Gim Gee Teng

American College of Rheumatology 2008 Recommendations for the Use of Nonbiologic and Biologic Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis

Guidelines and recommendations developed and/or endorsed by the American College of Rheumatology (ACR) are intended to provide guidance for particular patterns of practice and not to dictate the care of a particular patient. The ACR considers adherence to these guidelines and recommendations to be voluntary, with the ultimate determination regarding their application to be made by the physician in light of each patient’s individual circumstances. Guidelines and recommendations are intended to promote beneficial or desirable outcomes but cannot guarantee any specific outcome. Guidelines and recommendations developed or endorsed by the ACR are subject to periodic revision as warranted by the evolution of medical knowledge, technology, and practice.

Pathophysiology, clinical presentation and treatment of gout.

Gout is a common form of inflammatory arthritis that has been managed primarily in general medical practices for centuries. It appears that there has been an increasing prevalence of gout over the past decades, implying a growing public health burden. Accurate diagnosis and recognition of the various stages and manifestations of gout enable realistic goal setting for management. Recent evidence suggests new risk factors and potentially refutes others. Management of gout requires characterising and modifying risk factors and associated disorders, and commonly initiating drug therapy. Pharmacotherapy of gout includes the management of acute flares with anti-inflammatory agents such as NSAIDs and glucocorticoids and long-term treatment with urate-lowering drugs. Although pharmacotherapy is generally safe and effective, there are caveats and limitations to all gout therapies. Patient non-adherence and errors with the use of drugs for gout treatment are important factors leading to medical failures. With early intervention, careful monitoring and patient education, gout is a condition that can be managed very effectively. The advent of new drugs (such as febuxostat and urate oxidase [uricase]) and enhanced understanding of the pathogenesis of gout continue to improve our therapeutic options, particularly in a subset of patients with refractory disease and those who are intolerant to currently available medications.

Mortality due to coronary heart disease and kidney disease among middle-aged and elderly men and women with gout in the Singapore Chinese Health Study

Objectives Whether the link between gout and mortality is causal or confounded by lifestyle factors or comorbidities remains unclear. Studies in Asia are warranted due to the rapid modernisation of the locale and ageing of the population. Methods The association between gout and mortality was examined in a prospective cohort, the Singapore Chinese Health Study, comprising 63 257 Singapore Chinese individuals, aged 45–74 years during the enrolment period of 1993–8. All enrollees were interviewed in person on lifestyle factors, current diet and medical histories. All surviving cohort members were contacted by telephone during 1999–2004 to update selected exposure and medical histories (follow-up I interview), including the history of physician-diagnosed gout. Cause-specific mortality in the cohort was identified via record linkage with the nationwide death registry, up to 31 December 2009. Results Out of 52 322 participants in the follow-up I interview, 2117 (4.1%) self-reported a history of physician-diagnosed gout, with a mean age at diagnosis of 54.7 years. After a mean follow-up period of 8.1 years, there were 6660 deaths. Relative to non-gout subjects, subjects with gout had a higher risk of death (HR 1.18; 95% CI 1.06 to 1.32), and specifically from death due to coronary heart disease (CHD) (HR 1.38, 95% CI 1.10 to 1.73) and kidney disease (HR 5.81, 95% CI 3.61 to 9.37). All gout–mortality risk associations were present in both genders but the risk estimates appeared higher for women. Conclusion Gout is an independent risk factor for mortality, and specifically for death due to CHD and kidney disease.

Abatacept: a costimulatory inhibitor for treatment of rheumatoid arthritis

T cell costimulation is believed to be crucial in orchestrating immune responses that lead to inflammation and destruction in rheumatoid arthritis (RA). Abatacept is a novel recombinant CTLA4Ig fusion protein that selectively modulates costimulation via interrupting the CD28:CD80/86 pathway, resulting in downregulation of T cell activation and multiple ensuing effector mechanisms. Abatacept has been shown to be efficacious, either when given alone or in combination with methotrexate, in patients with active RA, including anti-TNF failures. Improvements in clinical signs and symptoms, slowing of radiological progression, and enhancement in patient function and pain have been reported in clinical trials. Infusions were well-tolerated with a favourable safety profile similar to placebo and no appreciable immunogenicity. Abatacept is the first in a new class of biological response modifiers called costimulatory blockers.

Association of infections and tuberculosis with antitumor necrosis factor alpha therapy.

Purpose of reviewRheumatoid arthritis patients have higher risk for infections due to comorbidities, underlying immunosuppresion and use of glucocorticoids and disease modifying antirheumatic drugs. The association between treatment with antitumor necrosis factor alpha agents and serious infections, including opportunistic infections such as tuberculosis, in rheumatoid arthritis patients remains controversial. We present recent literature on this topic with a focus on clinical applications of this new data. Recent findingsProspective cohort studies and population-based registries have described the incidence and risk of serious infections in large rheumatoid arthritis patient populations of antitumor necrosis factor alpha users. Although some studies have suggested a one and one-half to two-fold increased risk, especially immediately after initiating the treatment, not all have shown an elevated risk for serious bacterial infections or tuberculosis. SummaryAlthough antitumor necrosis factor alpha agents may be independent risk factors for infections there is an absolute low rate of infection in those treated with these agents (approximately 5 per 100 patient-years). Screening for latent tuberculosis with tuberculin skin testing is effective, and compliance with the recommendations for preventing this disease in recipients of antitumor necrosis factor alpha agents has partially decreased the risk of infections. Clinical suspicion toward developing infection in those being treated with antitumor necrosis factor alpha agents, particularly earlier in the treatment course, is important for effective management of patients.

Biologics and heart failure in rheumatoid arthritis: are we any wiser?

Purpose of reviewTo summarize the recent literature concerning the role of TNF-α in heart failure, epidemiology of heart failure in rheumatoid arthritis and risk of heart failure associated with biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Recent findingsTNF-α has been implicated in the pathogenesis of heart failure. It has direct deleterious effects on the myocardium in the setting of acute injury or chronic heart failure. In animal models, TNF-α is important in cardiac remodeling, leading to cardiac dysfunction following acute injury. Both incident and worsening heart failure have been reported in patients with rheumatoid arthritis who are treated with anti-TNF-α therapy. Recent cohort studies, however, have shown no increased risk and, in some, a protective effect on the risk of heart failure. Certain traditional cardiovascular risk factors have a relatively lesser contribution to cardiovascular morbidity and mortality in patients with rheumatoid arthritis, suggesting that disease-related perturbations of the cytokine network may contribute to the excess risk of heart failure in these patients. SummaryOverall mortality in rheumatoid arthritis has remained stagnant despite advances in rheumatoid arthritis and heart failure management and improved cardiovascular mortality in the general population. Heart failure prevalence is increased in patients with rheumatoid arthritis and leads to greater mortality. Despite current expert consensus contraindicating the use of anti-TNF-α agents in patients with moderate to severe heart failure, epidemiological studies in rheumatoid arthritis have not consistently substantiated this association.

The NLRP3 inflammasome affects DNA damage responses after oxidative and genotoxic stress in dendritic cells

The NOD‐like receptor (NLR) family pyrin domain‐containing 3 (NLRP3) inflammasome is a cytoplasmic protein complex that mediates inflammatory responses to a broad array of danger signals. The inflammasome drives caspase‐1 activation and promotes secretion of the pro‐inflammatory cytokines IL‐1β and IL‐18, and might also participate in other cellular processes. Here, we tried to identify new pathways regulated by the NLRP3 inflammasome in murine dendritic cells (DCs) in response to monosodium urate (MSU) crystals. Using a transcriptomic approach, we found that DCs from Nlrp3−/− mice responded to MSU with differential expression of genes involved in the DNA damage response and apoptosis. Upon exposure to MSU or other ROS‐mobilizing stimuli (rotenone and γ‐radiation), DNA fragmentation was markedly ameliorated in Nlrp3−/− and casp‐1−/− DCs compared with WT DCs. Moreover, Nlrp3−/− DCs experienced significantly less oxidative DNA damage mediated by ROS. A significant decrease of the expression of several genes involved in double‐strand and base‐excision DNA repair was observed in WT DCs. Basal DNA repair capacity in WT DCs resulted in activation and stabilization of p53 in vitro and in vivo, which resulted in increased cell death compared with that in Nlrp3−/− DCs. These data provide the first evidence for the involvement of the NLRP3 inflammasome in DNA damage responses induced by cellular stress.

Serum Urate Levels and Consumption of Common Beverages and Alcohol Among Chinese in Singapore

Western studies suggest that beverages may affect serum urate (SU) levels, but data from Asian populations are scarce. We evaluated the associations between beverages and SU levels in Singaporean Chinese.

C5a Regulates IL-1β Production and Leukocyte Recruitment in a Murine Model of Monosodium Urate Crystal-Induced Peritonitis

Gouty arthritis results from the generation of monosodium urate (MSU) crystals within joints. These MSU crystals elicit acute inflammation characterized by massive infiltration of neutrophils and monocytes that are mobilized by the pro-inflammatory cytokine IL-1β. MSU crystals also activate the complement system, which regulates the inflammatory response; however, it is unclear whether or how MSU-mediated complement activation is linked to IL-1β release in vivo, and the various roles that might be played by individual components of the complement cascade. Here we show that exposure to MSU crystals in vivo triggers the complement cascade, leading to the generation of the biologically active complement proteins C3a and C5a. C5a, but not C3a, potentiated IL-1β and IL-1α release from LPS–primed MSU-exposed peritoneal macrophages and human monocytic cells in vitro; while in vivo MSU–induced C5a mediated murine neutrophil recruitment as well as IL-1β production at the site of inflammation. These effects were significantly ameliorated by treatment of mice with a C5a receptor antagonist. Mechanistic studies revealed that C5a most likely increased NLRP3 inflammasome activation via production of reactive oxygen species (ROS), and not through increased transcription of inflammasome components. Therefore we conclude that C5a generated upon MSU-induced complement activation increases neutrophil recruitment in vivo by promoting IL-1 production via the generation of ROS, which activate the NLRP3 inflammasome. Identification of the C5a receptor as a key determinant of IL-1-mediated recruitment of inflammatory cells provides a novel potential target for therapeutic intervention to mitigate gouty arthritis.

Neurosjögren: early therapy is associated with successful outcomes.

Background Primary Sjögren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 0.6%. The frequency of neurologic manifestations in PSS varies widely from 0% to 60%. Methods We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore. Eight consecutive women (median age, 51 years [range, 38–67 years]) with neurologic manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations. Results Six of 8 patients with neurosjögren had their neurologic manifestation at time of PSS diagnosis. The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years, respectively. Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients. All our patients received early aggressive therapy with pulse corticosteroids and intravenously administered cyclophosphamide. The mean duration from initial presentation to initiation of treatment was 11 days (1–26 days). All achieved good recovery regardless of the type or site of neurologic involvement, initial erythrocyte sedimentation rate, immunoglobulin and complement levels. Conclusions Neurologic disease, when present, is a strong contributor to disease activity and damage. Confirmatory tests should be conducted early regardless of the presence of sicca symptoms. Vigilance for the development of new neurologic symptoms is imperative even in chronic, apparently stable patients. It is likely that early initiation of treatment contributed to good recovery in our patients.