The association of cytokines with disease activity and damage scores in systemic lupus erythematosus patients.

OBJECTIVE: The aim of this study was to explore the role of cytokines in the pathogenesis of SLE in a genetically homogeneous Caucasian SLE patient population. METHODS: Serum levels of the following cytokines were determined by ELISA in SLE patients (diagnosed as per ACR diagnostic criteria): IL-1ß, IL-10, IL-12p70 and TNF-α. Demographic data, disease activity as per the SLEDAI and damage scores (SLICC) at the 5-year follow-up were calculated. RESULTS: Enhanced production of TNF-α, IL-1 and IL-10 were observed in SLE patients compared with controls. A strong positive correlation was seen between levels of IL-12p70 and IL-10. In addition, IL-10, TNF-α and IL-1 demonstrated a significant relationship with disease activity. Interestingly, elevated levels of IL-10 were observed in SLE patients with CNS involvement while patients with elevated levels of TNF-α were more likely to have renal involvement and sustain damage over the follow-up period. Additionally, the ratio of all cytokines assayed to IL-12p70 levels were significantly higher in SLE patients when compared with controls, with an association seen between damage accrual and the IL-1ß/IL-12p70 ratio (r = 0.431, P = 0.003), IL-10/IL-12p70 ratio (r = 0.351, P = 0.018) and TNF-α/IL-12p70 ratio (r = 0.33, P = 0.028). When the respective ratios were analysed for organ-specific disease, significant differences were observed for the IL-1ß/IL-12p70 ratio (0.79 vs 0.47, P = 0.036), IL-10/IL-12p70 ratio (4.29 vs 1.87, P = 0.018) and TNF-α/IL-12p70 ratio (7.49 vs 5.21, P = 0.018) with respect to renal involvement. CONCLUSION: Increased levels of a number of immunomodulatory cytokines relative to IL-12p70 in this Caucasian SLE patient population are seen in patients with renal involvement and are associated with increased accrual of damage at the 5-year follow-up.

Elevated B lymphocyte stimulator levels are associated with increased damage in an Irish systemic lupus erythematosus cohort.

OBJECTIVE: The overall aim of this study is to identify clinical and serological features that are associated with B lymphocyte stimulator (BLyS) elevation in a homogeneous Caucasian SLE population and thereby identify patients who are most likely to benefit from BLyS blockade. METHODS: Patients with SLE (as per ACR criteria) were recruited. Clinical history, disease activity measures and laboratory measures of disease were recorded. BLyS levels were determined by ELISA. RESULTS: BLyS elevation was defined as being higher than the 95th percentile of BLyS levels measured in controls. Patients were divided into two groups: those with elevated BLyS levels (group 1, n = 23) and those with normal BLyS levels (group 2, n = 22). Elevated BLyS levels were significantly associated with patients of younger age and shorter disease duration. In keeping with previous reports, patients with elevated BLyS levels had more active disease (SLEDAI 5.1 vs 0.86, P < 0.001); however, our analysis also demonstrates that BLyS elevation was significantly associated with increased organ damage at 5-year follow-up [Systemic Lupus International Collaborating Clinics/ACR Damage Index (SLICC/ACR DI) 0.53 vs 0.13, P = 0.012]. Furthermore, the presence of Sm autoantibody significantly predicted elevated BLyS levels in a Caucasian population. BLyS levels were significantly higher in those with musculoskeletal involvement, malar rash, renal disease and evidence of immunological activity. CONCLUSION: BLyS blockade may be most beneficial if introduced early in the course of disease in young Caucasian patients presenting with renal, musculoskeletal and skin disease in an effort to reduce long-term damage.

Impact of a fatigue management in work programme on meeting work demands of individuals with rheumatic diseases: A pilot study.

INTRODUCTION: Work disability and job loss are serious consequences of rheumatic diseases (RDs), and fatigue is a symptom of RDs commonly reported to have an impact on work performance. A FAtigue ManagEment in Work (FAME-W) programme was developed to facilitate the self-management of fatigue in work. The present pilot study explored if FAME-W could facilitate individuals with RDs to manage fatigue in work and improve their ability to meet work demands. METHODS: Twenty-seven individuals with a variety of rheumatic diagnoses completed a 4-week, 2-h occupational therapy-led self-management programme. Each week focused on fatigue-related topics, including fatigue and activity management, pain management and joint protection, mental well-being, effective communication with employers and work colleagues, and employment legislation. Individual workplace ergonomic assessments were also offered. Study measures (work function, fatigue, pain, mood and self-efficacy) were completed prior to starting FAME-W, immediately post-intervention and 12 weeks post-intervention. RESULTS: Participants (56% male) had a mean age of 43 years. No significant improvements were observed immediately post-programme. However, at the 12-week follow-up, significant improvements were reported in meeting work demands (scheduling [p = 0.046], output [p = 0.002], physical [p = 0.003], mental [p = 0.016]), fatigue [p = 0.001], pain [p = 0.01], anxiety [p = 0.001], depression [p < 0.001], self-efficacy [p < 0.001] and Arthritis Impact Measurement Scales 2-Short Form (physical: p = 0.005; symptoms: p = 0.010; affect: p = 0.010; social: p = 0.001). CONCLUSIONS: Significant improvements were reported in participants' ability to meet various demands of their work 3 months post-FAME-W. These findings suggest that FAME-W has the potential to assist individuals with RDs to meet the demands of their work, although further research is required to test the effectiveness of this intervention.

Fatigue and Activity Management Education for Individuals with Systemic Lupus Erythematosus.

BACKGROUND: Fatigue and Activity Management Education (FAME) is a six-week occupational therapy-led programme focusing on fatigue and stress management, exercise, nutrition, and joint protection. Each session consists of education and goal setting. OBJECTIVES OF STUDY: To assess the impact of FAME on occupational participation and fatigue management. METHODS: Three programmes were facilitated with twenty-one women with SLE. A mixed methods design was used. Quantitative data were collected using self-reported questionnaires administered before, immediately after, and eight weeks after intervention. Data were analysed using descriptive and nonparametric inferential statistics. Qualitative data were collected through focus groups and interviews. Thematic analysis was carried out on the qualitative data. FINDINGS: There was a statistically significant improvement in depression as measured by the Hospital Anxiety and Depression Scale and categories of "burden to others" and "fatigue" in the LupusQoL. There were nonsignificant improvements in fatigue, occupational participation, self-efficacy, and anxiety. Participants reported an improved understanding of fatigue and the impact of stress on fatigue. They also identified self-management strategies they were using on a daily basis.

Impact of Fatigue in Rheumatic Diseases in the Work Environment: A Qualitative Study.

Fatigue is a symptom of arthritis that causes difficulty at work. An improved understanding of this symptom could assist its management in the work environment. The aim of this study was to explore people with rheumatic diseases' experiences of fatigue in work. A qualitative descriptive design was used with semi-structured interviews and a constant comparative method of data analysis. There were 18 participants, the majority of them female with Rheumatoid Arthritis (RA) and working full-time. Three themes were identified: "Impact of fatigue on work performance" with cognition, mood and physical abilities being the main difficulties reported. In the second theme "Disclosure at Work" participants discussed disclosing their disease to employers but reported a lack of understanding of fatigue from colleagues. The final theme "work-based fatigue management strategies" included cognitive strategies and energy management techniques, which were mainly self-taught. In this study, fatigue was reported to impact on many areas of work performance with limited understanding from colleagues and employers. Interventions from health professionals to assist with development of work-related self-management skills are required to assist with symptom management in the work place. Such interventions should include education to employers and colleagues on the nature of fatigue in Rheumatic diseases.

Infections and biological therapy in rheumatoid arthritis.

Infections are common in patients with rheumatic disorders. Reasons for such vulnerability include alterations of immunoregulation, disease severity, debility, co-morbid illnesses and the use of immunosuppressive medications. The advent of new biological agents has precipitated a further examination of the links between infection, the underlying disease and its treatment, resulting in several interesting observations. Interleukin-1 (IL-1) and tumour necrosis factor alpha (TNF-alpha), the major pro-inflammatory cytokines, play important roles in host defence against infection. Inhibition of their activity could therefore be anticipated to augment the risk of infection in patients with pre-existing abnormalities of immune regulation. Slight increases in the rates of infection were noted in the clinical trials of IL-1 receptor antagonist (IL-1Ra). In addition, a small number of opportunistic infections have been observed with the TNF inhibitor, etanercept. However, a marked increase in opportunistic infection, particularly tuberculosis, has occurred with the use of infliximab, an agent that also blocks TNF activity. The precise mechanisms by which these agents predispose to infection are currently being explored. The answers are likely to add significantly to our knowledge of how immune dysfunction contributes both to the pathophysiology of disease and the complications of therapy.

The impact of hepatitis screening on diagnosis and treatment in rheumatoid arthritis.

Identification of patients with exposure to viral hepatitis is an important part of the care of patients with inflammatory arthritis. This study was conducted to assess the extent of hepatitis B and C screening, and the prevalence of viral hepatitis in a cohort of patients with established rheumatoid arthritis (RA). The medical records of 100 consecutive RA patients were retrospectively analysed for screening of hepatitis B surface antigen, surface antibody and core antibody and hepatitis C antibody. A teaching session was then conducted with the rheumatology team, emphasising the rationale for viral hepatitis testing. We then prospectively analysed 100 more RA patients to see if hepatitis screening improved. In the initial 100 patients (21 % male, mean age 65 years), 85 % were taking methotrexate and 22 % biologic treatments. A complete hepatitis screen was present in 8 %, while 12 % had hepatitis B core antibody checked and 53 % had been tested for hepatitis C.The second cohort of patients was similar to the first in terms of demographics and treatment. A complete hepatitis screen was available in 63 %, while 65 % had hepatitis B core antibody checked and 81 % had been tested for hepatitis C.In total, we identified 4 new cases of positive hepatitis B core antibody, 11 cases of positive hepatitis B surface antibody and 1 case of positive hepatitis C antibody. Even in populations where hepatitis B or C is non-endemic, screening will reveal new cases. Educational initiatives are helpful in teaching staff to screen patients.

Estrogen receptor α regulates tripartite motif-containing protein 21 expression, contributing to dysregulated cytokine production in systemic lupus erythematosus.

OBJECTIVE: To examine the role of 17ß-estradiol in the regulation of the autoantigen tripartite motif-containing protein 21 (TRIM-21) in patients with systemic lupus erythematosus (SLE). METHODS: Monocytes isolated from healthy control subjects and patients with SLE were stimulated with 17ß-estradiol and/or the estrogen receptor α (ERα) antagonist methyl-piperidino-pyrazole dihydrochloride. TRIM-21, ERα, and CREMα expression was determined by real-time polymerase chain reaction (PCR) analysis. MatInspector software was used to identify putative binding sites within the TRIM-21 promoter. ERα binding to the TRIM-21 gene promoter region in monocytes was analyzed by chromatin immunoprecipitation (ChIP) assay. TRIM-21 and interferon regulatory factor 3 protein levels were analyzed by Western blotting. RESULTS: Real-time PCR analysis demonstrated a role of estrogen in the regulation of TRIM-21 expression in monocytes, which correlated positively with ERα gene expression in patients with SLE. Investigations into the human TRIM-21 promoter revealed the presence of an estrogen response element, with ChIP assays confirming ERα binding to this site. Studies into estrogen-induced TRIM-21 expression revealed a hyperresponsiveness of SLE patients to 17ß-estradiol, which led to the enhanced levels of TRIM-21 observed in these individuals. CONCLUSION: Our results demonstrate a role of estrogen in the regulation of TRIM-21 expression through an ERα-dependent mechanism, a pathway that we observed to be overactive in SLE patients. Treatment of monocytes with an ERα antagonist abrogated estrogen-induced TRIM-21 expression and, as a consequence, decreased the expression of interleukin-23. These findings identify TRIM-21 as a novel ERα-regulated gene and provide novel insights into the link between estrogen and the molecular pathogenesis of SLE.

Safety of joint and soft tissue injections in patients on warfarin anticoagulation.

Performance of joint and soft tissue injections in patients receiving anticoagulation is subject to different protocols, some of which suggest continuing treatment within the therapeutic range, while others recommend stopping the treatment prior to procedures. The aim of this study was to evaluate the safety of two approaches to the management of patients prescribed warfarin requiring joint or soft tissue injection. A systematic literature review on this subject was undertaken. Our departmental protocol was changed from one where anticoagulation treatment was temporarily stopped prior to joint/soft tissue injection to one where treatment was continued in the context of a therapeutic international normalised ratio (INR) level within 24 h of the procedure. In patients in whom warfarin was withheld, 32 procedures were performed in 18 patients (13 rheumatoid arthritis, 11 osteoarthritis, 5 spondyloarthritis and 1 each of adhesive capsulitis, rotator cuff tendinopathy and trochanteric bursitis). Of these, 30 were joint injections and 2 were soft tissue injections. In patients who continued warfarin, 32 procedures were performed in 21 patients (11 rheumatoid arthritis, 7 osteoarthritis, 6 crystal arthritis, 4 rotator cuff tendinopathy, 2 spondyloarthritis and 1 each of adhesive capsulitis and carpal tunnel syndrome). Of these, 27 were joint injections and 5 were soft tissue injections. There were no clinical hemarthroses or complications in either group. Joint and soft tissue injections appear to be safe in patients receiving warfarin anticoagulation with an INR <3. Continuation of anticoagulants reduces staff workload and patient inconvenience with no evidence of increased risk of complications.

The effect of oral contraceptives and estrogen replacement therapy on the risk of rheumatoid arthritis: a population based study.

OBJECTIVE: Epidemiologic evidence for a protective effect of exogenous female sex hormones on the development of rheumatoid arthritis (RA) is contradictory. We examined whether exposure to either oral contraceptives (OC) or postmenopausal estrogen replacement therapy (ERT) is associated with the development of RA in women. METHODS: We separately examined the relationship between use of OC and ERT on the risk of RA in a population based case-control study. Case patients, including all female residents of Rochester, Minnesota, > or = 18 years of age, who first fulfilled 1987 American College of Rheumatology criteria for RA between 1955 and 1994 (n = 445), were compared with age matched female controls from the community. Multivariable conditional logistic regression models were used to determine whether OC or ERT exposure had an effect on RA development after controlling for potential confounders. RESULTS: We observed an inverse association between ever-use of OC and the risk of RA, which persisted after adjusting for potential confounders in multivariate analyses (OR 0.56, 95% CI 0.34, 0.92). Earlier calendar-year of first exposure to OC was associated with lower OR for RA. We found no evidence of a significant association of ERT with RA risk (adjusted OR 1.11, 95% CI 0.69, 1.78). CONCLUSION: Exposure to OC, but not ERT, significantly reduces the risk of development of RA. The risk of developing RA is lower when OC exposure occurred in earlier years, which suggests that the higher doses of estrogens and progestins contained in earlier OC preparations may have a stronger protective effect against developing RA. While this protective effect is strong, it only explains a small portion of the observed decrease in RA incidence over the past few decades because the proportion of Rochester women exposed to OC is quite small.

Predictors of longterm outcome in ankylosing spondylitis.

OBJECTIVE: To determine predictors of longterm outcome in ankylosing spondylitis (AS). METHODS: Data were collected retrospectively on constitutional and environmental factors that may predict outcome in AS in 311 patients (252 men, 81%). Univariate statistics and multivariable linear regression analyses were used to identify factors correlated with disease outcome, which was defined in terms of radiological (Bath AS Radiology Index, BASRI) and functional status (Bath AS Functional Index, BASFI). RESULTS: Disease duration, sex, and iritis are independently associated with BASRI and account for 23% (p < 0.001) of variation in radiological scores (BASRI-t), a measure that includes the hip joint in the score. Radiological hip involvement is significantly associated with higher scores of spinal radiological change (BASRI-s) (p < 0.001). Cigarette smoking, radiological status, and Bath AS Disease Activity Index score (BASDAI) are independently associated with and account for 50% of variability in functional status (p < 0.001). CONCLUSION: Much of the variability in disease severity in AS remains unexplained. All but one of the factors associated with outcome in this study are inherent. This suggests that genetic factors have a greater influence than environmental factors on radiological progression and disability in AS. It may, however, be possible to improve longterm functional outcome in AS by targeting high risk individuals early in the disease course with more aggressive management strategies and encouraging smoking cessation in all patients with AS.

Frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based study.

OBJECTIVE: A high frequency of infections complicating rheumatoid arthritis (RA) has been described in reports of case series. This retrospective longitudinal cohort study was undertaken to compare the frequency of infections in a population-based incidence cohort of RA patients with that in a group of individuals without RA from the same population. METHODS: RA patients included all members of an incidence cohort of Rochester, Minnesota residents ages >or=18 years who were first diagnosed as having RA between 1955 and 1994. One age- and sex-matched subject without RA was selected for each patient with RA. Study subjects were followed up by review of their entire medical record until death, migration from the area, or study end (January 1, 2000), and details of all documented infections, along with information on potential risk factors for infection, were recorded. Hazard ratios for infections were estimated using stratified Andersen-Gill proportional hazards models, with adjustment for potential confounders. RESULTS: The 609 RA patients and 609 non-RA study subjects (mean age 58.0 years; 73.1% female) were followed up for a mean of 12.7 years and 15.0 years, respectively, reflecting higher mortality among the group with RA. Hazards ratios for objectively confirmed infections, infections requiring hospitalization, and any documented infection in patients with RA were 1.70 (95% confidence interval [95% CI] 1.42-2.03), 1.83 (95% CI 1.52-2.21), and 1.45 (95% CI 1.29-1.64), respectively, after adjustment for age, sex, smoking status, leukopenia, corticosteroid use, and diabetes mellitus. Sites of infection with the highest risk ratios were bone, joints, skin, soft tissues, and the respiratory tract. CONCLUSION: In this study, patients with RA were at increased risk of developing infections compared with non-RA subjects. This may be due to immunomodulatory effects of RA, or to agents with immunosuppressive effects used in its treatment.

Predictors of infection in rheumatoid arthritis.

OBJECTIVE: Patients with rheumatoid arthritis (RA) have been shown to have an increased susceptibility to the development of infections. The exact causes of this increased risk are unknown, but may relate to immunologic disturbances associated with the disease or to the immunosuppressive effects of agents used in its treatment. This study was undertaken to identify predictors of serious infections among patients with RA. Identification of such factors is the necessary first step in reducing the excess risk of infection in RA. METHODS: Members of a population-based incidence cohort of Rochester, Minnesota residents ages >or=18 years, who had been diagnosed with RA between 1955 and 1994, were followed up longitudinally through their complete medical records until January 1, 2000. We examined potential risk factors for the development of all objectively confirmed (by microbiology or radiology) infections and for infections requiring hospitalization. Potential risk factors included RA severity measures (rheumatoid factor positivity, elevated erythrocyte sedimentation rate, extraarticular manifestations of RA, and functional status), comorbidities (diabetes mellitus, alcoholism, and chronic lung disease), and other risk factors for infection (presence of leukopenia, smoking). Predictors were identified using multivariate time-dependent Cox proportional hazards modeling. RESULTS: The 609 RA patients in the cohort had a total followup time of 7,729.7 person-years (mean 12.7 years per patient). A total of 389 patients (64%) had at least 1 infection with objective confirmation, and 290 (48%) had at least 1 infection requiring hospitalization. Increasing age, presence of extraarticular manifestations of RA, leukopenia, and comorbidities (chronic lung disease, alcoholism, organic brain disease, and diabetes mellitus), as well as use of corticosteroids, were strong predictors of infection (P < 0.004) in both univariate and multivariate analyses. Notably, use of disease-modifying antirheumatic drugs was not associated with increased risk of infection in multivariate analyses, after adjustment for demographic characteristics, comorbidities, and disease-related variables. CONCLUSION: We identified a number of strong predictors of infections in a population-based cohort of patients with RA. These results can be used to prospectively identify high-risk patients, who may benefit from closer followup and implementation of preventive strategies.

Declining use of orthopedic surgery in patients with rheumatoid arthritis? Results of a long-term, population-based assessment.

OBJECTIVE: To describe the use of orthopedic surgery, including joint replacement surgery, in a well-defined, population-based cohort of patients with rheumatoid arthritis (RA) and to identify characteristics that predict such use. METHODS: A retrospective medical record review was performed of cases of RA incident in Rochester, Minnesota, during the years 1955-1995. All joint surgeries were recorded. RESULTS: Of the total 609 RA incident cases, 242 patients underwent 1 or more (maximum of 20/patient) surgical procedures involving joints during their followup. Overall, this RA cohort had 7.4 surgeries per 100 person-years of followup; the cumulative incidence for joint surgery for RA-related joint disease at 30 years was 33.7% +/- SEM 3.8%. The risk of having a disease-related joint surgery for RA is increased in patients who are women, younger, positive for rheumatoid factor, and have rheumatoid nodules. When adjusted for duration of followup, patients with RA diagnosed after 1985 were significantly less likely to have undergone joint surgery for RA (P < 0.001). Survival of patients who underwent total joint arthroplasty was similar to those who did not. CONCLUSION: Reconstructive surgeries are common in RA, although patients diagnosed after 1985 are less likely to require joint surgery. These findings may reflect trends in medical disease management and have importance for health care resource utilization planning.

Trends in incidence and mortality in rheumatoid arthritis in Rochester, Minnesota, over a forty-year period.

OBJECTIVE: To determine time trends in the epidemiology of rheumatoid arthritis (RA) in a population-based cohort. METHODS: An inception cohort of residents of Rochester, Minnesota > or = 18 years of age who first fulfilled the American College of Rheumatology 1987 criteria between January 1, 1955 and December 31, 1994 (applied retrospectively, as appropriate) was assembled and followed up until January 1, 2000. Incidence rates were estimated and were age- and sex-adjusted to the 1990 white population of the US. A birth cohort analysis was performed, and survival rates over time were examined. RESULTS: The incidence cohort comprised 609 patients, 445 (73.1%) of whom were female and 164 (26.9%) were male, with a mean age at incidence of 58.0 years. The overall age- and sex-adjusted annual incidence of RA among Rochester, Minnesota, residents > or = 18 years of age was 44.6/100,000 population (95% confidence interval 41.0-48.2). While the incidence rate fell progressively over the 4 decades of study, from 61.2/100,000 in 1955-1964, to 32.7/100,000 in 1985-1994, there were indications of cyclical trends over time. Birth cohort analysis showed diminishing incidence rates through successive cohorts following a peak in the 1880-1890 cohorts. Incidence rates increased with age until age 85, but peaked earlier in women than in men. The survival rate in RA patients was significantly lower than the expected rate in the general population (P < 0.001), and no improvement was noted over time. CONCLUSION: The secular trends demonstrated in this study population, including the progressive decline in the incidence of RA over the last 40 years, suggest that an environmental factor may play a role in the etiology of RA.