Adalimumab long-term safety: infections, vaccination response and pregnancy outcomes in patients with rheumatoid arthritis.

BACKGROUND: Adalimumab has been used in patients with moderately to severely active rheumatoid arthritis (RA) for over 10 years and has a well-established safety profile across multiple indications. OBJECTIVE: To update adverse events (AEs) of special interest from global adalimumab clinical trials in patients with RA. METHODS: This analysis includes 15 132 patients exposed to adalimumab in global RA clinical trials. AEs of interest included overall infections, laboratory abnormalities and AEs associated with influenza vaccination. Pregnancy outcome data were collected from the Adalimumab Pregnancy Registry. RESULTS: Serious infections and tuberculosis occurred at a rate of 4.7 and 0.3 events/100 patient-years, respectively. Two patients experienced hepatitis B reactivation. No significant laboratory abnormalities were reported with adalimumab-plus-methotrexate compared with placebo-plus-methotrexate. Influenza-related AEs occurred in 5% of vaccinated patients compared with 14% of patients not vaccinated during the study. Relative risk of major birth defects and spontaneous abortions in adalimumab-exposed women were similar between that of unexposed women with RA and healthy women. CONCLUSIONS: This analysis confirms and expands the known safety profile of adalimumab and reports no additional safety risk of laboratory abnormalities, hepatitis B reactivation and pregnancy outcomes, including spontaneous abortions and birth defects. The benefits of influenza vaccination are reinforced. TRIAL REGISTRATION NUMBERS: NCT00195663, NCT00195702, NCT00448383, NCT00049751, NCT00234845, NCT00650390, NCT00235859, NCT00647920, NCT00649545, NCT00647491, NCT00649922, NCT00538902, NCT00420927, NCT00870467, NCT00650156, NCT00647270, NCT01185288, NCT01185301.

Benefit of biologics initiation in moderate versus severe rheumatoid arthritis: evidence from a United States registry.

Objectives: To compare clinical outcomes and treatment patterns among patients with moderate vs severe RA following biologic DMARD initiation. Methods: Biologics-naive patients with moderate to severe RA [Clinical Disease Activity Index (CDAI) >10] who initiated a biologic DMARD were selected from the Corrona registry (2001-13). CDAI, functional status [modified HAQ (mHAQ)] and patterns of drug use were compared at 1 and 2 years post-initiation between patients with moderate (CDAI >10⩽22) vs severe (CDAI >22) baseline disease activity. Results: A total of 1596 patients (817 severe, 779 moderate) had ⩾1 year of follow-up and 1269 (635 severe, 634 moderate) had ⩾2 years of follow-up. Patients with severe vs moderate baseline disease activity experienced greater improvements in disease activity [mean change in CDAI -18.9 vs -6.0 at year 1; -21.0 vs -7.1 at year 2 ( P < 0.0001)] and physical function [mean change in mHAQ -0.2 vs -0.1 ( P < 0.0001) at year 1; -0.2 vs -0.1 ( P = 0.0013) at year 2]. Greater proportions of patients with moderate vs severe disease activity achieved remission (CDAI ⩽2.8) [22.7 vs 15.8% ( P = 0.0003) at year 1; 25.9 vs 20.9% ( P = 0.0396) at year 2] or low disease activity (CDAI <10) [60.1 vs 41.2% at year 1; 66.7 vs 49.4% at year 2 ( P < 0.0001)]. Most patients remained on the original biologic drug (>70% at year 1; >62% at year 2). Conclusion: With biologic therapy, RA patients with higher baseline disease activity achieved greater improvements in measures of disease activity than those with lower levels of disease, but less often achieved the common targets of remission or low disease activity.

Perceived functioning has ethnic-specific associations in systemic sclerosis: another dimension of personalized medicine.

OBJECTIVE: To measure self-reported physical and mental functioning and associated clinical features at study entry in 3 ethnic groups with systemic sclerosis (SSc). METHODS: Sixty Hispanic, 39 African American, and 104 Caucasian patients with recent-onset SSc (< 5 yrs) were assessed for perceived physical and mental functioning, using the Medical Outcomes Study Short Form-36 (SF-36) and Scleroderma-Health Assessment Questionnaire (Scleroderma-HAQ). Socioeconomic, demographic, clinical, immunologic, immunogenetic, behavioral, and psychological variables (Interpersonal Support Evaluation List, ISEL; Illness Behavior Questionnaire, IBQ; and Arthritis Helplessness Index, AHI) were analyzed by linear regression models for associations with SF-36 and mHAQ scores as dependent variables. RESULTS: Perceived physical functioning scores had ethnic-specific associations with AHI > fatigue scores > IBQ > clinical variables (hypertension, skin score, and percentage predicted DLCO). Scleroderma-HAQ scores had ethnic-specific associations with IBQ > AHI scores > most clinical and laboratory variables. Decreased mental component summary (MCS) scores associated with AHI > ISEL. Ethnic-specific immunogenetic variables HLA-DQB1*0202 (Caucasian) and HLA-DRB 1*11 (African American), and HLA-DQA1*0501 (Hispanic) also associated with MCS. Antinuclear autoantibodies, anti-topoisomerase I, and RNA polymerases I and III also demonstrated associations with functioning in African American and Hispanic groups. CONCLUSION: Clinical, psychosocial, and immunogenetic variables had ethnic-specific associations with perceived physical and mental functioning. Consideration of ethnic-specific psychological and behavioral support in designing more personalized, relevant therapeutic interventions for the patient may improve therapeutic efficacy in SSc.

Pulmonary involvement in systemic sclerosis: associations with genetic, serologic, sociodemographic, and behavioral factors.

OBJECTIVE: To determine the relative contributions of genetic, clinical, serologic, sociodemographic, and behavioral/psychological variables to early pulmonary involvement in the Genetics versus Environment in Scleroderma Outcome Study cohort. METHODS: At the baseline visit (V0), 203 patients with systemic sclerosis (SSc) were examined (104 whites, 39 African Americans, and 60 Hispanics). We obtained sociodemographic, behavioral/psychological (illness behavior, social support, learned helplessness, smoking, drinking), clinical, serologic (autoantibodies), and genetic (HLA class II and FBN1 genotypes) factors; pulmonary function test results; electrocardiograms; and chest radiographs. Data analysis included Fisher's exact test, chi-square test, Student's t-test, analysis of variance, and stepwise linear and logistic regression methods. RESULTS: Significant pulmonary involvement was seen in 25% of patients within 2.8 years of SSc diagnosis. At V0, pulmonary fibrosis was significantly higher in African Americans compared with whites or Hispanics. African Americans had significantly lower percent predicted forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV(1)) compared with whites and significantly lower percent predicted diffusing capacity for carbon monoxide (DLCO) compared with whites and Hispanics. Significant, independent associations impacting early pulmonary involvement included African American ethnicity, skin score, serum creatinine and creatine phosphokinase values, hypothyroidism, and cardiac involvement. Anticentromere antibody seropositivity was a significant, independent, protective factor for restrictive lung disease and FVC or DLCO values. African Americans had significantly increased frequencies of anti-topoisomerase I, fibrillarin, and RNP autoantibodies compared with whites. African Americans scored significantly lower on the Interpersonal Support Evaluation List and significantly higher on the Illness Behavior Questionnaire. CONCLUSION: Early pulmonary involvement in SSc appears to be influenced by several factors delineated by ethnicity, including racial, socioeconomic, behavioral, and serologic determinants.

Important determinants of bone strength: beyond bone mineral density.

Osteoporosis is a systemic skeletal disorder characterized by compromised bone strength that predisposes individuals to increased fracture risk. Bone strength is determined by its material and structural properties. Bone mineral density (BMD) is a useful tool for diagnosis; however, this parameter provides information regarding only the quantity of mineral in bone, which is only one component of bone strength. Osteoporosis treatments have been shown to have beneficial effects on bone turnover, microarchitecture, and/or mineralization, all of which can help account for the reductions in fracture risk above and beyond changes in BMD. Newer noninvasive imaging methods are being developed that assess bone strength independent of BMD, and these methods should improve the assessment of fracture risk and response to treatment. These imaging methods are not currently available for routine clinical use, and therefore, clinicians need to continue for now to rely on surrogate markers of bone fragility, including BMD, prevalent fracture, and other important risk factors for fracture.

Systemic lupus erythematosus in three ethnic groups: XVI. Association of hydroxychloroquine use with reduced risk of damage accrual.

OBJECTIVE: To examine whether hydroxychloroquine (HCQ) usage is associated with a reduced risk of damage accrual in patients with systemic lupus erythematosus (SLE). METHODS: Patients (n = 518) meeting the American College of Rheumatology criteria for diagnosis of SLE and with

Systemic lupus erythematosus in three ethnic groups. XIV. Poverty, wealth, and their influence on disease activity.

OBJECTIVE: To determine the impact of wealth on disease activity in the multiethnic (Hispanic, African American, and Caucasian) LUMINA (Lupus in Minorities, Nature versus nurture) cohort of patients with systemic lupus erythematosus (SLE) and disease duration < or =5 years at enrollment. METHODS: Variables (socioeconomic, demographic, clinical, immunologic, immunogenetic, behavioral, and psychological) were measured at enrollment and annually thereafter. Four questions from the Women's Health Initiative study were used to measure wealth. Disease activity was measured with the Systemic Lupus Activity Measure (SLAM). The relationship between the different variables and wealth was then examined. Next, the impact of wealth on disease activity was examined in regression models where the dependent variables were the SLAM score and SLAM global (physician). Variables previously found to impact disease activity plus the wealth questions were included in the models. RESULTS: Questions on income, assets, and debt were found to distinguish patients into groups, wealthier and less wealthy. Less wealthy patients tended to be younger, women, noncaucasian, less educated, unmarried, less likely to have health insurance, and more likely to live below the poverty line. They also tended to have more active disease, more abnormal illness-related behaviors, less social support, and lower levels of self reported mental functioning. None of the wealth questions was retained in the regression models, although other socioeconomic features (such as African American ethnicity, poverty, and younger age) did. CONCLUSIONS: Wealth, per se, does not appear to have an additional predictive value, over and above traditional measures of socioeconomic status, in SLE disease activity.

Systemic lupus erythematosus in three ethnic groups. XI. Sources of discrepancy in perception of disease activity: a comparison of physician and patient visual analog scale scores.

OBJECTIVE: To compare patient's and physician's assessment of disease activity in a multiethnic (Hispanic, African American, and Caucasian) cohort of systemic lupus erythematosus (SLE) patients. METHODS: Three hundred patients with SLE from the LUMINA (Lupus in Minority populations: Nature versus nurture) cohort were included. Disease activity was assessed with the Systemic Lupus Activity Measure (SLAM); patients and physicians assessed disease activity using a 10-cm anchored visual analog scale (VAS). The difference between VAS scores was termed discrepancy (>1 cm was considered a priori clinically relevant). Selected sociodemographic, clinical, behavioral, and psychological variables were examined in relation to discrepancy in univariable and multivariable models adjusting for the physician global VAS score in order to eliminate ceiling and floor effects. RESULTS: A discrepancy was exhibited by 58% of the patients. Abnormal laboratory findings were negatively associated with discrepancy, and poor self-perceived functioning and joint involvement were positively associated with discrepancy. Ethnicity did not account for discrepant perception of disease activity. CONCLUSION: Patients and physicians rate disease activity in SLE differently. Physicians appear to place more emphasis on laboratory features while patients place more emphasis on function.

Systemic lupus erythematosus in three ethnic groups. XIX. Natural history of the accrual of the American College of Rheumatology criteria prior to the occurrence of criteria diagnosis.

OBJECTIVE: To determine how the American College of Rheumatology (ACR) criteria for the classification of systemic lupus erythematosus (SLE) accrue in a multiethnic cohort of SLE patients. METHODS: SLE patients enrolled in a longitudinal study of outcome were analyzed (LUMINA; Lupus in Minorities: Nature versus nurture) for the manner in which ACR criteria manifestations occurred prior to the accrual of 4 of them. Time at which a criterion was said to be present was determined by review of all previously available medical records and interview. Univariable and multivariable Cox proportional hazard models were examined for the association with time to accrual of 4 ACR criteria; results were reported as hazard ratios. RESULTS: There were 103 Texas Hispanic (of Mexican or Central America ancestry) patients, 55 Puerto Rico Hispanics, 176 African Americans, and 137 Caucasians. The mean +/- SD and median (range) time to accrual of 4 ACR criteria were 29.4 +/- 52.0 months and 9.1 (0-328.7) months; time was shortest for the Texas Hispanics (18.4 +/- 42.8 and 5.0 [0-248] months) and longest for the Caucasians (39.9 +/- 59.3 months and 17.7 [0-324.6] months). Arthritis was the most frequent first criterion (34.5%); it was followed by photosensitivity (18.8%). When 2 criteria occurred from the outset, the most frequent combination was arthritis and antinuclear antibody positivity followed by malar rash and photosensitivity. A Cox-regression multivariable model identified Hispanic ethnicity (from Texas) and HLA-DRB1*0301 as predictors of short time to criteria accrual, whereas older age and married/living together were associated with long time to criteria accrual. CONCLUSION: Significant variability in the evolution of ACR criteria manifestations does occur. Texas Hispanics are more likely to have a rapid evolution of criteria manifestations, but several years may elapse before ACR criteria are accrued.

Systemic lupus erythematosus in three ethnic groups. X. Measuring cognitive impairment with the cognitive symptoms inventory.

OBJECTIVE: To determine the factor structure of the Cognitive Symptoms Inventory (CSI) in patients with systemic lupus erythematosus (SLE) participating in a multiethnic longitudinal study of outcome, the Lupus in Minority populations, Nature versus nurture (LUMINA) study. METHODS: LUMINA patients of Hispanic (n = 48), African American (n = 64), and Caucasian (n = 44) ethnicity who had a study visit (enrollment or followup) between January 1 and September 30, 2000 were included. Patients completed the CSI, a 21-item self-report measure of cognitive function. Sociodemographic, clinical, immunologic, psychosocial, and behavioral variables were ascertained per protocol and as previously described. Data were analyzed with SPSS. The factor structure of the CSI was determined using the principal axis method with oblique rotation as decided by Gorsuch. All factors having an Eigenvalue greater than 1 were considered. A 4-factor solution was derived that accounted for 42.6% of the common variance. The correlations between patient factor scale scores and variables from the demographic, clinical, psychosocial, and behavioral domains were then examined. RESULTS: The four factors and their respective variance are, Attention/Concentration (28.8%), Pattern Recognition/Activity Management (5.7%), Intermediate Memory (4.7%), and Initiation of Executive Functions (3.4%); each factor correlated with the total CSI score. Overall, patients' factor scale scores were positively and significantly correlated with other measures of cognitive dysfunction such as the Systemic Lupus Activity Measure (neuromotor domain) or the Systemic Lupus International Collaborating Clinics Damage Index (neurocognitive impairment), as well as with measures of fatigue, maladaptive coping skills, poor mental functioning, poor social support, and helplessness. They were, however, not correlated with sociodemographic or clinical variables. CONCLUSIONS: In addition to demonstrating that the CSI can be used to measure cognitive impairment in patients with SLE in the research setting, we have determined a 4-factor solution for the CSI that appears to have adequate metric properties. At present, the CSI may best be used as a screen for difficulties in daily activities involving intermediate memory, concentration, attention, and executive function. Nevertheless, further work with the CSI items and factor scales is necessary to establish internal and test-retest reliability of the factor scales; and provide additional evidence of the convergent and predictive validity of these scales in larger samples of patients from each ethnic subgroup.

Systemic lupus erythematosus in a multiethnic lupus cohort (LUMINA). XVII. Predictors of self-reported health-related quality of life early in the disease course.

OBJECTIVE: To determine the baseline factors predictive of self-reported health-related quality of life (HRQOL) early in the course of systemic lupus erythematosus patients (SLE) from a multiethnic LUMINA (Lupus in Minorities: Nature versus nurture) cohort. METHODS: LUMINA patients with > or =2 visits were studied. Self-reported HRQOL was examined with the 8 subscales and 2 summary measures (the Physical Component Summary [PCS], and the Mental Component Summary [MCS]) of the Short Form 36 (SF-36). Bivariable and multivariable analyses were done with the PCS, MCS and 8 subscales as the dependent variables. The analyses were performed including and excluding the corresponding SF-36 measure from the independent variables. Age, sex, and ethnicity were included in all models. Time was modeled in all regressions. RESULTS: A total of 1,351 visits (346 patients [80 Hispanics-Texas, 34 Hispanics-Puerto Rico, 126 African Americans, and 106 Caucasians]) were included in these analyses. Mean +/- SD PCS and MCS scores were 36.7 +/- 12.0 and 46.6 +/- 11.5, respectively. The scores for the eight subscales of the SF-36 were also lower than those for the general population. Baseline SF-36 measures were highly predictive of subsequent HRQOL. In the same set of regressions, older age was found to consistently predict poor self-reported HRQOL whereas fibromyalgia, helplessness, fatigue, and abnormal illness-related behaviors were also predictive, but less consistently. Estimated adjusted variances in these regressions ranged from 23% (Role-Emotional [RE]) to 43% (Physical Functioning [PF]). CONCLUSION: In patients with SLE, poor baseline HRQOL was highly predictive of subsequent poor HRQOL. Other predictive variables of poor functioning were primarily psychological/behavioral and socioeconomic-demographic.

Systemic lupus erythematosus in three ethnic groups. XVIII. Factors predictive of poor compliance with study visits.

OBJECTIVE: To determine the baseline factors predictive of poor compliance with study visits in a longitudinal multiethnic lupus cohort study. METHODS: Patients with systemic lupus erythematosus (n = 344) representing a total of 2,069 potential study visits were studied. Of the participants, 24.4% were Hispanic, 43.3% African American, and 32.3% Caucasian. Noncompliance was defined as missing 2 or more study visits. For the purpose of these analyses, visits completed only by review of medical records were considered missing. Baseline socioeconomic-demographic, clinical, and psychosocial features between compliant and noncompliant patients were compared. Variables with P < 0.10 were then entered into a multivariable logistic regression analysis with compliance being the dependent variable. RESULTS: There were 178 compliant and 166 noncompliant patients. Noncompliant patients were more likely to be young, unmarried, of African American ethnicity, live closer to the medical centers, and have longer disease duration and greater disease activity as assessed by the physician than the compliant patients. In the multivariable model, longer disease duration (P = 0.010), higher level of disease activity (P = 0.009), and shorter distance to travel to study visits (P = 0.046) were predictors of noncompliance; their odds ratios and confidence intervals were below 1. CONCLUSIONS: We have identified baseline patient characteristics that may predict noncompliance with study visits (disease duration, disease activity, and distance to the medical center). This information will serve as the basis for developing interventions to curtail noncompliance. Our data may have applicability in other lupus cohort studies.