No increased mortality in patients with rheumatoid arthritis treated with biologics: results from the biologics register of six rheumatology institutes in Japan

Objective

To investigate the influence of biologics on mortality and risk factors for death in rheumatoid arthritis (RA) patients.

Methods

RA patients treated with at least one dose of biologics in daily practice in six large rheumatology institutes (“biologics cohort”) were observed until 15 May 2010 or death, whichever occurred first. Mortality of the biologics cohort and the “comparator cohort” (comprising patients among the IORRA cohort who had never been treated with biologics) was compared to that of the Japanese general population. Factors associated with mortality were assessed by a Cox model.

Results

Among 2683 patients with 6913.0 patient-years of observation, 38 deaths were identified in the biologics cohort. The probability of death in patients lost to follow-up, calculated using the weighted standardized mortality ratio (SMR), was 1.08 [95 % confidence interval (CI) 0.77–1.47] in the biologics cohort and 1.28 (95 % CI 1.17–1.41) in the comparator cohort. Pulmonary involvement was the main cause of death (47.4 %), and the disease-specific SMR of pneumonia was 4.19 (95 % CI 1.81–8.25). Risk factors for death included male gender [hazard ratio (HR) 2.78 (95 % CI 1.24–6.22)], advanced age (HR 1.07, 95 % CI 1.03–1.11), and corticosteroid dose (HR 1.08, 95 % CI 1.01–1.17).

Conclusion

Mortality in RA patients exposed to biologics did not exceed that in patients not exposed to biologics, but death from pulmonary manifestations was proportionally increased in RA patients exposed to biologics.     

Serum osteoprotegerin concentration is associated with carotid atherosclerotic plaque in patients with rheumatoid arthritis

Objective

Osteoprotegerin (OPG), a regulator of bone resorption, is involved in the pathogenesis of rheumatoid arthritis (RA) and atherosclerosis. OPG is elevated in patients with coronary artery disease, and high OPG levels are associated with cardiac disease severity and mortality in the general population. The purpose of this study was to investigate the relationship of serum OPG levels, traditional coronary risk factors, and RA-related factors to carotid atherosclerosis in RA patients.

Methods

Ninety-one RA patients were studied (85 % women, age 60 ± 10 years). Serum OPG levels were measured by an enzyme-linked immunosorbent assay. The prevalence of carotid plaque was assessed by ultrasonographic imaging in all patients. The relationship between various clinical characteristics, OPG, and carotid plaque was examined.

Results

Serum OPG levels were significantly higher in patients with carotid plaque than in those without plaque (median level 1,397 vs. 887 pg/mL, respectively; P = 0.006). There were no significant differences between RA patients with and without carotid plaque with respect to sex, duration of RA, blood pressure, body mass index, smoking, low-density lipoprotein cholesterol, Disease Activity Score-28, van der Heijde-modified Sharp score, and prednisolone dose. After adjusting for age, sex, and C-reactive protein, elevated levels of OPG were still associated with a higher prevalence of carotid plaque in patients with RA (P = 0.038).

Conclusion

RA patients suffer from accelerated atherosclerosis and also have increased levels of OPG. The serum OPG level is independently associated with carotid plaque.     

Disability is the major negative predictor for achievement of Boolean-based remission in patients with rheumatoid arthritis treated with tocilizumab

Objective

To analyze the efficacy of tocilizumab (TCZ) and the factors that influence achievement of Boolean-based remission in patients with rheumatoid arthritis (RA) treated with TCZ in daily clinical practice.

Methods

The efficacy of TCZ at 24 weeks after initiation of TCZ in 80 patients with RA was analyzed by comparing achievement of “DAS28 remission” with that of “Boolean-based remission”. The predictive factors that influence achievement of Boolean-based remission were determined using multiple logistic regression analysis using a step-wise method.

Results

DAS28 remission and Boolean-based remission were achieved in 50.0 and 12.5 % of patients, respectively. Significant differences in achieving Boolean-based remission were observed when patients were stratified by disease duration in tertiles (p < 0.05) and by physical function in tertiles (p < 0.05); no such differences were observed for achieving DAS28 remission. The least achievable component among the Boolean-based remission criteria was patient’s global assessment. The predictive factor for not achieving Boolean-based remission at 24 weeks was having a worse baseline physical function (odds ratio, 3.66; 95 % confidence interval, 1.17–14.48).

Conclusions

This study suggests that baseline disability predicts a lack of achievement of Boolean-based remission. Thus, better responses to TCZ may be obtained when TCZ is initiated in RA patients before disability develops.     

Effects of adalimumab therapy on musculoskeletal manifestations and health-related quality of life in patients with active psoriatic arthritis

Objectives

Adalimumab, a fully human anti-tumor necrosis factor monoclonal antibody, was retrospectively evaluated for its effect on musculoskeletal manifestations and health-related quality of life in patients with psoriatic arthritis (PsA) during daily clinical practice.

Methods

Patients who initiated adalimumab therapy after March 2010 were followed for at least 24 weeks with the clinical outcome measures. Eleven patients, all men with a mean age of 45.4 years, had mean psoriasis durations of 16.2 and 8.4 years at baseline.

Results

After 24 weeks, 72.7, 63.6, and 45.5 % of the patients met the ACR 20, 50, and 70 response criteria, respectively, while 81.8 % achieved the PsA response criteria. Disease Activity Score using the 28-joint count and CRP declined from 3.2 ± 1.2 at baseline to 1.3 ± 0.4 at week 24 (P < 0.01). The Bath Ankylosing Spondylitis Disease Activity Index and Bath Ankylosing Spondylitis Functional Index scores also decreased significantly (both P values were <0.01). After 24 weeks, three out of eight dimensions of the Medical Outcomes Study 36-Item Short Form Health Survey and Physical Component Summary were significantly improved (all P values were <0.05).

Conclusions

Adalimumab exerted its effect as early as week 4, and it was sustained until the end of the 24-week observation period in the PsA patients.     

High concentrations of omega-3 fatty acids are associated with the development of atrial fibrillation in the Japanese population

The favorable effect of fish oils rich in n-3 polyunsaturated fatty acids (PUFAs) on the development of atrial fibrillation (AF) is controversial. The relationship between the serum concentrations of n-3 PUFAs and the incidence of AF is unclear; therefore, in the present study, we aimed to elucidate this relationship. We evaluated the serum concentrations of n-3 PUFAs in 110 patients with AF, 46 patients with ischemic heart disease (IHD) and no AF, and 36 healthy volunteers. Thirty-six patients had a history of IHD (IHD-AF group) and 74 did not (L-AF group). The eicosapentaenoic acid (EPA) levels in the L-AF group were higher than those in the IHD-AF and control groups (117 ± 64, 76 ± 30, and 68 ± 23 μg/ml, respectively); the docosahexaenoic acid (DHA) levels showed the same pattern (170 ± 50, 127 ± 27, and 126 ± 35 μg/ml, respectively). In both the L-AF and IHD-AF groups, the EPA levels in patients with persistent and permanent AF were higher than those in patients with paroxysmal AF (L-AF 131 ± 74 vs. 105 ± 51 μg/ml; IHD-AF 82 ± 28 vs 70 ± 33 μg/ml). Multivariate analysis showed that cases of AF were associated with higher levels of EPA but not DHA. In this Japanese population study, the EPA and DHA levels in patients with L-AF were higher than those in normal subjects. In particular, the EPA level was associated with the incidence of AF. These findings suggest that an excess of EPA might be a precipitating factor of AF.     

Risk of peritoneal carcinomatosis by endoscopic ultrasound-guided fine needle aspiration for pancreatic cancer

Background

Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is an accurate method for cytological confirmation of pancreatic malignancy, but peritoneal dissemination caused by EUS-FNA could be a matter of concern because it may lead to poorer prognosis. Our aim was to estimate the risk of peritoneal carcinomatosis by EUS-FNA for pancreatic cancer.

Methods

Two hundred and seventeen patients with cytopathologically proven pancreatic cancer in a tertiary referral center were retrospectively reviewed. They were divided into two groups: 161 patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) alone (ERCP group), and 56 patients who had ever undergone EUS-FNA (EUS-FNA group). Peritoneal carcinomatosis was diagnosed by computed tomography and/or cytology during follow-up. Hazard ratios of factors including EUS-FNA for the development of peritoneal carcinomatosis were analyzed by the Cox proportional hazard model.

Results

There was no significant difference in baseline characteristics between ERCP and EUS-FNA groups. Peritoneal carcinomatosis developed in 14.9 % (24/161) during an average follow-up period of 545 days, and 17.9 % (10/56) during 599 days among ERCP and EUS-FNA group, respectively. The EUS-FNA was not identified as a significant risk factor with hazard ratios (HR) of 1.07 [95 % confidence interval (CI) 0.51–2.25, p = 0.85] by univariate analysis and 1.35 (95 % CI 0.62–2.95, p = 0.45) by multivariate analysis. Nodal involvement (HR 2.19, 95 % CI 1.03–4.63, p = 0.04) and non-resection (HR 2.64, 95 % CI 1.11–6.25, p = 0.03) were shown to be statistically significant risk factors by multivariate analysis.

Conclusions

EUS-FNA for pancreatic cancer did not significantly increase the risk of peritoneal carcinomatosis.     

From the Cover: Insects groom their antennae to enhance olfactory acuity

Grooming, a common behavior in animals, serves the important function of removing foreign materials from body surfaces. When antennal grooming was prevented in the American cockroach, Periplaneta americana, field emission gun scanning electron microscopy images revealed that an unstructured substance accumulated on nongroomed antennae, covering sensillar pores, but not on groomed antennae of the same individuals. Gas chromatography analysis of antennal extracts showed that over a 24-h period nongroomed antennae accumulated three to four times more cuticular hydrocarbons than groomed antennae. Moreover, nongroomed antennae accumulated significantly more environmental contaminants from surfaces (stearic acid) and from air (geranyl acetate) than groomed antennae. We hypothesized that the accumulation of excess native cuticular hydrocarbons on the antennae would impair olfactory reception. Electroantennogram experiments and single-sensillum recordings supported this hypothesis: antennae that were prevented from being groomed were significantly less responsive than groomed antennae to the sex pheromone component periplanone-B, as well as to the general odorants geranyl acetate and hexanol. We therefore conclude that antennal grooming removes excess native cuticular lipids and foreign chemicals that physically and/or chemically interfere with olfaction, and thus maintains the olfactory acuity of the antennae. Similar experimental manipulations of the German cockroach (Blattella germanica), carpenter ant (Camponotus pennsylvanicus), and the housefly (Musca domestica), which use different modes of antennal grooming, support the hypothesis that antennal grooming serves a similar function in a wide range of insect taxa.Insects, like most animals, groom themselves regularly (1), but the diverse functions of self-grooming have been scarcely investigated. Major proposed functions of grooming are to remove debris (2, 3), parasitoids (4), and pathogens (5). It has also been shown that grooming can be evoked by irritant chemicals (6, 7), but grooming-facilitated removal of environmental chemicals has not been demonstrated. Mutual grooming (allogrooming), likewise, can remove pathogens, especially from nestmates in social insects (8, 9). Self-grooming also serves to redistribute antimicrobial substances over the body surface (10), and a similar function has been suggested for redistribution of cuticular lipids (2).Paradoxically, however, insects meticulously self-groom, especially their sensory appendages (e.g., antennae), even in clean environments free of pathogens and dust. Although it is intuitively evident that sensory organs should be regularly groomed to keep them responsive to the environment, and the mechanics of these behaviors have been comprehensively described in various insect species (2, 11–17), the composition of the materials removed by regular grooming has not been analyzed and the adaptive outcomes of this behavior have not been investigated.We observed that antennae of the American cockroach, Periplaneta americana (Linnaeus) (Blattodea, Blattidae), that were immobilized for electrophysiological studies, accumulated a shiny substance on their surface (18). We hypothesized that grooming might serve to remove these excess native secretions and compared groomed and nongroomed antennae of male P. americana cockroaches using field emission gun scanning electron microscopy (FEG SEM). We also investigated the chemical nature of the accumulated material and the relationship between antennal grooming and the amount of this material on the antennae of four species representing three insect orders with different means of antennal grooming. In the American cockroach, and the German cockroach, Blattella germanica (L.) (Blattodea, Blattellidae), a foreleg serves the contralateral antenna to the mouth, which cleans the antenna from base to tip (15, 16). In the carpenter ant, Camponotus pennsylvanicus (De Geer) (Hymenoptera, Formicidae), a specialized structure on the foreleg—the basitarsal brush—grooms the ipsilateral antenna, and then the basitarsal brush is orally groomed (17). The house fly, Musca domestica (L.) (Diptera, Muscidae), does not use its mouth for antennal grooming, but instead sweeps the forelegs, and rarely the middle legs, over the head and cleans head appendages (19). By preventing antennal grooming we now demonstrate that large amounts of cuticular hydrocarbons (CHCs) accumulate on nongroomed antennae of all four species. We further tested whether grooming also removes environmental contaminants from the antennae, and using electroantennogram (EAG) and single-sensillum recordings (SSRs) we assessed whether grooming enhances the olfactory acuity of the antennae of P. americana. Our results support the notion that self-grooming physically removes excess native cuticular lipids as well as extrinsic chemicals from olfactory sensilla and thus maintains the insect’s olfactory acuity to all odorants.