Cytokines in rheumatoid arthritis: new therapeutic possibilities

The ingress of inflammatory leukocytes into the synovium is important for the pathogenesis of rheumatoid arthritis. Soluble inflammatory mediators regulate the inflammatory, chemotactic, adhesive, angiogenic events, as well as osteopenia associated with this disease. In this review authors discuss the role of a number of inflammatory mediators, such as cytokines, chemokines and growth factors in these processes. The outcome of arthritis is highly dependent on the imbalance between pro-inflammatory and anti-inflammatory mediators. Cytokine-related research also has important clinical relevance. Many of these proteins are detectable in the serum of rheumatoid patients and may eventually serve as useful laboratory markers of disease activity. Antirheumatic therapy currently used for the treatment of rheumatoid arthritis is often limited. Therefore, we need to consider alternative therapeutic regimens, such as the inhibition of cytokines and other soluble mediators, in order to prevent severe joint destruction. While there are many complex interactions involving cytokine networks and cascades in the arthritic joint, there are promising attempts to eliminate a single cytokine in clinical trials, such as ablation of tumor necrosis factor-alpha. Hopefully, the study of cytokines and their networks will lead to specific immunomodulatory therapies that will benefit rheumatoid patients by preventing joint destruction.     

The role of nitric oxide in heart failure. Potential for pharmacological intervention

There is now considerable evidence that nitric oxide (NO) production and action are abnormal in patients with heart failure. Spontaneous NO release from the vascular endothelium is preserved or enhanced in patients with heart failure and this may help to maintain tissue perfusion by blunting the vasoconstriction induced by various neurohumoral factors. On the other hand, endothelial NO release in response to various stimuli including exercise appears to be diminished and this may contribute to the impaired exercise capacity of patients with heart failure. It is now apparent that NO produced within the heart plays an important role in the modulation of cardiac contractility under physiological conditions. In patients with heart failure, however, increased myocardial NO production in response to cytokines such as tumour necrosis factor-alpha may contribute to reduced contractility and myocyte injury. Our understanding of the role of NO in the control of vascular tone has provided an explanation for the efficacy of nitrovasodilators in heart failure and has stimulated novel approaches to augmenting endogenous vascular NO production. There is also evidence that ACE inhibitors act to restore normal endothelial function in patients with heart failure. Increased NO production within the heart, particularly that produced via the pro-inflammatory inducible NO synthase, may be detrimental. It remains to be determined whether selective inhibition of inducible NO synthase can favourably modify the course of this lethal condition.     

Cytokines, their receptors and inhibitors. Importance in laboratory diagnosis of rheumatoid arthritis

The present paper reviews the literature on biological activities of human cytokines in homeostasis, as modulated by their secretion, expression of membrane-bound and soluble receptors as well as by means of other cytokines and specific inhibitors, respectively. The role of structure and properties of interleukins 1, 2, 6 and their receptors in pathophysiology and laboratory diagnostics of rheumatoid arthritis, is discussed. Methods of quantitative determination of cytokines are described.     

Interstitial cells of Cajal as targets for pharmacological intervention in gastrointestinal motor disorders

Interstitial cells of Cajal (ICCs) have recently been identified as the pacemaker cells for contractile activity of the gastrointestinal tract. These cells generate the electrical 'slow-wave' activity that determines the characteristic frequency of phasic contractions of the stomach, intestine and colon. Slow waves also determine the direction and velocity of propagation of peristaltic activity, in concert with the enteric nervous system. Characterization of receptors and ion channels in the ICC membrane is under way, and manipulation of slow-wave activity markedly alters movement of contents through the gut organs. Here Jan Huizinga, Lars Thuneberg, Jean-Marie Vanderwinden and Jüri Rumessen, suggest that, as ICCs are unique to the gut, they might be ideal targets for pharmacological intervention in gastrointestinal motility disorders, which are very common and costly.     

A cognitive-behavioral treatment for rheumatoid arthritis.

Tested a cognitive-behavioral rheumatoid arthritis treatment designed to confer skills in managing stress, pain, and other symptoms of the disease. It was hypothesized that the treatment would reduce symptoms and possibly improve both immunologic competence and psychological functioning. 15 22–75 yr old women in the treatment group received instruction in self-relaxation, cognitive pain management, and goal setting. 15 similar controls received a widely available arthritis helpbook. Evidence of an enhancement of perceived self-efficacy, reduced pain and joint inflammation, and improved psychosocial functioning was found in the treated Ss based on their responses to an arthritis self-efficacy scale, the Zung Self-Rating Depression Scale, a perceived stress scale (developed by S. Cohen et al, 1983), and the UCLA Loneliness Scale. Magnitude of improvements was correlated with degree of self-efficacy enhancement. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Coping with rheumatoid arthritis.

Argues that despite the widespread assumption that psychological processes play an important role in rheumatoid arthritis (RA), and despite the recent intense activity in health psychology, RA has been ignored by psychological researchers. Questions concerning the extent and variability of dysfunction resulting from RA and the coping mechanisms that may mediate functional capacity are raised. The background literature to address these questions is reviewed, including information concerning diagnostic problems and approaches, adjustment to RA, and methodological problems in studies to date. It is suggested that the literature is clouded by diagnostic inconsistencies and neglect of the variety of areas of adjustment that may be affected by the disease, including employment and financial, physical (including pain), social, self-concept, and emotional. A project underway at the University of Saskatchewan, in which RA patients are being studied for coping behaviors that may contribute to their adaptation and functional capacity, is introduced as one means of addressing some of the outstanding issues in the area. (French abstract) (63 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Helplessness and depression in rheumatoid arthritis.

Found that scores on a measure of helplessness mediated the relationship between severe, disabling rheumatoid arthritis (RA) and depression in 106 RA patients (aged 23–81 yrs). This association was independent of a previously demonstrated correlation between cognitive distortion and depression in RA patients. However, the association between disease severity and depression was mediated by Ss' views of their ability to control or cope with their disease. Both helplessness and cognitive distortion may be important factors in the development and treatment of depression among RA patients. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Specific therapy for rheumatoid arthritis

A study of 6 series of concentrated and purified -- by ultracentrifugation -- dry cultural rabies vaccine inactivated with ultra-voilet rays demonstrated that in case of a 31--316 increase of concentration immunogenicity of the preparation rose 3--13-fold. Purification of the vaccine took place with its concentration. Additional purification of the concentrated vaccine on aluminium oxide led to a partial loss of the viral protein and to reduction of immunogenicity.     

Cytokines as targets for the inhibition of eosinophilic inflammation

Eosinophilic inflammation is thought to play a central role in the pathogenesis of asthma. The immunoregulatory effects of interleukin (IL)-4, IL-5 and immunoglobulin (Ig)E suggest that these molecules play key roles in the effector function of eosinophils and mast cells. IL-4 regulates the development of CD4+ TH2-type cells, which elicit essential signals through IL-4 and IL-5 for the regulation of IgE production and eosinophilia, respectively. IL-5-regulated pulmonary eosinophilia and airways dysfunction can also occur independently of IL-4 and allergen-specific Igs. Such IL-4-independent pathways may also play a substantive role in the aetiology of asthma. Thus, evidence is now emerging that allergic airways disease is regulated by humoral and cell-mediated components. The essential and specific role of IL-5 in regulating eosinophilia, and the subsequent involvement of this leukocyte in the induction of lung damage and airways dysfunction, identifies IL-5 as a primary therapeutic target for the relief of airways dysfunction in asthma.     

Tumors in rheumatoid arthritis

Benign (bTu) and malignant tumours (mTu) were studied in a randomised autopsy material of 161 patients with rheumatoid arthritis (RA). The tissue specimens were fixed in 8% formaldehyde solution at pH 7.6 and embedded in paraffin. The tumours were diagnosed histologically and confirmed by immunohistochemical methods. Five benign (3.1%), and thirteen malignant tumours (8.1%) found observed in 18 (11.2%) of 161 cases. There was no significant difference between laboratory parameters of patients with malignant tumours and without tumours. One benign (0.62%) and seven malignant (4.35%) tumours led to death in 8 (4.97%) of 18 cases altogether. Neoplasms were detected clinically in 8 of 18 cases (44.4 rel%). None of tumorous patients received immunosuppressive treatment and only five had gold (Tauredon) therapy. Paraneoplastic syndromes with rheumatoid complaints may be excluded by the onset and duration of RA and tumours. Benign neurogenic tumours and malignant bronchioloalveolar carcinoma were frequently associated with RA not treated by immunosuppressive drugs. Our data do not support the assumption of a high risk of malignant lymphomas associated with RA treated with immunosuppressive therapy.     

Osteoporosis in rheumatoid arthritis

Patients with rheumatoid arthritis (RA) develop both periarticular and generalized osteoporosis. Periarticular osteopenia in appendicular bones occurs early in the course of RA and is one of the earliest radiological signs of RA. An uncoupled state in bone resorption-formation linkage, contributes to the development of periarticular osteopenia and it might be mediated through an increased productions of cytokines and prostaglandins by synovium and bone marrow. Accordingly, early suppression of rheumatoid synovitis is necessary for the prevention of periarticular osteopenia. Generalized osteoporosis is also common in RA and leads to increased risk of fractures. Generalized osteoporosis considered to be multifactorial and factors contributing to lumbar osteoporosis might be different from those to loss of appendicular bones, such as femur and radius. Corticosteroids and menopausal state are important risk factors for lumbar osteoporosis. Rheumatoid activity and reduced physical activity are also important determinants. According to the previous studies, however, the influence of functional impairment is more prominent in the femoral BMD compared to spinal BMD. In addition to control of RA and maintenance of physical activity, hormone replacement therapy (HRT) and bisphosphonate are possible agents for the treatment of osteoporosis in RA patients, especially postmenopausal women.     

Infection in rheumatoid arthritis

Sepsis is an unusually common cause of illness and death in RA. All sorts of infections occur, but pyarthrosis produces exceptional problems. Clinically, pyarthrosis, empyema, and purulent pericarditis mimic bland rheumatoid effusions. Aspiration of the attendant effusions is the only reliable diagnostic procedure. Subcutaneous nodules on the sacrum and back are easily overlooked. Necrosis and ulceration of these nodules may provoke septicemia. Those with Felty's syndrome do not uniformly have problems with recurrent infection. Splenectomy may not benefit such patients. The belief that corticosteroids cause increased infections in rheumatoid patients is not totally justifiable at present. Steroids can, however, disguise underlying sepsis and hamper proper diagnosis.     

Osteoporosis in rheumatoid arthritis

In cases of rheumatoid arthritis, osteoporosis may be local or general. The aetiology is multifactorial. Reduced bodily function, synovial inflammation, steroids and menopause are important risk factors. Studies have shown that, in cases of primary osteoporosis, bone mineral density measurements in the distal radius may predict risk of fracture at other sites, such as the neck of the femur and the dorsal vertebrae. Such a connection is not found for rheumatoid arthritis. Bone density measurements in the distal radius may overestimate the risk of fractures due to localised periarticular osteoporosis. Overall bone quality is assumed to be poorer, however, in patients with rheumatoid arthritis, leading to higher risk of fracture than the bone mineral density measurements seem to show. Data are lacking on the effect of antiresorptive drugs on this condition. Treatment with oestrogen and the bisphosphonate pamidronate has been shown to increase bone mineral density. Data are lacking on fractures. As shown in the case of primary osteoporosis, decreased risk of fracture is to be expected also in patients with secondary osteoporosis.