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1.  Incidence and Risk Factors of Prosthetic Joint Infection After Total Hip or Knee Replacement in Patients With Rheumatoid Arthritis 
Arthritis and rheumatism  2008;59(12):1713-1720.
Prosthetic joint infection is one of the most dreaded complications after total joint arthroplasty, a common procedure in patients with rheumatoid arthritis (RA). We conducted a study to evaluate potential risk factors of prosthetic joint infection and to clarify if RA is an independent predictor of this complication.
This study included all patients with RA who underwent total hip or knee replacement at the Mayo Clinic Rochester between January 1996 and June 2004. The association of potential risk factors with prosthetic joint infection was examined using Cox models. A matched cohort of patients with osteoarthritis (OA) was assembled to determine whether RA is an independent risk factor for prosthetic joint infection.
We identified 462 patients with RA who underwent a total of 657 hip or knee replacements. Overall, 23 (3.7%) joint arthroplasties were complicated by an infection during a mean ± SD followup of 4.3 ± 2.4 years. Revision arthroplasty (hazard ratio [HR] 2.99, 95% confidence interval [95% CI] 1.02–8.75) and a previous prosthetic joint infection of the replaced joint (HR 5.49, 95% CI 1.87–16.14) were significant predictors of postoperative prosthetic joint infection. Comparison of RA patients with a matched cohort of OA patients identified an increased risk of prosthetic joint infections (HR 4.08, 95% CI 1.35–12.33) in patients with RA.
Patients with RA who undergo total hip or knee replacement are at increased risk of prosthetic joint infection, which is further increased in the setting of revision arthroplasty and a previous prosthetic joint infection. These findings highlight the importance of perioperative prophylactic measures and vigilance during the postoperative period.
PMCID: PMC3923416  PMID: 19035425
2.  Utilization of Orthopedic Surgery Among Patients with Rheumatoid Arthritis 1980–2007: A Population Based Study Focused on Rates of Surgery, Patient Gender and Mortality 
The Journal of rheumatology  2012;39(3):481-485.
To describe current trends in arthritis related joint surgery among a population based cohort of patients with rheumatoid arthritis (RA) and to examine the influence of joint surgery on mortality.
A retrospective medical record review was performed of all orthopedic surgeries following diagnosis in cases of adult onset RA in Olmsted County, Minnesota incident in 1980–2007. Surgeries included primary total joint arthroplasty, joint reconstructive procedures (JRP), soft tissue procedures (STP) and revision arthroplasty. Cumulative incidence (CI) of surgery was estimated using Kaplan-Meier methods. Time trends, sex differences and mortality were examined using Cox models with time-dependent covariates for surgery.
A total of 189 of 813 patients underwent ≥1 surgical procedures involving joints during follow-up. The cumulative incidence of any joint surgery at 10 years after RA incidence for the 1980–1994 cohort was 27.3% compared to 19.5% for the 1995–2007 cohort (p=0.08). The greatest reduction was in STP, which decreased from 12.1% in 1980–1994 to 6.0% in 1995–2007 at 10 years after RA incidence (p=0.012). Obese patients, and women (cumulative incidence 26.6% at 10 years for women; 20.4% for men; p=0.049) had more surgery. JRP was significantly associated with mortality (hazard ratio [HR]: 2.6; 95 % CI 1.8, 3.9; p <0.001) compared to patients not requiring JRP.
The rates of joint surgery continue to decrease for patients more recently diagnosed with RA. JRP, is associated with increased mortality. These findings may reflect both improved treatments for RA as well as continued higher disease burden among some patients.
PMCID: PMC3634337  PMID: 22247350
3.  Contribution of Obesity to the Rise in Incidence of Rheumatoid Arthritis 
Arthritis care & research  2013;65(1):71-77.
To determine whether the “obesity epidemic” could explain the recent rise in the incidence of RA.
Obesity is an under-recognized risk factor for RA. In recent years both the prevalence of obesity and the incidence of RA have been rising.
An inception cohort of Olmsted County, Minnesota residents who fulfilled 1987 American College of Rheumatology criteria for RA in 1980–2007 was compared to population-based controls (matched on age, sex and calendar year). Heights, weights and smoking status were collected from medical records. Obesity was defined as body mass index (BMI) ≥ 30 kg/m2. Conditional logistic regression was used to assess the influence of obesity on developing RA. Population attributable risk was used to estimate the incidence of RA in the absence of obesity.
The study included 813 patients with RA and 813 controls. Both groups had extensive medical history available prior to incidence/index date (mean 32.2 years), and approximately 30% of each group were obese at incidence/index date. The history of obesity was a significantly associated with developing RA (OR:1.24; 95 % CI: 1.01, 1.53 adjusted for smoking status). In 1985–2007 the incidence of RA rose by an increment of 9.2 per 100,000 among women. Obesity accounted for 4.8 per 100,000 (or 52%) of this increase.
Obesity is associated with a modest risk for developing RA. Given the rapidly increasing prevalence of obesity, this has had a significant impact on RA incidence and may account for much of the recent increase in incidence of RA.
PMCID: PMC3707391  PMID: 22514156
rheumatoid arthritis; obesity; incidence; population attributable risk; body mass index
4.  Primary Sjögren's syndrome 1976–2005 and associated interstitial lung disease: a population-based study of incidence and mortality 
BMJ Open  2013;3(11):e003569.
A very few studies describe the epidemiology of primary Sjögren's syndrome (pSS). The reported frequency of pulmonary involvement in pSS varies widely depending on the detection method employed, and consists mainly of various forms of airways disease. We aimed to evaluate the incidence and mortality of pSS and of lung disease in pSS, focusing on interstitial lung disease (ILD).
A population-based incidence cohort of patients diagnosed with pSS in 1976–2005 was assembled. Diagnosis was based on the 2002 American-European Consensus Group criteria for pSS. Cumulative incidence adjusted for the competing risk of death was estimated. A Cox model with a time-dependent covariate was used to determine the incidence and the standardised mortality HR of pSS.
85 patients with pSS were identified (mean age 59.9 years; 91% women). The annual incidence of pSS was 4.2, 95% CI (3.3 to 5.1)/100 000 population and it increased with higher age at pSS diagnosis (18–44 years: 2.1/100 000 vs ≥75 years: 12.3/100 000). Standardised mortality ratio in pSS compared with the general population was 0.92, 95% CI (0.57 to 1.41). A total of 105 patients with pSS and ILD were identified (mean age 58.1 years; 91% women). Among patients with pSS without prior ILD, the cumulative incidence of ILD in patients with pSS was 10% (±3%) at 1 year after diagnosis of pSS and increased to 20% (±4%) by 5 years after pSS. The development of lung disease in pSS was associated with poor survival (HR 2.16; 95% CI 0.99 to 4.74).
pSS incidence seems to be almost the same as was reported in a previous study conducted among Olmsted County Minnesota population. Survival among patients with pSS and general population does not differ substantially. However, patients with pSS who have ILD likely have increased premature mortality.
PMCID: PMC3845035  PMID: 24282246
5.  Immune response profiling in early rheumatoid arthritis: discovery of a novel interaction of treatment response with viral immunity 
Arthritis Research & Therapy  2013;15(6):R199.
It remains challenging to predict the outcomes of therapy in patients with rheumatoid arthritis (RA). The objective of this study was to identify immune response signatures that correlate with clinical treatment outcomes in patients with RA.
A cohort of 71 consecutive patients with early RA starting treatment with disease-modifying antirheumatic drugs (DMARDs) was recruited. Disease activity at baseline and after 21 to 24 weeks of follow-up was measured using the Disease Activity Score in 28 joints (DAS28). Immune response profiling was performed by analyzing multi-cytokine production from peripheral blood cells following incubation with a panel of stimuli, including a mixture of human cytomegalovirus (CMV) and Epstein-Barr virus (EBV) lysates. Profiles identified via principal components analysis (PCA) for each stimulus were then correlated with the ΔDAS28 from baseline to follow-up. A clinically meaningful improvement in the DAS28 was defined as a decrease of ≥1.2.
A profile of T-cell cytokines (IL-13, IL-4, IL-5, IL-2, IL-12, and IFN-γ) produced in response to CMV/EBV was found to correlate with the ΔDAS28 from baseline to follow-up. At baseline, a higher magnitude of the CMV/EBV immune response profile predicted inadequate DAS28 improvement (mean PCA-1 scores: 65.6 versus 50.2; P = 0.029). The baseline CMV/EBV response was particularly driven by IFN-γ (P = 0.039) and IL-4 (P = 0.027). Among patients who attained clinically meaningful DAS28 improvement, the CMV/EBV PCA-1 score increased from baseline to follow-up (mean +11.6, SD 25.5), whereas among patients who responded inadequately to DMARD therapy, the CMV/EBV PCA-1 score decreased (mean -12.8, SD 25.4; P = 0.002). Irrespective of the ΔDAS28, methotrexate use was associated with up-regulation of the CMV/EBV response. The CMV/EBV profile was associated with positive CMV IgG (P <0.001), but not EBV IgG (P = 0.32), suggesting this response was related to CMV exposure.
A profile of T-cell immunity associated with CMV exposure influences the clinical response to DMARD therapy in patients with early RA. Because CMV latency is associated with greater joint destruction, our findings suggest that changes in T-cell immunity mediated by viral persistence may affect treatment response and possibly long-term outcomes of RA.
PMCID: PMC3978471  PMID: 24267267
The Journal of rheumatology  2012;39(11):2148-2152.
Spondyloarthritis is an extraintestinal manifestation of inflammatory bowel disease with important clinical impact, although the frequency is uncertain. We sought to assess the cumulative incidence and clinical spectrum of spondyloarthritis in patients with Crohn’s disease (CD) in a population-based cohort.
The medical records of a population-based cohort of Olmsted County, Minnesota residents diagnosed with CD between 1970 and 2004 were reviewed. Patients were followed longitudinally until migration, death, or December 31, 2010. We used the European Spondyloarthropathy Study Group, Assessment of Spondyloarthritis international Society (ASAS) criteria and modified New York criteria to identify patients with spondyloarthritis. The Kaplan-Meier method was used to estimate the cumulative incidence of spondyloarthritis following CD diagnosis.
The cohort included 311 patients with CD (49.8% females; median age, 29.9 years [range, 8–89]). Thirty-two patients developed spondyloarthritis based on ASAS criteria. The cumulative incidence of spondyloarthritis after CD diagnosis was 6.7% (95% confidence interval, 2.5%–6.7%) at 10 years, 13.9% (8.7%–18.8%) at 20 years, and 18.6% (11.0%–25.5%) at 30 years. The 10-year cumulative incidence of ankylosing spondylitis was 0 while both the 20-year and 30-year cumulative incidences were 0.5% (95% CI, 0–1.6%).
We have for the first time defined the actual cumulative incidence of spondyloarthritis in CD using complete medical record information in a population-based cohort. The cumulative incidence of all forms of spondyloarthritis increased to approximately 19% by 30 years from CD diagnosis. Our results emphasize the importance of maintaining a high level of suspicion for spondyloarthritis when following patients with CD.
PMCID: PMC3496378  PMID: 22984277
Spondyloarthritis; Crohn’s disease; epidemiology; ankylosing spondylitis
7.  Development and Validation of a Risk Score for Serious Infections in Patients with Rheumatoid Arthritis 
Arthritis and rheumatism  2012;64(9):2847-2855.
Infection risk is increased in patients with rheumatoid arthritis (RA), and accurate assessment of infection risk could inform clinical decision-making. The purpose of this study was to develop and validate a score to predict the 1 year risk of serious infections.
We utilized a population based cohort of Olmsted County, Minnesota residents with incident RA ascertained in 1955–1994 that were followed longitudinally through their complete medical records until January 2000. The validation cohort included residents with incident RA ascertained in 1995–2007. The outcome measures included all serious infections (requiring hospitalization or intravenous antibiotics). Potential predictors were examined using multivariable Cox models. The risk score was estimated directly from the multivariable model and performance was assessed in the validation cohort using Harrell’s c-statistic.
Among the 584 patients with RA (mean age 58 years; 72% female; median follow-up 9.9 years), 252 had ≥ 1 serious infection (646 total infections). The risk score included age, previous serious infection, corticosteroid use, elevated erythrocyte sedimentation rate, extraarticular manifestations of RA and comorbidities (coronary heart disease, heart failure, peripheral vascular disease, chronic lung disease, diabetes mellitus, alcoholism). Validation revealed good discrimination (c-statistic =0.80).
RA disease characteristics and comorbidities can be used to accurately assess the risk of serious infection in patients with RA. Knowledge of risk of serious infections in patients with RA can influence clinical decision making and inform strategies to reduce and prevent the occurrence of these infections.
PMCID: PMC3424339  PMID: 22576809
8.  The Rochester Epidemiology Project: exploiting the capabilities for population-based research in rheumatic diseases 
The Rochester Epidemiology Project (REP) is a patient record-based database based upon a medical records-linkage system for all residents of the Olmsted County, MN, USA. This comprehensive system includes all health-care providers of patients resident in this geographically defined region. It uniquely enables long-term population-based studies of all medical conditions occurring in this population; their incidence and prevalence; permits examination of disease risk and protective factors, health resource utilization and cost as well as translational studies in rheumatic diseases.
PMCID: PMC3716332  PMID: 20627969
Rheumatic diseases; Epidemiology; Registry; Health sciences research; Outcomes; Cost
9.  Usefulness of Risk Scores To Estimate the Risk of Cardiovascular Disease in Patients with Rheumatoid Arthritis 
The American Journal of Cardiology  2012;110(3):420-424.
Patients with rheumatoid arthritis (RA) suffer from an excess burden of cardiovascular disease (CVD). CV risk scores for the general population may not accurately predict CV risk for patients with RA. A population-based inception cohort of patients who fulfilled 1987 American College of Rheumatology criteria for RA in 1988–2007 was followed until death, migration, or 12/31/2008. CV risk factors and CVD (myocardial infarction, CV death, angina, stroke, intermittent claudication and heart failure) were ascertained by medical record review. The 10 year predicted CVD risk was calculated using the general Framingham and the Reynolds risk scores. Standardized incidence ratios were calculated to compare observed and predicted CVD risks. The study included 525 patients with RA aged ≥30 years without prior CVD. The mean follow-up was 8.4 years, during which 84 patients developed CVD. The observed CVD risk was 2-fold higher than the Framingham risk score predicted in women and 65% higher in men, and the Reynolds risk score revealed similar deficits. Patients aged ≥75 years had observed CVD risk >3 times the Framingham predicted risk. Patients with positive rheumatoid factor or persistently elevated erythrocyte sedimentation rate also experienced more CVD events than predicted. In conclusion, the Framingham and Reynolds risk scores substantially underestimated CVD risk in patients with RA of both sexes, especially in older ages and in patients with positive rheumatoid factor. These data underscore the need for more accurate tools to predict CVD risk in patients with RA.
PMCID: PMC3398213  PMID: 22521305
rheumatoid arthritis; cardiovascular disease; risk scores
10.  Increased Incidence and Impact of Upper and Lower Gastrointestinal Events in Patients with Rheumatoid Arthritis in Olmsted County, Minnesota: A Longitudinal Population-based Study 
The Journal of Rheumatology  2012;39(7):1355-1362.
To assess the incidence and mortality impact of upper and lower gastrointestinal (GI) events in rheumatoid arthritis (RA) compared to non-RA subjects.
We identified incident upper and lower GI events and estimated their incidence rates using person-year methods in a population-based incident RA cohort of residents of Olmsted County, Minnesota, USA (1987 American College of Rheumatology criteria first fulfilled between January 1, 1980, and January 1, 2008) and non-RA subjects from the same population.
The study included 813 patients with RA and 813 non-RA subjects (mean followup 10.3 and 10.8 yrs, respectively); 68% women; mean age 55.9 yrs in both cohorts. The rate of upper GI events/100 person-years was 2.9 in RA versus 1.7 in the non-RA cohort (rate ratio 1.7, 95% CI 1.4, 2.2); for lower GI events, the rates were 2.1 in RA versus 1.4 in the non-RA cohort (rate ratio 1.5, 95% CI 1.1, 1.9). The incidence of upper GI bleed, perforation, ulcer, obstruction, and any upper GI event in RA declined over calendar time; the incidence of lower GI events remained unchanged. Exposure to glucocorticoids, prior upper GI disease, abdominal surgery, and smoking were associated with lower GI events in RA. Both upper and lower GI events were associated with increased mortality risk in RA.
There is increased risk of serious upper and lower GI events in RA compared to non-RA subjects, and increased GI-related mortality in RA. Prominent declines in incidence of upper, but not lower GI events in RA highlight the need for studies investigating lower GI disease in patients with RA.
PMCID: PMC3389143  PMID: 22467929
11.  Utility of Erythrocyte Sedimentation Rate and C-Reactive Protein for the Diagnosis of Giant Cell Arteritis 
1) To evaluate the utility of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) for the diagnosis of giant cell arteritis (GCA) 2) to determine the frequency of normal ESR and CRP at diagnosis of GCA.
All patients undergoing temporal artery biopsy (TAB) between 2000 and 2008 were identified. Only subjects with both ESR and CRP at the time of TAB were included. The medical records of all patients were reviewed.
We included 764 patients (65% women), mean age 72.7 (±9.27) years, who underwent TAB. Biopsy was consistent with GCA in 177 patients (23%). Elevated CRP and elevated ESR provided a sensitivity of 86.9% and 84.1% respectively, for a positive TAB. The odds ratio (OR) of a concordantly elevated ESR and CRP for positive TAB was 3.06 (95% CI 2.03, 4.62) while the OR for concordantly normal ESR and CRP was 0.49 (95% CI 0.29, 0.83).
Seven patients (4%) with a positive TAB for GCA had a normal ESR and CRP at diagnosis. Compared to GCA patients with elevated markers of inflammation, a greater proportion of these patients had polymyalgia rheumatica symptoms (p=0.008) while constitutional symptoms, anemia and thrombocytosis were observed less often (p<0.05).
CRP is a more sensitive marker than ESR for a positive TAB that is diagnostic of GCA. There may be clinical utility in obtaining both tests in the evaluation of patients with suspected GCA. A small proportion of patients with GCA may have normal inflammatory markers at diagnosis.
PMCID: PMC3307891  PMID: 22119103
12.  Development of Outcome Measures for Large-vessel Vasculitis for Use in Clinical Trials: Opportunities, Challenges, and Research Agenda 
The Journal of rheumatology  2011;38(7):1471-1479.
Giant cell (GCA) and Takayasu’s arteritis (TAK) are 2 forms of large-vessel vasculitis (LVV) that involve the aorta and its major branches. GCA has a predilection for the cranial branches, while TAK tends to affect the extracranial branches. Both disorders may also cause nonspecific constitutional symptoms. Although some clinical features are more common in one or the other disorder and the ages of initial presentation differ substantially, there is enough clinical and histopathologic overlap between these disorders that some investigators suggest GCA and TAK may be 2 processes within the spectrum of a single disease. There have been few randomized therapeutic trials completed in GCA, and none in TAK. The lack of therapeutic trials in LVV is only partially explained by the rarity of these diseases. It is likely that the lack of well validated outcome measures for LVV and uncertainties regarding trial design contribute to the paucity of trials for these diseases. An initiative to develop a core set of outcome measures for use in clinical trials of LVV was launched by the international OMERACT Vasculitis Working Group in 2009 and subsequently endorsed by the OMERACT community at the OMERACT 10 meeting. Aims of this initiative include: (1) to review the literature and existing data related to outcome assessments in LVV; (2) to obtain the opinion of experts and patients on disease content; and (3) to formulate a research agenda to facilitate a more data-based approach to outcomes development.
PMCID: PMC3653638  PMID: 21724719
13.  Hypothyroidism as a risk factor for development of cardiovascular disease in patients with rheumatoid arthritis 
The Journal of rheumatology  2012;39(5):954-958.
To determine the frequency of hypothyroidism in patients with rheumatoid arthritis (RA), and to elucidate the association of hypothyroidism and development of cardiovascular disease in these patients.
A retrospective medical record review was performed using all incident cases of adult onset RA from a defined geographic population base that fulfilled criteria for RA in the years 1988–2007. Patients with and without thyroid disease were followed longitudinally for the development of cardiovascular disease (CVD).
A cohort of 650 patients with RA and an age and sex matched comparison cohort of 650 patients without RA was assembled (both cohorts mean age 55.8; 69% female). There was no significant difference between cohorts in the presence of hypothyroid disease or subclinical hypothyroidism at time of RA diagnosis. No significant difference was found in the cumulative incidence of hypothyroid disease between the two cohorts. Hypothyroid disease was found to be significantly associated with CVD in patients with RA (hazard ratio 2; 95% confidence interval 1.1,3.6). This difference remained significant and unchanged after adjustment for traditional cardiovascular risk factors (HR: 2.0; 95% CI: 1.1, 3.6).
No significant difference was found in either incidence or prevalence of hypothyroidism between patients with or without RA. Hypothyroid disease was significantly associated with CVD in patients with RA, even after adjustment for other traditional cardiovascular risk factors.
PMCID: PMC3518421  PMID: 22337246
Rheumatoid arthritis; Hypothyroidism; Cardiovascular Disease
14.  Necrotizing Lymphocytic Vasculitis Limited to the Peripheral Nerves: Report of Six Cases and Review 
Background. The systemic vasculitides are syndromes characterized by inflammation and injury (necrosis or thrombosis) of blood vessels, resulting in clinical manifestations according to the affected vascular bed, but not classically in stocking-glove neuropathy. Objective. To describe a form of primary vasculitis affecting strictly peripheral nerves manifesting as stocking-glove neuropathy. Methods. Case series of 110 patients seen in three centers in Bogotá who presented with symptoms and signs of polyneuropathy and/or were identified with vasculitis affecting only the peripheral nerves, and who underwent sural nerve biopsy. Results. Six patients had a vasculitis affecting only the peripheral nerves diagnosed on sural nerve biopsy which demonstrated a mixed infiltrate of monocytes/macrophages and lymphocytes especially in the small epineurial blood vessels. Over time, all had worsening of symptoms, with grip weakness and motor deficits in the hand and feet. Serologies and acute phase reactants were normal in all patients. Treatment response to immunosuppression was satisfactory in 5 patients; 1 patient had progressive neurologic damage. Conclusions. There is a distinct form of primary vasculitis of the peripheral nervous system characterized by distal sensory polyneuropathy with stocking-glove distribution with good prognosis, few and minor relapses and good response to treatment even after delayed diagnosis.
PMCID: PMC2830575  PMID: 20204175
15.  Lack of Detection of Human Retrovirus-5 Proviral DNA in Synovial Tissue and Blood Specimens From Individuals With Rheumatoid Arthritis or Osteoarthritis 
Arthritis and rheumatism  2006;55(1):123-125.
Prior studies have suggested an association of human retrovirus 5 with rheumatoid arthritis. The purpose of this study was to determine if human retrovirus-5 proviral DNA is present in synovial tissue and blood specimens from patients with rheumatoid arthritis or osteoarthritis, or those without joint disease.
Synovial tissue and whole blood from 75 patients with rheumatoid arthritis, 75 patients with osteoarthritis, and 50 patients without a primary arthritis diagnosis were assayed by real-time quantitative polymerase chain reaction (PCR) using primers that amplify a 186-bp fragment of human retrovirus-5 proviral DNA.
A total of 200 tissue specimens, 200 mononuclear cells, and 196 of 200 granulocyte specimens tested negative for human retrovirus-5 proviral DNA. No association between human retrovirus 5 and rheumatoid arthritis or osteoarthritis (P = 0.516) was identified. Granulocyte specimens from 4 patients, 2 with rheumatoid arthritis and 2 with osteoarthritis, yielded a low positive human retrovirus-5 proviral DNA signal (83–1,365 copies of human retrovirus-5 proviral DNA/ml blood).
Contrary to prior reports, we did not find an association between human retrovirus 5 and rheumatoid arthritis or osteoarthritis using a real-time PCR assay. Our findings are consistent with the recent finding that human retrovirus 5 is actually rabbit endogenous retrovirus H.
PMCID: PMC1464419  PMID: 16463423
Human retrovirus-5; Rheumatoid arthritis; Osteoarthritis
16.  Noncardiac vascular disease in Rheumatoid Arthritis: Increase in Venous Thromboembolic Events? 
Arthritis and rheumatism  2012;64(1):53-61.
To investigate the incidence of noncardiac vascular disease in a community-based incidence cohort of patients with rheumatoid arthritis (RA) and compare to that in the general population. To investigate trends in incidence of noncardiac vascular disease in patients with RA.
A population-based inception cohort of patients with RA in Olmsted County, Minnesota with incident RA between 1/1/1980 and 12/31/2007 and a cohort of non-RA subjects from the same population base was assembled and followed until 12/31/2008. Venous thromboembolic events (VTE), cerebrovascular events, and peripheral arterial events were ascertained by medical record review.
The study population included 813 patients with RA (mean age [SD] 55.9 [15.7] years, 68% women), with average length of follow-up of 9.6 years [SD 6.9]. Compared to non-RA subjects of similar age and sex, patients diagnosed with RA between 1995 and 2007 had a higher incidence (%) of VTE compared to non-RA subjects (cumulative incidence [±SE] 6.7 ± 1.7 vs 2.8 ± 1.1, respectively; p=0.005), but similar rates of cerebrovascular and peripheral arterial events. Among patients with RA, the incidence of VTE, cerebrovascular events, and peripheral arterial events was similar in the 1995–2007 time period compared to the 1980–1994 time period.
The incidence of VTE appears to be increased in patients with RA compared to non-RA subjects. The incidence of cerebrovascular events and peripheral vascular disease events was similar in patients with RA compared to non-RA subjects. Among patients with RA, the incidence of noncardiac vascular disease has remained stable in recent decades.
PMCID: PMC3474372  PMID: 21905005
17.  My Treatment Approach to Rheumatoid Arthritis 
Mayo Clinic Proceedings  2012;87(7):659-673.
The past decade has brought important advances in the understanding of rheumatoid arthritis and its management and treatment. New classification criteria for rheumatoid arthritis, better definitions of treatment outcome and remission, and the introduction of biologic response-modifying drugs designed to inhibit the inflammatory process have greatly altered the approach to managing this disease. More aggressive management of rheumatoid arthritis early after diagnosis and throughout the course of the disease has resulted in improvement in patient functioning and quality of life, reduction in comorbid conditions, and enhanced survival.
PMCID: PMC3538478  PMID: 22766086
ACPA, anti–citrullinated protein antibody; ACR, American College of Rheumatology; BeSt, Behandel-Strategieën [trial]; CDAI, Clinical Disease Activity Index; CRP, C-reactive protein; CTLA-4:Ig, cytotoxic T lymphocyte–associated antigen 4:immunoglobulin fusion protein; DAS28, Disease Activity Score in 28 joints; DMARD, disease-modifying antirheumatic drug; EULAR, European League Against Rheumatism; HCQ, hydroxychloroquine; MTX, methotrexate; SDAI, Simplified Disease Activity Index; SSZ, sulfasalazine; TEAR, Treatment of Early Aggressive Rheumatoid Arthritis [study]; TNF, tumor necrosis factor
18.  Cardiovascular Risk in Psoriasis: A Population-Based Analysis with Assessment of the Framingham Risk Score 
Scientifica  2013;2013:371569.
Objective. To examine the utility of the Framingham risk score (FRS) in estimating cardiovascular risk in psoriasis. Methods. We compared the predicted 10-year risk of cardiovascular events, namely, cardiovascular death, myocardial infarction, heart failure, percutaneous transluminal coronary angioplasty, and coronary artery bypass grafting using the FRS, to the observed risk of cardiovascular events in a population-based cohort of patients with psoriasis. Patients with incident or prevalent adult-onset psoriasis aged 30–79 years without prior history of cardiovascular disease were included. Results. Among the 1197 patients with predicted risk scores, the median FRS was 6.0%, while the observed 10-year cardiovascular risk was 6.9% (standardized incidence ratio (SIR): 1.14; 95% confidence interval (CI): 0.92–1.42). The SIR was not elevated for women nor for men. The differences between observed and predicted cardiovascular risks in patients <60 years (SIR: 1.01; 95% CI: 0.73–1.41) or ≥60 years (SIR: 1.26; 95% CI: 0.95–1.68) were not statistically significant. Conclusion. There was no apparent difference between observed and predicted cardiovascular risks in patients with psoriasis in our study. FRS reasonably estimated cardiovascular risk in both men and women as well as in younger and older psoriasis patients, suggesting that FRS can be used in risk stratification in psoriasis without further adjustment.
PMCID: PMC3820308  PMID: 24278773
19.  Trends in lipid profiles in patients with psoriasis: a population-based analysis 
BMC Dermatology  2012;12:20.
Psoriasis is associated with an atherogenic lipid profile but longitudinal changes in lipids around disease onset are unknown. The purpose of our study is to examine the effect of psoriasis onset on serum lipid profiles.
We compared changes in lipid profiles in a population based incident cohort of 689 patients with psoriasis and 717 non-psoriasis subjects. All lipid measures performed 5 years before and after psoriasis incidence/index date were abstracted. Random-effects models adjusting for age, sex and calendar year were used to examine trends in lipid profiles.
There were significant declines in total cholesterol (TC) and low-density lipoprotein (LDL) levels during the 5 years before and after psoriasis incidence/index date in both the psoriasis and the non-psoriasis cohorts, with a greater decrease noted in the TC levels (p=0.022) and LDL (p=0.054) in the non-psoriasis cohort. High-density lipoprotein (HDL) levels increased significantly both before and after psoriasis incidence date in the psoriasis cohort. Triglyceride (TG) levels were significantly higher (p<0.001), and HDL levels significantly lower (p=0.013) in patients with psoriasis compared to non-psoriasis subjects. There were no differences in prescriptions for lipid lowering drugs between the two cohorts.
Patients with psoriasis had a significant decrease in TC and LDL levels during the 5 years before psoriasis incidence. Higher mean TG and lower mean HDL levels were noted in the 5 years before psoriasis incidence. These changes are unlikely to be caused by lipid lowering treatment alone and require further exploration.
PMCID: PMC3520693  PMID: 23110323
Psoriasis; Lipids; Epidemiology
20.  Assessing Immune Function by Profiling Cytokine Release from Stimulated Blood Leukocytes and the Risk of Infection in Rheumatoid Arthritis 
Persons with rheumatoid arthritis (RA) suffer a high burden of infections, but currently no biomarkers are available to identify individuals at greatest risk. A prospective longitudinal study was therefore conducted to determine the association between the responsiveness of ex vivo cytokine production and 6-month risk of infections. Infections were identified by billing codes and validated by medical record review. At baseline, the release of 17 cytokines by peripheral blood mononuclear cells in response to stimulation, or media alone, was measured using multiplexed cytokine analysis. Production of IL-2, IL-8, IL-10, IL-17, TNF-α, IFN-γ, and GM-CSF, induced by various conditions, was significantly associated with the occurrence of infections. A multivariable prediction model based on these data provided new information on the risk of infection beyond standard assessments of disease activity, severity, and treatment. Future studies could utilize this information to devise new biomarkers for the prediction of infection in patients with RA.
PMCID: PMC3183136  PMID: 21703930
Immune signature; immune response; peripheral blood mononuclear cells
21.  Safety of Tumor Necrosis Factor Inhibitors during Pregnancy and Breastfeeding 
Tumor necrosis factor (TNF) inhibitors are useful in the treatment of numerous inflammatory and immunologic disorders. Since many of these conditions occur in women of childbearing age, safety during pregnancy and breastfeeding is of considerable importance.
This paper is a review of the literature on the safety of TNF inhibitors during pregnancy and breastfeeding published between 2001 and 2011.
TNF inhibitors do not appear to be associated with a high risk of teratogenicity or intrauterine death. However, a small magnitude increase in risk cannot be ruled out given the paucity of data on the subject. Although TNF inhibitor use may be associated with a higher rate of preterm delivery, this may in fact be due to an active, underlying disease. Therefore, the decision to use these medications should be made on a case-by-case basis. If the disease cannot be managed with first line agents, TNF inhibitors may be helpful in reducing the number of disease exacerbations. Nevertheless, when using TNF inhibitors, it is prudent to discontinue treatment around the third trimester when transfer across the placenta is greatest and to restart postpartum.
PMCID: PMC3763882  PMID: 24049706
tumor necrosis factor (TNF) inhibitors; uveitis; pregnancy; breastfeeding
22.  Golimumab in patients with active rheumatoid arthritis who have previous experience with tumour necrosis factor inhibitors: results of a long-term extension of the randomised, double-blind, placebo-controlled GO-AFTER study through week 160 
Annals of the Rheumatic Diseases  2012;71(10):1671-1679.
The aim of this study was to assess long-term golimumab therapy in patients with rheumatoid arthritis (RA) who discontinued previous tumour necrosis factor alpha (TNFα) inhibitor(s) for any reason.
Results through week 24 of this multicentre, randomised, double-blind, placebo-controlled study of active RA (≥4 tender, ≥4 swollen joints) were previously reported. Patients received placebo (Group 1), 50 mg golimumab (Group 2) or 100 mg golimumab (Group 3) subcutaneous injections every 4 weeks. Patients from Groups 1 and 2 with <20% improvement in tender/swollen joints at week 16 early escaped to golimumab 50 mg and 100 mg, respectively. At week 24, Group 1 patients crossed over to golimumab 50 mg, Group 2 continued golimumab 50/100 mg per escape status and Group 3 maintained dosing. Data through week 160 are reported.
459 of the 461 randomised patients were treated; 236/459 (51%) continued treatment through week 160. From week 24 to week 100, ACR20 (≥20% improvement in American College of Rheumatology criteria) response and ≥0.25 unit HAQ (Health Assessment Questionnaire) improvement were sustained in 70–73% and 75–81% of responding patients, respectively. Overall at week 160, 63%, 67% and 57% of patients achieved ACR20 response and 59%, 65% and 64% had HAQ improvement ≥0.25 unit in Groups 1, 2 and 3, respectively. Adjusted for follow-up duration, adverse event incidences (95% CI) per 100 patient-years among patients treated with golimumab 50 mg and 100 mg were 4.70 (2.63 to 7.75) and 8.07 (6.02 to 10.58) for serious infection, 0.95 (0.20 to 2.77) and 2.04 (1.09 to 3.49) for malignancy and 0.00 (0.00 to 0.94) and 0.62 (0.17 to 1.59) for death, respectively.
In patients with active RA who discontinued previous TNF-antagonist treatment, golimumab 50 and 100 mg injections every 4 weeks yielded sustained improvements in signs/symptoms and physical function in ∼57–67% of patients who continued treatment. Golimumab safety was consistent with other anti-TNF agents, although definitive conclusions regarding long-term safety require further monitoring.
PMCID: PMC3439650  PMID: 22459542
23.  A Signature of Aberrant Immune Responsiveness Identifies Myocardial Dysfunction in Rheumatoid Arthritis 
Arthritis and rheumatism  2011;63(6):1497-1506.
Heart failure is an important cause of mortality in patients with rheumatoid arthritis (RA). Evidence suggests that immune mechanisms contribute to myocardial injury and fibrosis, leading to left ventricular diastolic dysfunction (LVDD). In this study, we sought to identify a signature of LVDD in patients with RA by analyzing the responsiveness of the innate and adaptive immune systems to stimulation ex vivo.
Subjects (n=212) enrolled prospectively from a population-based cohort underwent echocardiography, and left ventricular function was classified as normal, mild LVDD, or moderate-to-severe LVDD. The release of 17 cytokines by blood mononuclear cells in response to stimulation with a panel of 7 stimuli or in media alone was analyzed using multiplexed immunoassays. Logistic regression models were used to test for associations between a multi-cytokine immune response score and LVDD after adjusting for clinical covariates.
An 11-cytokine profile effectively differentiated subjects with moderate-to-severe LVDD from those with normal LV function. An immune response score (range 0 – 100) was strongly associated with moderate-to-severe LVDD (odds ratio per 10 units: 1.5; 95% confidence interval: 1.2, 2.1) after adjusting for serum IL-6, brain natriuretic peptide, and glucocorticoid use, as well as other RA characteristics and LVDD risk factors.
The major finding of this study is that aberrant systemic immune responsiveness is associated with advanced myocardial dysfunction in patients with RA. The unique information added by the immune response score on the likelihood of LVDD warrants future longitudinal studies of its value in predicting future deterioration in myocardial function.
PMCID: PMC3106129  PMID: 21384332
24.  Incidence of extra-articular rheumatoid arthritis in Olmsted County, Minnesota in 1995–2007 vs 1985–1994: a population-based study 
The Journal of rheumatology  2011;38(6):983-989.
To assess incidence and mortality impact of extra-articular rheumatoid arthritis (ExRA) in patients with incident rheumatoid arthritis (RA) in 1995–2007 vs 1985–1994.
Data on incident ExRA were abstracted from medical records of RA patients, Olmsted County, Minnesota residents who first met the 1987 ACR criteria for RA between 1/1/1995 and 12/31/2007. Patients were followed until death, migration from Olmsted County, or 12/31/2008. ExRA were classified using the predefined criteria and compared to the corresponding 1985–1994 inception RA cohort (n=147).
The 1995–2007 cohort included 463 RA patients followed for a mean of 6.3 years. Mean age was 55.6 years (69% female; 67% rheumatoid factor [RF] positive). The 10-year cumulative incidence of any ExRA (50.1%) and severe ExRA (6.7%) in 1995–2007 cohort was similar to the 1985–1994 cohort (46.2% and 9.7%, respectively). The 10-year cumulative incidence of vasculitis, but not other ExRA, was significantly lower in 1995–2007 cohort (0.6%) compared to the 1985–1994 cohort (3.6%). RF positivity, erosions/destructive changes, use of methotrexate, other disease-modifying antirheumatic drugs and systemic corticosteroids were significantly associated with ExRA in the 1995–2007 cohort. ExRA were associated with mortality risk (HR 2.1, 95%CI 1.2, 3.7) in the 1995–2007 cohort. The decrease in mortality following ExRA in the 1995–2007 cohort vs 1985–1994 cohort did not reach statistical significance (HR 0.6, 95%CI 0.3, 1.2, p=0.16).
ExRA remain a common complication associated with increased mortality in RA. The occurrence of vasculitis appears to be decreasing in the recent years.
PMCID: PMC3193155  PMID: 21459933
rheumatoid arthritis; extra-articular manifestations; incidence; mortality; risk factors
25.  The Lifetime Risk of Adult-Onset Rheumatoid Arthritis and Other Inflammatory Autoimmune Rheumatic Diseases 
Arthritis and rheumatism  2011;63(3):633-639.
Understanding of the personal risks for rheumatoid arthritis (RA) and other rheumatic diseases remains poor, despite advances in knowledge of their pathogenesis, therapeutics, and clinical impact, in part because the personal lifetime risk of developing these diseases is unknown.
To estimate the lifetime risk of RA, as well as other inflammatory autoimmune rheumatic diseases, including systemic lupus erythematosus, psoriatic arthritis, polymyalgia rheumatica (PMR), giant cell arteritis, ankylosing spondylitis, and Sjögren’s syndrome, and to provide an overall estimate of the risk for developing inflammatory autoimmune rheumatic disease over a lifetime.
Using the incidence rates obtained from our population-based studies of rheumatic diseases among residents of Olmsted County, Minnesota, and mortality rates from life tables for the general population, we estimated sex-specific lifetime risk of rheumatic disease.
The lifetime risk of RA developing in US adults is 3.6% for women and 1.7% for men, and the lifetime risk of rheumatoid factor positive RA is 2.4% for women and 1.1% for men. The second most common inflammatory autoimmune rheumatic disease is PMR with a lifetime risk of 2.4% for women and 1.7% among men. The overall lifetime risk of inflammatory autoimmune rheumatic disease was 8.4% for women and 5.1% for men.
One in 12 women and 1 in 20 men will develop inflammatory autoimmune rheumatic disease during their lifetime. These results can serve as useful guides in counseling patients regarding their lifetime risk of these conditions and have important implications for disease awareness campaigns.
PMCID: PMC3078757  PMID: 21360492

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