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.     

A simple index to assess disease activity in rheumatoid arthritis

Changes in clinical and laboratory measures of disease activity were studied prospectively in 12 European centers. Altogether 282 rheumatoid patients were evaluated during 6 months of therapy with slow-acting drugs. Patients' global assessment was taken to indicate overall response. The number of swollen joints and number of tender joints correlated highly with this. The erythrocyte sedimentation rate (ESR) correlated less well but was more uniform across centers. Grip strength, C-reactive protein and hemoglobin performed poorly between centers. There were cultural and linguistic difficulties using the Health Assessment Questionnaire in a European setting. Physician's global assessments were similar to the patient's global assessments and provided redundant information. The best measures are: the number of swollen joints, the number of tender joints, the ESR, and the patient's global assessment. It may also help to measure articular pain.     

A new approach to psychopathology

A new approach to psychopathology based on the psychology of integration as applied to psychological states is outlined. Because all raw behavior occurs only in the form of psychological states, all formulations of psychopathology must refer to integrative disorders that are postulated to underlie all pathological or defective behaviors. Disintegration is the one common factor found in all mental disorders. Lack of integration underlies most inadaptability. The classical field of psychopathology, which formerly was limited to the consideration of formal psychiatric disorders, now is expanded to include deficits, imbalances and disintegrations of acute or chornic nature that result in erroneous or less than perfect judgments. Judgment is considered to reflect the quality of underlying integrative processes. Judgmental defects that lead to maladaptive decisions inevitably must result in maladjustment and/or less than perfect performance. It is necessary to differentiate between (a) integrative disorders per se, and (b) the personal-social effects of positive or negative integrations organized by healthy or unhealthy factors. Criminals may be well integrated in their asocial activities, but socially undesirable because organized about the criminal ethic. Postulates are presented that outline the theoretical assumptions upon which integrative psychopathology is based. This approach utilizes classic theories such as the Freudian psychopathology of everyday life when valid and relevant within the larger framework of integrative psychology. A differentiation is made between hierarchical levels of increasingly complex factors that may organize integration.     

Why do we need new treatments for rheumatoid arthritis?

It is being increasingly appreciated that a substantial number of patients with congestive heart failure (CHF) have relatively preserved systolic function. Although these individuals appear to have a somewhat better prognosis than those with low ejection fractions, they experience significant symptoms and frequently require hospitalization. In these patients, CHF is often attributed to left ventricular diastolic dysfunction, but this represents a potentially misleading over-simplification. In contrast to CHF associated with left ventricular systolic dysfunction, little is known about how to treat patients with preserved systolic function. Perhaps the major point of consensus has been that the use of digitalis glycosides is inappropriate in this group. Unexpectedly, however, in the recently completed Digitalis Investigators Group trial, a subgroup of nearly 1,000 patients with radionuclide ejection fractions > or = 45% experienced a similar reduction in heart failure endpoints with digoxin therapy as patients with 25% to 44% ejection fractions. The purpose of this article is to review the diverse causes of CHF with preserved systolic function and to examine the potential mechanisms by which digoxin may be producing beneficial effect in this setting.     

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)     

Juvenile rheumatoid arthritis

JRA is a multisystem disease characterized by exacerbations and remissions. Recognition of the three modes of onset can important in early diagnosis, identification of extra-articular manifestations, and prognosis. This is a chronic illness that requires consideration of the whole patient, his family, and his place in society, both in the present and in the future. With a positive, comprehensive approach and an awareness of the pitfalls of seeking immediate relief, the physician can help to assure a good functional outcome.     

Pathways to gene therapy in rheumatoid arthritis

OBJECTIVE: To document a cumulative experience with removal of the Telectronics 330-801 Accufix atrial lead after it was withdrawn from the market. DESIGN: We reviewed our results with 96 attempted lead extraction procedures through Dec. 1, 1995. MATERIAL AND METHODS: All patients underwent preoperative assessment, including fluoroscopic screening of the lead. Patients had blood typing and screening done before the extraction procedure, and extractions were performed with cardiac surgical intervention available. Pacing dependence was assessed to determine the need for temporary pacing. RESULTS: The mean patient age was 65.7 +/- 1.6 years and the mean duration of lead implantation was 31.0 +/- 1.4 months. Of the 96 lead extractions attempted, 94 were successful. Of the 96 cases, the retention wires were normal in 29, fractured without protrusion in 34, and fractured with protrusion in 33. Fifty-three leads were removed with use of simple traction only, and seven leads were removed by using a locking stylet and telescoping sheaths. The Cook workstation was used in the removal of 32 leads through the femoral vein; in 1 of these 32 patients, the retention wire was removed before lead extraction. The retention wire was removed but the lead was left intact in one patient. One lead was removed during an opertive maze procedure. Associated complications were minimal. CONCLUSION: Although lead extraction is a potentially fatal procedure, the Telectronics 330-801 Accufix atrial lead can be extracted safely with minimal morbidity when performed by experienced personnel.     

Noninfectious canine arthritis: rheumatoid arthritis

Chronic unremitting, generally symmetric, erosive polyarthritis was studied in 8 dogs. The disease had clinical, serologic, radiographic, and pathologic changes similar to those of rheumatoid arthritis of man. The condition occurred mainly in smaller breeds of dogs, with time of onset from 8 months to 8 years of age, Characteristic radiographic changes were seen in the joints several weeks to several months after the appearance of the initial lameness. Synovial fluid contained an increased number of neutrophils, and synovial fluid and synovial tissues were sterile for anaerobic and aerobic bacteria, mycoplasma, chlamydia, and viruses. Corticosteroids were therapeutically ineffective in all of the cases; however, corticosteroids, cyclophosphamide, and azathioprine were effective when used in combination in several dogs.     

New approaches to the therapy of rheumatoid arthritis

Design of highly selective biological substances made use of three basic components of a complex pathogenetic model of RA: the presence of antigen-presenting cells, genetic defects and autoimmune aggression. Efforts now are directed to development of monoclonal antibodies (MAB) to receptors of T-cells, B lymphocytes, MAB to CD 18 and CD54, cytokines, search for natural inhibitors of cytokines, introduction of cytokines. Many of such preparations including recombinant interferons proved clinically promising.     

DQCAR microsatellite polymorphism and susceptibility to rheumatoid arthritis

Somatic mutations seem to accumulate slowly with age during adult life in both mice and men. There is, however, a substantial mutant frequency at birth, suggesting that the rate of accumulation is much higher before birth. This suggests that DNA replication plays an important role in the generation of spontaneous mutations. Since most cell division and accompanying DNA replication occurs early in development, more mutations would arise during growth and development. Indeed, if the mutations are genetically neutral, the mutant frequency would rise very rapidly during early fetal growth, more slowly during later fetal growth and development and still more slowly after birth. To test this hypothesis, we have assayed the mutant frequencies from before birth to 28 days after birth, by which time most growth has occurred. We have used the F1 mice generated by crossing SWR females and MutaMouse males. The MutaMouse has a rescuable lacZ/lambda shuttle vector that can be assayed for an in vivo mutation in an in vitro system. Up to and including birth we assayed the entire animal for mutants; at 14 and 28 days after birth we assayed the small intestine. The data show that, as expected, many mutations arise early in development, by 12.5 days after conception, and confirms the non-linearity of mutation with age. In these mice, about one third of mutations arise before birth, about one third during growth to adulthood and the remaining during the rest of the animal's life, although this depends somewhat on the tissue.     

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.     

Etiopathogenesis of rheumatoid arthritis

We studied osmoregulation of plasma vasopressin in 5 patients with newly diagnosed diabetes mellitus. All patients showed typical symptoms of uncontrolled diabetes mellitus such as marked hyperglycemia, polyuria, and polydipsia, but did not have advanced diabetic complications. Vasopressin release was studied using 5% hypertonic saline infusion test twice: before treatment when the patient was hyperglycemic, and after treatment 1 to 2 months later when the patient was euglycemic. Plasma vasopressin was measured by a sensitive and specific radioimmunoassay. The mean basal plasma vasopressin value in the patients was significantly higher in the hyperglycemic compared with the euglycemic state (3.75 +/- 0.70 vs 1.18 +/- 0.46 pmol/l, respectively; P < 0.05). The relationship of plasma vasopressin with serum sodium, but not plasma osmolality, during hyperglycemia showed an apparent hypersecretion of vasopressin. In both cases, the sensitivity of the vasopressin response to osmotic stimuli was significantly decreased. During euglycemia, the sensitivity of vasopressin secretion to either sodium or osmolality was almost normal, although a slight rise in the osmostat was observed compared with normal subjects. Together, we found that the positive correlation of vasopressin with sodium or osmolality is maintained but significantly altered in patients with untreated diabetes mellitus. Especially noteworthy is the lowered threshold and decreased sensitivity of osmotically-induced vasopressin secretion during hyperglycemia, which may be caused by multiple factors such as diabetes-associated hypovolemia, osmogenic effects of glucose and other osmoles, depletion of the pool of vasopressin available for release, and the metabolic derangement of osmoreceptor/magnocellular neurons.