Lyme disease: a rigorous review of diagnostic criteria and treatment.

Lyme disease was originally identified in Lyme, Connecticut, based upon an unusual cluster of what appeared to be patients with juvenile rheumatoid arthritis. It was subsequently identified as a new clinical entity originally called Lyme arthritis based on the observation that arthritis was a major clinical feature. However, Lyme arthritis is now called Lyme disease based upon the understanding that the clinical features include not only arthritis, but also potential cardiac, dermatologic and neurologic findings. Lyme disease typically begins with an erythematous rash called erythema migrans (EM). Approximately 4-8% of patients develop cardiac, 11% develop neurologic and 45-60% of patients manifest arthritis. The disease is transmitted following exposure to a tick bite containing a spirochete in a genetically susceptible host. There is considerable data on spirochetes, including Borrelia burgdorferi (Bb), the original bacteria identified in this disease. Lyme disease, if an organism had not been identified, would be considered as a classic autoimmune disease and indeed the effector mechanisms are similar to many human diseases manifest as loss of tolerance. The clinical diagnosis is highly likely based upon appropriate serology and clinical manifestations. However, the serologic features are often misinterpreted and may have false positives if confirmatory laboratory testing is not performed. Antibiotics are routinely and typically used to treat patients with Lyme disease, but there is no evidence that prolonged or recurrent treatment with antibiotics change the natural history of Lyme disease. Although there are animal models of Lyme disease, there is no system that faithfully recapitulates the human disease. Further research on the effector mechanisms that lead to pathology in some individuals should be further explored to develop more specific therapy.

Immune-mediated adverse effects of biologicals used in the treatment of rheumatic diseases.

Biological agents represent a major advance in the treatment of rheumatic diseases, most particularly in the prevention of irreversible structural damage. While generally well tolerated, their increasing use continues to reveal a variety of immune-mediated adverse effects. The most frequent adverse events are infusion reactions and injection site reactions, but despite their fairly common occurrence the precise mechanisms are not fully understood. Another adverse event that became appreciated early in the era of biologicals is the increased risk of Mycobacterium tuberculosis and other granulomatous infections in patients treated with tumor necrosis factor (TNFα) antagonists. Although it is evident that this enhanced susceptibility to intracellular infections must be due to immunosuppression arising from the blockade of TNFα, the mechanisms have not been fully elucidated; such an understanding is likely to provide important insights into the role of TNFα in granulomatous and other infectious diseases. In addition, the biologicals may paradoxically induce autoimmunity. The development of autoantibodies is seen in a considerable proportion of patients, but clinical autoimmune disease develops much less commonly, including systemic lupus erythematosus, multiple sclerosis and other demyelinating diseases, psoriasis, sarcoidosis, and interstitial lung disease. The mechanisms leading to their induction are very poorly understood, but an intriguing hypothesis is that interferon α provides a common link, at least for lupus, psoriasis and possibly sarcoidosis. Finally, the potential risk of infection with use of the biologicals is an issue that clinicians should always be aware of. These comments aside, the biologics are the most important advance in the treatment of rheumatic disease in the history of rheumatology and their usage has not only greatly helped patient care, but also provided key data on the immunobiology of the disease processes.

The implications of autoimmunity and pregnancy.

There are multiple epidemiological studies that document the potential adverse affects of autoimmunity on nearly every aspect of reproduction, even in the absence of clinically manifest autoimmune disease. Two decades ago, it was suggested that women with autoimmune diseases avoid pregnancy due to inordinate risks to the mother and the child. In contrast, newer epidemiological data demonstrated that advances in the treatment of autoimmune diseases and the management of pregnant women with these diseases have similarly improved the prognosis for mother and child. In particular, if pregnancy is planned during periods of inactive or stable disease, the result often is giving birth to healthy full-term babies without increased risks of pregnancy complications. Nonetheless, pregnancies in most autoimmune diseases are still classified as high risk because of the potential for major complications. These complications include disease exacerbations during gestation and increased perinatal mortality and morbidity in most autoimmune diseases, whereas fetal mortality is characteristic of the anti-phospholipid syndrome (APS). In this review, we will discuss these topics, including issues of hormones, along with potential long-term effects of the microchimerism phenomenon. With respect to pregnancy and autoimmune diseases, epidemiological studies have attempted to address the following questions: 1) Is it safe for the mother to become pregnant or are there acute or chronic effects of pregnancy on the course of the disease? 2) Does the disease alter the course and/or the outcome of a pregnancy and thereby represent an inordinate risk for the fetus and infant? And do new therapeutic and management approaches improve the pregnancy outcomes in women with autoimmune diseases? 3) Does passage of maternal autoantibodies represent a risk to the child? 4) Do pregnancy, parity, or other factors influencing hormonal status explain the female predominance of many autoimmune diseases, and is the pregnancy effect related to microchimerism? Answering these questions has taken on additional importance in recent decades as women in western countries now frequently choose to delay pregnancies and have some or all of their pregnancies after disease onset. In this paper, we primarily focus on APS, systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), and type 1 diabetes (T1D).

Probiotics and immunity.

Probiotics are defined as live microorganisms that, when administered in adequate amounts, confer a health benefit on the host, including the gastrointestinal tract. While this beneficial effect was originally thought to stem from improvements in the intestinal microbial balance, there is now substantial evidence that probiotics can also provide benefits by modulating immune functions. In animal models, probiotic supplementation is able to provide protection from spontaneous and chemically induced colitis by downregulating inflammatory cytokines or inducing regulatory mechanisms in a strain-specific manner. In animal models of allergen sensitization and murine models of asthma and allergic rhinitis, orally administered probiotics can strain-dependently decrease allergen-specific IgE production, in part by modulating systemic cytokine production. Certain probiotics have been shown to decrease airway hyperresponsiveness and inflammation by inducing regulatory mechanisms. Promising results have been obtained with probiotics in the treatment of human inflammatory diseases of the intestine and in the prevention and treatment of atopic eczema in neonates and infants. However, the findings are too variable to allow firm conclusions as to the effectiveness of specific probiotics in these conditions.

Stevens-Johnson syndrome and toxic epidermal necrolysis.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, but potentially life threatening, diseases characterized by widespread epidermal necrosis, and are predominantly medication-induced. Unfortunately, though they are often associated with long-term debilitating sequelae, there are currently no efficacious pharmaceutical interventions proven through large clinical trials. It has been well established that the epidermal damage in these diseases is due to keratinocyte apoptosis. Although drug-specific T cells are implicated in this process, our understanding of the immunopathology is far from complete. The scenario suggested by today's literature points towards drug-specific CD8+ cytotoxic T cells utilizing perforin/granzyme B trigger keratinocyte apoptosis. Subsequently, there may be an expansion of apoptosis involving the interaction of either membrane-bound or soluble Fas ligand (sFasL) with its receptor Fas. The cellular source of sFasL remains controversial, with both peripheral lymphocytes and keratinocytes themselves as potential candidates. Cytokines produced by T lymphocytes, macrophages or keratinocytes may participate by activating keratinocytes and enhancing their expression of Fas and FasL, or by promoting the skin recruitment of lymphocytes by upregulating adhesion molecules. A better understanding of the underlying immunological mechanisms is required to identify appropriate therapeutic interventions. Finally, clinicians must remain vigilant about drug hypersensitivity to prevent SJS/TEN.

Smoking cessation: significance and implications for children.

A number of people in the USA who are still current smokers remain a staggering figure. Although this number continues to decrease, there is still a considerable amount of second-hand smoke. More importantly and for the purpose of this review, the detrimental effects of passive smoke in children is significant. We will not review the specific health effects of passive smoke, but for pediatricians, in particular, it is important to place in perspective programs that are available to influence the parents of children to stop smoking. Indeed, approximately 25% of all children aged 3-11 live in a household with at least one smoker. Despite the increasing number of communities in the states that have instituted restrictions or complete bans on smoking in the workplace and in many public areas, the principal site of smoking remains the home.

The immunobiology of mushrooms.

There has been enormous interest in the biologic activity of mushrooms and innumerable claims have been made that mushrooms have beneficial effects on immune function with subsequent implications for inhibition of tumor growth. The majority of these observations are anecdotal and often lack standardization. However, there remains considerable data on both in vitro and in vivo effects that reflect on the potential of mushroom compounds to influence human immunity. A number of these effects are beneficial but, unfortunately, many responses are still characterized based on phenomenology and there is more speculation than substance. With respect to tumor biology, although many neoplastic lesions are immunogenic, tumor antigens frequently are self antigens and induce tolerance and many patients with cancer exhibit suppressed immune responses, including defective antigen presentation. Therefore, if and when mushroom extracts are effective, they more likely function as a result of improved antigen presentation by dendritic cells than by a direct cytopathic effect. In this review we attempt to place these data in perspective, with a particular focus on dendritic cell populations and the ability of mushroom extracts to modulate immunity. There is, at present, no scientific basis for the use of either mushrooms or mushroom extracts in the treatment of human patients but there is significant potential for rigorous research to understand the potential of mushrooms in human disease and thence to focus on appropriate clinical trials to demonstrate effectiveness and/ or potential toxicity.

Ankylosing spondylitis: a contemporary perspective on diagnosis and treatment.

OBJECTIVES: In recent years, great progress has been made in the development of diagnostic tools, therapeutic approaches, and validated outcome measures in the understanding of the pathogenesis of ankylosing spondylitis (AS). The purpose of this review was to summarize these developments. METHODS: We performed a PubMed search for the period 1978 to 2005, using the keyword, "ankylosing spondylitis," resulting in a total of 4878 publications, including 778 reviews. Articles were then selected based on their discussion of recent diagnostic tools and new treatment approaches in the pathogenesis of AS, leading to a final total of 104 articles. RESULTS: In recent years, there have been 2 major developments in the management of AS that make earlier diagnosis possible and offer the hope of alleviating pain and preventing structural changes that result in loss of function. These developments include the use of magnetic resonance imaging to visualize the inflammatory changes in the sacroiliac joint and the axial spine, and the demonstration that tumor necrosis factor blocking agents are highly efficacious in reducing spinal inflammation and possibly in slowing radiographic progression. CONCLUSIONS: There have been major advances in both the diagnostic tools and the therapeutic regimens available for patients with AS.

Drug-induced lupus.

Drug-induced lupus (DIL) is a rare adverse reaction to a large variety of drugs with features resembling those of idiopathic systemic lupus erythematosus (SLE). It usually develops only after months and, quite commonly, years of treatment with the offending agent, although latencies of days or weeks have been described in some instances. There are some indications that the risk of DIL can increase with higher daily and cumulative doses and with longer duration of therapy. There are no definitive and commonly accepted diagnostic criteria for DIL, but the following guidelines have been proposed: (a) sufficient and continuing exposure to a specific drug, (b) at least one symptom compatible with SLE, (c) no history suggestive of SLE before starting the drug, and (d) resolution of symptoms within weeks (sometimes months) after discontinuation of the putative offending agent. In addition, it is frequently suggested that the presence of ANA is required for the diagnosis of DIL. However, negative ANA test results should not automatically preclude such a diagnosis, particularly if a patient has other autoantibodies associated with SLE/DIL.

The history and contemporary challenges of the US Food and Drug Administration.

BACKGROUND: The year 2006 marks the 100th anniversary of the regulatory agency now known as the US Food and Drug Administration (FDA), the first consumer protection agency of the federal government and arguably the most influential regulatory agency in the world. The FDA thus plays an integral role in the use of pharmaceuticals, not only in the United States but worldwide. OBJECTIVE: The goal of this review was to present an overview of the FDA and place its current role in the perspectives of history and contemporary needs. METHODS: Relevant materials for this review were identified through a search of the English-language literature indexed on MEDLINE (through 2006) using the main search terms United States Food and Drug Administration, FDA, history of the FDA, drug approvals, drug legislation, and FDA legislation. Results from the initial searches were then explored further. RESULTS: The statute that created the bureau which later became the FDA established this agency to prohibit interstate commerce of adulterated foods, drinks, and drugs. The Food, Drug, and Cosmetic Act that replaced it in 1938, and subsequent food and drug laws and amendments, expanded the FDA's responsibilities to cosmetics, medical devices, biological products, and radiation-emitting products. These amendments have also established the FDA as a mainly preventive regulatory agency that relies chiefly on pre-market control. As such, the FDA has played an important role in shaping the modern pharmaceutical industry by making the scientific approach and the clinical trial process the standard for establishing safety and efficacy and by making rigorous scientific analysis the predominant component of the process for pharmaceutical regulation. CONCLUSIONS: As shown in this review, the evolution of the FDA can be described as a series of "crisis-legislation-adaptation" cycles: a public health crisis promoted the passage of congressional legislation, which was then followed by implementation of the law by the FDA. However, the crises the FDA faces currently are likely to be overcome only under strong and permanent leadership willing to redefine the role and procedures of the FDA with an open mind.

The clinical relevance of complex regional pain syndrome type I: The Emperor's New Clothes.

The management of patients with chronic pain is a nearly daily challenge to rheumatologists, neurologists, orthopedic surgeons, pain specialists and indeed a issue in nearly every clinical practice. Among the myriad of causes of pain are often included a unique syndrome, generally referred to as complex regional pain syndrome type I (CRPS). Unfortunately CRPS I has become a catch all phase and there are serious questions on whether it exists at all; this has led to an extraordinary number of poorly defined diagnostic criteria. It has also led to an etiologic quagmire that includes features as diverse as autoimmunity to simple trauma. These, in turn, have led to overdiagnosis and often overzealous use of pain medications, including narcotics. In a previous paper, we raised the issue of whether CRPS type I reflected a valid diagnosis. Indeed, the diagnostic criteria for CRPS I, and therefore the diagnosis itself, is unreliable for a number of reasons: 1) the underlying pathophysiology of the signs and symptoms of CPRS I are not biologically plausible; 2) there are no consistent laboratory or imaging testing available; 3) the signs and symptoms fluctuate over time without a medical explanation; 4) the definitions of most studies are derived from statistical analysis with little consideration to required sample size, i.e. power calculations; 5) interobserver reliability in the assessment of the signs and symptoms are often only fair to moderate, and agreement on the diagnosis of "CRPS I" is poor. Even physicians who still believe in the concept of "CRPS I" admit that it is vastly overdiagnosed and has become a diagnosis of last resort, often without a complete differential diagnosis and an alternative explanation. Finally, one of the most convincing arguments that there is no clinical entity as "CRPS I" comes from the enormous heterogeneity in sign and symptom profiles and the heterogeneity of pathophysiological mechanisms postulated. This observation is underscored by the diversity of responses among "CRPS I" patients to essentially all treatment modalities. It has even led to the concept that the signs and symptoms of CRPS can spread throughout the body, as if it is an infectious disease, without any medical plausible explanation. If true progress is to be made in helping patients with pain, it will require entirely new and different concepts and abandoning CRPS I as a legitimate diagnosis.

Mold and Human Health: a Reality Check.

There are possibly millions of mold species on earth. The vast majority of these mold spores live in harmony with humans, rarely causing disease. The rare species that does cause disease does so by triggering allergies or asthma, or may be involved in hypersensitivity diseases such as allergic bronchopulmonary aspergillosis or allergic fungal sinusitis. Other hypersensitivity diseases include those related to occupational or domiciliary exposures to certain mold species, as in the case of Pigeon Breeder's disease, Farmer's lung, or humidifier fever. The final proven category of fungal diseases is through infection, as in the case of onchomycosis or coccidiomycosis. These diseases can be treated using anti-fungal agents. Molds and fungi can also be particularly important in infections that occur in immunocompromised patients. Systemic candidiasis does not occur unless the individual is immunodeficient. Previous reports of "toxic mold syndrome" or "toxic black mold" have been shown to be no more than media hype and mass hysteria, partly stemming from the misinterpreted concept of the "sick building syndrome." There is no scientific evidence that exposure to visible black mold in apartments and buildings can lead to the vague and subjective symptoms of memory loss, inability to focus, fatigue, and headaches that were reported by people who erroneously believed that they were suffering from "mycotoxicosis." Similarly, a causal relationship between cases of infant pulmonary hemorrhage and exposure to "black mold" has never been proven. Finally, there is no evidence of a link between autoimmune disease and mold exposure.

Juvenile idiopathic arthritis.

One of the most enigmatic problems in rheumatology has been juvenile idiopathic arthritis (JIA). Firstly, the classification has often depended on clinical features that have variations between patients. Secondly, there are different classification schemes in usage and there are few objective serologic tests that help to resolve the differences between the criteria sets. Thirdly, only recently have significant advances been made in understanding the immunology and immunopathology of JIA and, in particular, new treatment options. In this review, we will define the historical basis of JIA and emphasize not only the clinical features, but also the immunological characteristics, the pathogenesis, and treatment options. We will also discuss, in particular, quality of life, psychosocial functioning, socioeconomic outcomes and the difficult area of mortality. Finally, this review will attempt to bridge genetic observations with clinical presentation. JIA represents a relatively common syndrome of pediatric onset rheumatologic disease and a better understanding of the clinical definition, the relationship to autoimmunity, and novel treatments with biologic agents are critical for improved patient care.

Airborne environmental injuries and human health.

The concept that the environment in which we live can have detrimental effects on our health has existed for centuries. Obvious examples of substances that can cause human diseases include infectious agents, poisons, chemicals and other noxious agents, drugs, and physical stimuli such as bright lights and loud sounds. Some less obvious agents can include allergens, nontangible agents such as colorless, odorless gases and aerosolized toxins. In recent decades, humans have developed various new materials and compounds. Additionally, we are now producing known compounds, and even naturally occurring substances, in vastly increased amounts. Many of these substances are generally believed to threaten the health of our environment. However, there is also a considerable amount of hype and exaggeration regarding some of these agents (e.g., mold) that is unsubstantiated. This article extensively reviews the data on a large number of airborne-related illnesses and attempted to place scientific reality in the context of clinical medicine.

The Basis of Structure/Function Claims of Nutraceuticals.

In the United States, as in most of the world, there are large numbers of nutraceuticals that are sold and which people take to boost their immune response. There are, in addition, almost an equal number of products sold to reduce allergies. However, very few consumers, and indeed physicians, are aware of what a structure/function claim is. Structure/function claims are labeling claims that can be used to describe the potential effects of a dietary ingredient or similar substance on the structure or function of the human body. This category of claims was created by legislation contained in the Dietary Supplement Health and Education Act. The intent was to supply consumers with reasonably substantiated information that would allow them to make educated choices about their diet and health. They were not intended to have the same weight and substantiation as the claims made for conventional prescription pharmaceuticals. Rather, they were proposed to fill the gap between consumer desire for over-the-counter supplements and foods, and rigorous and generally more potent and potentially "toxic" prescription medications. The legally mandated disclaimer, stating that the U.S. Food and Drug Administration has not evaluated the structure/function claim, often leads to misinterpretation. While there should be a biologic premise underlying the claim, there is not an absolute requirement for a conventional rigorous placebo-controlled dose response trial. While this may not be the clinical standard that a typical scientific oriented society might desire, it reflects the attempts of the FDA to find common grounds and to allow consumers to use products that are generally considered as safe based on historical use and biologic comparisons. The logic of, indeed need for, structure/function claims is straightforward; however, of equal importance is that nutraceuticals should be properly labeled, have accuracy in their ingredients, be free of contamination, be safe, and have a reasonable body of data that supports their efficacy.

Neuropsychiatric features of systemic lupus erythematosus.

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a serious and well known complication of systemic lupus erythematosus that remains a significant source of morbidity and mortality. Fortunately, advances in neuroimaging techniques and cognitive testing have improved the diagnosis of this disease and allowed earlier and more successful therapeutic intervention. Further, the association of NPSLE with the anti-phospholipid syndrome, other autoantibodies and inflammatory cytokines have also provided clues to the diagnosis and pathophysiology. Treatment of NPSLE is largely symptom based with outcome based on appropriate diagnosis.

NOD mice and autoimmunity.

The NOD mouse has been an important model of type 1 diabetes and autoimmune diseases for over 20 years. Experimental and genetic manipulations of the NOD mouse have demonstrated a broad susceptibility to multiple autoimmune syndromes. This predisposition to autoimmunity is due to defects in both central and peripheral tolerance. The defect of central tolerance is likely secondary to improper negative selection mediated by the unique MHC Class II molecule, I-A(g7) as well as intrinsic T cell signaling defects. The genetic basis for impaired peripheral tolerance is controlled by over 20 susceptibility loci termed insulin-dependent diabetes (idd) loci. The maintenance of peripheral tolerance is impaired by alterations in T cell signaling and apoptosis. In addition, insufficient co-stimulation from accessory cells, and defective regulatory T cells, may promote the production of autoreactive T cells.

Transforming growth factor beta (TGF-beta) and autoimmunity.

TGF-beta1 deficient mice develop multifocal inflammatory autoimmune disease and serve as a valuable animal model of autoimmunity. Transgenic expression of a dominant negative form of TGF-beta receptor type II in T cells have enabled the study of cell lineage specific effects of TGF-beta providing clues to the potential etiology of autoimmunity. These studies suggest that TGF-beta deficiency may induce autoimmune disease by influencing a number of immunological phenomena including lymphocyte activation and differentiation, cell adhesion molecule expression, regulatory T cell function, the expression of MHC molecules and cytokines, and cell apoptosis. The spectrum of effects appears to be significant in mucosal immunity and may contribute to the pathogenesis of inflammatory bowel disease.

Fibromyalgia: A Critical and Comprehensive Review.

Fibromyalgia is a disorder that is part of a spectrum of syndromes that lack precise classification. It is often considered as part of the global overview of functional somatic syndromes that are otherwise medically unexplained or part of a somatization disorder. Patients with fibromyalgia share symptoms with other functional somatic problems, including issues of myalgias, arthralgias, fatigue and sleep disturbances. Indeed, there is often diagnostic and classification overlap for the case definitions of a variety of somatization disorders. Fibromyalgia, however, is a critically important syndrome for physicians and scientists to be aware of. Patients should be taken very seriously and provided optimal care. Although inflammatory, infectious, and autoimmune disorders have all been ascribed to be etiological events in the development of fibromyalgia, there is very little data to support such a thesis. Many of these disorders are associated with depression and anxiety and may even be part of what has been sometimes called affected spectrum disorders. There is no evidence that physical trauma, i.e., automobile accidents, is associated with the development or exacerbation of fibromyalgia. Treatment should be placed on education, patient support, physical therapy, nutrition, and exercise, including the use of drugs that are approved for the treatment of fibromyalgia. Treatment should not include opiates and patients should not become poly pharmacies in which the treatment itself can lead to significant morbidities. Patients with fibromyalgia are living and not dying of this disorder and positive outlooks and family support are key elements in the management of patients.

Surviving the butterfly and the wolf: mortality trends in systemic lupus erythematosus.

OBJECTIVE: To address changes in survival of patients with systemic lupus erythematosus (SLE) and to compare mortality statistics with associated disease specific as well as comorbid conditions. METHODS: Review of the international literature on survival of patients with SLE. RESULTS: During the first half of the 20th century, SLE was considered a rapidly progressive and almost invariably fatal disease. Since the 1950s, the estimated 5-year survival of SLE patients in developed countries rose from <50% to >95% and similar increases were seen in 10-year survival. Mortality rates of SLE patients, however, remain approximately 3 times that of an age- and sex-matched population in most studies, indicating that death still occurs prematurely in a substantial portion of patients, albeit later in the disease course. This improved prognosis does not appear to have been shared equally by all racial/ethnic groups. This appears to be attributable more to socioeconomic and sociocultural factors than to true differences in disease manifestations. Along with the increased survival of SLE patients, there has been a change in the causes of death. Most notably, there has been a dramatic increase in the proportionate mortality from vascular disease, particularly accelerated atherosclerosis. Both disease and therapeutic modalities, in particular corticosteroids, appear to contribute to the high prevalence of coronary artery disease (CAD). CONCLUSIONS: Much progress has been made in improving the survival of SLE, but there is need for further improvement. Aggressive treatment of risk factors for CAD is advisable, but it remains to be assessed to what extent such interventions can further reduce mortality.