Depressive symptoms predict future simple disease activity index scores and simple disease activity index remission in a prospective cohort of patients with early inflammatory polyarthritis.

OBJECTIVE: To determine whether depressive symptoms assessed in treated patients with early inflammatory polyarthritis (EPA) influence disease activity during follow-up. METHODS: Consecutively recruited EPA patients were actively treated to remission. Simple disease activity index (SDAI) and Center for Epidemiologic Studies Depression Scale (CES-D) scores were calculated at inclusion and up to 42 months into disease. SDAI scores were log-transformed to compute univariate and multivariate linear regressions. Parametric interval-censored Kaplan-Meier and survival regressions using Weibull distribution were used to assess time to and predictors of SDAI remission. RESULTS: A total of 275 EPA patients were recruited at a median of 4 months into disease. In multivariate linear regression models, accounting for baseline demographic, clinical, serological and functional variables and 12-month inflammation markers, CES-D scores at 12 months into disease were correlated (r(2) = 0.14) with subsequent SDAI scores. Patients with 12-month high CES-D (≥19; suggestive of depression) had a lower proportion of SDAI remission (31.3% vs 84.3%; P < 0.001) and reached SDAI remission less rapidly [hazard ratio = 0.25 (95% CI 0.12, 0.53); P < 0.001]. CONCLUSION: Each follow-up SDAI correlated significantly with 12-month depressive symptoms, a median of 7 months after initiation of treatment. CES-D scores suggestive of depression at 12 months were strongly correlated with delay and failure to reach remission later on. Depressive symptoms in treated EPA patients represent important clinical issues with long-term association with disease activity. Interventions to alleviate persistent depressive symptoms in treated EPA warrant careful evaluation of their potential to improve disease remission rates.

Serum C-X-C motif chemokine 13 is elevated in early and established rheumatoid arthritis and correlates with rheumatoid factor levels.

INTRODUCTION: We hypothesized that serum levels of C-X-C motif chemokine 13 (CXCL13), a B-cell chemokine, would delineate a subset of rheumatoid arthritis (RA) patients characterized by increased humoral immunity. METHODS: Serum from patients with established RA (the Dartmouth RA Cohort) was analyzed for CXCL13, rheumatoid factor (RF) levels, anticitrullinated peptide/protein antibody (ACPA) and total immunoglobulin G (IgG); other parameters were obtained by chart review. A confirmatory analysis was performed using samples from the Sherbrooke Early Undifferentiated PolyArthritis (EUPA) Cohort. The Wilcoxon rank-sum test, a t-test and Spearman's correlation analysis were utilized to determine relationships between variables. RESULTS: In both the Dartmouth and Sherbrooke cohorts, CXCL13 levels were selectively increased in seropositive relative to seronegative RA patients (P = 0.0002 and P < 0.0001 for the respective cohorts), with a strong correlation to both immunoglobulin M (IgM) and IgA RF levels (P < 0.0001). There was a weaker relationship to ACPA titers (P = 0.03 and P = 0.006, respectively) and total IgG (P = 0.02 and P = 0.14, respectively). No relationship was seen with regard to age, sex, shared epitope status or inclusion high-sensitivity C-reactive protein (hsCRP) in either cohort or regarding the presence of baseline erosions in the Sherbrooke Cohort, whereas a modest relationship with Disease Activity Score in 28 joints CRP (DAS28-CRP) was seen in the Dartmouth cohort but not the Sherbrooke cohort. CONCLUSION: Using both established and early RA cohorts, marked elevations of serum CXCL13 levels resided nearly completely within the seropositive population. CXCL13 levels exhibited a strong relationship with RF, whereas the association with clinical parameters (age, sex, DAS28-CRP and erosions) or other serologic markers (ACPA and IgG) was either much weaker or absent. Elevated serum CXCL13 levels may identify a subset of seropositive RA patients whose disease is shaped by or responsive to RF production.

Predictors of pain for patients with early inflammatory polyarthritis.

OBJECTIVE: To identify predictors of pain at 1 year in patients with early inflammatory polyarthritis (EIP). METHODS: Using a prospective design, patients were examined by a rheumatologist and completed questionnaires at baseline and at 1 year after symptom onset. Separate regression analyses were run for pain intensity, sensory pain, and affective pain. Age and sex were adjusted in cross-sectional and longitudinal analyses; baseline potential predictors consisted of measures for corresponding pain values and disease activity, depression, coping scores, medication use, rheumatoid arthritis criteria being met, and duration of symptoms. RESULTS: A total of 211 patients were enrolled in the study (mean ± SD age 58.8 ± 14.2 years, 63% women). There were significant improvements at 1 year for disease activity, instrumental coping, emotional coping, depression, and all 3 pain measures. At baseline, disease activity and depression were positively associated with all types of pain; in addition, instrumental coping was positively associated with sensory pain and palliative coping was positively associated with affective pain. At 1 year, pain intensity was predicted by baseline pain intensity, duration of symptoms, use of disease-modifying antirheumatic drugs (DMARDs), and emotional coping. Sensory pain was predicted by baseline sensory pain and DMARD use. Affective pain was predicted by baseline affective pain, DMARD use, and emotional coping. CONCLUSION: The majority of treated EIP patients can expect improvements in clinical and psychosocial variables over the first year of their illness. Emotional coping at baseline may contribute to pain in the future, and therefore it may be useful for patients to learn other means of dealing with this chronic disease.

Outcomes in recent-onset inflammatory polyarthritis differ according to initial titers, persistence over time, and specificity of the autoantibodies.

OBJECTIVE: To prospectively evaluate the predictive value of initial titers and subsequent variations of 3 rheumatoid arthritis­associated antibodies for outcomes at 30 months in patients with recent-onset polyarthritis. METHODS: IgM rheumatoid factor (RF), anti-Sa (citrullinated vimentin) antibodies, anti­ cyclic citrullinated peptide 2 (anti­CCP-2) antibodies, modified Health Assessment Questionnaire score, Disease Activity Score in 28 joints, and Sharp/van der Heijde radiologic scores were determined at baseline and at 18 and 30 months in a cohort of consecutive HLA­DR-typed treated patients with recent-onset polyarthritis aiming at remission. RESULTS: At inclusion, 113 (44.7%), 58 (22.9%), and 97 (38.3%) of 253 recent-onset polyarthritis patients were positive for RF, anti-Sa, and anti­CCP-2, respectively; at 30 months, 85 (33.6%), 31 (12.4%), and 100 (39.5%) patients were similarly positive. A low titer of any particular antibody was associated with higher risks for seroreversion. Similar to their persistent absence, reversion of RF and anti­CCP-2 was associated with low risks for severity. Patients who acquired RF or anti­CCP-2 after inclusion trended toward a poor prognosis. Relative to RF and anti­CCP-2 antibodies, only the presence of anti-Sa at inclusion, especially at higher titers and even when it subsequently disappeared, significantly predicted more rapid radiographic damage and lower remission rates at 30 months. CONCLUSION: In treated recent-onset polyarthritis, anti­CCP-2 prevalence is stable or increases slightly, whereas anti-Sa and RF frequently disappear. Subsequent reversion and conversion of RF and anti­CCP-2 blur the prognostic significance of initial RF and anti­CCP-2 positivity. Of the 3 antibodies, only anti-Sa, even if it disappears afterward, independently predicts severe outcomes.

The DERAA HLA-DR alleles in patients with early polyarthritis: protection against severe disease and lack of association with rheumatoid arthritis autoantibodies.

OBJECTIVE: To define the association of alleles encoding the HLA-DR rheumatoid arthritis (RA) protective epitope (DERAA) with the presence of RA-associated antibodies at study inclusion and with severe outcome in patients with early polyarthritis (EPA). METHODS: Consecutive EPA patients (n = 210) were evaluated early (mean of 4.8 months after diagnosis) and prospectively (for 30 months). HLA class II typing was performed by polymerase chain reaction using sequence-specific primers, and HLA-DR alleles DERAA, RA-associated shared epitope (SE), and non-SE/non-DERAA (neither SE nor DERAA) were identified. RA-associated antibodies identified were anti-Sa/citrullinated vimentin, anti-cyclic citrullinated peptide 2, and IgM rheumatoid factor. Severe disease was defined according to a preset threshold of joint destruction and/or functional limitation. RESULTS: DERAA and SE alleles were present in 62 and 110 of the 210 EPA patients, respectively. At 30 months, severe disease was present in 78 patients (37%). In contrast to SE alleles, DERAA alleles were not associated with the production of RA-associated antibodies, but were strongly protective against severe disease at 30 months (odds ratio 0.30, P < 0.001). DERAA alleles emerged as a strong, independent protective marker on multivariate analysis. The protective effect of DERAA was seen only in patients who did not already have erosions at study inclusion, was independent of the presence of antibodies, but was not associated with spontaneous remission. CONCLUSION: In our EPA cohort, the presence of a DERAA sequence was a strong independent predictor of a better prognosis, but only in the absence of erosive disease that was already present at inclusion. Identification of DERAA alleles may help in managing the large subgroup of EPA patients who do not have erosions at baseline.

Anti-Sa antibodies and antibodies against cyclic citrullinated peptide are not equivalent as predictors of severe outcomes in patients with recent-onset polyarthritis.

The prognostic value of two antibodies targeting citrullinated antigens, anti-Sa and anti-cyclic citrullinated peptide (CCP), present at inclusion, was evaluated prospectively in a cohort of 165 consecutive patients with recent-onset or early polyarthritis (EPA) followed for up to 30 months. Patients were treated according to current Good Clinical Practice standards. Predefined outcomes were severe arthritis and persistent arthritis. At inclusion, a median of 3 months after disease onset, 133 (81%) patients fulfilled at least four American College of Rheumatology criteria for rheumatoid arthritis and 30 (18%) had erosive changes on radiographs of hands and feet. Disease-modifying anti-rheumatic drugs were used in close to 80% of the patients at 30 months. Joint damage increased linearly over time, whereas disease activity declined markedly and remained low at each follow-up. Autoantibodies were identified in 76 (46%) patients: rheumatoid factor (RF) in 68 (41%), anti-CCP in 53 (33%), and anti-Sa in 46 (28%). All three antibodies were correlated, but anti-Sa antibodies best predicted severity at 18 and 30 months. RF and anti-CCP performed less well. For both outcomes, anti-Sa alone performed better than any combination of antibodies. The presence of any autoantibody identified about 50 to 60% of the patients with poor outcomes. In multivariate analysis, anti-Sa (odds ratio (OR) 8.83), the presence of erosions at inclusion (OR 3.47) and increasing age (OR 1.06/year) were significantly associated with severity, whereas RF and anti-CCP were not significant predictors. Persistent arthritis was present in up to 84% of patients; autoantibodies were specific but poorly sensitive predictors of this outcome. We conclude that assays for antibodies against citrullinated antigens differ in their ability to predict poorer outcomes in patients with EPA. In our EPA cohort treated in accordance with current standards, detection of anti-Sa but not of RF or anti-CCP antibodies, in combination with clinical and radiological variables present at the first encounter, allowed the identification of a subgroup of EPA patients suffering more rapid and more severe joint damage over 30 months.

Severe and resistant hypoglycemia associated with concomitant gatifloxacin and glyburide therapy.

Severe and resistant hypoglycemia occurred in two patients with diabetes mellitus who were receiving concomitant gatifloxacin and glyburide. An 84-year-old woman treated with glyburide for type 2 diabetes mellitus experienced, for the first time, a severe episode of hypoglycemia after 2 days of gatifloxacin 400 mg/day for nonproductive cough. Her blood glucose level on hospital admission was 28 mg/dl. Gatifloxacin and glyburide were discontinued, and the patient was treated with intravenous dextrose infused over 36 hours. Glyburide was restarted before her discharge, with no recurrence of hypoglycemia. A 79-year-old man with type 2 diabetes mellitus treated with glyburide was prescribed gatifloxacin 400 mg/day for pneumonia. After 1 day of therapy, the patient was admitted to the emergency department in a coma. His blood glucose level was 18 mg/dl. Despite discontinuation of gatifloxacin and oral hypoglycemic therapy, hypoglycemia was reversed only after administration of multiple boluses of intravenous dextrose, followed by intravenous dextrose infused over 48 hours. On hospital day 7, gliclazide and levofloxacin were started; the patient experienced no recurrence of hypoglycemia and was discharged on day 10. Several cases of severe and resistant hypoglycemia associated with gatifloxacin therapy have been reported in the recent literature. Although the exact mechanism is not fully understood, it may be linked to a gatifloxacin-induced closing of the adenosine 5'-triphosphate-sensitive potassium channels in the pancreatic beta cells, leading to insulin secretion. The onset of hypoglycemia in relation to the start of gatifloxacin suggests that the drug precipitated this adverse event. Patients receiving oral hypoglycemic agents are at greater risk of experiencing gatifloxacin-induced hypoglycemia than patients not receiving these agents. Clinicians should be aware of this potentially life-threatening adverse event and monitor blood glucose levels in all patients receiving concomitant oral hypoglycemic agents and gatifloxacin.