Body Mass Index,Weight Loss,and Cause‐Specific Mortality in Rheumatoid Arthritis

Objective

To examine associations of body mass index (BMI) and weight loss with cause‐specific mortality in rheumatoid arthritis (RA).

Methods

A cohort of US veterans with RA was followed until death or through 2013. BMI was categorized as underweight, normal, overweight, and obese. Weight loss was calculated as the 1) annualized rate of change over the preceding 13 months, and 2) cumulative percent. Vital status and cause of death were obtained from the National Death Index. Multivariable competing‐risks regression models were utilized to assess the time‐varying associations of BMI and weight loss with cause‐specific mortality.

Results

Among 1,600 participants and 5,789 patient‐years of followup, 303 deaths occurred (95 cardiovascular, 74 cancer, and 46 respiratory). The highest weight‐loss rate and weight‐loss percent were associated with a higher risk of cardiovascular mortality (rate: subdistribution hazard ratio [sHR] 2.27 [95% confidence interval (95% CI) 1.61–3.19]; percent: sHR 2.31 [95% CI 1.06–5.01]) and cancer mortality (rate: sHR 2.36 [95% CI 1.11–5.01]; percent: sHR 1.90 [95% CI 1.00–3.62]). Overweight BMI was protective of cardiovascular mortality (sHR 0.59 [95% CI 0.38–0.91]), while underweight BMI was associated with a near 3‐fold increased risk of respiratory mortality (sHR 2.93 [95% CI 1.28–6.67]). Incorporation of time‐varying BMI and weight loss in the same models did not substantially alter individual associations for cardiovascular and cancer mortality, but an association between weight‐loss percentage and respiratory mortality was attenuated after BMI adjustment.

Conclusion

Both BMI and weight loss are predictors of cause‐specific mortality in RA. Weight loss is a strong predictor of cardiovascular and cancer mortality, while underweight BMI is a stronger predictor of respiratory mortality.     

Smoking Behavior Changes in the Early Rheumatoid Arthritis Period and Risk of Mortality During Thirty‐Six Years of Prospective Followup

Objective

To investigate whether rheumatoid arthritis (RA) diagnosis influences smoking behavior changes and whether these changes were associated with mortality.

Methods

We identified an incident RA cohort in the Nurses' Health Study (NHS; 1976–2012). Behavioral data were collected through biennial questionnaires. We created a comparison cohort, matching RA cases to women without RA by age and calendar year at the index date of RA diagnosis. To investigate smoking behavior changes in the early RA period, sustained cessation was defined as permanently quitting within 4 years of the RA/index date. We used Cox regression to obtain hazard ratios (HRs) for mortality, comparing sustained smoking cessation to continued smoking.

Results

Among 121,700 women in the NHS, we identified 938 with incident RA matched to 8,951 non‐RA comparators. Among current smokers, 40.0% with RA permanently quit smoking in the early RA period, compared to 36.1% of comparators (odds ratio for sustained cessation 1.18 [95% confidence interval (95% CI) 0.88, 1.58]). There were 313 deaths (33.4%) in the RA cohort and 2,042 (22.8%) among comparators. Compared to continued smoking, sustained cessation was associated with similarly decreased mortality in both the RA (HR 0.58 [95% CI 0.33, 1.01]) and comparison (HR 0.47 [95% CI 0.39, 0.58]) cohorts. Women with RA had higher mortality for >5 post‐RA pack‐years (HR 3.67 [95% CI 2.80, 4.81]) than comparators with >5 post‐index pack‐years (HR 1.88 [95% CI 1.62, 2.17]; P < 0.001 for interaction; reference: ever‐smoker non‐RA women with 0 post‐index pack‐years).

Conclusion

Sustained smoking cessation within 4 years of RA diagnosis reduced mortality risk, with a similar effect observed among non‐RA comparators. Smoking >5 pack‐years after RA diagnosis significantly increased mortality beyond the risk of non‐RA comparators.     

No increased mortality in patients with rheumatoid arthritis treated with biologics: results from the biologics register of six rheumatology institutes in Japan

Objective

To investigate the influence of biologics on mortality and risk factors for death in rheumatoid arthritis (RA) patients.

Methods

RA patients treated with at least one dose of biologics in daily practice in six large rheumatology institutes (“biologics cohort”) were observed until 15 May 2010 or death, whichever occurred first. Mortality of the biologics cohort and the “comparator cohort” (comprising patients among the IORRA cohort who had never been treated with biologics) was compared to that of the Japanese general population. Factors associated with mortality were assessed by a Cox model.

Results

Among 2683 patients with 6913.0 patient-years of observation, 38 deaths were identified in the biologics cohort. The probability of death in patients lost to follow-up, calculated using the weighted standardized mortality ratio (SMR), was 1.08 [95 % confidence interval (CI) 0.77–1.47] in the biologics cohort and 1.28 (95 % CI 1.17–1.41) in the comparator cohort. Pulmonary involvement was the main cause of death (47.4 %), and the disease-specific SMR of pneumonia was 4.19 (95 % CI 1.81–8.25). Risk factors for death included male gender [hazard ratio (HR) 2.78 (95 % CI 1.24–6.22)], advanced age (HR 1.07, 95 % CI 1.03–1.11), and corticosteroid dose (HR 1.08, 95 % CI 1.01–1.17).

Conclusion

Mortality in RA patients exposed to biologics did not exceed that in patients not exposed to biologics, but death from pulmonary manifestations was proportionally increased in RA patients exposed to biologics.     

The risk of congestive heart failure in rheumatoid arthritis: A population‐based study over 46 years

Objective

It is hypothesized that the systemic inflammation associated with rheumatoid arthritis (RA) promotes an increased risk of cardiovascular (CV) morbidity and mortality. We examined the risk and determinants of congestive heart failure (CHF) in patients with RA.

Methods

We assembled a population‐based, retrospective incidence cohort from among all individuals living in Rochester, Minnesota, in whom RA (defined according to the American College of Rheumatology 1987 criteria) was first diagnosed between 1955 and 1995, and an age‐ and sex‐matched non‐RA cohort. After excluding patients in whom CHF occurred before the RA index date, all subjects were followed up until either death, incident CHF (defined according to the Framingham Heart Study criteria), migration from the county, or until January 1, 2001. Detailed information from the complete medical records (including all inpatient and outpatient care provided by all local providers) regarding RA, ischemic heart disease, and traditional CV risk factors was collected. Cox models were used to estimate the effect of RA on the development of CHF, adjusting for CV risk factors and/or ischemic heart disease.

Results

The study population included 575 patients with RA and 583 subjects without RA. The CHF incidence rates were 1.99 and 1.16 cases per 100 person‐years in patients with RA and in non‐RA subjects, respectively (rate ratio 1.7, 95% confidence interval [95% CI] 1.3–2.1). After 30 years of followup, the cumulative incidence of CHF was 34.0% in patients with RA and 25.2% in non‐RA subjects (P< 0.001). RA conferred a significant excess risk of CHF (hazard ratio [HR] 1.87, 95% CI 1.47–2.39) after adjusting for demographics, ischemic heart disease, and CV risk factors. The risk was higher among patients with RA who were rheumatoid factor (RF) positive (HR 2.59, 95% CI 1.95–3.43) than among those who were RF negative (HR 1.28, 95% CI 0.93–1.78).

Conclusion

Compared with persons without RA, patients with RA have twice the risk of developing CHF. This excess risk is not explained by traditional CV risk factors and/or clinical ischemic heart disease.

     

The mortality of rheumatoid vasculitis compared with rheumatoid arthritis

Objective. To determine whether the mortality of patients with rheumatoid vasculitis (RV) is increased in comparison with that of patients with rheumatoid arthritis (RA). Methods. The mortality of all RV patients identified in 1980–1992 (n = 61) was compared with that of 244 RA controls matched for the year the diagnosis was made in the RV cases. Hazard ratios (HR) of death were calculated with a multivariate survival analysis, adjusting for age, sex, comorbidity, treatment, and parameters of RA severity. Results. The unadjusted risk of death (HR) in RV patients compared with RA controls was 1.65 (95% confidence interval [95% CI] 1.05–2.58). After adjustment for prognostic factors, the HR was reduced to 1.26 (95% CI 0.79–2.01), mainly due to removal of the effects of age and sex. No excess mortality was seen in RV patients with severe organ involvement when compared with RV patients without severe organ involvement, although the former patients were treated more often with cytostatic and immunosuppressive drugs. Infection was the main cause of death in the RV patients, and cardiovascular disease in the RA controls. Vasculitis was reported as the cause of death in only 1 RV patient. Conclusion. After allowance for general risk factors such as age and sex, there remains only a slight excess mortality in RV patients compared with RA controls.     

Mortality trends in rheumatoid arthritis: the role of rheumatoid factor

OBJECTIVE: We previously demonstrated a widening in the mortality gap between subjects with rheumatoid arthritis (RA) and the general population. We examined the contribution of rheumatoid factor (RF) positivity on overall mortality trends and cause-specific mortality. METHODS: A population-based RA incidence cohort (1955-1995, and aged >or= 18 yrs) was followed longitudinally until death or January 1, 2006. The underlying cause of death as coded from national mortality statistics and grouped according to ICD-9/10 chapters was used to define cause-specific mortality. Expected cause-specific mortality rates were estimated by applying the age-, sex-, and calendar-year-specific mortality rates from the general population to the RA cohort. Poisson regression was used to model the observed overall and cause-specific mortality rates according to RF status, accounting for age, sex, disease duration, and calendar year. RESULTS: A cohort of 603 subjects (73% female; mean age 58 yrs) with RA was followed for a mean of 16 years, during which 398 died. Estimated survival at 30 years after RA incidence was 26.0% in RF+ RA subjects compared to 36.0% expected (p < 0.001), while in RF- RA subjects, estimated survival was 29.1% compared to 28.3% expected (p = 0.9). The difference between the observed and the expected mortality in the RF+ RA subjects increased over time, resulting in a widening of the mortality gap, while among RF- RA subjects, observed mortality was very similar to the expected mortality over the entire time period. Among RF+ RA subjects, cause-specific mortality was higher than expected for cardiovascular [relative risk (RR) 1.50; 95% confidence interval (CI) 1.22, 1.83] and respiratory diseases [RR 3.49; 95% CI 2.51, 4.72]. Among RF- RA subjects, no significant differences were found between observed and expected cause-specific mortality. CONCLUSION: The widening in the mortality gap between RA subjects and the general population is confined to RF+ RA subjects and largely driven by cardiovascular and respiratory deaths.     

Association of a rheumatoid arthritis susceptibility variant at the CCL21 locus with premature mortality in inflammatory polyarthritis patients

Objective

To investigate whether recently identified rheumatoid arthritis (RA) susceptibility loci are also associated with disease severity, specifically all‐cause and cardiovascular disease (CVD) mortality, in patients with inflammatory polyarthritis (IP).

Methods

Subjects with recent‐onset IP were recruited from the Norfolk Arthritis Register. Seventeen RA susceptibility single‐nucleotide polymorphisms (SNPs) were tested using Sequenom MassArray iPLEX chemistry. Vital status was ascertained from central records. The association of SNP allele carriage with mortality risk was assessed using Cox proportional hazards models after adjusting by sex. The mortality risks of those SNP alleles found to be associated were then stratified by baseline anti–citrullinated peptide (anti‐CCP) antibody and shared epitope (SE) status.

Results

All SNPs were successfully genotyped in 2,324 IP subjects. The presence of 2 copies of the risk allele rs2812378 mapping to the CCL21 gene predicted all‐cause mortality (hazard ratio [HR] 1.40, 95% confidence interval [95% CI] 1.04–1.87), whereas risk allele carriage also predicted increased CVD mortality (HR 1.33, 95% CI 1.01–1.75). The highest mortality risks were seen in anti‐CCP antibody–positive subjects with 2 copies of the CCL21 risk alleles and 2 copies of the SE (all‐cause HR 3.20, 95% CI 1.52–6.72; CVD HR 3.73, 95% CI 1.30–10.72).

Conclusion

In this large study, we found that carriage of CCL21 risk alleles was associated with premature mortality in IP independently of anti‐CCP antibody and SE status. Interestingly, CCL21 expression has been reported in atherosclerotic plaques supporting the thesis that the increased CVD mortality in IP patients may be mediated by shared inflammatory mechanisms.     

Predictors of congestive heart failure mortality in elderly people from the general population

Congestive heart failure (CHF) is highly prevalent in the elderly. The aim of this study was to identify the predictors of CHF mortality in patients over 65 years of age who were free of CHF at initial screening. A total of 3,282 elderly subjects were recruited in a population-based frame and 12-year events were recorded. Continuous items were divided into tertiles and for each tertile adjusted the relative risk (RR) with 95% confidence intervals (CI) was derived in both genders from multivariate Cox analysis of CHF mortality. Age > or = 72 years ([RR]: 2.24; 95% CI 1.56 - 3.24), male gender ([RR]: 1.4; 95%CI 1.02 - 1.76), clinical history of coronary artery disease ([RR]: 1.25; 95% CI 1.02 - 1.76), pulse pressure > or = 79 mmHg ([RR]: 1.33; 95% CI 1.03 - 1.87), heart rate > or = 81 bpm ([RR]: 1.32; 95% CI 1.10 - 1.96), atrial fibrillation ([RR]: 1.82; 95% CI 1.18 - 2.81), left ventricular hypertrophy ([RR]: 1.42; 95% CI 1.01 - 2.02), diabetes ([RR]: 1.35; 95% CI 1.02 - 1.78), vital capacity < or = 81% of the theoretical value ([RR]: 2.50; 95% CI 1.88 - 3.32), forced expiratory volume in 1 second < or = 72% of the theoretical value ([RR]: 2.02; 95% CI 1.55 - 2.72) and serum sodium level < or = 139 mmol/L ([RR]: 1.95; 95% CI 1.44 - 2.63) predicted CHF mortality. This model is able to identify elderly people at increased risk of death from CHF.     

Hepatitis B or hepatitis C coinfection in HIV-infected pregnant women in Europe

Objectives

The aim of the study was to investigate the prevalence of and risk factors for hepatitis C or B virus (HCV or HBV) coinfection among HIV‐infected pregnant women, and to investigate their immunological and virological characteristics and antiretroviral therapy use.

Methods

Information on HBV surface antigen (HBsAg) positivity and HCV antibody (anti‐HCV) was collected retrospectively from the antenatal records of HIV‐infected women enrolled in the European Collaborative Study and linked to prospectively collected data.

Results

Of 1050 women, 4.9% [95% confidence interval (CI) 3.6–6.3] were HBsAg positive and 12.3% (95% CI 10.4–14.4) had anti‐HCV antibody. Women with an injecting drug use(r) (IDU) history had the highest HCV‐seropositivity prevalence (28%; 95% CI 22.8–35.7). Risk factors for HCV seropositivity included IDU history [adjusted odds ratio (AOR) 2.92; 95% CI 1.86–4.58], age (for ≥35 years vs. <25 years, AOR 3.45; 95% CI 1.66–7.20) and HBsAg carriage (AOR 5.80; 95% CI 2.78–12.1). HBsAg positivity was associated with African origin (AOR 2.74; 95% CI 1.20–6.26) and HCV seropositivity (AOR 6.44; 95% CI 3.08–13.5). Highly active antiretroviral therapy (HAART) use was less likely in HIV/HCV‐seropositive than in HIV‐monoinfected women (AOR 0.34; 95% CI 0.20–0.58). HCV seropositivity was associated with a higher adjusted HIV RNA level (+0.28log₁₀ HIV‐1 RNA copies/mL vs. HIV‐monoinfected women; P=0.03). HIV/HCV‐seropositive women were twice as likely to have detectable HIV in the third trimester/delivery as HIV‐monoinfected women (AOR 1.95; P=0.049).

Conclusions

Although HCV serostatus impacted on HAART use, the association between HCV seropositivity and uncontrolled HIV viraemia in late pregnancy was independent of HAART.     

The importance of the disease process and disease‐modifying antirheumatic drug treatment in the development of septic arthritis in patients with rheumatoid arthritis

Objective

To evaluate the effect of disease‐modifying antirheumatic drugs (DMARDs) on the likelihood of patients with rheumatoid arthritis (RA) developing septic arthritis (SA).

Methods

The United Kingdom General Practice Research Database (GPRD) was used to identify adults with RA, and age‐, sex‐, and practice‐matched control subjects. Subjects were studied between 1987 and 2002. The risk of developing SA (excluding infected joint replacements) for individuals with RA was calculated and the effect of DMARD use determined.

Results

A total of 136,977 subjects (34,250 patients with RA, 102,747 controls) were identified. SA was identified in 345 subjects, of which 321 (236 in patients with RA, 85 in controls) cases occurred during the study period. The incidence rate of SA was 12.9 times higher in subjects with RA than in those without (95% confidence interval [95% CI] 10.1–16.5, P < 0.001). The incident rate ratios (IRRs) for developing SA while receiving DMARDs compared with receiving no DMARDs were different for different medications. Penicillamine (adjusted IRR 2.51, 95% CI 1.29–4.89, P = 0.004), sulfasalazine (adjusted IRR 1.74, 95% CI 1.04–2.91, P = 0.03), and prednisolone (adjusted IRR 2.94, 95% CI 1.93–4.46, P < 0.001) were associated with an increased incidence of SA when compared with not receiving any DMARD. The use of other DMARDs including methotrexate showed no such effect.

Conclusion

Individuals with RA have an increased risk of developing SA. This increased risk can be attributed to both the disease process and the use of DMARDs.     

Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: A population‐based cohort study

Objective

To examine the risk of clinical coronary heart disease (CHD) in patients with rheumatoid arthritis (RA) compared with age‐ and sex‐matched non‐RA subjects, and to determine whether RA is a risk factor for CHD after accounting for traditional CHD risk factors.

Methods

We assembled a population‐based incidence cohort of 603 Rochester, Minnesota residents ages ≥18 years who first fulfilled the American College of Rheumatology (ACR) 1987 criteria for RA between January 1, 1955 and January 1, 1995, and 603 age‐ and sex‐matched non‐RA subjects. All subjects were followed up through their complete inpatient and outpatient medical records, beginning at age 18 years until death, migration, or January 1, 2001. Data were collected on CHD events and traditional CHD risk factors (diabetes mellitus, hypertension, dyslipidemia, body mass index, smoking) using established diagnostic criteria. CHD events included hospitalized myocardial infarction (MI), unrecognized MI, coronary revascularization procedures, angina pectoris, and sudden CHD deaths. Conditional logistic regression and Cox regression models were used to estimate the risk of CHD associated with RA, both prior to and following RA diagnosis, after adjusting for CHD risk factors.

Results

During the 2‐year period immediately prior to fulfillment of the ACR criteria, RA patients were significantly more likely to have been hospitalized for acute MI (odds ratio [OR] 3.17, 95% confidence interval [95% CI] 1.16–8.68) or to have experienced unrecognized MIs (OR 5.86, 95% CI 1.29–26.64), and less likely to have a history of angina pectoris (OR 0.58, 95% CI 0.34–0.99) compared with non‐RA subjects. After the RA incidence date, RA patients were twice as likely to experience unrecognized MIs (hazard ratio [HR] 2.13, 95% CI 1.13–4.03) and sudden deaths (HR 1.94, 95% CI 1.06–3.55) and less likely to undergo coronary artery bypass grafting (HR 0.36, 95% CI 0.16–0.80) compared with non‐RA subjects. Adjustment for the CHD risk factors did not substantially change the risk estimates.

Conclusion

Patients with RA have a significantly higher risk of CHD when compared with non‐RA subjects. RA patients are less likely to report symptoms of angina and more likely to experience unrecognized MI and sudden cardiac death. The risk of CHD in RA patients precedes the ACR criteria–based diagnosis of RA, and the risk cannot be explained by an increased incidence of traditional CHD risk factors in RA patients.

     

Prognostic importance of low body mass index in relation to cardiovascular mortality in rheumatoid arthritis

OBJECTIVE: Various etiologic mechanisms have been implicated in the observed increase in cardiovascular mortality in rheumatoid arthritis (RA). Body mass index (BMI) is associated with cardiovascular mortality in the general population. This study compared the effect of BMI on cardiovascular mortality in a population-based cohort of subjects with RA with that in a cohort of individuals without RA from the same population. METHODS: The RA cohort comprised all members of an incidence cohort of Rochester, Minnesota residents ages > or =18 years who were first diagnosed with RA (by the American College of Rheumatology 1987 criteria) from 1955 through 1994. An age- and sex-matched comparison cohort of subjects without RA was assembled. Both cohorts were followed up longitudinally through their complete (inpatient, outpatient) medical records beginning at age 18 years and continuing until death, migration, or January 1, 2001, and the details of weight and height changes during this period were recorded. High BMI was defined as a BMI >30 kg/m(2) and low BMI as <20 kg/m(2). Cox regression models were used to estimate the effect of BMI on cardiovascular mortality after accounting for traditional cardiac risk factors and malignancies. RESULTS: RA subjects with low BMI at incidence had a significantly higher risk of cardiovascular death (hazard ratio [HR] 3.34, 95% confidence interval [95% CI] 2.23-4.99) compared with non-RA subjects with normal BMI, after adjusting for age, sex, personal cardiac history, smoking status, and presence of diabetes, hypertension, and malignancies. RA subjects with normal BMI at incidence who experienced low BMI during followup also had a higher risk of cardiovascular death (HR 2.09, 95% CI 1.50-2.92) when compared with non-RA subjects who maintained normal BMI throughout followup. CONCLUSION: Among patients with RA, low BMI is associated with a significantly increased risk of cardiovascular death.     

Patients with chronic gastrointestinal ischemia have a higher cardiovascular disease risk and mortality

ObjectivesWe determined the prevalence of classical risk factors for atherosclerosis and mortality risk in patients with CGI.MethodsA case–control study was conducted. Patients referred with suspected CGI underwent a standard work-up including risk factors for atherosclerosis, radiological imaging of abdominal vessels and tonometry. Cases were patients with confirmed atherosclerotic CGI. Controls were healthy subjects previously not known with CGI. The mortality risk was calculated as standardized mortality ratio derived from observed mortality, and was estimated with ten-year risk of death using SCORE and PREDICT.ResultsBetween 2006 and 2009, 195 patients were evaluated for suspected CGI. After a median follow-up of 19 months, atherosclerotic CGI was diagnosed in 68 patients. Controls consisted of 132 subjects. Female gender, diabetes, hypercholesterolemia, a personal and family history of cardiovascular disease (CVD), and current smoking are highly associated with CGI. After adjustment, female gender (OR 2.14 95% CI 1.05–4.36), diabetes (OR 5.59, 95% CI 1.95–16.01), current smoking (OR 5.78, 95% CI 2.27–14.72), and history of CVD (OR 21.61, 95% CI 8.40–55.55) remained significant. CGI patients >55 years had a higher median ten-year risk of death (15% vs. 5%, P = 0.001) compared to controls. During follow-up of 116 person-years, standardized mortality rate was higher in CGI patients (3.55; 95% CI 1.70–6.52).ConclusionsPatients with atherosclerotic CGI have an increased estimated CVD risk, and severe excess mortality. Secondary cardiovascular prevention therapy should be advocated in patients with CGI.     

Serum sodium and hydration status predict transplant-free survival independent of MELD score in patients with cirrhosis

Background and Aim: Serum sodium may have prognostic value in addition to the model for end‐stage liver disease (MELD) score for prediction of early mortality in patients listed for liver transplant. In patients with cirrhosis, over‐hydration is a common feature but its prognostic value has not been evaluated. This study examines the independent prognostic significance of MELD, serum sodium and hydration status on long‐term survival in patients with cirrhosis. Methods: Serum sodium and hydration (total body water as a percentage of fat‐free mass) were measured in 227 consecutive cirrhotic patients (146 male, 81 female; median age 49 years, range 19–73 years; median MELD score 13, range 6–36). Patients with hepatocellular carcinoma or listed for liver transplantation at the time of initial assessment were excluded. A competing risks Cox proportional hazards analysis was performed to evaluate the influence of MELD, sodium and hydration on risk of death or transplant. Results: Median follow‐up was 52 (range 4–93) months. Serum sodium and hydration were each associated with reduction in time to death or transplant on univariate analysis (sodium: hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.87–0.94, P < 0.0001; hydration: HR 1.20, 95% CI 1.10–1.30, P < 0.0001). On multivariate analysis, MELD, serum sodium and hydration were independently predictive of death or transplant (MELD: HR 1.12, 95% CI 1.06–1.19, P < 0.0001; sodium: HR 0.93, 95% CI 0.87–0.99, P = 0.04; hydration: HR 1.17, 95% CI 1.02–1.33, P = 0.02). Conclusions: In non‐waitlisted patients with cirrhosis, serum sodium is predictive of transplant or death independent of MELD score.     

The TTTT B lymphocyte stimulator promoter haplotype is associated with good response to rituximab therapy in seropositive rheumatoid arthritis resistant to tumor necrosis factor blockers

Objective

To investigate the polymorphisms in the promoter region of the B lymphocyte stimulator (BLyS) gene as markers of response to rituximab (RTX) in rheumatoid arthritis (RA).

Methods

The study was first conducted in 152 Italian RA patients and then replicated in an additional 117 RA patients (73 Italian, 44 British). The European League Against Rheumatism response criteria were used to evaluate the response rate at months 4 and 6 after the first cycle of RTX, by means of the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate; patients were classified according to the best response shown between months 4 and 6. BLyS promoter polymorphisms were analyzed by polymerase chain reaction followed by the analysis of the restriction fragments, BLyS promoter haplotypes were analyzed using the expectation‐maximization algorithm, and BLyS serum levels were analyzed using enzyme‐linked immunosorbent assay. Odds ratios (ORs) were calculated with 95% confidence intervals (95% CIs).

Results

The TTTT BLyS promoter haplotype appeared to be significantly associated with response to RTX only in the subset of seropositive patients (those positive for rheumatoid factor and/or anti–cyclic citrullinated peptide). The replication study confirmed that this association was limited to seropositive RA patients in whom treatment with anti–tumor necrosis factor (anti‐TNF) agents had previously failed. In the whole series of seropositive patients in whom anti‐TNF agents had previously failed, patients carrying the TTTT BLyS promoter haplotype were more prevalent in good responders (18 of 43 [41.9%]) than in moderate responders (20 of 83 [24.1%]) or in nonresponders (1 of 21 [4.8%]) (for good responders versus nonresponders, OR 14.4 [95% CI 1.77–117.39], P = 0.0028). Furthermore, multivariate analysis selected the TTTT BLyS promoter haplotype as an independent marker of good response to RTX (for good responders versus nonresponders, OR 16.2 [95% CI 1.7–152.5], P = 0.01; for good responders versus moderate responders and nonresponders combined, OR 3.1 [95% CI 1.2–7.8], P = 0.02). The relationship between BLyS polymorphisms and BLyS serum levels remained unclear.

Conclusion

BLyS promoter genotyping may be suitable for identifying seropositive RA patients who may have a good response to RTX after anti‐TNF agents have failed.

     

Impact of underlying chronic adrenal insufficiency on clinical course of hospitalized patients with adrenal crisis: A nationwide cohort study

BackgroundChronic adrenal insufficiency (AI) is an established risk factor for adrenal crisis (AC). However, the proportion of patients with newly diagnosed chronic AI during admission for AC is unclear.MethodsThis retrospective cohort study used a Japanese claims database involving 7.39 million patients at 145 acute care hospitals between 2003 and 2014. Study patients with AC met these criteria: 1) newly coded in claims as AI; 2) glucocorticoid therapy administered; 3) admission; and 4) age ≥ 18 years. We investigated the prevalence of underlying chronic AI and assessed in-hospital mortality. Additionally, we explored risk factors for in-hospital mortality through multivariate analysis using a Cox proportional hazards model.ResultsAmong 504 patients with AC, chronic AI was diagnosed before and during admission in 73 (14.5%) and 86 (17.1%) patients, respectively. In-hospital mortality rates were 1.4% and 5.8%, respectively, lower than that of the total population (14.1%). Significant risk factors for increased mortality were: age (hazard ratio [HR] 1.45/10 years; 95% confidence interval [CI] 1.17–1.78), requiring mechanical ventilation (HR 3.81; 95% CI 1.88–7.72), vasopressor administration (HR 2.05; 95% CI 1.16–3.64), sepsis (HR 3.79; 95% CI 1.57–9.14), AI-related symptoms (HR 2.00; 95% CI 1.02–3.93), and liver disease (HR 3.24; 95% CI 1.10–9.58).ConclusionsRelative to patients without chronic AI, those diagnosed before admission tended to survive to discharge; however, the difference with those diagnosed during admission was not significant. Hospital admission due to nonspecific AI-related symptoms was associated with an increased risk of in-hospital mortality.     

A gene–environment interaction between smoking and shared epitope genes in HLA–DR provides a high risk of seropositive rheumatoid arthritis

Objective

The main genetic risk factor for rheumatoid arthritis (RA) is the shared epitope (SE) of HLA–DR, while smoking is an important environmental risk factor. We studied a potential gene–environment interaction between SE genes and smoking in the etiology of the 2 major subgroups of RA: rheumatoid factor (RF)–seropositive and RF‐seronegative disease.

Methods

A population‐based case–control study involving incident cases of RF‐seropositive and RF‐seronegative RA (858 cases and 1,048 controls) was performed in Sweden. Cases and controls were classified according to their cigarette smoking status and HLA–DRB1 genotypes. The relative risk of developing RA was calculated for different gene/smoking combinations and was compared with the relative risk in never smokers without SE genes.

Results

The relative risk of RF‐seropositive RA was 2.8 (95% confidence interval [95% CI] 1.6–4.8) in never smokers with SE genes, 2.4 (95% CI 1.3–4.6) in current smokers without SE genes, and 7.5 (95% CI 4.2–13.1) in current smokers with SE genes. Smokers carrying double SE genes displayed a relative risk of RF‐seropositive RA of 15.7 (95% CI 7.2–34.2). The interaction between smoking and SE genes was significant, as measured by the attributable proportion due to interaction, which was 0.4 (95% CI 0.2–0.7) for smoking and any SE, and 0.6 (95% CI 0.4–0.9) for smoking and a double SE. Neither smoking nor SE genes nor the combination of these factors increased the risk of developing RF‐seronegative RA.

Conclusion

The disease risk of RF‐seropositive RA associated with one of the classic genetic risk factors for immune‐mediated diseases (the SE of HLA–DR) is strongly influenced by the presence of an environmental factor (smoking) in the population at risk.

     

Prospective study of cytomegalovirus seropositivity and risk of mortality from diabetes

Cytomegalovirus (CMV) infects 40 % of the world population and has been suggested to be associated with diabetes; however, no prospective study has ever examined diabetes mortality associated with the infection. A cohort of 14,404 non-diabetic adult participants aged 17–90 years from the Third National Health and Nutrition Examination Survey (1988–1994) was prospectively followed for mortality through 2006. CMV immunoglobulin G was measured by enzyme-linked immunosorbent assay and immunofluorescence assay. Diabetes death was assessed with death records from the National Death Index. Cox proportional hazards modeling was used to determine diabetes mortality risk associated with CMV infection, adjusting for socio-demographics, diabetes risk factors, and comorbidities. At baseline, 76.8 % of subjects were CMV seropositive, and after an average follow-up of 13.7 years, diabetes mortality rate per 10,000 person-years was 6.8 (95 % CI 5.7, 8.0). Among seropositive participants, the diabetes death rate (8.4, 95 % CI 7.0, 9.9) was more than four times the rate in seronegative ones (2.0, 95 % CI 1.1, 3.6) (P value for the difference <0.001). In the adjusted Cox proportional hazards analysis, CMV seropositivity more than doubled the risk of diabetes mortality (HR 2.06, 95 % CI 1.05, 4.06). CMV infection may thus predict future mortality from diabetes in non-diabetic people.     

Association of the HLA–DRB1 gene with premature death,particularly from cardiovascular disease,in patients with rheumatoid arthritis and inflammatory polyarthritis

Objective

To examine the role of the variants of the PTPN22 and HLA–DRB1 genes as predictors of mortality in inflammatory polyarthritis (IP) and rheumatoid arthritis (RA).

Methods

Patients were recruited from a primary care–based inception cohort of patients with IP and were followed up prospectively. For patients who died, the cause and date of death was obtained. Cox proportional hazards regression models were used to assess the association of the HLA–DRB1 (including the shared epitope [SE]) and PTPN22 genes with the risk of death from all causes and from cardiovascular disease (CVD) and to assess the interactions between SE, smoking, and anti–cyclic citrullinated peptide (anti‐CCP) status, adjusted by age at symptom onset and sex.

Results

DNA samples were available from 1,022 IP patients. During followup, 751 of them (74%) satisfied the American College of Rheumatology 1987 criteria for RA, and 242 of them (24%) died. Carriage of 2 copies of SE alleles predicted death from all causes (hazard ratio [HR] 1.57 [95% confidence interval (95% CI) 1.1–2.2]) and from CVD (HR 1.68 [95% CI 1.1–2.7]). This effect was most marked for individuals with the HLA–DRB1*01/*04 combination. An interaction of smoking, SE alleles, and anti‐CCP antibodies was observed and was associated with the greatest risk of death from CVD (HR 7.81 [95% CI 2.6–23.2]). No association of the PTPN22 gene with mortality was detected.

Conclusion

SE alleles, particularly compound heterozygotes, are associated with death from all causes and from CVD, independently of autoantibody status. However, the combination of SE, smoking, and anti‐CCP antibodies is associated with a high risk of premature death in patients with IP and RA, which raises the possibility of a targeted strategy to prevent CVD in these patients.

     

Seronegative rheumatoid arthritis.

Measurement of serum rheumatoid factor (RF) by conventional methods in patients with rheumatoid arthritis (RA) has repeatedly identified a subpopulation of patients without detectable RF. Previous investigators have consistently confirmed the association of HLA–DR4 with seropositive RA, but studies of seronegative RA have been limited and contradictory. We studied 140 randomly selected patients from Alabama, all of whom had either classic or definite RA, and we were able to obtain complete HLA typing for 110 of these individuals. Eighty were consistently seropositive (on at least 2 separate occasions) and 30 were consistently seronegative (on at least 3 separate determinations). There was no statistically significant difference between the seronegative RA patients and 123 control subjects in the distribution of DR antigens. In seropositive RA, there was a significant increase in DR4 (P<0.001; relative risk = 8.02; attributable risk = 49.2%) and a significant decrease in DR3 (P<0.001; relative risk = 0.14) and DR7 (0.01>P>0.001; relative risk = 0.33). The clinical data also distinguished between seropositive RA and seronegative RA; subcutaneous nodules (37.5%) and vasculitis (6.3%) were present only in seropositive RA. DR4 positivity did not correlate with any of the clinical variables measured in the seropositive RA group. In contrast, DR4 in the seronegative RA group was associated with more destructive disease. The data suggest that seronegative RA represents a disease entity clinically and immunogenetically distinct from seropositive RA. Moreover, our results indicate that DR4 may be a previously undisclosed marker for disease severity in seronegative RA.