Incidence of new carotid plaques in rheumatoid arthritis patients: 6-Year prospective results of the TOMORROW study.

OBJECTIVES: The purpose of this study was to evaluate the new incidence of carotid plaques in rheumatoid arthritis (RA) patients over a 6-year prospective follow-up and to assess the risk factors. METHODS: This is a 10-year prospective cohort study that included 208 RA patients and 205 age- and gender-matched controls. Ultrasound assessment of the bilateral carotid arteries was performed in 2011 and 2017. RESULTS: There were no differences in the incidence of new carotid atherosclerotic plaques over 6 years between the two groups (35.5% vs. 37.0%, respectively; p = .936). The mean Disease Activity Score 28-C-reactive protein over 6 years in RA patients was 2.73 ± 0.95. Multiple logistic regression analysis showed that RA was not a risk factor for new carotid atherosclerotic plaques (odds ratios, 0.708; 95% confidence interval, 0.348-1.440; p = .340). An average glucocorticoid dose of >1.8 mg/day over 6 years was a risk factor for new carotid atherosclerotic plaques (odds ratios, 8.54; 95% confidence interval, 1.641-44.455; p = .011). CONCLUSIONS: Incidence of new carotid atherosclerotic plaques was similar between well-controlled disease activity RA patients and control subjects. A mean glucocorticoid dose of >1.8 mg/day over 6 years was a risk factor for new carotid atherosclerotic plaques.

Comparison of median nerve stiffness with and without rheumatoid arthritis by ultrasound real-time tissue elastography: A propensity score matching study.

Objectives: This study aimed to compare median nerve stiffness measured by ultrasound real-time tissue elastography in patients with and without rheumatoid arthritis (RA and non-RA groups, respectively).Methods: Altogether, 402 hands of 201 RA group and 222 hands of 111 non-RA group were included in the study. Ultrasonography was performed to evaluate the circumference, cross-sectional area (CSA) and strain ratio as an elasticity of the median nerve at the inlet level of the carpal tunnel and the proximal portion of the carpal tunnel inlet. Using propensity score matching, the difference between RA and non-RA group were analyzed.Results: After propensity score matching, 135 hands in 104 RA group and 70 non-RA group were finally analyzed. There were no significant differences in the circumference and CSA of the median nerve between the two groups. The strain ratio of the median nerve was significantly higher in RA group than in non-RA group only at the inlet of the carpal tunnel level.Conclusions: The nerve stiffness in patients with RA measured by ultrasound real-time tissue elastography was higher than without RA. Inflammatory condition of the flexor tendon and wrist joint in patients with RA may generate fibrotic changes in the median nerve.Trial registration: University Hospital Medical Information Network Clinical Trials Registry: UMIN000015314.

Soybean isoflavone can protect against osteoarthritis in ovariectomized rats.

Osteoarthritis (OA) is a chronic and incurable disease and a leading cause of significant pain and disability that is closely associated with aging and obesity. An appropriate long-term therapy regimen is presently unknown. An estrogen deficiency after menopause increases the incidence and severity of OA in women. Soybean isoflavone have weak estrogenic effects in several organs and have been considered as a potentially safe natural selective estrogen receptor modulator. The present study aimed to determine the effects of isoflavone on cartilage degradation in ovariectomized rats. Six-month-old female Sprague-Dawley (SD) rats (n = 40) were randomly assigned to sham operation (n = 10), ovariectomy (OVX) (n = 15) or OVX + isoflavone (OVXI) (n = 15) groups. The OVXI group was fed with soybean isoflavone (51.0 mg/kg/day) for nine weeks, then knee joints were excised. Cartilage degradation was evaluated by toluidine blue staining joint specimens, and by comparing values for serum C-telopeptides of Type II collagen (CTX-II) and cartilage oligomeric matrix protein (COMP) between baseline and the end of the study. Cartilage damage scored by Toluidine blue staining was significantly lower in the OXVI, than the OVX group (P < 0.016). The CTX-II values before the surgical procedure and the end of experiment, did not significantly differ among the groups. Values for COMP in all samples were below detection limits in all samples. Soy bean isoflavone limited the degeneration of cartilage induced by OVX in rats.

Abatacept might increase bone mineral density at femoral neck for patients with rheumatoid arthritis in clinical practice: AIRTIGHT study.

We investigated the influence of abatacept (ABT) on bone mineral density (BMD) and bone metabolic markers (BMMs) in patients with rheumatoid arthritis (RA) compared to other biologic disease-modifying anti-rheumatic drugs (bDMARDs). This prospective, comparative, non-randomized study (the AIRTIGHT study; UMIN000005570) investigated the effects of ABT and other bDMARDs on bone metabolism. A total of 165 RA patients were divided into ABT (n = 50) and non-ABT (n = 115). We evaluated percentage changes in BMD (%ΔBMD) at the lumbar spine and femoral neck using dual-energy X-ray absorptiometry. Urinary levels of cross-linked N-telopeptide of type I collagen (uNTx) and bone-specific alkaline phosphatase (BAP) were used as markers of bone resorption and formation, respectively. No significant differences in 1-year completion rates were seen between ABT (64%) and non-ABT (72%; p = 0.387). The %ΔBMD at the femoral neck was significantly higher in the ABT group (0.97%) than in the non-ABT group (- 2.19%; p = 0.026). Whereas, no significant difference in %ΔBMD at the lumbar spine was observed between groups (ABT, - 0.40%; Non-ABT, - 1.67%; p = 0.524). No significant differences were observed in changes to uNTx or BAP. ABT treatment was significantly associated with increased BMD at the femoral neck (odds ratio (OR) 8.84; 95% CI 1.08-72.4; p = 0.04), and baseline lumbar osteoarthritis was significantly associated with BMD at the lumbar spine (OR 2.97; 95% CI 1.23-7.13; p = 0.02). The efficacy of ABT for increasing BMD at the femoral neck was superior to that of other bDMARDs. ABT may offer good efficacy for improving BMD at the femoral neck in patients with RA.

Use of bisphosphonate might be important to improve bone mineral density in patients with rheumatoid arthritis even under tight control: the TOMORROW study.

Although patients with rheumatoid arthritis (RA) are prone to osteoporosis, tight control of disease activity might have a positive effect on bone metabolism. We aimed to determine whether bisphosphonate use is still important to improve bone mineral density (BMD) in RA patients whose disease activity was tightly controlled and the dose of glucocorticoid was reduced. This study was a sub-analysis of the 10-year prospective cohort TOtal Management Of Risk factors in Rheumatoid arthritis patients to lOWer morbidity and mortality: the TOMORROW which started from 2010. We compared BMD between 192 patients with RA and age- and sex-matched volunteers between 2010 and 2013 using dual-energy X-ray absorptiometry (DXA) in whole body mode. We then determined ratios of changes in BMD (%ΔBMD) to assess factors influencing increases in BMD among the patients using multivariate logistic regression analysis. The BMD was significantly lower in the patients than in the controls at all sites surveyed during 2010 and 2013. The %ΔBMD of the total spine was significantly higher among the patients treated with, than without bisphosphonate (6.2 vs. 1.8%, P = 0.0001). Multivariate logistic regression analysis revealed that use of bisphosphonate was a significant factor contributing to BMD increase (odds ratio 2.13; 95% confidence interval, 1.03-4.38, P = 0.041). Meanwhile, use of biologic agents, reducing glucocorticoid dose, and control of disease activity were not significant factors for gain of BMD. The BMD was lower among patients with RA than non-RA controls. Use of bisphosphonate significantly increased the BMD of the spine in patients over a period of 3 years and was important for maintaining the BMD among patients with RA under the control of inflammation and disease activity.

Incidence rate of falls and its risk factors in patients with rheumatoid arthritis compared to controls: Four years of the TOMORROW study.

OBJECTIVE: Patients with rheumatoid arthritis (RA) have been recognized to experience falls frequently due to functional disabilities. The aim of this study was to prospectively investigate factors influencing falls in patients with RA compared to controls. METHODS: We compared the frequency of falls in 208 RA patients and 205 age- and sex-matched volunteers for four years and analyzed risk factors for falls in RA patients using multivariate regression analysis. RESULTS: No significant difference in the incidence rate of falls (/person-year) between patients with RA (median [interquartile range]: 0 [0, 0.5]) and controls (0 [0, 0.5]) was evident during four years. Logistic regression analysis identified age, sex, body mass index, history of falls, and lower limb implant at baseline as significant risk factors for falls. The highest quartile of anti-CCP antibody level (>300.6 U/ml) was the strongest predictor for multiple falls (odds ratio, 2.97; 95% confidence interval, 1.12-7.91, p = 0.029) among RA patients. CONCLUSION: During four years we could not observe the higher incidence rate of falls in RA patients compared to controls in our cohort. Subjects with a higher titer of anti-CCP antibody might be at higher risk of frequent falls among RA patients.

High frequency of vertebral fracture and low bone quality in patients with rheumatoid arthritis-Results from TOMORROW study.

OBJECTIVES: Osteoporosis is one of the complications in patients with rheumatoid arthritis (RA). In this study, we researched the morbidity of existing vertebral fractures and the risk factors for vertebral fractures in patients with RA. METHODS: This study included 413 participants, 208 patients with RA, and 205 age- and sex-matched controls without RA. Clinical data, radiographic assessment of vertebral fracture from T4 to L4 in thoracic and lumber spine, bone mineral density (BMD), and bone metabolic markers (BMM) were analyzed. RESULTS: Vertebral fractures were observed more frequently, severe and multiple in patients with RA. In the logistic regression analysis, age (adjusted odds ratios (OR): 1.07, 95% confidence interval (CI): 1.04-1.09) and RA (adjusted OR: 1.72, 95% CI: 1.04-2.83) were risk factors for existing vertebral fracture. Moreover, two bone matrix-related markers, undercarboxylated osteocalcin (ucOC) (adjusted OR: 1.68, 95% CI: 1.02-2.78), and urinary pentocidine (adjusted OR: 2.51, 95% CI: 1.48-4.24) were associated with existing vertebral fracture. CONCLUSIONS: High frequent, multiple, and severe vertebral fractures were found in patients with RA compared to the controls. Low bone quality might be the cause of the frequent prevalence of vertebral fracture in patients with RA.

Loss of lean body mass affects low bone mineral density in patients with rheumatoid arthritis - results from the TOMORROW study.

OBJECTIVES: Osteoporosis is one of the complications for patients with rheumatoid arthritis (RA). Rheumatoid cachexia, the loss of lean body mass, is another. However, the relationship between decreased lean body mass and reduced bone mineral density (BMD) in patients with RA has not been well studied. METHODS: This study included 413 participants, comprising 208 patients with RA and 205 age- and sex-matched healthy volunteers. Clinical data, BMD, bone metabolic markers (BMM) and body composition, such as lean body mass and percent fat, were collected. Risk factors for osteoporosis in patients with RA including the relationship BMD and body composition were analyzed. RESULTS: Patients with RA showed low BMD and high BMM compared with controls. Moreover, lean body mass was lower and percent fat was higher in patients with RA. Lean body mass correlated positively and percent fat negatively with BMD. Lean body mass was a positive and disease duration was a negative independent factor for BMD in multivariate statistical analysis. CONCLUSION: BMD and lean body mass were significantly lower in patients with RA compared to healthy controls. Lean body mass correlated positively with BMD and decreased lean body mass and disease duration affected low BMD in patients with RA. TRIAL REGISTRATION: [UMIN Clinical Trials Registry, http://www.umin.ac.jp/ctr/ , UMIN000003876].

Levels of interleukin-1 beta can predict response to tocilizumab therapy in rheumatoid arthritis: the PETITE (predictors of effectiveness of tocilizumab therapy) study.

Predicting the responses of patients with rheumatoid arthritis (RA) to tocilizumab is difficult, because inflammatory markers such as C-reactive protein rapidly normalize regardless of clinical efficacy. We aimed to identify factors that could predict response to tocilizumab. Sixty-five patients completed 52 weeks of tocilizumab therapy. Serum fibrinogen, D-dimer and interleukin (IL)-1ß levels were measured at baseline and after 4 weeks of therapy. Clinical responses to tocilizumab were assessed using disease activity score 28-erythrocyte sedimentation rate and the clinical disease activity index at baseline and after 52 weeks of therapy (UMIN Clinical Trials Registry No. UMIN000002246). Mean age was 60.5 years (range 22-85 years). Mean disease duration was 11.2 years (range 0-45 years). All patients had moderate-to-severe disease activity and were resistant to disease-modifying anti-rheumatic drugs and/or other biologics. Baseline IL-1ß levels were significantly lower in responders than in non-responders (p = 0.045), but multiple logistic regression analysis found no significant difference (adjusted odds ratio 2.74; 95 % confidence interval 0.84-8.95; p = 0.096). Low D-dimer and IL-1ß levels at 4 weeks predicted greater decrease in disease activity after 52 weeks of treatment (p = 0.005 and p < 0.001, respectively). Effects of tocilizumab at 52 weeks could be predicted from D-dimer and IL-1ß levels after 4 weeks of tocilizumab treatment. These markers might be more useful than current inflammatory markers for early-stage prediction of response to tocilizumab in RA.

Hyperleptinemia suppresses aggravation of arthritis of collagen-antibody-induced arthritis in mice.

BACKGROUND: Leptin is an adipocytokine produced by adipocytes and controlling body weight. It is unclear whether leptin works as a proinflammatory or an anti-inflammatory cytokine. We investigated the effects of hyperleptinemia on leptin transgenic (LepTg) mice in terms of cartilage destruction, bone destruction, joint synovitis, and serum cytokine levels by using a mouse model of collagen-antibody-induced arthritis (CAIA). METHODS: CAIA was induced for female age-matched 6- to 8-week-old C57BL/6 J control mice and LepTg mice. Mice were injected intraperitoneally with 5 mg of a combination of monoclonal antibody specific for type II collagen on day 0 and 12.5 mg of lipopolysaccharide (LPS) on day 3. Clinical evaluation of arthritis was monitored for 14 days, and hind paws were examined clinically and histologically. Serum cytokine levels of interleukin (IL)-1ß, IL-6, IL-10, and IL-17 and tumor necrosis factor alpha (TNF-α) were also analyzed on days 0 and 5. Moreover, THP-1 cells, which are human monocytic cell line derived from an acute monocytic leukemia patient, were cultured and differentiated into macrophages. The effects of leptin on messenger RNA (mRNA) expression of IL-6 were examined by real-time quantitative polymerase chain reaction (RT-PCR). RESULTS: Serum leptin concentrations were approximately ninefold higher in LepTg mice (62.0 ± 20.7 ng/ml) than in control mice (7.2 ± 0.5 ng/ml). Severity of clinical paw swelling, arthritis score, synovial hyperplasia, and cartilage damage were suppressed in LepTg mice with CAIA. Although serum cytokine levels of IL-1ß, IL-17, and IL-10 and TNF-α showed no significant changes in two mice, serum levels of IL-6 in LepTg mice were suppressed at day 5. Moreover, in vitro study showed that IL-6 elevation following LPS exposure in THP-1 cells was suppressed with high leptin concentrations. CONCLUSION: Our finding suggests that hyperleptinemia suppress IL-6 responses and progression of joint inflammation. Leptin may play an anti-inflammatory role under hyperleptinemia.

Relationships between serum 25-hydroxycalciferol, vitamin D intake and disease activity in patients with rheumatoid arthritis--TOMORROW study.

OBJECTIVES: The effect of serum 25-hydroxycalciferol [25(OH)D] on rheumatoid arthritis (RA) activity remains controversial. This study was undertaken with an aim to clarify the relationship between serum 25(OH)D and RA activity, and to determine the effects of dietary vitamin D intake and age on serum 25(OH)D level. METHODS: A total of 208 outpatients with RA were matched according to age and sex with 205 individuals without RA (controls) from the TOMORROW study (UMIN000003876). We excluded 27 patients with RA and 19 control subjects who had been prescribed vitamin D medication or were taking vitamin D supplements. Vitamin D intake was assessed in the remaining 181 patients and 186 controls using the brief-type dietary history questionnaire. Serum 25(OH)D levels were measured using a radioimmunoassay. RESULTS: Serum 25(OH)D levels were significantly lower in patients with RA than in the controls (p < 0.001). There was a significant and positive correlation between age and 25(OH)D in the patients (r = 0.283, p < 0.001), as with vitamin D intake and 25(OH)D, even after adjusting for age (r = 0.313, p < 0.001). Disease activity and 25(OH)D did not significantly correlate. CONCLUSIONS: Patients with RA were observed to have serum 25(OH)D levels which correlated with vitamin D intake and age but not disease activity.

Preference of surgical procedure for the forefoot deformity in the rheumatoid arthritis patients--A prospective, randomized, internal controlled study.

OBJECTIVES: The deformed rheumatoid forefoot may be treated with resection of lesser metatarsal heads combined with arthrodesis or resection of the first metatarsophalangeal joint. Recurrent hallux valgus deformity has been reported by resection. We performed a prospective, randomized, internal-controlled study to compare results between arthrodesis and resection. METHODS: We resected the lesser metatarsal heads bilaterally and performed arthrodesis of the first metatarsophalangeal joint on one side and resection on the opposite side. We investigated 26 patients (52 feet) who were followed at least one year. Patients were assessed for clinical score, hallux valgus angle (HVA), angle between first and second metatarsals, and angle between first and fifth metatarsals preoperatively, postoperatively and at final follow-up. We evaluated callosities, claw toes, recurrences, and procedure preferences. RESULTS: The mean follow-up period was 4.1 years. No significant differences between arthrodesis and resection were seen, with the exception of HVA. That was significantly less on arthrodesis side (11.5°) than on resection side (17.0°, p < 0.05). Seven callosities on resection side and four on arthrodesis side were observed. On resection side, hallux valgus deformity often recurred (15.3%). Patients expressed a significant preference for arthrodesis over resection (p = 0.008). CONCLUSIONS: Arthrodesis provides better results for maintaining HVA.

The limited effects of anti-tumor necrosis factor blockade on bone health in patients with rheumatoid arthritis under the use of glucocorticoid.

We investigated the effects of biologics for rheumatoid arthritis (RA) patients on bone mineral density (BMD) and bone metabolic markers (BMM), retrospectively, and also clarified the effects of bisphosphonates (alendronate or risedronate 35 mg/week) and glucocorticoids. Participants in this study comprised 219 patients with RA, including 117 patients treated with biologics (infliximab, n = 90; etanercept, n = 27) and 102 patients with conventional disease-modifying anti-rheumatic drugs (DMARDs) for 1 year. Changes in BMD at the lumbar spine and total hip and BMMs [urinary type I collagen cross-linked N-telopeptide (NTX) and bone-specific alkaline phosphatase] were measured. BMD of the lumbar spine in both groups and total hip BMD in the biologics group were unchanged during treatment with biologics. However, BMD of the total hip was significantly decreased in the DMARDs group (from 0.731 ± 0.135 to 0.706 ± 0.135 g/cm2). Patients receiving glucocorticoids without bisphosphonates showed significant decrease in BMD of the total hip compared with patients not receiving glucocorticoids or receiving glucocorticoids with bisphosphonates in both biologics and DMARDs groups. Furthermore, BMD of the lumbar spine increased (p < 0.05) for patients in the biologics group who received bisphosphonates. NTX was significantly decreased only in the biologics group. Multiple regression analysis showed that BMD and bone metabolic marker levels correlated positively with bisphosphonate and biologics use and negatively with glucocorticoid use. BMD of the total hip was maintained in the patients using biologics without glucocorticoids or with bisphosphonates, but it was not maintained in the DMARDs patients, even without glucocorticoids or with bisphosphonates. Even if biologics have protective effect against bone loss of RA patients, we should consider reducing the dose of glucocorticoids and adding bisphosphonates for the treatment of osteoporosis.

MRI evaluation of lumbar endplate and facet erosion in rheumatoid arthritis.

STUDY DESIGN: A cross-sectional study. OBJECTIVE: This study was aimed to quantify the extent of lumbar endplate and facet joint erosion in patients with rheumatoid arthritis (RA) using magnetic resonance imaging, to calculate the prevalence of erosion, and sought correlated factors. SUMMARY OF BACKGROUND DATA: Few studies have examined the lumbar spine in RA, especially the relationship between endplate and facet joint erosions and lumbar lesions induced by RA. METHODS: A total of 201 patients with RA were enrolled. Lumbar endplate and facet joint erosion were defined as irregularities and low-intensity change on magnetic resonance imaging, and graded utilizing the Rheumatoid Arthritis Magnetic Resonance Imaging Score. Lumbar lesions were defined as scoliosis, spondylolisthesis, and vertebral fracture on plain x-ray. Multivariable logistic regression analysis was used to seek correlations between the erosion and spinal level, RA-related factors and x-ray findings. RESULTS: Lumbar endplate and facet erosion were detected in 70.6% and 76.6% of individuals, respectively, and at 33.8% and 38.7% of lumbar intervertebral levels, respectively. The severity of erosion in individual patients correlated with lumbar lesions. Endplate and facet erosion at each level correlated with high disease activity, and were most common at mid-lumbar and lower-lumbar levels. Strong correlations were observed between endplate erosion and adjacent vertebral body fracture or disk degeneration, and between facet erosion and spondylolisthesis. CONCLUSIONS: Lumbar endplate and facet erosion are common in RA, and are observed more frequently at mid-low levels and when RA is poorly controlled. This pattern of erosion may play a crucial role in the generation of lumbar lesions in RA.

Current prevalence and characteristics of cervical spine instability in patients with rheumatoid arthritis in the era of biologics.

OBJECTIVES: Cervical spine instability (CSI) is commonly involved in patients with rheumatoid arthritis (RA). Although the treatment for RA has dramatically changed due to methotrexate and biologics, it is unclear whether this change contributes to the prevalence of CSI or not. Our objectives were to update the current prevalence of CSI and to investigate the factors associated with CSI. METHODS: A cross-sectional study of patients with RA was conducted in our outpatient clinic. Clinical information and symptoms related to CSI were obtained. Plain radiography and magnetic resonance imaging were performed. CSI included atlantoaxial subluxation (AAS), vertical subluxation (VS), and subaxial subluxation (SAS). RESULTS: Two hundred and twenty patients were analyzed, 93 (42%) of whom had CSI. A ≥ 10-year disease duration, Steinbrocker stage III, and three or more narrowed disc spaces from C2/3 to C6/7 were significantly associated with CSI. A neck pain VAS was associated with VS, but not with AAS and SAS. In contrast, methotrexate and biologics had no effect on CSI. CONCLUSION: The prevalence of CSI in this study was lower compared to previous reports before the approval of biologic, although we failed to detect the effect of biologics. Further prospective studies are needed to elucidate the efficacy.

[Fall risk and fracture. Associated factors for falls in patients with inflammatory polyarthritis].

Patients with rheumatoid arthritis (RA) have an increased risk of falls compared to healthy controls. Previous studies reported that the incidence of fractures in RA patients was mainly caused by falls. Some factors including tender and/or swollen joint counts, low levels of physical activity and history of falls are reported to be associated with falls in the patients with RA. Control of disease activity in the patients is essential to reduce the risk of falls and the burden of fracture. Moreover, potential interventions to prevent falls such as osteoporosis therapy and balance training are necessary for the patients.

Comparison of joint destruction between standard- and low-dose etanercept in rheumatoid arthritis from the Prevention of Cartilage Destruction by Etanercept (PRECEPT) study.

OBJECTIVE: To evaluate the prevention of joint destruction and clinical efficacy of low-dose etanercept (ETN) (25 mg/week) compared with standard-dose ETN (50 mg/week) in RA. METHODS: In this prospective, randomized, open-label study, 70 patients were assigned to receive ETN at either 50 or 25 mg/week for 52 weeks. The primary endpoint was the variation in modified total Sharp score (mTSS), and secondary endpoints were variations in disease activity score in 28 joints (DAS-28), modified HAQ and adverse event rate. Values of mTSS were calculated at baseline and after 52 weeks. Non-progression was estimated as ΔmTSS ≤0.5, and the non-progression rate was compared between groups. RESULTS: Mean values at baseline were as follows: disease duration 9.2 years; DAS-28 5.45; and annual progression of mTSS 26.1. No significant differences in background were seen between groups. At 52 weeks, the non-progression rate was significantly less in the 25 mg/week group (36.7%) than in the 50 mg/week group (67.7%) (P = 0.041). Mean ΔmTSS was higher at 25 mg/week (1.03) than at 50 mg/week (-0.13). DAS-28 was significantly improved at 4 weeks, and the effect of treatment lasted for 52 weeks in both groups. No differences in adverse event rates were seen between groups. CONCLUSION: Low-dose ETN is not inferior to standard-dose ETN in terms of effects on clinical manifestations. However, in terms of the radiographic non-progression rate, the effects of low-dose ETN may be inferior to the effects of standard-dose ETN. TRIAL REGISTRATION: UMIN Clinical Trials Registry, http://www.umin.ac.jp/ctr/, UMIN000001798.

Acquired leptin resistance by high-fat feeding reduces inflammation from collagen antibody-induced arthritis in mice.

OBJECTIVES: Rheumatoid arthritis (RA) patients with high body mass index (BMI) show lower mortality than thinner patients, indicating a paradoxical effect of body mass on mortality in RA. We considered that leptin might play some part in this mechanism. Leptin regulates not only body weight, but also inflammatory processes. Furthermore, hyperleptinemia decreases sensitivity to leptin (leptin resistance). This study examined whether high-fat diet-induced hyperleptinemic obese mice with acquired leptin resistance show reduced inflammation induced by collagen antibody-induced arthritis (CAIA). METHODS: Diet therapies were induced in mice by exposure to 50% fat to obesity for 6 weeks. We examined serum leptin concentrations and leptin responses after 6 weeks and induced CAIA. Leptin effects were examined by intraperitoneal (IP) or intracerebroventricular (ICV) leptin administration after CAIA. Hindpaw swelling was monitored daily. Histopathological features were also determined at sacrifice. RESULTS: Serum leptin concentrations were approximately 5-fold higher than in normal mice. IP leptin did not inhibit food intake, but ICV leptin did. Obese mice thus acquired peripheral leptin resistance. Arthritis was reduced approximately 30% compared with normal controls and was not exacerbated by IP leptin injection, but ICV leptin injection exacerbated arthritis to levels equal to normal controls. Histopathological assessment showed that cartilage damage was reduced by 76% compared to normal controls. CONCLUSIONS: High-fat diet-induced obese mice acquired peripheral leptin resistance reducing the development of CAIA. Leptin sensitivity was associated with severity of arthritis. These results suggest that RA patients with high BMI who acquire leptin resistance may show reduced inflammation. However, the real function of leptin in the immune system remains partly unclear.

Impact of disease burden or inflammation on nutritional assessment by the GLIM criteria in female patients with rheumatoid arthritis.

BACKGROUND & AIMS: In 2018, the Global Leadership Initiative on Malnutrition (GLIM) released a global standard for evaluating malnutrition. The etiologies of malnutrition in the GLIM criteria includes disease burden/inflammation, but how this view affects nutritional assessment remains unclear. This study aimed to investigate the impact of disease burden/inflammation on the proportion of malnourished patients defined by GLIM criteria, and how differences in methods for determining disease burden/inflammation in GLIM criteria affect existing nutritional indices among patients with rheumatoid arthritis (RA). We also investigated factors associated with malnutrition in RA patients. METHODS: Data from 135 female RA patients (66.8 ± 12.6 years) were cross-sectionally analyzed. Among the etiologies of malnutrition, disease burden/inflammation was defined as: (1) moderate or higher disease activity score (disease activity score composite of the 28-joint score and erythrocyte sedimentation rate [DAS28-ESR] ≥ 3.2) [DAS-malnutrition (MN)]; (2) elevated C-reactive protein (CRP) ≥0.5 mg/dL (CRP-MN); and (3) presence of RA (RA-MN). In each of the three conditions, nutritional indicators between well-nourished and malnourished groups were compared by analysis of covariance. Factors associated with malnutrition were analyzed with logistic regression analysis. RESULTS: The frequencies of malnutrition as defined by DAS-MN, CRP-MN, and RA-MN were 39%, 30%, and 71%, respectively. When malnutrition was defined by the DAS-MN and/or the CRP-MN, grip strength and serum ceruloplasmin, iron, and zinc levels showed significant differences between the well-nourished and malnourished groups (p < 0.05). The use of targeted synthetic or biological disease-modifying antirheumatic drugs (ts-/b-DMARD) (OR = 0.29; 95% CI 0.11-0.82), grip strength (OR = 0.83; 95% CI 0.75-0.91), subjective reduction in walking speed (OR = 5.24; 1.85-14.86) were significantly associated with malnutrition as determined by DAS-MN. CONCLUSION: Differences in disease burden/inflammation affect nutritional assessments. The number of malnourished patients with RA was negatively associated with the use of ts-/b-DMARDs and high physical function in women.

Change in dietary inflammatory index score is associated with control of long-term rheumatoid arthritis disease activity in a Japanese cohort: the TOMORROW study.

BACKGROUND: The dietary inflammatory index (DII®), a quantitative measure of the inflammatory potential of daily food and nutrient intake, and associations between a variety of health outcomes have been reported. However, the association between DII score and disease activity of rheumatoid arthritis (RA) is unclear. Therefore, this study was designed to test whether higher DII score contributes to disease activity and as a corollary, whether reducing DII score helps to achieve or maintain low disease activity or remission in patients with RA. METHODS: We performed a cross-sectional and longitudinal analysis using 6 years of data (from 2011 to 2017) in TOMORROW, a cohort study consisting of 208 RA patients and 205 gender- and age-matched controls started in 2010. Disease activity of RA patients was assessed annually using DAS28-ESR (disease activity score 28 joints and the erythrocyte sedimentation rate) as a composite measure based on arthritic symptoms in 28 joints plus global health assessment and ESR. Dietary data were collected in 2011 and 2017 using the brief-type self-administered diet history questionnaire (BDHQ). Energy-adjusted DII (E-DII™) score was calculated using 26 nutrients derived from the BDHQ. Data were analyzed with two-group comparisons, correlation analysis, and multivariable logistic regression analysis. RESULTS: One hundred and seventy-seven RA patients and 183 controls, for whom clinical and dietary survey data were available, were analyzed. RA patients had significantly higher E-DII (pro-inflammatory) score compared to controls both in 2011 and 2017 (p < 0.05). In RA patients, E-DII score was not a factor associated with significant change in disease activity. However, anti-inflammatory change in E-DII score was associated maintaining low disease activity (DAS28-ESR ≤ 3.2) or less for 6 years (OR 3.46, 95% CI 0.33-8.98, p = 0.011). CONCLUSIONS: The diets of RA patients had a higher inflammatory potential than controls. Although E-DII score was not a factor associated with significant disease activity change, anti-inflammatory change in E-DII score appeared to be associated with maintaining low disease activity in patients with RA. TRIAL REGISTRATION: UMIN Clinical Trials Registry, UMIN000003876 . Registered 7 Aug 2010-retrospectively registered.