We are currently witnessing an explosion of information about the genetic contribution to complex human diseases such as systemic lupus erythematosus (SLE). These genetic discoveries have profound implications for efforts to more fully characterize etiologic pathways and mechanisms. Further, these etiologic insights should lead to improved diagnostic and prognostic tools and inform the development of more specifc therapies for SLE and related conditions. The article summarizes the evidence supporting a role for genetic factors in SLE, highlights the clinical and genetic complexity of the disease, reviews the genes that have established contributions to the risk of SLE and specifc disease manifestations, and discusses the recent data emerging from genomewide association studies of SLE.

Cardiovascular morbidity and mortality in SLE is increased in patient with established disease, and SLE itself has been determined to be an independent risk factor for cardiovascular events. Autopsy studies have demonstrated that the coronary vessels of SLE patients have atherosclerotic plaque, and most cardiovascular events are not attributable to active vasculitis. It is believed that patients with infammatory disease, including SLE, are more likely to have vulnerable plaque rupture, accounting for more frequent events. Elevated homocysteine levels have been associated with the presence and progression of atherosclerotic plaque. Enzyme polymorphisms involved in the folatehomocysteine pathway do not seem to contribute to differences in homocysteine concentration or atherosclerotic plaque. Recently, endothelial dysfunction has been identifed as an early abnormality in ASCVD, and has been demonstrated in the vessels of SLE patients. Premature cardiovascular disease in SLE patients is likely attributable to the consequences of infammation. There is preliminary evidence that type I interferons maybe the initial stimulation of the cascade of atherosclerotic development, starting with endothelial damage, and abnormal vascular repair.

This review addresses new clinical issues (revealed at the 2006 Sydney update of the 1999 Sapporo Classifcation criteria; cardiac, renal, and multiple sclerosis-like disease; catastrophic syndrome), mechanisms of action of antiphospholipid antibody (very likely complement mediated), current therapies (moderate dose warfarin recommended for prophylaxis, aspirin not recommended for primary prophylaxis), and potential new therapies.

Systemic sclerosis (SSc) is a complex and heterogeneous chronic illness characterized by substantial patient to patient variability in clinical manifestations, internal organ involvement, and outcome. Genetic factors contribute to disease susceptibility, but environmental infuences also play a significant role. The pathogenesis of SSc encompasses vascular, immunological, and fbrotic processes, which contribute to clinical manifestations and morbidity and must be addressed in the treatment plan. Although vascular interventions appear to reduce the frequency and severity of complications, such as scleroderma renal crisis and pulmonary hypertension, current therapies generally target the immune component of SSc in a non-selective fashion and have largely failed as diseases-modifying interventions. Newer insights into the mechanisms underlying autoimmunity, vascular injury and destruction, and particularly tissue fbrosis provide novel potential targets for therapy. Transforming growth factor-ß is a ubiquitous cytokine that appears to contribute to fbroblast activation, collagen overproduction, and pathological tissue fbrosis. Neutralizing antibodies and small molecules that block TGF-ß activation or function are effective in shutting down TGF-ß signaling and selectively inhibit the progression of fbrosis and may be entering clinical trials for the treatment of SSc.

There has been a burgeoning interest in the spondyloarthritides (SpAs) due to a confuence of elements. Basic science research has provided new insight into the unique pathophysiology of synovium, enthesium, and bone, highlighting the important differences from rheumatoid arthritis (RA). Through collaborative research of international working groups, classifcation criteria for psoriatic arthritis (PsA) and ankylosing spondylitis (AS) have been developed or are being refned to aid characterization and diagnosis of SpAs and aid in research. These same working groups, under the umbrella of Outcome Measures in Rheumatology Clinical Trials (OMERACT), have developed domain core sets to be measured in clinical trials and registries, and which allow validation of reliable outcome measures. Both through clinical trials and observational data from national clinical registries, the relative effectiveness and safety of old and new therapies are being demonstrated. This has been particularly shown with long-term data on anti-TNF therapy. Newer anti-TNF therapies are being developed, as are treatments with different mechanisms of action in order to treat patients who do not have long-term effectiveness or develop side effects to older disease modifying therapy and anti-TNFs. International treatment recommendations have been or are being developed based on the evidence base from clinical trials.

Therapeutics options for rheumatoid arthritis (RA) have increased tremendously in the past decade with the introduction of biological agents in 1999. Several different cellular and cytokine targets have been identifed, with specifc inhibitors now approved to treat RA, including the tumor necrosis factor (TNF) antagonists (adalimumab, etanercept, infiximab), an interleukin 1 (IL1) antagonist (anakinra), an inhibitor of T cell co-stimulation (abatacept), and a selective depleter of B cells (rituximab). As research has progressed, additional promising targets have been identifed. Results from RA studies using several new agents have been reported in the last year. Some of these compounds are similar to agents already available, with additional TNF inhibitors (certolizumab pegol, golimumab) and agents targeting CD20 (ocrelizumab, ofatumumab, TRU-015) in development. Other agents are directed toward new cytokine targets, including IL-6 (tocilizumab), and lymphotoxin pathways (briobacept), as well as other B-cell targets, to include BLyS and APRIL (belimumab, atacicept). Additional small molecule therapies have been studied that are directed against intracellular kinases, including JAK-3 and Syk. This article provides a brief update of data from selected clinical trials in RA, highlighting effcacy, and mechanism-based safety concerns.

A quantitative count of swollen and tender joints is a primary measure to assess patients with rheumatoid arthritis (RA), and is weighted of higher value than the other 5 Core Data Set measures in all indices in which it is included. However a number of limitations of the swollen and tender joint count have been described in the rheumatology literature, including poor reproducibility, with a requirement to be performed by the same observer at each visit; likelihood to improve with placebo treatment as much or more than the other 5 RA Core Data Set measures in clinical trials; similar or lower relative effciencies than global and patient measures to document differences between active and control treatments in clinical trials; improvement over 5 years in clinical care, while joint damage and functional disability may progress; and lower sensitivity to detect infammatory activity than ultrasound. Most visits to a rheumatologist do not include a formal quantitative joint count. It may be suggested that a careful qualitative joint count, supplemented by quantitative patient self-report questionnaire scores, may be more than adequate to monitor and document changes in patient status in busy clinical settings.

In the feld of autoimmunity, much has been learned from studying circulating and tissue bound immune-reactive cells, cytokines and antibodies. However, what has brought those cells to the site of injury, for most forms of vasculitis remains a mystery. Might the etiology of at least certain forms of vasculitis be related to generation of neoantigens in the native vessel, making that vessel the target of a pathogenic immune response? How might one explain organ targeting and patterns of disease that are so critical to the diagnostic process? Embryologists have demonstrated great diversity in the vasculature of different organs. Unique quantitative and qualitative features become apparent in vascular territories as early as the third week of gestation. These differences are later amplifed by the effects of further development, aging, infection, spontaneous mutations and other co-morbidities. Based on data from these observations a testable hypothesis would be that many forms of vasculitis may begin with emergence of new antigens within affected vessel walls and the resulting immune response may in fact be a normal reaction to perceived foreign protein(s).

Vasculitic syndromes are among the most complicated diseases for primary care physicians and rheumatologists to diagnose and treat. There are a myriad of symptoms that can be mimicked by other conditions, and choice of medications can be complex. Some agents are toxic and determining which to prescribe and for how long can be a multifaceted, complex decision process. Developing new treatments and new ways of using already available therapies, while minimizing potential side effects, are of paramount importance. This review will focus on recently published data that could have an impact on the way we treat systemic vasculitis patients.

Gout is the most common infammatory arthritis in the United States, with more than three million sufferers. Management of gout has changed relatively little in the past 50 years, despite the fact that many gout patients have contrain-dications to one or more currently available gout therapies. However, recent insights into gout pathophysiology suggest that time is ripe for a change. This article reviews recent updates in the management of gout, including new insights into dietary management that may permit better control of hyuperuricemia. Also reviewed are the biological and clinical data behind newly-developed drugs for gout that are likely to receive wserious consideration for FDA approval, and clinical use, in the foreseeable future.

Estimating an individual’s fracture risk is the most signifcant factor for determining the need to initiate bone strengthening treatment in the postmenopausal woman. Fracture risk in inversely and most strongly related to an individual’s bone mineral density values, but other factors including age, prior fracture history, body mass index, general health, family history of fractures, corticosteroid use, and smoking history also infuence the risk of subsequent fractures. Fracture risk assessment tools such as the World Health Organization’s FRAX tool and the Study of Osteoporotic Fractures Index provide 10- and 5-year fracture probability estimates, respectively, and using these tools can be particularly helpful in assessing the immediate need to initiate treatment in younger postmenopausal women. Perimenopausal and postmenopausal bone loss averages about 1% per year with more annual bone loss occurring in trabecular than cortical bone and during a normal life span such bone loss can exceed 35% of an individual’s bone mass. Younger postmenopausal women with low bone mineral density values, a history of a previous fracture, greater rates of bone loss as measured by bone turnover markers are more likely to need bone strengthening treatment at an earlier age in the postmenopausal period. Treatment measures include adequate amounts of dietary and supplemental calcium and vitamin D, a routine of regular exercises and medications that reduce the rate of new fractures.

While research in osteoarthritis has focused on the events that lead to the destruction of articular cartilage, recent evidence suggests that two other components of the joints—bone and synovium—also play key roles in pathogenesis. All three tissues undergo alterations in concert at the structural levels in response to mechanical stress and joint malalignment. Advanced imaging studies such as MRI support this interdependence, revealing the classical changes of joint space narrowing and cartilage degeneration as well as the more recently appreciated bone marrow lesions and synovitis that may correlate with clinical symptoms. Molecular evidence also points to a coordinated release of cytokines and other inflammatory mediators from each of the three tissues together in progression of disease, although we are still in search of biochemical signatures that will predict the subset of patients who progress more quickly—and who will provide key clues to successful molecular targets in future therapies. At this time we lack definitive evidence pointing to which, if any, of the three tissues should serve as the main target for disease modification or structure protection, although most efforts have focused on cartilage. Thus current therapies focus on controlling symptoms, while research efforts search for reliable imaging and molecular biomarkers to help guide future trials of potential disease-modifying agents

Historically plain radiography has been the primary investigative tool by which structure in osteoarthritis is measured. Magnetic resonance imaging (MRI) is widely used in medical diagnosis for its various advantageous features, such as high-resolution capability, the ability to produce an arbitrary anatomic cross-sectional image, and wide range of available tissue contrast. Its ability to image features such as the subchondral bone, cartilage and soft tissue structures means that its application in knee osteoarthritis (OA) raises hope of improving our understanding of structural associations of pain and function in OA joints, previously based on conventional radiography. Additionally, MRI has the potential for assessing the effect of risk factors for epidemiologic investigation and the effectiveness of therapeutic interventions in OA clinical trials.

We are currently witnessing an explosion of information about the genetic contribution to complex human diseases such as systemic lupus erythematosus (SLE). These genetic discoveries have profound implications for efforts to more fully characterize etiologic pathways and mechanisms. Further, these etiologic insights should lead to improved diagnostic and prognostic tools and inform the development of more specifc therapies for SLE and related conditions. The article summarizes the evidence supporting a role for genetic factors in SLE, highlights the clinical and genetic complexity of the disease, reviews the genes that have established contributions to the risk of SLE and specifc disease manifestations, and discusses the recent data emerging from genomewide association studies of SLE.

Cardiovascular morbidity and mortality in SLE is increased in patient with established disease, and SLE itself has been determined to be an independent risk factor for cardiovascular events. Autopsy studies have demonstrated that the coronary vessels of SLE patients have atherosclerotic plaque, and most cardiovascular events are not attributable to active vasculitis. It is believed that patients with infammatory disease, including SLE, are more likely to have vulnerable plaque rupture, accounting for more frequent events. Elevated homocysteine levels have been associated with the presence and progression of atherosclerotic plaque. Enzyme polymorphisms involved in the folatehomocysteine pathway do not seem to contribute to differences in homocysteine concentration or atherosclerotic plaque. Recently, endothelial dysfunction has been identifed as an early abnormality in ASCVD, and has been demonstrated in the vessels of SLE patients. Premature cardiovascular disease in SLE patients is likely attributable to the consequences of infammation. There is preliminary evidence that type I interferons maybe the initial stimulation of the cascade of atherosclerotic development, starting with endothelial damage, and abnormal vascular repair.

This review addresses new clinical issues (revealed at the 2006 Sydney update of the 1999 Sapporo Classifcation criteria; cardiac, renal, and multiple sclerosis-like disease; catastrophic syndrome), mechanisms of action of antiphospholipid antibody (very likely complement mediated), current therapies (moderate dose warfarin recommended for prophylaxis, aspirin not recommended for primary prophylaxis), and potential new therapies.

Systemic sclerosis (SSc) is a complex and heterogeneous chronic illness characterized by substantial patient to patient variability in clinical manifestations, internal organ involvement, and outcome. Genetic factors contribute to disease susceptibility, but environmental infuences also play a significant role. The pathogenesis of SSc encompasses vascular, immunological, and fbrotic processes, which contribute to clinical manifestations and morbidity and must be addressed in the treatment plan. Although vascular interventions appear to reduce the frequency and severity of complications, such as scleroderma renal crisis and pulmonary hypertension, current therapies generally target the immune component of SSc in a non-selective fashion and have largely failed as diseases-modifying interventions. Newer insights into the mechanisms underlying autoimmunity, vascular injury and destruction, and particularly tissue fbrosis provide novel potential targets for therapy. Transforming growth factor-ß is a ubiquitous cytokine that appears to contribute to fbroblast activation, collagen overproduction, and pathological tissue fbrosis. Neutralizing antibodies and small molecules that block TGF-ß activation or function are effective in shutting down TGF-ß signaling and selectively inhibit the progression of fbrosis and may be entering clinical trials for the treatment of SSc.

There has been a burgeoning interest in the spondyloarthritides (SpAs) due to a confuence of elements. Basic science research has provided new insight into the unique pathophysiology of synovium, enthesium, and bone, highlighting the important differences from rheumatoid arthritis (RA). Through collaborative research of international working groups, classifcation criteria for psoriatic arthritis (PsA) and ankylosing spondylitis (AS) have been developed or are being refned to aid characterization and diagnosis of SpAs and aid in research. These same working groups, under the umbrella of Outcome Measures in Rheumatology Clinical Trials (OMERACT), have developed domain core sets to be measured in clinical trials and registries, and which allow validation of reliable outcome measures. Both through clinical trials and observational data from national clinical registries, the relative effectiveness and safety of old and new therapies are being demonstrated. This has been particularly shown with long-term data on anti-TNF therapy. Newer anti-TNF therapies are being developed, as are treatments with different mechanisms of action in order to treat patients who do not have long-term effectiveness or develop side effects to older disease modifying therapy and anti-TNFs. International treatment recommendations have been or are being developed based on the evidence base from clinical trials.

Therapeutics options for rheumatoid arthritis (RA) have increased tremendously in the past decade with the introduction of biological agents in 1999. Several different cellular and cytokine targets have been identifed, with specifc inhibitors now approved to treat RA, including the tumor necrosis factor (TNF) antagonists (adalimumab, etanercept, infiximab), an interleukin 1 (IL1) antagonist (anakinra), an inhibitor of T cell co-stimulation (abatacept), and a selective depleter of B cells (rituximab). As research has progressed, additional promising targets have been identifed. Results from RA studies using several new agents have been reported in the last year. Some of these compounds are similar to agents already available, with additional TNF inhibitors (certolizumab pegol, golimumab) and agents targeting CD20 (ocrelizumab, ofatumumab, TRU-015) in development. Other agents are directed toward new cytokine targets, including IL-6 (tocilizumab), and lymphotoxin pathways (briobacept), as well as other B-cell targets, to include BLyS and APRIL (belimumab, atacicept). Additional small molecule therapies have been studied that are directed against intracellular kinases, including JAK-3 and Syk. This article provides a brief update of data from selected clinical trials in RA, highlighting effcacy, and mechanism-based safety concerns.

A quantitative count of swollen and tender joints is a primary measure to assess patients with rheumatoid arthritis (RA), and is weighted of higher value than the other 5 Core Data Set measures in all indices in which it is included. However a number of limitations of the swollen and tender joint count have been described in the rheumatology literature, including poor reproducibility, with a requirement to be performed by the same observer at each visit; likelihood to improve with placebo treatment as much or more than the other 5 RA Core Data Set measures in clinical trials; similar or lower relative effciencies than global and patient measures to document differences between active and control treatments in clinical trials; improvement over 5 years in clinical care, while joint damage and functional disability may progress; and lower sensitivity to detect infammatory activity than ultrasound. Most visits to a rheumatologist do not include a formal quantitative joint count. It may be suggested that a careful qualitative joint count, supplemented by quantitative patient self-report questionnaire scores, may be more than adequate to monitor and document changes in patient status in busy clinical settings.

In the feld of autoimmunity, much has been learned from studying circulating and tissue bound immune-reactive cells, cytokines and antibodies. However, what has brought those cells to the site of injury, for most forms of vasculitis remains a mystery. Might the etiology of at least certain forms of vasculitis be related to generation of neoantigens in the native vessel, making that vessel the target of a pathogenic immune response? How might one explain organ targeting and patterns of disease that are so critical to the diagnostic process? Embryologists have demonstrated great diversity in the vasculature of different organs. Unique quantitative and qualitative features become apparent in vascular territories as early as the third week of gestation. These differences are later amplifed by the effects of further development, aging, infection, spontaneous mutations and other co-morbidities. Based on data from these observations a testable hypothesis would be that many forms of vasculitis may begin with emergence of new antigens within affected vessel walls and the resulting immune response may in fact be a normal reaction to perceived foreign protein(s).

Vasculitic syndromes are among the most complicated diseases for primary care physicians and rheumatologists to diagnose and treat. There are a myriad of symptoms that can be mimicked by other conditions, and choice of medications can be complex. Some agents are toxic and determining which to prescribe and for how long can be a multifaceted, complex decision process. Developing new treatments and new ways of using already available therapies, while minimizing potential side effects, are of paramount importance. This review will focus on recently published data that could have an impact on the way we treat systemic vasculitis patients.

Gout is the most common infammatory arthritis in the United States, with more than three million sufferers. Management of gout has changed relatively little in the past 50 years, despite the fact that many gout patients have contrain-dications to one or more currently available gout therapies. However, recent insights into gout pathophysiology suggest that time is ripe for a change. This article reviews recent updates in the management of gout, including new insights into dietary management that may permit better control of hyuperuricemia. Also reviewed are the biological and clinical data behind newly-developed drugs for gout that are likely to receive wserious consideration for FDA approval, and clinical use, in the foreseeable future.

Estimating an individual’s fracture risk is the most signifcant factor for determining the need to initiate bone strengthening treatment in the postmenopausal woman. Fracture risk in inversely and most strongly related to an individual’s bone mineral density values, but other factors including age, prior fracture history, body mass index, general health, family history of fractures, corticosteroid use, and smoking history also infuence the risk of subsequent fractures. Fracture risk assessment tools such as the World Health Organization’s FRAX tool and the Study of Osteoporotic Fractures Index provide 10- and 5-year fracture probability estimates, respectively, and using these tools can be particularly helpful in assessing the immediate need to initiate treatment in younger postmenopausal women. Perimenopausal and postmenopausal bone loss averages about 1% per year with more annual bone loss occurring in trabecular than cortical bone and during a normal life span such bone loss can exceed 35% of an individual’s bone mass. Younger postmenopausal women with low bone mineral density values, a history of a previous fracture, greater rates of bone loss as measured by bone turnover markers are more likely to need bone strengthening treatment at an earlier age in the postmenopausal period. Treatment measures include adequate amounts of dietary and supplemental calcium and vitamin D, a routine of regular exercises and medications that reduce the rate of new fractures.

While research in osteoarthritis has focused on the events that lead to the destruction of articular cartilage, recent evidence suggests that two other components of the joints—bone and synovium—also play key roles in pathogenesis. All three tissues undergo alterations in concert at the structural levels in response to mechanical stress and joint malalignment. Advanced imaging studies such as MRI support this interdependence, revealing the classical changes of joint space narrowing and cartilage degeneration as well as the more recently appreciated bone marrow lesions and synovitis that may correlate with clinical symptoms. Molecular evidence also points to a coordinated release of cytokines and other inflammatory mediators from each of the three tissues together in progression of disease, although we are still in search of biochemical signatures that will predict the subset of patients who progress more quickly—and who will provide key clues to successful molecular targets in future therapies. At this time we lack definitive evidence pointing to which, if any, of the three tissues should serve as the main target for disease modification or structure protection, although most efforts have focused on cartilage. Thus current therapies focus on controlling symptoms, while research efforts search for reliable imaging and molecular biomarkers to help guide future trials of potential disease-modifying agents

Historically plain radiography has been the primary investigative tool by which structure in osteoarthritis is measured. Magnetic resonance imaging (MRI) is widely used in medical diagnosis for its various advantageous features, such as high-resolution capability, the ability to produce an arbitrary anatomic cross-sectional image, and wide range of available tissue contrast. Its ability to image features such as the subchondral bone, cartilage and soft tissue structures means that its application in knee osteoarthritis (OA) raises hope of improving our understanding of structural associations of pain and function in OA joints, previously based on conventional radiography. Additionally, MRI has the potential for assessing the effect of risk factors for epidemiologic investigation and the effectiveness of therapeutic interventions in OA clinical trials.