Adipocytokines are associated with radiographic joint damage in rheumatoid arthritis

Objective

Obesity protects against radiographic joint damage in rheumatoid arthritis (RA) through poorly defined mechanisms. Adipocytokines are produced in adipose tissue and modulate inflammatory responses and radiographic joint damage in animal models. The purpose of this study was to examine the hypothesis that adipocytokines modulate inflammation and radiographic joint damage in patients with RA.

Methods

We compared serum concentrations of leptin, resistin, adiponectin, and visfatin in 167 RA patients and 91 control subjects. The independent association between adipocytokines and body mass index (BMI), measures of inflammation (C‐reactive protein [CRP], interleukin‐6 [IL‐6], and tumor necrosis factor α [TNFα]), and radiographic joint damage (Larsen score; n = 93 patients) was examined in RA patients by multivariable regression analysis first controlling for age, race, and sex, and then for obesity (BMI) and inflammation (TNFα, IL‐6, and CRP).

Results

Concentrations of all adipocytokines were significantly higher in RA patients than in controls; for visfatin and adiponectin, this association remained significant after adjusting for BMI, inflammation, or both. Visfatin concentrations were associated with higher Larsen scores, and this association remained significant after adjustment for age, race, sex, disease duration, BMI, and inflammation (odds ratio [OR] 2.38 [95% confidence interval (95% CI) 1.32–4.29], P = 0.004). Leptin concentrations showed a positive association with the BMI (ρ = 0.58, P < 0.01) and showed a negative association with the Larsen score after adjustment for inflammation (OR 0.32 [95% CI 0.17–0.61], P < 0.001), but not after adjustment for BMI (OR 0.86 [95% CI 0.42–1.73], P = 0.67).

Conclusion

Concentrations of adipocytokines are increased in patients with RA and may modulate radiographic joint damage. Visfatin is associated with increased, and leptin with reduced, levels of radiographic joint damage.

     

The effects of tobacco smoking and rheumatoid factor seropositivity on disease activity and joint damage in early rheumatoid arthritis

OBJECTIVE: To study the effect of tobacco smoking and rheumatoid factor (RF) isotypes on disease activity and joint damage in early rheumatoid arthritis (RA). METHODS: One hundred early RA patients were followed prospectively for 2 yr. They were evaluated at recruitment and at 6 and 24 months. Sociodemographic information included smoking history, and radiographs of hands and feet were obtained. RF was monitored by IgM- and IgA-specific RF enzyme-linked immunosorbent assay and by agglutination, and serial measurements were also obtained for C-reactive protein. The influence of tobacco smoking and RF positivity on disease outcome was evaluated using multivariate analysis. Covariates for the regression analysis included sex, age, coffee consumption and IgA-RF positivity. RESULTS: A gradient of increase in disease activity was observed from never smokers to former smokers to current smokers during the 2 yr of observation, defined by number of swollen joints (SJC), tender joints (TJC) and visual analogue scale for pain (P<0.001, P=0.02 and P=0.005, respectively), but smoking status did not influence radiological progression. Ever smokers were more often IgA RF positive (P<0.05). IgA RF-positive patients had more active disease (SJC P=0.002, TJC P=0.01) and showed more radiological progression (P<0.0001) compared with IgA RF-negative patients. Of the RF-positive patients 22% had elevated IgM RF without IgA RF and these patients showed similar disease activity and radiological joint progression to the RF-negative patients. None of these associations were explained by possible confounders. CONCLUSION: Tobacco smoking has an adverse effect on patients with early RA and this is possibly immunologically mediated. IgM RF does not predict poorer prognosis in RA unless it is associated with a concomitant elevation of IgA RF.     

Exercise can reverse quadriceps sensorimotor dysfunction that is associated with rheumatoid arthritis without exacerbating disease activity

OBJECTIVES: To compare quadriceps sensorimotor function, lower limb functional performance and disability in patients with rheumatoid arthritis (RA) and healthy subjects, and to investigate the efficacy and safety of a brief rehabilitation regime. METHODS: Quadriceps strength, voluntary activation, proprioceptive acuity and the aggregate time [aggregate functional performance time (AFPT)] taken to perform four common activities [aggregate functional performance time (AFPT)] were compared between 103 RA patients who had lower limb involvement and 25 healthy subjects. In addition, disability (Health Assessment Questionnaire), clinical disease activity and the plasma concentration of proinflammatory cytokines were measured in the RA patients. In a follow-on randomized controlled trial of rehabilitation, these variables were used as baseline data for 93 of the RA patients, who were randomized to a rehabilitation or a control group. Changes in the variables were analysed within and between groups. RESULTS: Compared with healthy subjects, RA patients had weaker quadriceps [mean difference 157 N; 95% confidence interval (CI) 125-189], poorer activation (8%, 95% CI 4.5-15) and proprioceptive acuity (0.8 degrees, 95% CI 0.4-1.3) and took longer to perform the AFPT (34 s, CI 23.5-44.8). Rehabilitation increased quadriceps strength (mean increase 61 N, 95% CI 28-95) and voluntary activation (8%, 95% CI 3-12.4) and decreased the AFPT (12.3 s, 95% CI -2 to 27.7) and subjective disability (0.21 HAQ points, 95% CI 0-0.35) without exacerbating disease activity. All the improvements were maintained at the 6-month follow-up. There was no change during the control period. CONCLUSIONS: Patients with RA that affected their lower limb had quadriceps sensorimotor deficits that were associated with lower limb disability. A clinically applicable rehabilitation regime increased quadriceps sensorimotor function and decreased lower limb disability without exacerbating pain or disease activity. For patients with well-controlled RA that causes lower limb involvement, the regime is effective and safe.     

Rheumatoid factor in rheumatoid arthritis associated renal disease and in lupus nephritis.

To test the hypothesis that rheumatoid factor (RF) protects against (immune complex mediated) renal disease, patients with rheumatoid arthritis (RA; 48 with nephropathy of various types, 35 without renal disease) and systemic lupus erythematosus (SLE; 35 with and 17 without nephritis) were evaluated for the presence and titre of RF. There was no correlation between RF and nephropathy in RA, whereas in SLE RFs were almost exclusively seen in patients without nephropathy. This result supports the above hypothesis for lupus nephropathy but not for RA associated renal disease, and it may be explained by a more pronounced role for immune complexes in SLE and interference of RFs with the complexes.     

Rheumatoid factor seropositivity is inversely associated with oral contraceptive use in women without rheumatoid arthritis

OBJECTIVES: To examine whether oral contraceptive use is associated with the presence of serum rheumatoid factor in women of reproductive age without rheumatoid arthritis. METHODS: 304 women selected from parents of children who were at increased risk of developing type 1 diabetes were studied, because they were enriched with the human leucocyte antigen-DR4 allele, a susceptibility marker for both type 1 diabetes and rheumatoid arthritis. Participants visited a clinic where blood was drawn for rheumatoid factor testing, and exposure data were collected via questionnaires. A medical history and joint examination were performed to rule out rheumatoid arthritis. Participants and examiners were unaware of the participants' rheumatoid factor status at the time of examination and questionnaire. RESULTS: Use of oral contraceptives at any time was inversely associated with rheumatoid factor positivity (adjusted odds ratio (OR) 0.2, 95% confidence interval (CI) 0.07 to 0.52) independent of age, education and smoking. Smoking > or = 20 pack-years was also associated with rheumatoid factor positivity (adjusted OR 56.38, 95% CI 4.31 to 736.98) compared with never smoking. Smoking 1-19 pack-years was not associated with a positive rheumatoid factor. CONCLUSIONS: Our results suggest that oral contraceptive use, and possibly cigarette smoking, act early in the development of the immune dysregulation that occurs in rheumatoid arthritis.     

Rheumatoid arthritis: a disease associated with accelerated atherogenesis

OBJECTIVES: Rheumatoid arthritis (RA) is a systemic inflammatory disease associated with an increased prevalence of coronary heart disease and a high cardiovascular (CV) mortality. In this article, a review of mechanisms implicated in the development of accelerated atherogenesis in RA was performed. The potential role of treatment to reduce the incidence of CV events in RA was also discussed. METHODS: Retrospective review of the literature. The potential mechanisms implicated in the development of accelerated atherogenesis in RA, information on carotid ultrasonography, and the potential implication of treatment to prevent accelerated atherogenesis in individuals with RA were examined. RESULTS: Endothelial dysfunction, which is an early step in the development of atherosclerosis, has been observed in patients with RA. Deleterious effects resulting from persistent chronic inflammation may lead to endothelial dysfunction, insulin resistance, and a dyslipidemic pattern in these patients. Other mechanisms different from those related to classic atherogenesis risk factors, such as hyperhomocysteinemia and increased oxidative stress, are considered to be implicated in the pathogenesis of atherosclerosis in RA. Increased carotid intima-media thickness and carotid plaques have been found in RA patients compared with matched controls. Active MTX treatment of the disease has been associated with decreased CV mortality. Additional drugs such as statins may be considered in the management of these patients. CONCLUSIONS: The increased prevalence of CV mortality rate in RA cannot only be explained by the presence of traditional atherosclerotic risk factors. A chronic inflammatory response may promote the development of accelerated atherogenesis in these patients. Active treatment of the disease is required to reduce the risk of developing CV complications in individuals with RA.     

How reliable is ESR as a measure of disease activity in rheumatoid arthritis treated with hydroxychloroquine?

Summary Forty-two patients with active rheumatoid arthritis treated with hydroxychloroquine sulphate (400 mg day^–1) for six months have been compared with patients treated with D-penicillamine (n=14), aurothiomalate (n=13), sulphasalazine (n=15) and chloroquine (n=17) to compare the changes in articular index, plasma viscosity and ERS. Results indicate that while articular index and plasma viscosity show significant improvement for all treatments, the ESR fails to improve during hydroxychloroquine therapy.     

Inflammation and damage in an individual joint predict further damage in that joint in patients with early rheumatoid arthritis

OBJECTIVE; Several factors predict joint damage in early rheumatoid arthritis (RA). In the context of a trial in early RA, we studied the relationship between clinical signs in individual joints and their propensity to develop progressive damage. METHODS: The COBRA (Combinatietherapie Bij Reumatoide Artritis) multicenter trial compared the efficacy of prednisolone, methotrexate, and sulfasalazine against sulfasalazine alone in 155 patients with early RA. Two blinded observers interpreted radiographs in sequence (using the Sharp/Van der Heijde scoring system); in each center, one blinded observer performed clinical assessments every 3 months. The current analysis is based on clinical and radiologic data of the individual metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of 135 patients. Conditional stepwise logistic regression analyzed the relationship between damage (progression) and clinical signs at baseline and followup for each of these joints individually in each patient. RESULTS: Combination therapy strongly retarded the progression of damage. Progression was stronger in patients with rheumatoid factor, HLA-DR4, and high levels of disease activity at baseline. At baseline, 6% of the MCP and PIP joints showed damage; after 1 year, disease had progressed in 10% of these joints. Baseline damage, swelling, or pain in a joint independently and strongly predicted the progression of damage in that joint (P < 0.001). Each additional point in the swelling score (range 0-2) tripled the risk for subsequent progression. Each additional point on the Sharp scale (range 0-8 per joint) and each additional point on the pain scale (range 0-3) doubled the risk. The mean pain and swelling scores over the year were even stronger predictors of damage. CONCLUSION: Local expression of early RA disease activity, both at baseline and at 1-year followup, is strongly related to progression of damage in the individual joint.     

Patient self-administered joint tenderness counts in rheumatoid arthritis are reliable and responsive to changes in disease activity

OBJECTIVE: To examine whether self-assessment of tender and swollen joints by patients with rheumatoid arthritis (RA) can be used to evaluate changes in disease activity instead of joint counts by physicians. METHODS: Eighty-two patients with RA taking part in controlled studies were recruited for investigation. The patient's self-assessment of joint tenderness and swelling was completed both before and 30 minutes after examination by a physician. Examinations of tender and swollen joints by a rheumatologist were performed at baseline and 3 months later. The correlations and verification of agreement of these clinical assessments were analyzed. RESULTS: Within-patient and patient-physician correlations for joint tenderness counts were high (r = 0.96 and 0.78, respectively). Patient-physician correlation for joint swelling counts was still significant, although much lower (r = 0.34). Patients' and physicians' estimations of the change in disease activity over 3 months did not differ (p > 0.76 for all comparisons). CONCLUSION: Joint tenderness counts were consistent when comparing intra-patient and patient-physician assessments, while joint swelling counts were poorly correlated. Patient and physician assessments of change over 3 months were parallel and similar for joint tenderness count. Self-administered tender joint counts might be a useful tool to evaluate the response to therapy in RA.     

Vitamin K2 administration is associated with decreased disease activity in patients with rheumatoid arthritis

Objectives

Vitamin K2 (VitK2) is reported to induce not only bone mineralization of human osteoblasts and apoptosis of osteoclasts, but also apoptosis of rheumatoid arthritis (RA) synovial cells, while its clinical effect on disease activity of RA remains unknown.

Methods

158 female RA patients (mean age 62.5 years) who had not been treated with warfarin, biologics, or teriparatide were enrolled in this study. VitK2 (45 mg/day) was administered in 70 patients with a serum undercarboxylated osteocalcin level of >4.5 ng/ml or with decreased bone mineral density in spite of the treatment with other anti-osteoporosis medications, regardless of RA disease activity. A longitudinal study was conducted in 52 patients who were additionally treated with VitK2 without changing their other medications for three months.

Results

In the cross-sectional study, as compared to the VitK2-naïve group (n = 88), the VitK2-treated group (n = 70) showed lower serum CRP (1.7 ± 0.2 vs. 0.5 ± 0.1 mg/dl; P < 0.001), MMP-3 (220.4 ± 21.9 vs. 118.0 ± 14.4 ng/ml; P < 0.001), and DAS28-CRP (2.9 ± 0.1 vs. 2.4 ± 0.1; P < 0.05). In the longitudinal study, patients who were additionally treated with VitK2 showed significant decreases in serum CRP (1.1 ± 0.2 to 0.6 ± 0.2 mg/dl; P < 0.001), MMP-3 (160.1 ± 25.6 to 125.0 ± 17.8 ng/ml; P < 0.05), and DAS28-CRP (3.1 ± 0.2 to 2.4 ± 0.1; P < 0.001).

Conclusions

VitK2 may have the potential to improve disease activity besides osteoporosis in RA.     

IgA rheumatoid factor is associated with bone mineral density preservation in rheumatoid arthritis

Clinical Rheumatology - Autoantibodies such as IgM rheumatoid factor (RF) and anti-citrullinated proteins/peptides antibodies (ACPA) have previously been incriminated in systemic bone loss in...     

Ex vivo interleukin 1 receptor antagonist production on lipopolysaccharide stimulation is associated with rheumatoid arthritis and with joint damage

OBJECTIVES: (1) To assess innate ex vivo production of interleukin 1beta (IL1beta) and interleukin 1 receptor antagonist (IL1Ra) in patients with recent-onset rheumatoid arthritis (RA) as compared with healthy controls; (2) to assess the association of ex vivo IL1beta and IL1Ra production with progression of joint damage in RA; (3) to determine whether differences in ex vivo IL1beta production are explained by distribution of the IL1beta single nucleotide polymorphism C-511T. METHODS: Levels of IL1beta and IL1Ra (measured by ELISA after whole-blood stimulation with lipopolysaccharide) and distribution of IL1beta C-511T were compared in 76 patients with recent-onset RA who had received no disease-modifying antirheumatic drugs (DMARDs), and 63 healthy controls. ORs for RA based on ex vivo IL1beta and IL1Ra production were calculated. Association of ex vivo IL1beta and IL1Ra production with progression of joint damage (Sharp-van der Heijde score over 2 years) was determined by linear regression with correction for baseline characteristics. RESULTS: Patients with recent-onset RA showed lower ex vivo IL1beta and higher ex vivo IL1Ra production than healthy controls (p<0.001), with ORs for RA of 2.4 (95% CI 1.2 to 4.9) for low IL1beta-producers and 7.6 (95% CI 3.2 to 18.0) for high IL1Ra-producers. High ex vivo IL1Ra production was associated with progression of joint damage (p = 0.01). The IL1beta C-511T genotype distribution was not significantly different between patients and controls. CONCLUSIONS: Patients with recent-onset RA had decreased ex vivo IL1beta production and increased ex vivo IL1Ra production compared with controls. Ex vivo IL1Ra production is an independent predictor of progression of joint damage in recent-onset RA.     

Complement activation by 19S IgM rheumatoid factor: relationship to disease activity in rheumatoid arthritis

19S IgM rheumatoid factor (RF) in rheumatoid arthritis (RA) are polyclonal autoantibodies directed against the Fc piece of IgG. Rheumatoid patients with RF tend to have aggressive synovitis, nodules, and extraarticular manifestations. Although RF titer does not correlate with disease activity, RF activates complement (C) by the classical pathway. Thus, we postulated that selective stimulation of cell clones producing efficient C activating RF molecules might be associated with disease flares, independent of changes in serum RF concentration. To address the question, 42 patients with RA were evaluated prospectively. Serum RF concentration was measured by radioimmunoassay (RIA) and C activating activity by hemolytic assay. We then calculated the mean hemolysis (MH) of sensitized sheep erythrocytes (SRC) produced/ml of RF serum (MH/ml) and MH/microgram of RF as an expression of RF C activating properties (CAP). The following observations were made: RF CAP varied among the patients studied; RF CAP varied over time in individual patients; RF CAP differences varied in both groups independently from RF concentration; RF CAP correlated with both systemic and articular disease activity; and total RF concentration correlated with articular findings and nodules but less well with systemic disease activity.