A system for data analysis is the end product of study planning, form design, data entry, data verification, and statistical analysis. This article reviews these steps and considers the fundamental choices in software for data entry and analysis. The appendix includes a listing of general and specialized software for data management and statistical analysis.
The unique cis-triene structure of vitamin D and related metabolites makes it susceptible to oxidation, ultraviolet (UV) light-induced conformational changes, heat-induced conformational changes, and attacks by free radicals. Vitamin D-2 is much less bioactive than vitamin D-3 in humans. Metabolic activation and inactivation of vitamin D are well characterized and result in a plethora of metabolites, of which only 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)(2)D) provide any clinically relevant information. 25(OH)D-2 and 25(OH)D-3 are commonly known as calcifediol and the 1,25(OH)(2)D metabolites as calcitriol. In this review the current state of the science on the clinical assessment of circulating 25(OH)D and 1,25(OH)(2)D is described.
Identification of interleukin-17 (IL-17) as a powerful proinflammatory cytokine and the recent recognition of a T-helper cell subset that secretes it have focused attention on the role of IL-17 and Th17 cells in rheumatoid arthritis (RA) and other immune-mediated diseases. While understanding of its role in RA is still evolving, evidence from both animal models and human systems provides a compelling rationale for therapeutic targeting of IL-17 in RA. Both direct and indirect approaches to accomplish this are feasible. Mechanistic studies in the context of clinical trials will be required to understand why some strategies may be preferable from the perspectives of efficacy and safety.
Interleukin (IL)-18 is a new member of the IL-1 family of proinflammatory cytokines. Based on preclinical studies in animals, IL-18 likely plays a role in rheumatoid arthritis, and strategies to block IL-18 activity are underway in clinical trials. In one of these trials,a naturally occurring IL-18 binding protein (IL-18 BP) binds IL-18 with a high affinity and reduces disease severity in models of inflammatory diseases. IL-18 BP is not the soluble receptor for IL-18 but rather a distinct molecule, which appears to be distantly related to the IL-1 receptor type II, both structurally and functionally, and hence represents part of the IL-1 family of receptors.
Since Dr. Melish's presentation, the completed report of IV gammaglobulin treatment for Kawasaki syndrome has appeared in the New England Journal of Medicine. The study compared the efficacy of IV gammaglobulin plus aspirin with that of aspirin alone and addressed the issue of reducing the frequency of coronary artery abnormalities in children with Kawasaki syndrome. A multicenter randomized trial was conducted in a group of 168 children. Eighty-four children were randomly assigned to a group receiving intravenous gammaglobulin, 400 mg per kg of body weight per day for four consecutive days, and aspirin, 100 mg per kg per day throughout the fourteenth day of illness, and then 3 to 5 mg per kg per day thereafter. A control group of 84 children received only the aspirin regimen. Echocardiograms were done at enrollment and at two- and seven-week intervals and interpreted blindly and independently by two more readers. At the seven-week evaluation, 18 per cent of the children in the aspirin-only treatment group had echocardiographic abnormalities but only 4 per cent of the immunoglobulin treatment group had echocardiographic abnormalities. No serious adverse effects were detected. As there is currently no reliable method to predict which patients will develop coronary abnormalities, the authors recommend that all patients with Kawasaki Syndrome who are seen in the first 10 days of illness receive intravenous gamma globulin at a dose of 400 mg/kg/day for four consecutive days. A study comparing this dose with a single infusion of 2 gm/kg is currently in progress.
This article discusses lupus and pregnancy from experiences at the Hopkins Lupus Pregnancy Center. This center has made important strides in the understanding of lupus flares, maternal morbidity, and causes of preterm birth and pregnancy loss in lupus pregnancy.
Standard treatment of rheumatoid arthritis as illustrated by the pyramid does not prevent joint damage in most patients. The concept that slow-acting drugs are uniquely disease modifying is not supported by experience. Disease modification correlates best with control of inflammation and this has been demonstrated with prednisone. Many medications working by different mechanisms have a partial or temporary effect on inflammation. Following the example of cancer chemotherapy, we propose the step-down bridge, a therapeutic plan in which a combination of drugs is used to control inflammation early in the disease before joints become damaged. Medications are then sequentially discontinued as inflammation remains controlled.
There has been much discontent with the hazards and the uncertain responses of patients with juvenile rheumatoid arthritis (JRA) to time-honored modalities of management. The treatment of JRA is often thought of as a pyramid with the base formed by nonsteroidal anti-inflammatory drugs, patient and family education, physical therapy, occupational therapy, and family support. Mechanisms of human disease have begun to open the gates to understanding the why and when of connective tissue diseases; they also offer the prospect of direct therapeutic intervention. In this article, the authors scrutinize the paradigms that guide our treatment strategies, review current practices, update data derived from those practices, and propose reassessment of therapy in the 1990s.
The 1980s was a decade of immunologic, biochemical, and pharmaceutical advances in the treatment of patients with rheumatic diseases. The therapeutic revolution will continue into the 1990s, and this article reviews several areas of change and controversy that have developed.
The Hopkins Lupus Cohort is a decade-long prospective study, now numbering 800 patients with systemic lupus erythematosus. In this article, predictors of disease activity, disease damage (including accelerated atherosclerosis and antiphospholipid antibody syndrome) and health status are reviewed.
Classification criteria are created in an attempt to produce a homogenous group of subjects with rheumatoid arthritis (RA) who can be used for clinical and basic research. The 1987 revised criteria lead to improved performance and more confidence in correct classification compared with the 1958 criteria. As therapies were introduced and early, aggressive approaches to RA management became common, there was a growing need for clinical trials focusing on early RA. The 2010 criteria were created to facilitate study of subjects at earlier stages in the disease. This article reviews the diagnostic performance of the 2010 criteria.
During the past year several review articles have been published on the topic of osteoporosis in men. These reviews have highlighted recommendations for measuring bone mineral density (BMD) in older men as a means of screening for osteoporosis, use of the World Health Organization's Fracture Risk Assessment Tool for predicting the risk of hip and major osteoporotic fractures, frequency of secondary causes of osteoporosis, useful laboratory tests to evaluate these conditions, newer treatments for men with osteoporosis that increase BMD and may reduce the risk of fractures, and new data on the prevalence of low BMD and osteoporosis in men.
Infection continues to be a significant cause of morbidity and mortality in patients with rheumatic diseases, and, consequently, early diagnosis and treatment of infection is critical to the successful medical management of these patients. The intensity of immunosuppressive therapy is the dominant risk factor for infection in this patient population. Because the manifestations of infection in patients with rheumatic diseases are highly variable, the clinician must always be vigilant about the possibility of infection even if the clinical presentation is highly suggestive of an exacerbation of the underlying disease. We have stressed a systematic and individualized approach in the diagnostic evaluation of suspected infection in these patients. The first part of the evaluation involves forming a list of the most likely pathogens based on a detailed history and physical examination and the intensity and type of immunosuppressive therapy the patient is receiving. The physician must then formulate a plan designed to establish a diagnosis expeditiously and with the least morbidity.
This article reviews the current status of the classification and treatment of the juvenile idiopathic inflammatory myopathies. The intent of classification is to define homogeneous groups that share similar clinical features, disease courses, and responses to therapy. The classification scheme proposed includes clinicopathologic subsets, serologic subjects based on the presence of myositis-specific and myositis-associated autoantibodies, and environmental triggers of myositis. Juvenile dermatomyositis is the most common and widely recognized of these disorders. The second part reviews the history of treatment of juvenile dermatomyositis and discusses agents to consider for patients with refractory disease, unacceptable steroid toxicity, or poor prognostic factors.
Prognosis in the majority of patients with acute reactive arthritis is usually good, with most patients recovering in a few months. In about 15% to 30% of such patients, the disease progresses, and spondyloarthropathy and even ankylosing spondylitis develop in the following 10 to 20 years. A recurrent attack of reactive arthritis is common in patients with chlamydia-triggered arthritis, but it is rare in patients who have had enteroarthritis. In patients with chronic spondyloarthropathy without evidence of preceding infection, the disease can progress slowly into ankylosing spondylitis. When reactive chlamydia arthritis is indicated, a prolonged course of antibiotics is needed. For other forms of reactive arthritis, solid evidence in favor of antibiotic therapy is still lacking. Presence of hip pain, decreased mobility of thoracic cervical or thoracic spine, heel pain, inflammatory gut lesions, high erythrocyte sedimentation rate, positive family history, and presence of human leukocyte antigen B27 are indicators for chronicity. Sulfasalazine might be of use in chronic arthritis and ankylosing spondylitis, especially if the patient has peripheral arthritis.
Glucocorticoid use is associated with the risk of hyperglycemia in patients without known diabetes mellitus and worsened glycemic control in diabetic patients. The effects are greater in the fed than fasting state. Management includes use of diet and exercise (as appropriate for the individual) in all patients. Mild hyperglycemia can often be managed with oral agents, especially those with rapid onset of action. Marked hyperglycemia, especially in diabetic patients or patients with liver or renal disease, requires insulin. Adjustments in insulin can be done both in anticipation of the glucocorticoid effect and based on home glucose monitoring. The effects of glucocorticoids on hyperglycemia usually remit within 48 hours of discontinuation of oral administration.
Immunomodulatory agents represent a unique group of therapies that are not biologics and have relatively specific, noncytotoxic effects on the immune system. Cyclosporine has been the most widely tested of the immunomodulatory agents and shown efficacy in a variety of autoimmune diseases as well as monotherapy in established rheumatoid arthritis. FK-506 and rapamycin, agents similar to cyclosporine, are being tested in human transplantation, with only arthritis studies having been done in animals. Tilomisole, imuthiol, and mycophenolate mofetil have been studied in limited rheumatoid arthritis trials with positive effects. Although more specific and with manageable short-term side effects, this group of therapies requires more studies to establish their efficacy and long-term safety.
Abetimus sodium has been under development for the treatment of systemic lupus erythematosus since the early 1990s. Because its administration results in the selective reduction of circulating double-stranded DNA antibodies, La Jolla Pharmaceutical Company has focused on the agent's ability to prolong time to nephritic flare. Fourteen trials have been initiated since 1994, but the two pivotal registration trials failed to meet primary end points. The US Food and Drug Administration issued a letter in October 2004 that stated abetimus sodium was "approvable" pending the successful completion of a trial demonstrating clinical benefit. The fate of this agent lies in the ability of the company to successfully complete a phase III study.
Many chronic pain syndromes are associated with hypersensitivity to painful stimuli and with reduced endogenous pain inhibition. These findings suggest that modulation of pain-related information may be linked to the onset or maintenance of chronic pain. The combination of heightened pain sensitivity and reduced pain inhibition seems to predispose individuals to greater risk for increased acute clinical pain. It is unknown whether such pain processing abnormalities may also place individuals at increased risk for chronic pain. Psychophysical methods can be used for the evaluation of pain sensitivity and pain inhibition. Long-term prospective studies that could yield insight into the role of heightened pain sensitivity and pain disinhibition for the development of chronic pain disorders like fibromyalgia in the general population are lacking, however.
Fibromyalgia (FM) and chronic fatigue syndrome (CFS) fall into the spectrum of what might be termed stress-associated syndromes by virtue of frequent onset after acute or chronic stressors and apparent exacerbation of symptoms during periods of physical or emotional stress. These illnesses also share perturbation of the hypothalamic-pituitary-adrenal axis and sympathetic stress response systems. In this article, the authors discuss the specific neurohormonal abnormalities found in FM and CFS and potential mechanisms by which dysfunction of neurohormonal stress-response systems could contribute to vulnerability to stress-associated syndromes and to the symptoms of FM and CFS.
Juvenile rheumatoid arthritis (JRA) is the most common rheumatic disease of childhood. Although the etiology remains unknown, immunoregulatory imbalances are thought to be important in the pathogenesis of JRA. Numerous immunologic abnormalities have been described in these patients, but it remains unclear which are fundamental to the pathogenesis of the disease and which are secondary. In this article, the authors review lymphocyte and lymphokine abnormalities in children with JRA with emphasis on the possible role of these immune abnormalities in the pathogenesis of JRA.
A review of the acquisition of peak skeletal mass in normal children and studies that have been reported for children with JRA lead to the following tentative conclusions: (1) The appendicular skeleton is predominantly the overall status of skeletal mineralization; (2) a failure to develop adequate bone mineralization is virtually universal in children with JRA and is characterized by a failure of bone formation. A failure to undergo the normal increase in bone mass during puberty is common in children with JRA and markedly decreases their potential to achieve an adequate peak skeletal mass; (3) the onset of accelerated skeletal maturation with puberty is a critical period of potential intervention in JRA. Conversely, therapeutic interventions later during adolescence offer less promise of reversal of inadequate bone mineralization; and (4) the most important therapeutic maneuver is likely to be control of the inflammation process, although there is hope, at present unsubstantiated, that supplemental dietary calcium and vitamin D, and normalization of physical activity, many lead to some "catch-up" mineralization.
Weakness and fatigue are common symptoms in patients with scleroderma and may be due at least in part to underlying abnormalities of muscle. Various modalities, including electromyography, histologic examination of biopsy specimens, MR imaging, and MR spectroscopy are useful in defining muscle abnormalities in these patients. Recent studies using P-31 MR spectroscopy and near infrared spectroscopy demonstrate the presence of underlying metabolic abnormalities that may contribute to the clinical findings of weakness and fatigue.
The role of arthroscopic debridement for the treatment of degenerative arthritis of the knee is controversial. Success rates are dependent on multiple factors including the age of the patient, degree of arthritis, activity level, and length of follow-up. This article elaborates on and defines the indications and results of arthroscopic treatment of osteoarthritis of the knee and the role of abrasion arthroplasty.
The clinical approach to patients with inflammatory rheumatic diseases differs substantially from the approach to patients with many typical chronic diseases, such as hypertension or diabetes. Further elucidation of these differences may be informative in efforts to advance quantitative scientific patient assessment and management in rheumatic diseases, with improved patient outcomes.
New research has revealed common pathophysiologic and cellular mechanisms behind the development of osteoporosis and joint damage in rheumatoid arthritis (RA). Because osteoporosis is a direct consequence of the inflammatory disease process, bone mass measurements in principle could be an outcome marker of inflammation, of damage, and of response to therapeutic intervention. Several devices have been developed for quantitative bone mass assessment including dual energy x-ray absorptiometry (DXA), which is considered the reference standard. This article based on current data and understanding discusses the use of DXA as a diagnostic and assessment tool especially in early RA.
National manpower needs, length and clinical/research mix of fellowships, and incentives to attract residents to PR training, and trainees to faculty positions are important issues. We surveyed 142 American and Canadian pediatric chairpersons for their attitudes, and departmental clinical, research and economic needs related to rheumatology. A 28 item questionnaire utilized an educational psychologist, and a bio-statistician, to ensure optimal content clarity, completion speed, and statistical design. The response rate was 77% (1110/142). 71 departments had a PR, with 75% full- and 25% part-time. The chairs recruiting priority for a new full-time PR was “moderate-high” in 38%. Department size was: 15-25 MD and PhD faculty-24%; 26-40 faculty-26%; 41-75 faculty-34%; ≤76-16%; 39 Departments had 0-10% grant support of faculty salaries; 34 had 12-25%; 23 had 26-50%, and 5 had 51-80%. “Acute” disease trained chairpersons were less than half as likely to support having a PR, when compared to a chronic disease chair 65% of chairs believed an allergist/immunologist could provide rheumatic disease care only 0-25% of the time; 69% felt a rheumatologist gave a needed chronic disease/rehabilitation focus. Of interest, 54% of chairs stated that fellowships should be 3 years; another 17% preferred 4 years; all 71% desired a 50% research commitment: 31% of chairs would full/partial fund a rheumatology fellow to fill a faculty need, and 57% would provide 30-100% of initial faculty salaries (2-3 years). This survey reflects concerns about pediatric subspecialty manpower, training and research issues.
This article summarizes knowledge of the pathogenic mechanisms in autoimmune rheumatic diseases as risk factors for accelerated atherosclerosis. The studies described support a role for immunologic-inflammatory mechanisms in the pathogenesis of atherosclerosis. This immunologic-inflammatory state is evident in many autoimmune diseases, but also in the general population lacking an overt autoimmune disease. The ability to immunomodulate atherosclerosis (currently only experimental) should lead to future research into the mechanisms and treatment of atherosclerosis, the leading cause of death in the Western world.
Indirect data coming from animal studies and in vitro observations support the contention that the mere presence of antiphospholipid antibodies may be sufficient to increase atheroma development, regardless of other predisposing factors. It seems that humoral and cellular immune responses to beta 2-glycoprotein I can play an important role in mediating the increased propensity to atherosclerosis.
Increased cardiovascular morbidity and mortality due to the pre-mature or accelerated development of atherosclerosis has been reported in patients with systemic autoimmune diseases such as systemic lupus erythematosus. These findings motivated a great deal of research into the role of autoimmunity in atherogenesis. The relationship between atherosclerosis and cholesterol metabolism to atherosclerosis has been well established. However, the participation of newer inflammatory and immunologic mechanisms are emerging as relevant factors for the initiation and progression of atherosclerotic lesions.
Dr. Petty presents a thorough review of the current state of knowledge of the chronic uveitis that accompanies juvenile rheumatoid arthritis, especially the pauciarticular form of the disease. He presents the historical background and genetic, immunopathologic, and clinical associations of this disease, and current knowledge of prognosis and treatment. As a background to understanding this unique complication of JRA, animal models of the disease and their relevance to the human disorder are discussed along with the examples of uveitis induced by bacterial products, viruses, and ocular antigens. The author ends with some speculations and a hypothesis that may serve as stimulation for further investigations of this disorder.
Although rheumatology has been on the cutting edge of health services research for decades, there are many unresolved issues for patients, clinicians, insurers, and policy makers. This article explore three areas in which methodologic controversies present tradeoffs to a health care system that is grappling with larger issues around cost and access to care. Specifically, we examine issues around the use of large databases, the appropriate instruments for measuring patient-centered outcomes, and the questions that are raised from cost effectiveness studies of new treatments for rheumatoid arthritis. The issues are presented in the context of a need to provide better information to those who are providing care and those who are paying for it.
Some complement deficiencies predispose to systemic lupus erythematosus (SLE) early in life. Currently, there are no known unique physiologic or genetic pathways that can explain the variability in disease phenotypes. Children present with more acute illness and have more frequent renal, hematologic, and central nervous system involvement compared to adults with SLE. Almost all children require corticosteroids during the course of their disease; many are treated with immunosuppressive drugs. Mortality rates remain higher with pediatric SLE. Children and adolescents accrue more damage, especially in the renal, ocular and musculoskeletal organ systems. Conversely, cardiovascular mortality is more prevalent in adults with SLE.
A method is summarized to improve quality control of the patient history in the medical record, incorporating the patient as a partner to review and correct the information. This method has been implemented at every patient visit to the senior author since 2000, in the infrastructure of usual medical care, using a database. This procedure engenders a more accurate patient history with no effort on the part of the physician, saving time for the physician and improving the quality of the medical record.
Maintenance of mice on dietary regimens containing fish oil decreases severity of collagen-induced arthritis. Macrophages from fish oil fed animals had decreased omega-6 and significant amounts of omega-3 polyunsaturated fatty acids in membrane phospholipids and produced significantly less prostaglandins than macrophages from corn oil fed animals. Gender differences in both prostaglandin production and susceptibility to arthritis were noted.
Dietary supplementation omega-3 polyunsaturated fatty acids may inhibit (at least partially) three pathways of the synthesis of lipid mediators of inflammation: the platelet-activating factor synthesis pathway, the cyclooxygenase pathway, and the 5-lipoxygenase pathway. In addition, selected cellular functions of polymorphonuclear neutrophils may be modulated by dietary fish oil. The exact mechanism of the effects of dietary supplementation with omega-3 poly-unsaturated fatty acids on these pathways is not completely elucidated; it is quite probable that the effects will vary with the duration, dose, and composition of the omega-3 polyunsaturated fatty acid preparation, with background medical therapy, and the presence of and degree of activity of the underlying inflammatory disease state.
Dietary marine lipids that are enriched in omega-3, or n-3, fatty acids reduce the severity of autoimmune glomerulonephritis in several inbred murine strains. The protective effect of dietary n-3 fatty acids is also seen with a rat model of immune-complex induced vasculopathy, but no protective effects were seen with autoimmune vasculitis in the MRL/lpr mouse or with type II collagen-induced arthritis in rats. Dietary n-3 fatty acids are potential therapeutic agents for the treatment of autoimmune diseases, but careful clinical trials with the purified forms of n-3 fatty acids are needed to determine the usefulness of this intervention.
This article describes the various forms of acne and the clinical and radiographic features of the associated musculoskeletal manifestations. Occasionally, acne may occur together with hidradenitis suppurativa and dissecting cellulitis of the scalp, the so called "follicular occlusion triad." The current understanding of the etiology of these conditions and their treatment are also reviewed.
Articular involvement in acromegaly is one of the most frequent clinical complications and may be present as the earliest symptom in a significant proportion of patients. The involvement of other organs may be of clinical importance and contribute to increased morbidity and mortality of patients suffered from acromegaly. Early diagnosis and proper treatment of the diseases can prevent the development of irreversible complications of the disease and improve the quality of life in patients suffering from the disease.
Osteoarthritis is the most prevalent chronic joint disease worldwide. The incidence and prevalence are increasing as the population ages and lifestyle risk factors such as obesity increase. There are several evidence-based clinical practice guidelines available to guide clinician decision making, but there is evidence that care provided is suboptimal across all domains of quality: effectiveness, safety, timeliness and appropriateness, patient-centered care, and efficiency. System, clinician, and patient barriers to optimizing care need to be addressed. Innovative models designed to meet patient needs and those that harness social networks must be developed, especially to support those with mild to moderate disease.
Chronic widespread pain is the sine qua non of the fibromyalgia syndrome, differentiating this disorder from other related conditions such as chronic fatigue syndrome. Several lines of experimental data suggest that aspects of the pain of fibromyalgia (FM) are the result of changes in pain processing at the level of the central nervous system. In this article, an overview of the pharmacology of the central nervous system pain pathways is presented, focusing on both ascending and descending systems from the periphery to the level of the midbrain. The central sites of analgesic action of medications commonly used to treat the pain of FM are then reviewed.
Because of methotrexate's well-documented efficacy in the treatment of rheumatoid arthritis, it is important that we understand the mechanism of action of this drug. There are two biochemical mechanisms by which methotrexate may modulate inflammation: (1) promotion of adenosine release and (2) inhibition of transmethylation reactions. Evidence is reviewed that favors the notion that the endogenous anti-inflammatory autocoid adenosine mediates the anti-inflammatory effects of methotrexate. This insight should aid in the design of new agents for the treatment of rheumatoid arthritis and other inflammatory diseases.
Acute pain is a normal, and often beneficial, physiologic process. The indiscriminant blocking of all pain can delay healing or mask serious medical problems. On the other hand, persistent pain can be nonproductive or deleterious to recovery and can negatively affect a patient's quality of life. If the treatment of pain by pharmacologic means is determined to be desirable, it is important to select an analgesic, or combination of analgesics, that have appropriate mechanisms of action (i.e., those that modulate the appropriate physiologic pathway). OA pain is an example of a complex type of pain (i.e., it often originates from multiple causes and is transmitted by multiple mediators). Therefore, the choice of the analgesics for the patient who has OA should be based upon the most appropriate mechanisms of action.
The biochemical and genetic analysis of the VDR in patients with HVDRR has yielded important insights into the structure and function of the receptor in mediating 1,25(OH)2D3 action. Similarly, study of children affected by HVDRR continues to provide a more complete understanding of the biologic role of 1,25(OH)2D3 in vivo. A concerted investigative approach to HVDRR at the clinical, cellular, and molecular levels has proved valuable in gaining knowledge of the functions of the domains of the VDR and elucidating the detailed mechanism of action of 1,25(OH)2D3. These studies have been essential to promote the well-being of the families with HVDRR and in improving the diagnostic and clinical management of this rare genetic disease.
The recent identification, cloning, and characterization of two cyclooxygenases has provided insight into how nonsteroidal anti-inflammatory drugs can beneficially inhibit prostaglandin production in inflammation but also produce side-effects in the gut and kidney. The subtle differences in the sites in which these drugs bind the enzymes has allowed development of inhibitors that exhibit selectivity for the inflammatory cyclooxygenase and spare the housekeeping enzyme. This selectivity in theory should enhance the therapeutic potential of these new drugs.
The illustrated clinical and experimental results demonstrate the strong relationship between the MHC class I antigen HLA-B27 and synovial CD8+ T cells with specificity for bacterial and possible self-antigen in SpA. These new aspects obtained in recent experimental and clinical studies might also provide clues to the pathomechanisms of joint inflammation in SpA. In particular, the newly developed techniques will be of great relevance in the near future. New and more precise bioalgorithms reflecting new insights in the biology and biochemistry of proteins as recently presented [98, 99] can be helpful (e.g., a program with an improved prediction of the features of immunoproteasomes). Intracellular and secreted cytokine staining by FACScan allows examination of a great number of cells expressing certain antigens in response to certain stimuli. The analysis of T-cell responses with tetramer/peptide complexes can be useful to screen tissue sections for TCR, recognizing foreign or self-derived epitopes on those complexes loaded with selected (e.g., bacterial) peptides. Identification of arthritogenic peptides and a further understanding of the immunology of the pathomechanisms in SpA might open ways to design new peptide vaccines to prevent inflammation, autoimmunity, and other diseases by early intervention .
The events involved in T cell activation are initiated at the cell surface by the interaction of ligands with specific cell surface receptors on the T cell. Central to antigen-induced activation is the CD3/Ti complex, a complex multi-chain receptor responsible for antigen/MHC recognition and signal transduction. Triggering the CD3/Ti complex results in the generation of intracellular second messengers, IP3 and DG, which are derived from PI metabolism. The second messengers lead to increases in [Ca2+]i and activation of pkC, events causally linked to various cellular responses, including the production of IL-2 through as yet poorly defined pathways. Little is known about how other cell surface molecules that may provide an accessory function participate in such events. However, future genetic and biochemical studies are likely to shed light upon the mechanisms of signal transduction by the CD3/Ti complex and accessory molecules and the details of the intracellular events involved in the activation of a host of cellular genes associated with activation.
Individuals with rheumatic disorders, particularly those with more severe, chronic conditions, are likely to be frequent users of complementary and alternative medical therapies. Although large-scale clinical trials have yet to be conducted, there is moderately strong evidence that acupuncture may be effective for treating both osteoarthritis and fibromyalgia. The utility of acupuncture in treating rheumatoid arthritis has not been demonstrated in large, randomized controlled trials. Physicians who treat patients with rheumatic conditions should become knowledgeable about the literature on both the effectiveness of acupuncture for these conditions as well as its potential to cause adverse side effects in particular patient groups.