Cynthia S. Crowson

Lymphoid Neogenesis in Rheumatoid Synovitis

In rheumatoid arthritis (RA), tissue-infiltrating lymphocytes can be arranged in sophisticated organizations that resemble microstructures usually formed in secondary lymphoid organs. Molecular pathways and host risk factors involved in this process of lymphoid neogenesis remain to be defined. In a series of 64 synovial tissue biopsies, lymphoid follicles with germinal centers (GCs) were found in 23.4% of the patients. Follicular dendritic cells (FDCs) were exclusively present in tissues with GCs, suggesting that the recruitment or in situ maturation of FDCs is a critical factor for GC formation in the synovial membrane. Primary follicles were absent, emphasizing the role of Ag recognition in the generation of inflammation-associated lymphoid organogenesis. Multivariate logistic regression analysis of tissue cytokines and chemokines identified two parameters, in situ transcription of lymphotoxin (LT)-β and of B lymphocyte chemoattractant (BLC; BLC/CXCL13), that were predictors for FDC recruitment and synovial GC formation. LT-β and BLC/CXCL13 were found to be independent variables that could, in part, compensate for each other to facilitate GC formation. Prediction models incorporating in situ transcription of LT-β and BLC/CXCL13 had high negative yet moderate positive predictive values, suggesting that LT-β and BLC/CXCL13 are necessary but not sufficient. LT-β protein was detected on a subset of mantle zone and GC B cells, but also on T cells in follicular structures. BLC/CXCL13 was produced by FDCs in follicular centers, but was predominantly found in endothelial cells and synovial fibroblasts, suggesting heterotypic signaling between cells of the synovial membrane and infiltrating lymphocytes in regulating extranodal lymphoid neogenesis.

Epidemiology of Sarcopenia

OBJECTIVES: To examine patterns of muscle mass change with aging and to estimate the prevalence of sarcopenia.

Extra-articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years

Objective: To investigate the trends in incidence of extra-articular rheumatoid arthritis (ExRA) in a well defined community based cohort of patients with rheumatoid arthritis (RA), and to examine possible predictors of ExRA occurrence. Methods: Using the resources of the Rochester Epidemiology Project, a retrospective medical record review was conducted of a cohort of 609 cases of RA in Olmsted County, MN, diagnosed during 1955–94. These cases had been previously classified using the ACR 1987 criteria for RA. Patients were followed up from 1955 to 2000 (median follow up 11.8 years; range 0.1–42.8), and incident ExRA manifestations were recorded according to predefined criteria. Time to first presentation of ExRA was compared in patients with RA by decade of diagnosis. Possible ExRA risk factors were identified in case record reviews. Results: ExRA occurred in 247 patients (40.6%). A subgroup of 78 patients (12.8%) had ExRA manifestations considered to be severe in a previous study from Malmö, Sweden. The incidence of severe ExRA did not change significantly over the decades (p=0.165). In a multivariate analysis the main predictors of severe ExRA were smoking at RA diagnosis (risk ratio (RR)=2.94; 95% confidence interval (95% CI) 1.68 to 5.13) and early disability (Steinbrocker class III-IV at diagnosis) (RR=2.45; 95% CI 1.51 to 4.00). The effect of smoking overwhelmed the weaker effect of rheumatoid factor seropositivity. Conclusion: There was no decrease in the incidence of extra-articular manifestations in patients with RA diagnosed up to 1995. Smoking and early disability are independent risk factors for extra-articular RA.

Value of Immunological Markers in Predicting Responsiveness to Influenza Vaccination in Elderly Individuals

ABSTRACT Elderly individuals are at high risk for morbidity and mortality when infected with influenza virus. Vaccinations with inactivated virus are less effective in the elderly due to the declining competency of the aging immune system. We have explored whether immunological parameters predict poor anti-influenza virus vaccine responses and can be used as biological markers of immunosenescence. One hundred fifty-three residents of community-based retirement facilities aged 65 to 98 years received a trivalent influenza vaccine. Vaccine-induced antibody responses were determined by comparing hemagglutination inhibition titers before and 28 days after immunization. The composition of the T-cell compartment was analyzed by flow cytometry and the sizes of three T-cell subsets, CD4+CD45RO+ cells, CD4+ CD28null cells, and CD8+ CD28null cells, were determined. Only 17% of the vaccine recipients were able to generate an increase in titers of antibody to all three vaccine components, and 46% of the immunized individuals failed to respond to any of the three hemagglutinins. The likelihood of successful vaccination declined with age and was independently correlated with the expansion of a particular T-cell subset, CD8+ CD28null T cells. The sizes of the CD4+ CD45RO+ memory T-cell and CD4+ CD28null T-cell subsets had no effect on the ability to mount anti-influenza virus antibody responses. Frequencies of CD8+ CD28null T cells are useful biological markers of compromised immunocompetence, identifying individuals at risk for insufficient antibody responses.

Is the incidence of rheumatoid arthritis rising?: Results from Olmsted County, Minnesota, 1955–2007

OBJECTIVE To examine trends in the incidence and prevalence of rheumatoid arthritis (RA) from 1995 to 2007. METHODS To augment our preexisting inception cohort of patients with RA (1955-1994), we assembled a population-based incidence cohort of individuals >or=18 years of age who first fulfilled the American College of Rheumatology 1987 criteria for the classification of RA between January 1, 1995 and December 31, 2007 and a cohort of patients with prevalent RA on January 1, 2005. Incidence and prevalence rates were estimated and were age-and sex-adjusted to the white population in the US in 2000. Trends in incidence rates were examined using Poisson regression methods. RESULTS The 1995-2007 incidence cohort comprised 466 patients (mean age 55.6 years), 69% of whom were female and 66% of whom were rheumatoid factor positive. The overall age- and sex-adjusted annual RA incidence was 40.9/100,000 population. The age-adjusted incidence in women was 53.1/100,000 population (versus 27.7/100,000 population in men). During the period of time from 1995 to 2007, the incidence of RA increased moderately in women (P = 0.02) but not in men (P = 0.74). The increase was similar among all age groups. The overall age- and sex-adjusted prevalence on January 1, 2005 was 0.72% (95% confidence interval [95% CI] 0.66, 0.77), which is an increase when compared with a prevalence of 0.62% (95% CI 0.55, 0.69) in 1995 (P < 0.001). Applying the prevalence on January 1, 2005 to the US population in 2005 showed that an estimated 1.5 million US adults were affected by RA. This is an increase from the previously reported 1.3 million adults with RA in the US. CONCLUSION The incidence of RA in women appears to have increased during the period of time from 1995 to 2007. The reasons for this recent increase are unknown, but environmental factors may play a role. A corresponding increase in the prevalence of RA was also observed.

Fracture Incidence in Olmsted County, Minnesota: Comparison of Urban with Rural Rates and Changes in Urban Rates Over time

Abstract: Using the data resources of the Rochester Epidemiology Project, we carried out a descriptive study of fracture incidence among the residents of Olmsted County, Minnesota. During the 3-year period 1989–91, 2901 County residents ≥ 35 years of age experienced 3665 separate fractures. The age- and sex-adjusted (to 1990 United States whites) incidence of any fracture was 2205 per 100 000 person-years (95% CI, 2123 to 2286) and that of all fractures was 2797 per 100 000 (95% CI, 2705 to 2889). Age-adjusted fracture rates were 40% greater among women. Incidence rates increased with age in both sexes. One-third of the fractures involved the hip, spine or distal forearm – the skeletal sites traditionally associated with osteoporosis. The age- and sex-adjusted incidence of fractures due to moderate trauma (2205 per 100 000 person-years; 95% CI, 2106 to 2303) was twice that of fractures due to more severe trauma (1164 per 100 000; 95% CI, 1106 to 1223) and 12 times that of pathological fractures (178 per 100 000; 95% CI, 133 to 222). Overall fracture rates were 15% greater among residents of the central city of Rochester compared with the rural portion of Olmsted County. The incidence of limb fractures among Rochester residents was 14% higher than comparable rates documented for this community 20 years earlier in 1969–71, due mainly to a substantial increase in the incidence of leg fractures.

Forearm fractures as predictors of subsequent osteoporotic fractures

Abstract: To assess the ability of distal forearm fractures to predict future fractures, we conducted a population-based retrospective cohort study among the 1288 residents (243 men, 1045 women) of Rochester, Minnesota age 35 years or older who experienced their first distal forearm fracture in 1975–94. During 9664 person-years of follow-up, 548 patients experienced 1109 subsequent fractures, excluding 195 that occurred on the same day as the index forearm fracture. The cumulative incidence of any subsequent fracture was 55% by 10 years and 80% by 20 years following the initial distal forearm fracture. Compared to expected fracture rates in the community, the risk of a hip fracture following the index forearm fracture was increased 1.4-fold in women (95% CI, 1.1–1.8) and 2.7-fold in men (95% CI, 0.98–5.8). In women, the risk of hip fracture differed by age, as we had found in a previous study. Women over age 70 had a 1.6-fold increase (95% CI, 1.2–2.0) in subsequent hip fracture risk whereas women who sustained their first forearm fracture before age 70 years did not have significantly increased risk. By contrast, vertebral fractures were significantly increased at all ages, with a 5.2-fold increase (95% CI, 4.5–5.9) in risk among women and a 10.7-fold increase (95% CI, 6.7–16.3) among men following a first distal forearm fracture. The increased risk in men suggests that a sentinel forearm fracture should not be ignored. Among the women, we also found a missed opportunity for intervention as hormone replacement therapy was underutilized.

The epidemiology of rheumatoid arthritis in Rochester, Minnesota, 1955–1985

OBJECTIVE To describe trends in the epidemiology of rheumatoid arthritis (RA) over a period of 30 years in a population-based cohort. METHODS An inception cohort of Rochester, Minnesota residents who were > or =35 years of age and had RA (as defined by the 1987 American College of Rheumatology criteria for RA) first diagnosed between January 1, 1955 and January 1, 1985 was assembled and followed up until January 1, 1995. Incidence rates were age- and sex-adjusted to the 1970 US white population. Prevalence of RA in this cohort was estimated on January 1, 1985. A birth-cohort analysis was performed by calculating and comparing incidence rates in each of 16 birth cohorts. RESULTS Of the 425 Rochester residents who fulfilled the inclusion criteria, there were 113 men (26.6%) and 312 women (73.4%), with a mean age at diagnosis of 60.2 years. The mean followup time was 15.1 years. The overall age- and sex-adjusted annual incidence of RA among Rochester, Minnesota residents > or =35 years of age (1955-1985) was 75.3 per 100,000 population (95% confidence interval 68.0-82.5). This incidence was approximately double in women compared with that in men and increased steadily with age, until age 85, after which the incidence of RA decreased. Secular trends in the incidence of RA over the entire study period were demonstrated. The overall prevalence of RA on January 1, 1985 was approximately 1%. The birth-cohort analysis showed peak incidence rates in the 1880-1895 birth cohorts. CONCLUSION The epidemiology of RA is dynamic. The findings in this study lend further support to the hypothesis of a host-environment interaction in the pathogenesis of RA.

Incidence and Clinical Predictors of Psoriatic Arthritis in Patients With Psoriasis: A Population-Based Study

OBJECTIVE To determine the incidence and disease-specific predictors of clinically recognized psoriatic arthritis (PsA) in patients with psoriasis. METHODS We identified an incidence cohort of psoriasis subjects age >/=18 years diagnosed between January 1, 1970 and December 31, 1999 in a population-based setting. Psoriasis diagnoses were validated by confirmatory diagnosis in the medical record. Incident and clinically recognized PsA subjects were classified according to the Classification of Psoriatic Arthritis (CASPAR) criteria. Cox proportional hazards models were used to identify predictors of PsA within the psoriasis cohort. RESULTS The psoriasis incidence cohort comprised 1,633 subjects. Of these, 40 were diagnosed with PsA concurrently with psoriasis and were excluded from analysis. The remaining 1,593 psoriasis subjects had a mean age of 43 years and 50% were men. Over 20,936 person-years of followup, 57 subjects were clinically recognized with new-onset PsA, with a cumulative incidence of 1.7% (95% confidence interval [95% CI] 1.0-2.3%), 3.1% (95% CI 2.2-4.1%), and 5.1% (95% CI 3.7-6.6%) at 5, 10, and 20 years following psoriasis incidence, respectively. Psoriasis features associated with higher risk of PsA were scalp lesions (hazard ratio [HR] 3.89, 95% CI 2.18-6.94), nail dystrophy (HR 2.93, 95% CI 1.68-5.12), and intergluteal/perianal lesions (HR 2.35, 95% CI 1.32-4.19). Calendar year was not associated with risk of PsA (P = 0.15), indicating that the likelihood of PsA in psoriasis subjects did not change over time. CONCLUSION In this population-based study, <10% of patients with psoriasis developed clinically recognized PsA during a 30-year period. Psoriasis features associated with a higher likelihood of PsA were nail dystrophy, scalp lesions, and intergluteal/perianal psoriasis.

Do cardiovascular risk factors confer the same risk for cardiovascular outcomes in rheumatoid arthritis patients as in non-rheumatoid arthritis patients?

Objective: To compare the frequency of traditional cardiovascular (CV) risk factors in rheumatoid arthritis (RA) compared to non-RA subjects, and examine their impact on the risk of developing selected CV events (myocardial infarction (MI), heart failure (HF) and CV death) in these two groups. Methods: We examined a population-based incidence cohort of subjects with RA (defined according to the 1987 American College of Rheumatology criteria), and an age- and sex-matched non-RA cohort. All subjects were followed longitudinally through their complete community medical records, until death, migration, or 1 January 2001. Clinical CV risk factors and outcomes were defined using validated criteria. The χ2 test was used to compare the frequency of each CV risk factor at baseline. Person-years methods were used to estimate the rate of occurrence of each CV risk factor during follow-up. Cox models were used to examine the influence of CV risk factors on the development of CV outcomes. Results: A total of 603 RA and 603 non-RA subjects (73% female; mean age 58 years) were followed for a mean of 15 and 17 years (total: 8842 and 10 101 person-years), respectively. At baseline, RA subjects were significantly more likely to be former or current smokers when compared to non-RA subjects (p<0.001). Male gender, smoking, and personal cardiac history had weaker associations with CV events among RA subjects, compared to non-RA subjects. There was no significant difference between RA and non-RA subjects in the risk imparted with respect to the other CV risk factors (ie, family cardiac history, hypertension, dyslipidaemia, body mass index, or diabetes mellitus). Conclusion: While some traditional CV risk factors imparted similar risk among RA compared with non-RA subjects, others (ie, male gender, smoking and personal cardiac history) imparted significantly less risk for the development of CV disease. These differences in the overall impact of traditional CV risk factors suggest that strategies to prevent CV disease and mortality focused solely on controlling traditional CV risk factors may be relatively less beneficial in RA subjects than in the general population. Further research is needed to determine optimal approaches to reducing CV morbidity and mortality in persons with RA.