WRITING GROUP MEMBERS Emelia J. Benjamin, MD, SCM, FAHA Michael J. Blaha, MD, MPH Stephanie E. Chiuve, ScD Mary Cushman, MD, MSc, FAHA Sandeep R. Das, MD, MPH, FAHA Rajat Deo, MD, MTR Sarah D. de Ferranti, MD, MPH James Floyd, MD, MS Myriam Fornage, PhD, FAHA Cathleen Gillespie, MS Carmen R. Isasi, MD, PhD, FAHA Monik C. Jiménez, ScD, SM Lori Chaffin Jordan, MD, PhD Suzanne E. Judd, PhD Daniel Lackland, DrPH, FAHA Judith H. Lichtman, PhD, MPH, FAHA Lynda Lisabeth, PhD, MPH, FAHA Simin Liu, MD, ScD, FAHA Chris T. Longenecker, MD Rachel H. Mackey, PhD, MPH, FAHA Kunihiro Matsushita, MD, PhD, FAHA Dariush Mozaffarian, MD, DrPH, FAHA Michael E. Mussolino, PhD, FAHA Khurram Nasir, MD, MPH, FAHA Robert W. Neumar, MD, PhD, FAHA Latha Palaniappan, MD, MS, FAHA Dilip K. Pandey, MBBS, MS, PhD, FAHA Ravi R. Thiagarajan, MD, MPH Mathew J. Reeves, PhD Matthew Ritchey, PT, DPT, OCS, MPH Carlos J. Rodriguez, MD, MPH, FAHA Gregory A. Roth, MD, MPH Wayne D. Rosamond, PhD, FAHA Comilla Sasson, MD, PhD, FAHA Amytis Towfighi, MD Connie W. Tsao, MD, MPH Melanie B. Turner, MPH Salim S. Virani, MD, PhD, FAHA Jenifer H. Voeks, PhD Joshua Z. Willey, MD, MS John T. Wilkins, MD Jason HY. Wu, MSc, PhD, FAHA Heather M. Alger, PhD Sally S. Wong, PhD, RD, CDN, FAHA Paul Muntner, PhD, MHSc On behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee Heart Disease and Stroke Statistics—2017 Update

Heart Disease and Stroke Statistics—2017 Update: A Report From the American Heart Association

Objective The 1987 American College of Rheumatology (ACR; formerly the American Rheumatism Association) classifi cation criteria for rheumatoid arthritis (RA) have been criticised for their lack of sensitivity in early disease. This work was undertaken to develop new classifi cation criteria for RA. Methods A joint working group from the ACR and the European League Against Rheumatism developed, in three phases, a new approach to classifying RA. The work focused on identifying, among patients newly presenting with undifferentiated infl ammatory synovitis, factors that best discriminated between those who were and those who were not at high risk for persistent and/ or erosive disease—this being the appropriate current paradigm underlying the disease construct ‘RA’. Results In the new criteria set, classifi cation as ‘defi nite RA’ is based on the confi rmed presence of synovitis in at least one joint, absence of an alternative diagnosis better explaining the synovitis, and achievement of a total score of 6 or greater (of a possible 10) from the individual scores in four domains: number and site of involved joints (range 0–5), serological abnormality (range 0–3), elevated acute-phase response (range 0–1) and symptom duration (two levels; range 0–1). Conclusion This new classifi cation system redefi nes the current paradigm of RA by focusing on features at earlier stages of disease that are associated with persistent and/or erosive disease, rather than defi ning the disease by its late-stage features. This will refocus attention on the important need for earlier diagnosis and institution of effective disease-suppressing therapy to prevent or minimise the occurrence of the undesirable sequelae that currently comprise the paradigm underlying the disease construct ‘RA’.

/pdf/2010-rheumatoid-arthritis-classification-criteria-an-h6w7bcnbf6.pdf

2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative.

The 11th edition of Harrison's Principles of Internal Medicine welcomes Anthony Fauci to its editorial staff, in addition to more than 85 new contributors. While the organization of the book is similar to previous editions, major emphasis has been placed on disorders that affect multiple organ systems. Important advances in genetics, immunology, and oncology are emphasized. Many chapters of the book have been rewritten and describe major advances in internal medicine. Subjects that received only a paragraph or two of attention in previous editions are now covered in entire chapters. Among the chapters that have been extensively revised are the chapters on infections in the compromised host, on skin rashes in infections, on many of the viral infections, including cytomegalovirus and Epstein-Barr virus, on sexually transmitted diseases, on diabetes mellitus, on disorders of bone and mineral metabolism, and on lymphadenopathy and splenomegaly. The major revisions in these chapters and many

Harrison's Principles of Internal Medicine

Author(s): Writing Group Members; Mozaffarian, Dariush; Benjamin, Emelia J; Go, Alan S; Arnett, Donna K; Blaha, Michael J; Cushman, Mary; Das, Sandeep R; de Ferranti, Sarah; Despres, Jean-Pierre; Fullerton, Heather J; Howard, Virginia J; Huffman, Mark D; Isasi, Carmen R; Jimenez, Monik C; Judd, Suzanne E; Kissela, Brett M; Lichtman, Judith H; Lisabeth, Lynda D; Liu, Simin; Mackey, Rachel H; Magid, David J; McGuire, Darren K; Mohler, Emile R; Moy, Claudia S; Muntner, Paul; Mussolino, Michael E; Nasir, Khurram; Neumar, Robert W; Nichol, Graham; Palaniappan, Latha; Pandey, Dilip K; Reeves, Mathew J; Rodriguez, Carlos J; Rosamond, Wayne; Sorlie, Paul D; Stein, Joel; Towfighi, Amytis; Turan, Tanya N; Virani, Salim S; Woo, Daniel; Yeh, Robert W; Turner, Melanie B; American Heart Association Statistics Committee; Stroke Statistics Subcommittee

Heart Disease and Stroke Statistics—2016 Update: A Report From the American Heart Association

Objective The 1987 American College of Rheumatology (ACR; formerly the American Rheumatism Association) classification criteria for rheumatoid arthritis (RA) have been criticised for their lack of sensitivity in early disease. This work was undertaken to develop new classification criteria for RA. Methods A joint working group from the ACR and the European League Against Rheumatism developed, in three phases, a new approach to classifying RA. The work focused on identifying, among patients newly presenting with undifferentiated inflammatory synovitis, factors that best discriminated between those who were and those who were not at high risk for persistent and/or erosive disease—this being the appropriate current paradigm underlying the disease construct ‘RA’. Results In the new criteria set, classification as ‘definite RA’ is based on the confirmed presence of synovitis in at least one joint, absence of an alternative diagnosis better explaining the synovitis, and achievement of a total score of 6 or greater (of a possible 10) from the individual scores in four domains: number and site of involved joints (range 0–5), serological abnormality (range 0–3), elevated acute-phase response (range 0–1) and symptom duration (two levels; range 0–1). Conclusion This new classification system redefines the current paradigm of RA by focusing on features at earlier stages of disease that are associated with persistent and/or erosive disease, rather than defining the disease by its late-stage features. This will refocus attention on the important need for earlier diagnosis and institution of effective disease-suppressing therapy to prevent or minimise the occurrence of the undesirable sequelae that currently comprise the paradigm underlying the disease construct ‘RA’.

https://ard.bmj.com/content/annrheumdis/69/9/1580.full.pdf

2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative.

The validity of research into risk factors for the development of rheumatic conditions and their sequelae can be threatened by selection bias. In this Review, the authors outline potentially major selection bias issues in rheumatic disease research and suggest approaches which could be used to help limit the impact of these biases on future research. The identification of modifiable risk factors for the development of rheumatic conditions and their sequelae is crucial for reducing the substantial worldwide burden of these diseases. However, the validity of such research can be threatened by sources of bias, including confounding, measurement and selection biases. In this Review, we discuss potentially major issues of selection bias—a type of bias frequently overshadowed by other bias and feasibility issues, despite being equally or more problematic—in key areas of rheumatic disease research. We present index event bias (a type of selection bias) as one of the potentially unifying reasons behind some unexpected findings, such as the 'risk factor paradox'—a phenomenon exemplified by the discrepant effects of certain risk factors on the development versus the progression of osteoarthritis (OA) or rheumatoid arthritis (RA). We also discuss potential selection biases owing to differential loss to follow-up in RA and OA research, as well as those due to the depletion of susceptibles (prevalent user bias) and immortal time bias. The lesson remains that selection bias can be ubiquitous and, therefore, has the potential to lead the field astray. Thus, we conclude with suggestions to help investigators avoid such issues and limit the impact on future rheumatology research.

/pdf/selection-bias-in-rheumatic-disease-research-57uw9y2l2p.pdf

Selection bias in rheumatic disease research

Objective Patients with SLE have increased morbidity and premature mortality. Whether this mortality gap has improved in recent years, as in RA, is unknown. Methods We conducted a population-based cohort study using a medical records database representative of the general population of the UK. We identified incident SLE cases and matched non-SLE controls between 1999 and 2014, divided into two subgroups based on year of SLE diagnosis, forming the early cohort (1999-2006) and late cohort (2007-14). We compared the mortality rates and hazard ratios, adjusting for potential confounders. Results We identified 1470 and 1666 incident SLE cases in the early and late cohorts, respectively. In both cohorts, SLE patients had similar levels of excess mortality compared with their matched comparators [15.9 vs 7.9 deaths/1000 person-years (PY) in the early cohort and 13.8 vs 7.0 deaths/1000 PY in the late cohort]. The corresponding mortality hazard ratios were 2.15 (95% CI 1.63, 2.83) and 2.12 (95% CI 1.61, 2.80) in the early and late cohorts, respectively (P-value for interaction = 0.95). The absolute mortality differences were 8.0 (95% CI 4.3, 11.8) and 6.8 (95% CI 3.5, 10.0) deaths/1000 PY, respectively (P-value for interaction = 0.61). Conclusion This general population-based cohort study suggests that excess mortality has not improved among SLE patients in recent years, remaining greater than double that of comparators, unlike RA during the same period. This highlights a critical unmet need for the development of new therapeutic agents and improved management strategies for SLE and its comorbidities.

/pdf/unchanging-premature-mortality-trends-in-systemic-lupus-34ivcp93jz.pdf

Unchanging premature mortality trends in systemic lupus erythematosus: a general population-based study (1999-2014).

Objectives. While studies have suggested that gout and hyperuricaemia are associated with the risk of premature death, none has investigated the role of urate-lowering therapy on this critical outcome. We examined the impact of allopurinol, the most commonly used urate-lowering drug, on the risk of mortality in hyperuricaemic patients.

Methods. From a population of hyperuricaemic veterans of [serum urate level >416 μmol/l (7.0 mg/dl)] at least 40 years of age, we compared the risk of death between incident allopurinol users (n = 2483) and non-users (n = 7441). We estimated the multivariate mortality hazard ratio (HR) of allopurinol use with Cox proportional hazards models.

Results. Of the 9924 veterans (males, 98% and mean age 62.7 years), 1021 died during the follow-up. Patients who began treatment with allopurinol had worse prognostic factors for mortality, including higher BMI and comorbidities. After adjusting for baseline urate levels, allopurinol treatment was associated with a lower risk of all-cause mortality (HR 0.78; 95% CI 0.67, 0.91). Further adjustment with other prognostic factors did not appreciably alter this estimate (HR 0.77; 95% CI 0.65, 0.91). The mean change from baseline in serum urate within the allopurinol group was −111 μmol/l (−1.86 mg/dl). Adjusting for baseline urate level, allopurinol users had a 40 μmol/l (0.68 mg/dl) lower follow-up serum urate value than controls (95% CI −0.55, −0.81).

Conclusion. Our findings indicate that allopurinol treatment may provide a survival benefit among patients with hyperuricaemia.

Allopurinol and mortality in hyperuricaemic patients

Knee osteoarthritis (OA) is the most common joint disorder among adults in the US and severity of knee radiographic OA (ROA) is strongly associated with knee pain1. Pain from knee OA accounts for a large proportion of limitations with common activities of daily living2, and it is also the main reason for total knee replacement3. Because of the impact of symptoms from knee OA, people with symptomatic knee OA may be more motivated to take steps to prevent disease progression than those without ROA. Thus, investigators and persons with knee OA are particularly interested in risk factors that are associated with ROA progression because such knowledge will provide insightful guidance for secondary prevention4.

Over the past few decades, many observational studies have examined risk factors for the occurrence (i.e., incident) and worsening (i.e., progressive) of knee OA. Several risk factors (i.e., female gender, obesity, high bone mineral density (BMD), joint injury, repetitive occupational stress on joints, and certain sports) have been found to be strongly associated with an increased risk for incident knee ROA5, 6. In contrast, findings on risk factors for ROA progression have been inconclusive. Except for the level of serum hyaluronic acid and generalized OA, no other risk factor has been consistently associated with the risk of ROA progression7. Interestingly, some risk factors (e.g., high BMD, low vitamin C) increase the risk of incident knee ROA but are not associated with, or even decrease, the risk of ROA progression8-11.

This paradoxical phenomenon is not limited to studies of ROA. Many studies have shown that overweight and obesity increase the risk of cardiovascular disease; however, a number of studies have also reported that among subjects with preexisting cardiovascular disease, those who are overweight or moderately obese have an improved survival and lower risk of major cardiovascular events compared with subjects with normal weight12. These findings have been termed the “obesity paradox”. Similarly, while low body mass index (BMI) is associated with increased incident chronic obstructive pulmonary disease13, it does not, however, increase the risk of recurrent exacerbations of the disease14. While the risk factors for incident events may be biologically different from those for secondary events, there are also compelling methodological explanations behind such discrepancies.

In this paper, we provide several explanations that may underlie the discrepancy between findings for knee ROA progression and those for knee ROA incidence. To be consistent with most studies, we consider knees eligible for studies of ROA progression being those that have preexisting mild (K/L=2) or moderate (K/L=3) ROA at baseline. We discuss how study design, study implementation, and outcome measures in studies of ROA progression can potentially bias the effect estimates of risk factors of interest using causal diagrams15. We also present findings from several large prospective studies of ROA progression to facilitate our explanations wherever applicable.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/acr.20287

Methodologic challenges in studying risk factors for progression of knee osteoarthritis

Objectives. To evaluate the person-level impact of weight loss on serum urate levels among men with a high cardiovascular risk profile.

Methods. We analysed 12 379 men (mean serum urate level = 407 μmol/l) from the Multiple Risk Factor Intervention Trial, using data prospectively collected at baseline and annually over a 7-year period (78 881 visits). Our endpoint was normouricaemia, defined by serum urate levels ≤360 μmol/l, a widely accepted therapeutic target. Person-level effects were estimated using conditional logistic regression models to adjust for time-varying covariates (age, congestive heart failure, hypertension, diuretic use, renal function, alcohol intake and dietary factors).

Results. There was a graded relation between weight loss and achieving normouricaemia (P-value for trend <0.001). Compared with no weight change (−0.9 to 0.9 kg), the multivariate odds ratios of achieving normouricaemia for a weight loss of 1–4.9, 5–9.9 and ≥10 kg were 1.43 (95% CI: 1.33, 1.54), 2.17 (1.95, 2.40) and 3.90 (3.31, 4.61), respectively. The corresponding serum urate level changes were −7, −19 and −37 μmol/l (−0.12, −0.31 and −0.62 mg/dl). Similar levels of associations persisted among subgroups stratified by demographics, presence of gout, hypertension, diuretic use, renal insufficiency, alcohol intake, trial group assignment and adiposity categories (all P-values for trend <0.001).

Conclusions. Weight reduction could help achieve a widely accepted therapeutic urate target level (≤360 μmol/l) among men with a high cardiovascular risk profile. Although the urate-lowering effect appeared weaker than that of urate-lowering drugs, other associated health benefits would make weight reduction important, particularly in this population.

Hyon K. Choi

Papers

Selection bias in rheumatic disease research

Unchanging premature mortality trends in systemic lupus erythematosus: a general population-based study (1999-2014).

Allopurinol and mortality in hyperuricaemic patients

Methodologic challenges in studying risk factors for progression of knee osteoarthritis

The serum urate-lowering impact of weight loss among men with a high cardiovascular risk profile: the Multiple Risk Factor Intervention Trial