Correction to: Efficacy of certolizumab pegol with and without concomitant use of disease-modifying anti-rheumatic drugs over 4 years in psoriatic arthritis patients: results from the RAPID-PsA randomized controlled trial.

The above article originally published with an error present in Discussion section and presented correctly in this article. The original article was corrected.

Efficacy of certolizumab pegol with and without concomitant use of disease-modifying anti-rheumatic drugs over 4 years in psoriatic arthritis patients: results from the RAPID-PsA randomized controlled trial.

To report long-term efficacy of certolizumab pegol (CZP) treatment with and without concomitant DMARDs in patients with psoriatic arthritis (PsA). RAPID-PsA (NCT01087788) was double-blind and placebo-controlled to week 24, dose-blind to week 48, and open-label to week 216. Patients had active PsA with ≥ 1 failed DMARD. At baseline, patients were randomized 1:1:1 to CZP 200 mg every 2 weeks: CZP 400 mg every 4 weeks: placebo. CZP-randomized patients continued their dose into open-label. Observed case efficacy data are reported to week 216 for week 0 CZP-randomized patients (dose combined) with and without baseline DMARD use (DMARD+/DMARD-). Dactylitis (tenderness and ≥ 10% difference in swelling between affected and opposite digits) and enthesitis were measured using Leeds Dactylitis Index (LDI) and Leeds Enthesitis Index (LEI). 273/409 randomized patients received CZP from baseline: 199/273 (72.9%) DMARD+ and 74/273 (27.1%) DMARD- patients. 141/199 (70.9%) DMARD+ and 42/74 (56.8%) DMARD- patients completed Week 216. DMARD+ (79.7%) and 83.3% of DMARD- patients achieved ACR20 response at week 216; 79.2 and 78.1% achieved 75% improvement from baseline in Psoriasis Area and Severity Index (PASI75). High proportions of DMARD+/DMARD- patients with extra-articular manifestations at baseline reported total resolution at week 216; dactylitis 91.4% of DMARD+ and 93.3% of DMARD- patients, enthesitis 74.4% of DMARD+ and 87.5% of DMARD- patients. Long-term improvements in PsA symptoms were observed with CZP monotherapy or concomitant DMARDs, across important psoriatic disease domains, including joint disease, psoriasis, nail disease, dactylitis, and enthesitis.Trial registration: NCT01087788.

Early Disease Activity or Clinical Response as Predictors of Long-Term Outcomes With Certolizumab Pegol in Axial Spondyloarthritis or Psoriatic Arthritis.

OBJECTIVE: Early identification of patients unlikely to achieve good long-term disease control with anti-tumor necrosis factor therapy in axial spondyloarthritis (SpA) and psoriatic arthritis (PsA) is important for physicians following treat-to-target recommendations. Here we assess associations between disease activity or clinical response during the first 12 weeks of treatment and attainment of treatment targets at week 48 in axial SpA and PsA patients receiving certolizumab pegol. METHODS: The relationship between disease activity or clinical response during the first 12 weeks of treatment and achievement of week-48 targets (for axial SpA: inactive disease based on Ankylosing Spondylitis Disease Activity Score [ASDAS] using the C-reactive protein [CRP] level, or Bath Ankylosing Spondylitis Disease Activity Index <2 with normal CRP level; and for PsA: minimal disease activity) was assessed post hoc using RAPID-axSpA and RAPID-PsA trial data. RESULTS: A clear relationship between disease activity from week 2 to 12 and achievement of week-48 treatment targets was observed in both axial SpA and PsA populations. In axial SpA, week-48 ASDAS inactive disease was achieved by 0% of patients (0 of 21) with ASDAS very high disease activity at week 12, compared to 68% of patients (34 of 50) with week-12 ASDAS inactive disease. For PsA, week-48 minimal disease activity was achieved by 0% of patients (0 of 26) with Disease Activity Score in 28 joints (DAS28) using the CRP level >5.1 at week 12, compared to 73% of patients (57 of 78) with DAS28-CRP <2.6. Similar results were observed regardless of the disease activity measure used. Clinical response at week 12 also predicted week-48 outcomes, though to a lesser extent than disease activity. CONCLUSION: Using disease activity and the clinical response state during the first 12 weeks of certolizumab pegol treatment, it was possible to identify a subset of axial SpA and PsA patients unlikely to achieve long-term treatment goals.

Observed Incidence of Uveitis Following Certolizumab Pegol Treatment in Patients With Axial Spondyloarthritis.

OBJECTIVE: Axial spondyloarthritis (axial SpA) is characterized by inflammation of the spine and sacroiliac joints and can also affect extraarticular sites, with the most common manifestation being uveitis. Here we report the incidence of uveitis flares in axial SpA patients from the RAPID-axSpA trial, including ankylosing spondylitis (AS) and nonradiographic (nr) axial SpA. METHODS: The RAPID-axSpA (NCT01087762) trial is double-blind and placebo-controlled to week 24, dose-blind to week 48, and open-label to week 204. Patients were randomized to certolizumab pegol (CZP) or placebo. Placebo patients entering the dose-blind phase were re-randomized to CZP. Uveitis events were recorded on extraarticular manifestation or adverse event forms. Events were analyzed in patients with/without history of uveitis, and rates reported per 100 patient-years. RESULTS: At baseline, 38 of 218 CZP-randomized patients (17.4%) and 31 of 107 placebo-randomized patients (29.0%) had past uveitis history. During the 24-week double-blind phase, the rate of uveitis flares was lower in CZP (3.0 [95% confidence interval (95% CI) 0.6-8.8] per 100 patient-years) than in placebo (10.3 [95% CI 2.8-26.3] per 100 patient-years). All cases observed during the 24-week double-blind phase were in patients with a history of uveitis; in these patients, rates were similarly lower for CZP (17.1 [95% CI 3.5-50.1] per 100 patient-years) than placebo (38.5 [95% CI 10.5-98.5] per 100 patient-years). Rates of uveitis flares remained low up to week 96 (4.9 [95% CI 3.2-7.4] per 100 patient-years) and were similar between AS (4.4 [95% CI 2.3-7.7] per 100 patient-years) and nr-axial SpA (5.6 [95% CI 2.9-9.8] per 100 patient-years). CONCLUSION: The rate of uveitis flares was lower for axial SpA patients treated with CZP than placebo during the randomized controlled phase. Incidence of uveitis flares remained low to week 96 and was comparable to rates reported for AS patients receiving other anti-tumor necrosis factor antibodies.

Effect of certolizumab pegol over ninety-six weeks in patients with axial spondyloarthritis: results from a phase III randomized trial.

OBJECTIVE: Previous reports of the RAPID-axSpA trial (NCT01087762) described the efficacy and safety of certolizumab pegol (CZP) over 24 weeks in patients with axial spondyloarthritis (SpA), including ankylosing spondylitis (AS) and nonradiographic axial SpA. We report efficacy and safety data up to week 96 of the study. METHODS: The RAPID-axSpA trial is double-blind and placebo-controlled to week 24, dose-blind to week 48, and open-label to week 204. Outcome variables included Assessment of SpondyloArthritis international Society criteria for 20% and 40% improvement in disease activity (ASAS20/40), ASAS partial remission responses (analyzed by nonresponder imputation), AS Disease Activity Score (ASDAS), ASDAS inactive disease, ASDAS major improvement, Bath AS Disease Activity Index (BASDAI), Bath AS Functional Index (BASFI), and Bath AS Metrology Index (BASMI) linear score (analyzed by the last observation carried forward method). Safety data were collected for patients treated with ≥1 dose of CZP. RESULTS: Of the 325 patients who were randomized, 218 received CZP from week 0. Of these, 93% completed week 24, 88% completed week 48, and 80% completed week 96. Improvements in ASAS responses were maintained to week 96 (for ASAS20, 67.4%, 72.0%, and 62.8% at weeks 24, 48, and 96, respectively), as well as improvements in ASDAS, BASDAI (mean score 3.3, 3.1, and 3.0 at weeks 24, 48, and 96, respectively), BASFI, and BASMI linear score. Comparable improvements were observed with both dosing regimens (200 mg every 2 weeks or 400 mg every 4 weeks) and in patients with AS and those with nonradiographic axial SpA. In the safety set, adverse events occurred in 279 patients (88.6%) and serious adverse events in 41 (13.0%). No deaths or malignancies were reported. CONCLUSION: Clinical improvements to week 24 in both CZP dosing regimens were sustained to week 96. Similar sustained improvements were observed in AS and nonradiographic axial SpA subpopulations. The safety profile was consistent with previous reports from RAPID-axSpA, with no new safety signals observed with longer exposure.

Expression of CYP1A1, CYP1B1 and CYP3A, and polycyclic aromatic hydrocarbon-DNA adduct formation in bronchoalveolar macrophages of smokers and non-smokers.

Variability in the expression of enzymes metabolizing carcinogens derived from cigarette smoke may contribute to individual susceptibility to pulmonary carcinogenesis. This study was designed to determine the effects of smoking and 3 major cytochrome P450 (CYP) enzymes, i.e., CYP1A1, CYP1B1 and CYP3A, which metabolize polycyclic aromatic hydrocarbons (PAH) on PAH-DNA adduct formation in the bronchoalveolar macrophages (BAM) of 31 smokers and 16 non-smokers. CYP protein levels were determined by immunoblotting and PAH-DNA adduct levels by the nuclease P1 enhanced (32)P-postlabeling method. The expression of specific CYP forms was confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR) from 10 additional samples. CYP3A protein, CYP3A5 by RT-PCR, was detected in the majority of samples from smokers and non-smokers. The levels of CYP3A appeared to be lower in active smokers than in ex-smokers (p = 0.10) or never smokers (p = 0.02). CYP1A1 was not detectable by either immunoblotting or RT-PCR. The expression of CYP1B1 was low or undetectable in most samples. The PAH-DNA adduct levels were higher (mean 1.57/10(8) nucleotides) in samples from smokers compared with non-smokers (mean 0.42/10(8) nucleotides, p < 0.001) and the number of adducts correlated with the number of cigarettes smoked daily (regression analysis, p < 0. 001). Higher levels of adducts were detected in samples from smokers with a high level of CYP3A compared with those with a low level (regression analysis, p = 0.002). As CYP3A5 is abundant in both lung epithelial cells and BAM, its association with adduct formation suggests that this CYP form may be important in the activation of cigarette smoke procarcinogens.

Leukocyte adhesion--an integrated molecular process at the leukocyte plasma membrane.

Leukocyte adhesion is of pivotal functional importance, because most leukocyte functions depend on cell-cell contact. It must be strictly controlled, both at the level of specificity and strength of interaction, and therefore several molecular systems are involved. The most important leukocyte adhesion molecules are the selectins, the leukocyte-specific beta2-integrins and the intercellular adhesion molecules. The selectins induce an initial weak contact between cells, whereas firm adhesion is achieved through integrin intercellular adhesion molecular binding. Although studies during the past twenty years have revealed several important features of leukocyte adhesion much is still poorly understood, and further work dealing with several aspects of adhesion is urgently needed. In this short essay, we review some recent developments in the field.

Methodologic issues in epidemiologic risk assessment.

This paper reviews methodologic issues pertinent to the application of epidemiology in risk assessment and discusses concerns in the presentation of results from such an activity. Assessment of the health risks associated with occupational and environmental exposures involves four phases: hazard identification, i.e., the detection of the potential for agents to cause adverse health effects in exposed populations; exposure assessment, i.e., the quantification of exposures and the estimation of the characteristics and sizes of the exposed populations; dose-response assessment, i.e., the modeling for risk realization; and risk characterization, i.e., the evaluation of the impact of a change in exposure levels on public health effects. The risk-assessment process involves limitations of exposure data, many assumptions, and subjective choices that need to be considered when using this approach to provide guidance for health policy or action. In view of these uncertainties, we suggest that the provision of estimates of individual risk and disease burden in a population must be accompanied by the corresponding estimates of precision; risks should be presented in a sufficiently disaggregated form so that population heterogeneities are not lost in the data aggregation; and different scenarios and risk models should be applied. The methods are illustrated by an assessment on the health impacts of exposure to silica.

Spontaneous abortions among Finnish flight attendants.

We conducted a retrospective cohort study to investigate whether work as a cabin attendant is related to an increased risk for spontaneous abortion. Data on female cabin crew members were linked to medical records on pregnancies. There were 1751 eligible pregnancies for the final analysis. Flight attendants who worked during early pregnancy had a slightly elevated risk of spontaneous abortion, as compared with attendants who were pregnant outside a time span of active flying (odds ratio [OR] = 1.3; 95% confidence interval [CI], 0.9 to 1.8). During the earliest years of the study period (1973 through 1977), the risk seemed to be decreased (OR = 0.4; 95% CI, 0.2 to 1.1), whereas during the later years (1978 through 1994) the risk was increased (OR = 1.6; 95% CI, 1.1 to 2.4). The results are in agreement with earlier studies, showing suggestive evidence of a slightly increased risk of spontaneous abortion among female cabin crew members.

Shift work and reproductive health.

Nonstandard workhours may disturb normal body functions, but their relation to reproductive outcome is poorly understood. Two newly published studies suggest an association between rotating shift work and prolonged waiting time to pregnancy. Seven of nine studies on spontaneous abortion suggest that some forms of shift work may be associated with increased risk. Four studies indicate that shift work including night schedules may be related to preterm birth. Moreover, some results have related rotating schedules to intrauterine growth retardation. In the published studies, the type of work schedule examined has varied, and the applied definition of shift work has not necessarily been clear. The main interest areas, however, have been work involving evening and night shifts, rotating or changing schedules, and the irregularity of work patterns. Although the evidence is not ample and remains ambiguous, it is prudent to consider shift work as a potential risk to reproduction.

Pulmonary expression of glutathione S-transferase M3 in lung cancer patients: association with GSTM1 polymorphism, smoking, and asbestos exposure.

To characterize the relative roles of glutathione S-transferases (GST) M1 and M3 in the susceptibility to lung cancer, the pulmonary expression of GSTM3 was quantified immunochemically and related to the GSTM1 genotype in 100 lung cancer patients. Among active smokers and recent ex-smokers (for 6 years or less), parenchymal GSTM3 expression was lower in patients with a homozygous GSTM1 null genotype than in those who were GSTM1 positive and had similar smoking habits (P < 0.001 and P = 0.004, respectively). However, in long-term ex-smokers (for 15 years or longer) GSTM3 was not affected by the GSTM1 genotype. Among active smokers and recent ex-smokers who were homozygous GSTM1 null, those with a definite or probable exposure to asbestos expressed GSTM3 at significantly higher levels than those for whom it was unlikely (P = 0.04). A similar effect of the homozygous GSTM1 null genotype on GSTM3 expression was not detected in the bronchial epithelium when GSTM3 was visualized immunohistochemically. Different mechanisms may result in an increased risk of either squamous cell or adenocarcinomas in patients with the homozygous GSTM1 null genotype. Low expression of GSTM3 due to smoking in the parenchymal lung of GSTM1 null individuals can theoretically favor the development of adenocarcinoma. Our data indicated a predominance of this tumor type in patients with low expression of GSTM3.

Maternal pesticide exposure and pregnancy outcome.

Exposure to pesticides is inherent in many agricultural jobs. Most of the interest in connection with pesticides and pregnancy outcome has been directed to birth defects. Some indications of an elevated risk of limb anomalies have been associated with ecologic exposure, maternal environmental exposure to pesticides determined by the mother's place of residence, and parental occupation involving potential pesticide exposure. Orofacial clefts have been related to maternal environmental exposure to pesticides and exposure in agricultural work. Moreover, there is evidence that maternal agricultural occupation and pesticide exposure may be associated with elevated risk of spontaneous abortion and stillbirth. However, some studies have found no indication of reproductive hazards but, altogether, the epidemiologic evidence is inconclusive as regards the risk of adverse pregnancy outcome.

Female noise exposure, shift work, and reproduction.

In addition to having possible direct effects on the fetus, noise induces a stress reaction in the mother, possibly causing reproductive disturbances. In shift work, many physiological functions and systems that are circadian in nature can be disturbed. Study results indicate that occupational noise at the level of approximately 85 dB LAeq(8 h) or higher and shift work, especially rotating schedules, may have independent negative effects on birth weight and length of gestation. Some forms of shift work have also been associated with early fetal loss. Moreover, some results have related noise exposure and shift work to menstrual disturbance and infertility. Although the evidence is not ample, it is prudent to consider exposure to high-level noise and shift work as risks to reproduction.

Agricultural work during pregnancy and selected structural malformations in Finland.

We studied the relation between birth defects and maternal agricultural work in a nationwide time- and area-matched case-referent series of 1,306 pairs of infants (581 orofacial clefts, 365 central nervous system defects, 360 skeletal defects) obtained through the Finnish Register of Congenital Malformations. We supplemented the Register data, including the mothers' latest and previous pregnancies, diseases, consumption of drugs and alcohol, smoking habits, and the like, with detailed interviews on the mothers' work conditions. When all of the birth defects were pooled and agricultural work was compared with nonagricultural work in the first trimester of pregnancy, the adjusted odds ratio was 1.4 [95% confidence interval (CI) = 0.9-2.0]. For orofacial clefts, the corresponding odds ratio was 1.9 (95% CI = 1.1-3.5). An industrial hygienist's blinded assessment indicated that seven mothers of infants with orofacial clefts and three reference mothers had been exposed to pesticides in agricultural work; the adjusted odds ratio for work with pesticide exposure, when compared with unexposed agricultural work, was 1.9 (95% CI = 0.4-8.3). Exposure to solvents did not explain the observed association.

Combined effect of CYP1A1 inducibility and GSTM1 polymorphism on histological type of lung cancer.

The combinations of the CYP1A1 inducibility and GSTM1 polymorphism have been investigated in relation to the histological type and peripheral or bronchial location of lung cancer in 54 surgically treated, current smoker lung cancer patients. The induced CYP1A1 was detected in 46 patients (85%) and the homozygous GSTM1 null genotype in 32 patients (59%). The role of CYP1A1 inducibility was found to be more important than that of GSTM1 polymorphism, because the non-inducible CYP1A1 was associated solely with bronchial tumours (P = 0.001), mainly squamous cell carcinomas. In patients with inducible CYP1A1, the expressing GSTM1 gene appeared to have a protective effect against contracting bronchial lung cancer, since 88% (14/16) of the lung tumours in this patient group were peripheral, whereas almost equal numbers of peripheral and bronchial tumours were observed in those patients lacking the gene (P = 0.037).

Shift work, fetal development and course of pregnancy.

Information on 1475 mothers of infants with selected structural malformations and an equal number of mothers of "normal" babies was analyzed for a possible relationship between shift work and adverse pregnancy outcome or a complicated course of pregnancy. The primary data were obtained from the Finnish Register of Congenital Malformations supplemented by special interviews on the mothers' work conditions. No signs of a teratogenic risk were observed. The relationship between course of pregnancy and outcomes other than malformations was determined from the noncase mothers' experience. Threatened abortion and pregnancy-induced hypertension were not associated with rotating shift work alone, but in a noisy work environment moderate risks could not be ruled out. Rotating shift work was associated with a slight excess of babies small for their gestational age independently of noise exposure. The results suggest that further studies on the effects of different work schedules on pregnancy are worth consideration.