High-resolution (18)F-FDG PET/CT for assessing disease activity in rheumatoid and psoriatic arthritis: findings of a prospective pilot study.

OBJECTIVE: Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) commonly affect the small joints of the wrist and hand. We evaluated the performance of a new, high-resolution extremity positron emission tomography (PET)/CT scanner for characterizing and quantifying pathologies associated with the two arthritides in the wrist and hand joints. METHODS: Patients with RA or PsA underwent fluorine-18 fludeoxyglucose ((18)F-FDG) PET/CT wrist and hand imaging, respectively, on the high-resolution scanner. Calibrated CT images and co-registered PET images were reconstructed. PET/CT was derived for the radiocarpal and pisiform-triquetral compartments, joints with erosive changes, sites of synovitis or tenosynovitis and the nail bed and were correlated with clinical and MRI findings. RESULTS: Significantly elevated (18)F-FDG uptake was measured for the radiocarpal and pisiform-triquetral compartments and at sites of bone erosion, synovitis, pannus and oedema, compared with unaffected joints (p < 0.05) in patients with RA, consistent with their clinical findings. In patients with PsA, significantly elevated (18)F-FDG uptake was measured for joints with synovitis compared with unaffected joints (p < 0.05), with patterns of (18)F-FDG uptake along the tendons, at the enthesis and in the nail bed, consistent with tenosynovitis, enthesitis and nail dystrophy, respectively. CONCLUSION: High-resolution (18)F-FDG PET/CT imaging of the wrist and hand is feasible in an RA or PsA patient cohort and is capable of providing quantifiable measures of disease activity (synovitis, enthesitis, oedema and bone destruction). ADVANCES IN KNOWLEDGE: High-resolution PET/CT imaging shows promise as a tool for understanding the pathogenesis of the arthritic process and for non-invasive, objective assessment of RA or PsA severity and therapy selection.

Safety issues and concerns of new immunomodulators in rheumatology.

INTRODUCTION: The development of biologic therapies has been an enormous leap in the management of patients with rheumatoid and psoriatic arthritis. Since the first anti-TNF-α therapies, numerous molecules have been identified as targets of immunomodulatory therapies, such as IL-1 (anakinra, canakinumab), IL-6 (tocilizumab), CD20(+) B cells (rituximab), CTLA4 (abatacept) and two additional anti-TNF-α therapies (certolizumab pegol, golimumab). AREAS COVERED: In the present review, we will describe the safety issues related to the immunosuppressive action of these biologic drugs that are mainly represented by infection and malignancy. The risk of infection should be identified before initiating a biologic treatment and markers checked over time, in particular for tuberculosis and hepatitis B and C viruses. Other infections (bacterial, viral, parasitic; opportunistic; surgery-related) and safety issues may require temporary interruption of the treatment until complete resolution. No significantly increased risk of malignancy, both hematological and solid, has been associated with the use of biologic agents. In all cases, it is difficult to dissect the risks related to biologics from those related to baseline treatments. EXPERT OPINION: Detailed medical history and laboratory screening should be performed before starting biologic therapies. Clinicians should be aware of the different safety profiles associated with different molecules and they should follow up data coming out of the existing registries for biologics in regard to new or old side effects.

Multicentric reticulohistiocytosis: a rare yet challenging disease.

Multicentric reticulohistiocytosis (MRH) is a rare systemic inflammatory granulomatous disease that primarily manifests clinically with severe erosive arthritis and widespread papulonodular skin lesions but can involve multiple other organ systems. Despite the fact that this condition can become aggressive, debilitating as well as deforming with significant detrimental consequences, the etiology of this disease remains poorly understood. Moreover, the fact that MRH is such an uncommon disease has created an obstacle in the path of adequate clinical trials that are needed for better understanding of this phenomenon and for the development of treatment options for this patient population. In this review, we will attempt to discuss the epidemiology, pathophysiology, clinical features, associated conditions, differential diagnoses, diagnostic workup, and available treatments of MRH with the hope of creating a better understanding of this very challenging yet elusive disease process.

The SAPHO syndrome.

OBJECTIVE: To review the epidemiology, presentation, diagnosis, treatment, pathogenesis, and genetics of the syndrome known under the acronym of SAPHO for Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis to heighten awareness of this entity. METHODS: We conducted a Medline search using SAPHO syndrome, chronic recurrent multifocal osteitis/osteomyelitis, and related terms as keywords and extracted further relevant articles from the retrieved references. RESULTS: The SAHPO acronym identifies a syndrome encompassing a variety of osteoarticular disorders that are frequently accompanied by dermatoses characterized by neutrophilic pseudoabscesses, but can also occur in isolation. SAPHO syndrome is rare, although probably underrecognized because its diagnosis may be challenging because of the wide variability in its musculoskeletal and cutaneous manifestations. This is especially true when atypical sites are involved and when specific skin lesions are absent. There are no standardized treatment protocols available. Current treatments are empirical and have the objective of providing relief from the at times debilitating pain associated with SAPHO syndrome. They include nonsteroidal anti-inflammatory drugs and analgesics as first-line agents. Systemic corticosteroids, disease-modifying anti-rheumatic drugs, biologicals targeting tumor necrosis factor alpha and interleukin-1, and bisphosphonates have all been beneficial in some patients, but ineffective in others. This suggests that the pathogenesis of SAPHO syndrome is multifactorial, but this aspect remains poorly explored, although bacteria and immunological dysfunction are hypothesized to play a role. CONCLUSIONS: The early recognition, diagnosis, and prompt treatment of SAPHO syndrome can prevent the unnecessary use of long-term antibiotics or invasive procedures, while rapidly alleviating pain in a majority of affected patients.

Lupus nephritis: a critical review.

Lupus nephritis remains one of the most severe manifestations of systemic lupus erythematosus associated with considerable morbidity and mortality. A better understanding of the pathogenesis of lupus nephritis is an important step in identifying more targeted and less toxic therapeutic approaches. Substantial research has helped define the pathogenetic mechanisms of renal manifestations and, in particular, the complex role of type I interferons is increasingly recognized; new insights have been gained into the contribution of immune complexes containing endogenous RNA and DNA in triggering the production of type I interferons by dendritic cells via activation of endosomal toll-like receptors. At the same time, there have been considerable advances in the treatment of lupus nephritis. Corticosteroids have long been the cornerstone of therapy, and the addition of cyclophosphamide has contributed to renal function preservation in patients with severe proliferative glomerulonephritis, though at the cost of serious adverse events. More recently, in an effort to minimize drug toxicity and achieve equal effectiveness, other immunosuppressive agents, including mycophenolate mofetil, have been introduced. Herein, we provide a detailed review of the trials that established the equivalency of these agents in the induction and/or maintenance therapy of lupus nephritis, culminating in the recent publication of new treatment guidelines by the American College of Rheumatology. Although newer biologics have been approved and continue to be a focus of research, they have, for the most part, been relatively disappointing compared to the effectiveness of biologics in other autoimmune diseases. Early diagnosis and treatment are essential for renal preservation.

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.

Steroid induced osteonecrosis: An analysis of steroid dosing risk.

Osteonecrosis is a serious condition involving bone destruction that frequently requires surgical treatment to rebuild the joint. While there is an abundance of literature documenting corticosteroid related osteonecrosis, there is no consensus as to the relative risk of osteonecrosis after administration of steroids via parenteral, oral, topical, inhaled and other routes. This risk is an important prognostic indicator because identification and conservative intervention can potentially reduce morbidity associated with aggressive surgical treatment of osteonecrosis. This paper provides insight into establishing guidelines related to the risk of developing osteonecrosis as a result of corticosteroid use. Case studies, retrospective studies and prospective studies in humans on different corticosteroids and varied dosages were assessed. Most cases of osteonecrosis are secondary to systemically administered corticosteroids and/or high dose daily therapy, particularly in patients with underlying comorbidities including connective tissue diseases, hyperlipidemia, or previous trauma. Previous case reports of osteonecrosis related to inhaled or topical use of steroids are complicated by the fact that in the great majority of cases, the patients are also treated with systemic steroids prior to the development of osteonecrosis. Based on the literature, a set of recommendations regarding the risk of osteonecrosis in patients on steroids was formulated.

Dairy proteins and the response to pneumovax in senior citizens: a randomized, double-blind, placebo-controlled pilot study.

With the progressive aging of the world's population, immunosenescence is rapidly becoming a clinical concern as it accounts for a higher incidence of severe infections and poor response to vaccines. To identify nutritional approaches that may counteract immunosenescence is of obvious importance in clinical practice. Dairy products in general and whey proteins in particular share the capacity to stimulate the immune system within the digestive tract while the antibody response to Streptococcus pneumoniae vaccine is a good marker of the immune function. We performed a controlled, randomized, double-blind pilot study to determine if an eight-week supplementation with whey protein (or soy protein used as control) could enhance the serum response to pneumococcal vaccine in healthy senior citizens. Out of 127 volunteers, 17 subjects were eligible and completed the study receiving the vaccine after four weeks of supplementation. Antibody levels were measured at baseline and the end of the study against 14 pneumococcal types and a detailed nutritional questionnaire was administered to all subjects. Subjects receiving whey protein manifested a serum response higher compared to the control soy supplementation against 12/14 bacterial types. In particular, whey led to a higher frequency of response to all four more virulent types (4, 9, 14, and 23). Calorie and protein intake data suggest a better nutritional status in the whey group. Whey protein supplementation is a promising supplement to stimulate the immune response to vaccine in senior citizens and possibly to counteract immunosenescence while larger studies are warranted.

Currents concepts on the immunopathology of amyloidosis.

Amyloidosis is defined as the extracellular accumulation at systemic or organ-specific level of insoluble low molecular weight protein fibrils manifesting a beta pleated sheet configuration and a characteristic staining pattern. Several different types of proteins may lead to this phenomenon, and amyloidosis is defined by the biochemical nature of the protein in the deposits and further classified according to whether the deposits are localized or systemic, acquired or inherited, and by the resulting clinical phenotype. Amyloidosis includes subtypes such as light chain, associated with serum amyloid A protein, heritable and familial forms, dialysis-related disease, and organ-specific conditions. The pathogenesis and clinical features of these clinical and pathological entities will be critically discussed in this review article.

The geoepidemiology of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with manifold clinical manifestations and immunological abnormalities, affecting primarily women. Although accurate current data on its incidence and prevalence are largely lacking, there are numerous indications that SLE is far less common in Europeans and their descendants compared to all other ethnicities. The clinical manifestations of the disease show geographic or ethnic variation, generally being less severe in patients of European ancestry than in African, Asian, certain "Hispanic" or mestizo, and various indigenous populations. In particular, renal involvement is far more common in non-European patients. Genetic as well as environmental, sociodemographic and sociocultural factors are likely to contribute to the differences in the incidence and clinical expression of SLE.

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).

Colchicine revisited.

Purified from a Mediterranean plant nearly two centuries ago, colchicine has been discovered to inhibit many steps in the inflammatory process. The drug has good oral bioavailability and some enterohepatic recirculation, requiring dose adjustments for kidney disease and avoidance in liver disease. Toxicities are primarily gastrointestinal, hepatic, and hematologic. Colchicine is approved by the U.S. Federal Drug Administration for the treatment and prophylaxis of gout flares but has also been tried with varying success in the treatment of familial Mediterranean fever, primary biliary cirrhosis, psoriasis, Behçet's disease, aphthous stomatitis, linear IgA dermatosis, relapsing polychondritis, Sweet's syndrome, scleroderma, amyloidosis, leukocytoclastic vasculitis, epidermolysis bullosa, and dermatomyositis.

Common variable immunodeficiency: etiological and treatment issues.

One of the great advances in clinical medicine was the recognition of the pleomorphism of the immune response and the multiple afferent and efferent limbs of antigen processing and responsiveness. A significant contribution to this understanding was derived from studies of human immunodeficiency states, including both inherited and acquired syndromes. Amongst these syndromes, one of the most common, and least understood, is common variable immune deficiency (CVID). CVID is a syndrome that leads to a reduction in serum immunoglobulins and complications including recurrent infections. Management includes immunoglobulin replacement therapy; however, patients with CVID are at risk for complications of exogenous immunoglobulin administration as well as CVID-associated diseases such as autoimmune processes and malignancies. To assess the current state of knowledge in the field, we performed a literature review of a total of 753 publications covering the period of 1968 until 2008. From this list, 189 publications were selected for discussion. In this review, we demonstrate that while the molecular basis of CVID in many cases remains incompletely understood, significant strides have been made and it is now clear that there is involvement of several pathways of immune activation, with contributions from both T and B cells. Furthermore, despite the current gaps in our knowledge of the molecular pathogenesis of the syndrome, there have been dramatic advances in management that have led to improved survival and significantly reduced morbidity in affected patients.

Acute rheumatic fever and its consequences: a persistent threat to developing nations in the 21st century.

Acute rheumatic fever (ARF) is an autoimmune, multi-system response secondary to molecular mimicry following Lancefield group A streptococcus (GAS) pharyngitis; it is now most commonly found in the pediatric populations of developing nations. The major source of morbidity and mortality of ARF stems from rheumatic heart disease (RHD), although the cardinal symptoms of the disease also include polyarthritis, Sydenham's chorea, subcutaneous nodules, and erythema marginatum. Therapy is aimed towards treating the initial GAS infection, using anti-inflammatory medications for acute symptoms and surgery to correct RHD. Secondary prevention is crucial, given the high risk of recurrence, and includes long-term antibiotic prophylaxis. However, vaccination towards GAS may soon be on the horizon, which may assist in both decreasing the risk of initial infection in naïve patients and helping to lower the risk of recurrence.

Revisiting Libman-Sacks endocarditis: a historical review and update.

Libman-Sacks (LS) endocarditis was first described by Libman and Sacks in 1924, and is characterized by sterile, verrucous valvular lesions with a predisposition for the mitral and aortic valves. It is now regarded as both a cardiac manifestation of systemic lupus erythematosus and, in recent years, of the antiphospholipid syndrome (APS). Though typically mild and asymptomatic, LS endocarditis can lead to significant complications, including severe valvular insufficiency requiring surgery, infective endocarditis, and thromboembolic events, such as stroke and transient ischemic events. Improvements in imaging modalities, particularly in echocardiography, have allowed better estimation of the prevalence of the disease, but further investigation is still needed into its pathogenesis, treatment, and association with APS.

Recognizing calcific uremic arteriolopathy in autoimmune disease: an emerging mimicker of vasculitis.

Calcinosis has long been associated with autoimmune disease and has a distinctive profile in scleroderma, dermatomyositis, systemic lupus erythematosus, and overlap syndromes. However, there have also been a number of case studies of calcific uremic arteriolopathy, or calciphylaxis, described within vessels, including patients with chronic renal insufficiency and several forms of vasculitis. Interestingly, the calciphylaxis associated with vasculitis appears to be unique, although relatively uncommon and is likely secondary to a disruption in the calcium-phosphate-parathyroid hormone axis. However, there appears to be an additional trigger, given that calciphylaxis is seen both in the absence of chronic kidney disease, and in the absence of a deranged calcium-phosphate-parathyroid hormone axis. These additional triggers include a high female predominance, obesity, diabetes and, possibly, warfarin use. In this review, we describe the clinical features of calciphylaxis, particularly in the context of autoimmune disease.

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.

Pediatric angioedema.

Angioedema is a self-limited nonpitting edema generally affecting the deeper layers of the skin and mucous membranes. It is the result of increased vascular permeability causing the leakage of fluid into the skin in response to potent vasodilators released by immunologic mediators. Two main pathways are thought to be implicated in angioedema. The mast cell pathway in which preformed mediators, such as histamine, rapidly formed mediators, leukotrienes and prostaglandins, are released from mast cells through IgE or direct activation. This is the most common pathway among children, with food, medications, and infections commonly implicated. The second pathway is the kinin pathway, most notably affected by angiotensin-converting enzyme (ACE) inhibitors and hereditary forms of angioedema, which ultimately results in the formation of bradykinin, a potent vasodilator. Angioedema is being encountered with increasing frequency, particularly among children and is important to recognize and treat for its life-threatening associated manifestations such as anaphylaxis and airway obstruction. Although angioedema is still not fully understood, we have broadened our understanding of the possible causes and clinical course of angioedema. An understanding of these potential causes and mechanisms by which angioedema can occur may guide the clinician in determining the need for diagnostic testing and the extent of treatment.

The geo-epidemiology of temporal (giant cell) arteritis.

Giant cell arteritis (GCA) is the most common vasculopathy in patients over the age of 50. The majority of data on the geo-epidemiology of GCA is derived from Scandinavia, although there is very good documentation and epidemiological descriptions from studies throughout Europe and North America. There remains, however, a paucity of data on the incidence and prevalence of GCA in North American minority populations, as well as from Africa or Asia. The data that does exist suggests that the incidence of GCA is lower in Hispanic, Asian, and African American populations. It is interesting to note that as the population throughout the world continues to age, we anticipate an increased prevalence of disease based upon increases in annual incidence and improved survival. Considerable research is still needed to identify genetic, environmental, and gender-specific factors that influence not only the etiology, but also the natural history of disease.