimental systems. In animal studies, the onset of collagen-induced, adjuvant-induced, antigen-induced and pristane-induced arthritis has been delayed and the severity of ongoing disease diminished following feeding collagen type II. Mucosal tolerance has been clearly demonstrated in humans and clinical studies have been undertaken to treat rheumatoid arthritis using a similar approach. Results of initial clinical studies in rheumatoid arthritis indicated a modest improvement and further studies are ongoing in this and other autoimmune diseases (e.g. multiple sclerosis, autoimmune uveitis and insulin-dependent diabetes). This approach, if successful, could offer a new and novel therapeutic modality for preventing autoimmune and allergic disorders, and modulating ongoing disease.

The process of lymphocyte trafficking is mainly regulated by receptors that belong to a group of molecules referred to as adhesion molecules. These molecules can be divided, according to their molecular structure, into three broad families: the integrins; the selectins; and the immunoglobulin superfamily members. The alpha 4 beta 7 integrin is expressed on some lymphocytes with hallmarks of gut tropism. alpha 4 beta 7, among others, serves as a ligand for the mucosal vascular addressin MadCAM-1, which is selectively expressed on mucosal lymphoid organ high endothelial venules and on gut lamina propria venules. It is tempting to believe that related integrin receptors play a crucial role in the recirculation of activated lymphocytes between the gut mucosa and the synovial membrane.

There is great interest in the association between intestinal inflammation and the various arthropathies. However, most studies assessing intestinal function in these diseases are confounded by the fact that non-steroidal anti-inflammatory drugs (NSAIDs) have profound effects on the small intestine. Hence NSAIDs cause quite distinct and severe biochemical damage during drug absorption (uncoupling of mitochondrial oxidative phosphorylation proving to be most important) which results in increased intestinal permeability. All commonly used NSAIDs, apart from aspirin and nabumetone, are associated with increased intestinal permeability in man. Whilst reversible in the short term, it may take months to improve following prolonged NSAID use. Increased intestinal permeability appears to be the central mechanism of converting the biochemical damage to an inflammatory tissue reaction (NSAID enteropathy). The inflammatory enteropathy is not, however, unique to NSAIDs but similar changes are found with other permeability breakers. In intestinal infections and in diseases associated with reduced mucosal defence, suggesting that the small intestinal inflammation represents a common final pathway for a number of intestinal injuries. Spondylarthropathies are associated with a high prevalence of terminal ileitis, but as most patients have been receiving NSAIDs it has been difficult to dissociate the effects of NSAIDs on intestinal function from that of the ileitis itself. Nevertheless, two studies suggest that increased intestinal permeability in spondylarthropathies occur independently of NSAID ingestion. Whilst these findings may have implications for the development of arthritis, the permeability changes in spondylarthropathy do not differ quantitatively or qualitatively from that of NSAIDs or other permeability breakers. NSAID enteropathy can be differentiated from spondylarthropathic enteropathy by differences in location of disease and lack of predilection of certain HLA types. However, as the two may coexist both enteroscopy and ileocolonoscopy may be necessary for this distinction.

Gut inflammation plays a crucial role in the pathogenesis of spondylarthropathies (SpA) since ileocolonoscopic studies have demonstrated the presence of gut inflammation in different forms of this concept: in ankylosing spondylitis (AS) (60%), in enterogenic (90%) and urogenital reactive arthritis (20%), in undifferentiated SpA (65%), in the pauciarticular and axial forms of psoriatic arthritis (16%), in late onset pauciarticular juvenile chronic arthritis (80%) and in acute anterior uveitis (66%). The strong relationship between gut and joint inflammation was demonstrated by performing a second ileocolonoscopy: remission of the joint inflammation was always connected with a disappearance of gut inflammation, whereas persistence of locomotor inflammation was mostly associated with the persistence of gut inflammation. During further evolution 20% of the non-ankylosing spondylitis SpA patients can develop AS. About 6% of the total group SpA patients, in whom inflammatory bowel disease (IBD) was excluded, developed Crohn's disease 5 to 9 years later. All these patients initially presented with gut inflammation, which indicates that this finding has prognostic value. The high prevalence of evolution to IBD in SpA patients confirms the thesis that both disease entities bear common pathogenic mechanisms, and confirms the place of IBD in the concept of SPA. Sulphasalazine (SASP), a successful drug in the treatment of IBD, has demonstrated its effectiveness in the treatment of SpA. The beneficial effect of the drug in this disease entity could be due to its anti-inflammatory effect on the gut wall, by normalizing its permeability and by preventing the entrance of antigens through the defective gut wall. However, SASP could not prevent the evolution to IBD.

Recent studies strongly support the concept that gut and joint inflammation are closely related. Progress also has been made in identifying individual mechanisms that contribute to the pathogenesis of joint disease in IBD and in undifferentiated SpAs. However, the interrelationship of these mechanisms that result in chronic disease manifestations at a site distant from the initiating event remain to be elucidated. The local absence of homing molecule receptors in the gut wall combined with an expression of these receptors in target organs can be responsible for the transformation of the synovial membrane and/or the enthesis into an aberrant tertiary lymphoid organ of the gut.

Reactive arthritis is triggered by an infection, either of the genitourinary or gastrointestinal tracts; the common triggering bacteria in enteric ReA include salmonella, shigella, yersinia, and campylobacter. It is still not clear how such different bacteria can lead to a similar clinical picture and have a similar association with the MHC class I antigen HLA-B27. Common both to enterogenic and urogenic bacteria is the type of peripheral joint involvement. However, this is not so different from other bacteria-associated arthritides and is probably the consequence of bacteria persistent inside the joint. What is unique to these bacteria is the HLA-B27-association and the nearly exclusively B27-linked clinical manifestations as sacroiliitis and iritis. Shigella-induced ReA has the highest B27-association while in salmonella- and chlamydia-induced ReA a lower association can be found. Mucosal entry of enterogenic bacteria give easy access to macrophages which might be important for the transport into the joint. Although bacteria-specific antibodies are of diagnostic value, the humoral immune response does not explain the immunopathogenesis and MHC-association of this disease. Bacteria-specific T-cells have been constantly found in the synovial fluid from ReA patients and have been further analysed. The identification of immunodominant antigens of these bacteria is of great importance to understand the pathogenesis. Although an antigen shared by all bacteria has not been identified until now progress is being made in this field. We have also to consider the possibility that these bacteria are not only driving the immune response themselves but rather work as a trigger for autoimmunity.

Adaptive immune protection of mucous membranes is provided mainly by secretory IgA (SIgA) antibodies. This first-line defence is accomplished through an ingenious cooperation between the mucosal B-cell system and the epithelial glycoprotein called secretory component (SC). This is quantitatively the most important receptor of the immune system because it is responsible for external transport of locally produced polymeric IgA (pIgA), which is the major humoral mediator substance of the whole immune system. Transmembrane SC belongs to the Ig supergene family and functions as a general pIg receptor, also translocating pentameric IgM externally to form secretory IgM. The B-cells responsible for local pIg production are initially stimulated in lymphoepithelial structures, particularly the Peyer's patches in the distal small intestine, from which they migrate as memory cells to exocrine tissues all over the body. Mucous membranes are thus furnished with secretory antibodies in an integrated way, ensuring a variety of specificities at every secretory site. There is currently great interest in exploiting this integrated or "common' mucosal immune system for oral vaccination against pathogenic infectious agents and also to induce therapeutic peripheral tolerance to ameliorate T-cell-mediated autoimmune diseases. Much remains to be learnt about antigen uptake and processing necessary to elicit stimulatory or suppressive mucosal immune responses, and how normal homeostasis is maintained in the intestinal mucosa. Considerable information has accumulated about various types of immune deviation that may lead to local or extraintestinal hypersensitivity reactions against luminal antigen, but the crucial mechanisms remain obscure.

Biological agents have pointed out directions for future research, although none yet are therapies to be employed in the clinic. To date we have administered them at pharmacological; even industrial-strength doses, without demonstrating the desired cell- or diseased-specific effects. There are many issues specific to the clinical development of biological agents which distinguish them from pharmaceutical products. Most are immunologically active; early trials are performed in patients with disease, rather than normal volunteers. This poses multiple challenges: access to an appropriate patient population, as well as effecting immunomodulation without interfering with normal immune surveillance. Species-specificity of the agent may limit the use of preclinical animal models, and the duration of toxicology studies. Immunogenicity may preclude regular re-administration, necessitating prolonged benefit after single or limited treatment courses. Parenteral administration requires more careful monitoring, limits access to the agent, is associated with more expense, and may contribute to the high observed placebo response following treatment with biological agents. Requirements, and our expectations, for clinical benefit are therefore higher with these products than with traditional pharmaceuticals. Despite a scientific rationale and the use of biological markers, it is unlikely that development of a biological agent for the treatment of a chronic auto-immune disease can progress significantly faster than for a traditional pharmaceutical product. It is therefore important, particularly in the treatment of chronic RA, to develop a careful and rational step-by-step clinical development programme and to define the goals of the therapy: anti-inflammatory or symptom modification versus disease modification. Some biological agents may be expensive but safe NSAIDs. Others may treat disease flares. After 'induction therapy', utilizing a biological agent, followed by 'maintenance therapy' with a traditional DMARD agent, we may envisage 'combination chemotherapy', employing multiple biological products targeting different specific immunological aspects of the disease. We must therefore develop biological agents utilizing rigorous clinical trial principles, and follow suggested guidelines.

Patient education has a long history as an integral part of clinical practice; however, controlled clinical trials of psycho-educational interventions for the rheumatic disorders emerged in significant numbers over the last 15 to 20 years. In this chapter, the efficacy of these interventions was reviewed in 34 reports (54 separate treatment arms) published in the last 10 years. Psycho-educational interventions included both traditional educational or teaching activities and psychological interventions. The most common types of intervention were self-management programmes ((21 treatment arms) and cognitive-behavioral therapy (10 treatment arms). Both approaches emphasize learning new skills helpful in managing one's disease. Self-management programmes are broadly focused on using information, problem-solving and coping skills for symptom management. Cognitive-behavioural therapy usually emphasizes control of pain by understanding the interaction of emotions and cognition with the physical and behavioral aspects of pain. Other interventions, tested either individually or as comparisons for self-management or cognitive-behavioural therapy interventions, included traditional classroom-type programmes (four treatment arms), 'materials' including pamphlets, books and computerized instruction (seven treatment arms), individualized instruction (five treatment arms), psychotherapy (one), and support groups (three treatment arms). Sixty per cent of studies used clinic samples, 52% rheumatoid arthritis and 8% with osteoarthritis. The remaining studies recruited from community samples where the exact diagnosis was not always clear, though most had either RA or OA. The majority of self-management interventions used community samples. The average effect size for treatment compared to non-intervention controls (weighted for sample size) for RA patient pain, functional ability and depression at post intervention was 0.13, -0.16 and 0.01 compared with 0.44, 0.28 and 0.56 for OA patients and 0.21, 0.08 and 0.12 for community samples. At 3 months follow-up, self-management programmes demonstrated improvement compared to controls for self-efficacy (effect sizes 0.22 to 0.29) with community patients while cognitive-behavioural therapy interventions demonstrated similar improvements in active coping skills (effect sizes 0.09 to 0.18) with RA patients. Effect sizes ranged from 0.6 to 1.1 for exercise compliance following self-management interventions. In the few studies with follow-up evaluations extending beyond 3 months post-intervention, effects generally weaken. As expected, psycho-educational interventions do not alter physical functioning with functional abilities continuing to decline over time. Lorig and colleagues have demonstrated in 4-year outcome studies important reductions in the use of health care services for participants in self-management programmes despite the progression of functional disability. Psycho-educational interventions are difficult to evaluate because of the differences in interventions, methods of assessment and varying follow-up times. Studies of these interventions differ in quality, patient population, etc., precluding a useful meta analysis. Overall, there is improvement in pain, depressive symptoms, self-efficacy, coping abilities, and self-management behaviours such as exercise compliance following psycho-educational interventions, with a trend to greater improvement for OA than RA patients. Utilization of health care services may be reduced following educational interventions. Although the overall improvement is small, it is probably of the order of that seen with therapy with NSAIDs and is independent of medical treatment. Psycho-educational interventions are a useful additional modality in the management of rheumatic diseases and may improve treatment effects and patient quality of life.

Rheumatoid patients with intractable knee effusions may benefit from medical or radio-isotopic synoviorthesis. These offer more convenient, less costly alternatives to surgery with similar long-term outcome. Temporary symptomatic relief may be obtained, but disease progression is unaffected. Potential adverse effects include development of osteoarthrosis with osmic acid and teratogenicity and mutagenicity with alkylating agents and radioisotopes.

Choice of diet is one way in which an individual can influence his/her own health, and it is to be expected that patients will seek their physician's expert opinion regarding dietary matters. Respect for the legitimacy of these enquiries and balanced informed discussion, which includes general advice for a prudent diet, as well as disease-specific recommendations when indicated, can be the key to a productive relationship between patients and physician. The issue of dietary advice has an impact on the management of most forms of arthritis including osteoarthritis (obesity/energy balance), gout (dietary purines, energy balance, alcohol, fluid intake) and rheumatoid arthritis (n-3 fatty acids). Food hypersensitivity appears to be a rare cause of polyarthritis, and elimination diets and fasting have little or no place in routine practice. Strategies under investigation include oral tolerization, the utility of which remains to be established.

New interest in the use of antibiotics in the treatment of arthritis was stimulated by two factors: (1) observations that, in some forms of chronic arthritis, microbial antigens persist in the synovial membrane, and (2) the increasing knowledge of the anti-inflammatory and immunosuppressive effects of antibiotics. Recently, several published controlled studies reported a beneficial effect of tetracyclines on RA and reactive arthritis. Whether the anti-arthritic activity of the tetracyclines investigated is mediated by the antimicrobial, anti-inflammatory or immunomodulatory properties remains to be determined. It may be concluded from these studies that tetracyclines have a beneficial effect on RA, especially when laboratory parameters are considered. The effect on the clinical parameters is not unequivocal. The adverse effects seem to be mild but the long-term efficacy and safety of tetracyclines as disease-modifying antirheumatic drugs remain to be demonstrated.

A need remains for the development of more effective therapies for the treatment of rheumatoid arthritis (both NSAIDs and DMARDs). The NSAIDs remain the cornerstone of symptomatic therapy, but concern remains about their safety, potential for the delay in commencing definitive therapy and theoretical pro-inflammatory effects. Each of the NSAIDs reviewed here do provide an advantage over therapies previously available and should prove to be useful additions to the rheumatologists' therapeutic armament.