Serum and in vitro production of IL-1 receptor antagonist correlate with C-reactive protein levels in newly diagnosed, untreated lupus patients

OBJECTIVE: To examine the correlation between C-reactive protein (CRP) and CRP-inducing cytokines (IL-1 beta, IL-6, TNF-alpha) and IL-1 receptor antagonist (IL-1ra), as well as to study their relationship with systemic lupus erythematosus disease activity (SLEDAI) in newly diagnosed, untreated lupus patients. METHODS: Sera from newly diagnosed untreated lupus and rheumatoid arthritis (RA) patients were examined for CRP and cytokines. Data were compared among patient groups and correlated individually among the lupus group. Lupus monocytes and neutrophils were cultured in vitro to produce IL-1ra and experimental results were related to CRP levels and SLEDAI. RESULTS: Within lupus, serum CRP, IL-6, IL-1 beta and TNF-alpha levels were significantly lower than those of RA (all p values were < 0.005) and generally higher than those in the controls (p = 0.002, < 0.001, > 0.2, and < 0.001, respectively). Except IL-1ra, which was correlated with CRP (p = 0.045), no substantial correlation was discovered between CRP and IL-6, IL-1 beta or TNF-alpha individually. Moreover, excluding IL-1ra (p = 0.024), there was no association between cytokines and SLEDAI. In vitro IL-1ra as secreted by monocytes correlated with serum CRP and SLEDAI. CONCLUSION: In lupus patients, serum IL-1 beta, IL-6 or TNF-alpha levels failed to correlate with low CRP levels. This indicates a complicated CRP production process, which can not be explained solely by single cytokines as reported previously. Both serum and in vitro produced IL-1ra may be applied clinically as a surrogate CRP marker in untreated lupus patients as they are both correlated with serum CRP.     

Pituitary function in patients with newly diagnosed untreated systemic lupus erythematosus

OBJECTIVES: To determine whether hormonal dysfunction involving the hypothalamic-pituitary-adrenal (HPA) axis, prolactin (PRL) secretion, and sex hormone status contribute to development of systemic lupus erythematosus (SLE). METHODS: 11 patients with SLE and 9 healthy controls were tested for their total anterior pituitary gland reserve by simultaneous injection of corticotropin-, growth hormone- (GH), thyrotropin-, and gonadotropin-releasing hormone (GnRH). Serum concentrations of adrenocorticotropin (ACTH), cortisol, GH, thyroid stimulating hormone (TSH), PRL, luteinising hormone (LH), and follicle stimulating hormone (FSH) were measured at baseline and after injection. Baseline values of oestradiol, testosterone, and thyroxine were determined. RESULTS: Basal and stimulated serum concentrations of ACTH, cortisol, GH, and PRL were similar in both groups. In contrast, despite similar basal thyroxine levels the TSH response to TRH was significantly higher in patients than in controls. LH and FSH levels in premenopausal female patients of both groups were identical. In contrast, two of the three male patients were hypogonadal without compensatory increases of basal LH and FSH levels, but they retained excessive stimulatory capacity in response to GnRH. CONCLUSION: No significant alteration of the HPA axis was found in patients with SLE, which is inadequate in view of the continuing inflammation. GH and PRL secretion were normal. The pituitary-thyroid and pituitary-gonadal axes were affected in patients with newly diagnosed, untreated SLE.     

C-reactive protein levels in patients with rheumatoid arthritis: the impact of therapy

Summary C-reactive protein levels were measured in sera of 111 patients with rheumatoid arthritis and were compared with erythrocyte sedimentation rate. The patients were divided into six groups according to drug therapy. Comparison between the groups suggests that CRP correlates best with ESR in patients treated with penicillamine and in patients in clinical remission. Patients treated with gold, NSAID or methotrexate have a weaker correlation between the two parameters, while steroid therapy yields the poorest correlation which is not statistically significant. Our data suggest that although CRP is a sensitive index of disease activity, the specific drug taken by the patient must be considered before interpreting the results.     

Relationship between time-integrated C-reactive protein levels and radiologic progression in patients with rheumatoid arthritis

OBJECTIVE: An elevated acute-phase response is associated with increased radiologic damage in rheumatoid arthritis (RA), but development of damage in previously normal joints ("new joint involvement") has not previously been investigated. This study was undertaken to investigate the hypothesis that when there is suppression of disease activity as judged by the C-reactive protein level, new joint involvement is reduced to a greater extent than is progression in already damaged joints ("damaged joint progression"). METHODS: Three hundred fifty-nine patients with active RA were studied as part of a 5-year randomized, prospective, open-label study of disease-modifying antirheumatic drug therapy. Time-averaged CRP was calculated from samples obtained every 6 months, and patients were divided into groups with CRP values of <6, 6-<12, 12-<25, and > or =25 mg/liter. Radiographs of the hands and feet were scored by the Larsen method; a damaged joint was defined as one with a score of > or =2. RESULTS: The rank correlation between time-integrated CRP and increase in Larsen score was 0.50; the correlation increased to 0.59 for patients entering the study with disease duration of < or =2 years. The percentage of new joint involvement over 5 years varied markedly with time-integrated CRP, from 7.3% in the CRP <6 mg/liter group to 39.1% in the CRP > or =25 mg/liter group (5.4-fold increase). The percentage of damaged joint progression increased from 26.1% in the CRP <6 mg/liter group to 41.6% in the CRP > or =25 mg/liter group (1.6-fold increase). CONCLUSION: The results of this study provide further confirmation that high CRP levels over time are associated with greater radiologic progression. Although radiologic progression still occurred in both previously normal and damaged joints despite the presence of normal CRP levels, this consisted of proportionately less new joint involvement compared with damaged joint progression. These findings support the idea that disease-suppressive therapy should be instituted at an early stage in patients with RA, before erosive damage has occurred.     

Relationship between time-integrated C-reactive protein levels and radiologic progression in patients with rheumatoid arthritis

Conclusions: The results of this 5-year prospective study on the correlation of time-integrated CRP levels with radiographic progression provide further evidence that high CRP levels over time are associated with greater radiographic progression. There was less new joint involvement compared to damaged joint progression. Radiologic progression occurred in previously normal and damaged joints even with normal CRP levels. These data are consistent with those of other studies supporting early institution of therapies that can normalize CRP levels to prevent erosive damage.     

Prevalence of peripheral neuropathy in patients with newly diagnosed rheumatoid arthritis

ObjectiveTo look for the frequency and pattern of neuropathy in Indian patients with rheumatoid arthritis (RA).Patients and MethodsOne hundred newly diagnosed patients with RA (ACR 1987 revised criteria) visiting our hospital, over a period of 3 years were screened. Diabetics, outstation patients, chronic alcoholics, those with any known cause for peripheral neuropathy and patients having an overlap with the other rheumatological illness were excluded. Clinical assessment included detailed history and examination with special reference to extra-articular features and neuropathy with relevant clinical parameters like tender joint count, swollen joint count, etc. Routine laboratory investigations and autoantibodies (RF, ANA, anti-CCP) were obtained on all patients. All the patients with or without clinical manifestations of neuropathy underwent nerve conduction studies. Autonomic function studies were performed in selected patients.ResultsSubjects included 66 patients (M 13:F 53) with mean age of 42 (±13.42) years and median disease duration of 36 months (IQR-13.5, 60). Sensory symptoms were present in 9 patients (13.6%). None had motor symptoms. On neurological examination, 16 patients had sensory (24.2%) and 6 (9.09%) had motor abnormalities. Nerve conduction studies showed abnormality in 25 patients (37.87%). Evidence of entrapment neuropathy was found in 6 patients (9.09%; 5 patients with median nerve involvement [unilateral, 3 and bilateral, 2] and 1 patient with unilateral ulnar nerve involvement), 3 patients had only sensory neuropathy, 5 had mixed sensory motor and 3 had only motor neuropathy. Eight patients (12.12%) had only small fibre neuropathy as detected by sympathetic skin response and quantitative sensory testing.ConclusionThis study shows high prevalence of subclinical neuropathy in Indian patients with RA. This may be an important contributor to disability.     

Shoulder joint involvement in patients with newly diagnosed rheumatoid arthritis. Prevalence and associations

OBJECTIVE: To estimate the prevalence of reduced function, compared to normative values, and tenderness in the shoulder in patients with newly diagnosed rheumatoid arthritis (RA), and to investigate associated factors. METHODS: Eighty consecutive patients with RA, participating in a prospective study of early rheumatoid arthritis, were examined and assessed within one year of the onset of symptoms. RESULTS: The prevalence of tenderness from any of the shoulder joints was 50%, while 30% had decreased shoulder function, compared with age matched controls, in at least one shoulder. Both tender shoulder joints and decreased shoulder function were related to higher age and more severe disease, reflected by disability (HAQ) and the patient's assessment of pain and global disease activity. CONCLUSION: The shoulder girdle is involved early and often in rheumatoid arthritis and involvement is associated with a substantially more severe disease status. The study suggests that the shoulder should be given attention in patients with newly diagnosed rheumatoid arthritis, and that both tenderness and shoulder function should be evaluated.     

Early treatment reduces the cardiovascular risk factors in newly diagnosed rheumatoid arthritis patients

OBJECTIVE: To investigate subclinical atherosclerosis and the effect of treatment in patients with early rheumatoid arthritis (RA). PATIENTS AND METHODS: Forty patients with early RA who met the revised American College of Rheumatology (ACR) criteria and disease duration of <1 year were included in the study. Smokers and patients with classical risk factors for atherosclerosis were excluded. The serum levels of total cholesterol (TC), triglycerides, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol were determined in all patients before and after 1 year of therapy. Carotid artery intima-media thickness (IMT) and carotid plaque were measured before and after treatment. RA disease activity was measured using the 28 joint indices score (DAS-28) and clinical improvement was determined by the ACR response criteria. Forty-five age- and sex-matched nonsmoking volunteers were used as controls. All patients were treated with methotrexate and prednisone. RESULTS: RA patients had a baseline mild dyslipidemia characterized by a decrease in serum HDL-C levels and a high TC/HDL-C atherogenic ratio compared with controls. Both lipid parameters were significantly improved after treatment (P<0.01). Common carotid artery IMTs at baseline were higher in RA patients compared with controls (P<0.05). After 1 year of therapy there was a significant decrease in the IMTs (P<0.001). Thirty-five patients (88%) achieved the ACR 20%, while 30 (75%) reached the ACR 50% response criteria. A significant decrease of DAS-28 was observed after treatment (P<0.03). CONCLUSIONS: The atherogenic lipid profile and subclinical atherosclerosis are features of early RA, which improved after therapy. Early intervention and control of the disease activity may reduce the risk of atherosclerosis and cardiovascular events in patients with RA.     

Serum amyloid A and C-reactive protein levels may predict microalbuminuria and macroalbuminuria in newly diagnosed type 1 diabetic patients

BackgroundIn this study we evaluated the association of baseline levels of six different candidate proteins for the development of microalbuminuria and macroalbuminuria in type 1 diabetic patients, who were followed for approximately 30 years. Two of the proteins are markers of inflammation: serum amyloid A (SAA) and C-reactive protein (CRP), three are involved in lipid metabolism: apolipoprotein A1, apolipoprotein E and adiponectin and the last protein, fibronectin, is related to structural changes.MethodsA nested case control study population of 60 patients from an inception cohort of type 1 diabetic patients where 20 developed microalbuminuria followed by macroalbuminuria and 40 stayed normoalbuminuric during approximately 30 years of follow-up time was used to evaluate baseline levels of the six candidate biomarkers. The proteins were quantified by multiplexed immunoassays.ResultsLog SAA levels were borderline predictor of microalbuminuria, HR 2.31 (1–5.4) p = 0.053 in a univariate Cox regression model and predicted the development of macroalbuminuria HR 2.432 (1–6) p = 0.049, also univariate. When adjusting for covariates, log SAA predicted the development of microalbuminuria with an HR 4.131 (1.1–15) p = 0.03. Log CRP predicted the development of microalbuminuria, HR 2.928 (1.4–6.1) p = 0.004, and macroalbuminuria, HR 2.785 (1.3–5.8) p = 0.007 in univariate models. When adjusting for covariates, log CRP predicted the development of microalbuminuria with an HR 5.882 (1.7–20.9) p = 0.006 and macroalbuminuria with an HR 3.233 (1.1–9.8) p = 0.038. Apolipoprotein A1, apolipoprotein E, fibronectin and adiponectin were not associated with development of elevated albumin excretion rate.ConclusionsSAA and CRP baseline levels predicted development of micro- and macroalbuminuria during 30 years of follow up, supporting the theory that inflammation is involved in the progression of diabetic nephropathy. Further studies are needed to fully establish the two proteins’ potential as additional biomarkers for the development of diabetic nephropathy.     

Localization of C-reactive protein in synovium of patients with rheumatoid arthritis

Synovial biopsies from 8 patients with rheumatoid arthritis, 2 patients with degenerative osteoarthritis, and 4 patients with nonarthritic disease were studied for localization of C-reactive protein (CRP) using immuno-fluorescence microscopy. The nuclei of many synoviocytes and histiocytes in rheumatoid synovial membrane were found to bind CRP. Cultures of rheumatoid synovium in ¹⁴C-labeled amino acids produced radioactive IgG, IgM, IgA, and C3, but not CRP, indicating the synovial-bound CRP was not of local origin. A few CRP-binding nuclei were present in one osteoarthritic synovium, but none was found in the other and none in synovium from the 4 non-arthritic patients. The nature of the nuclear CRP ligand in rheumatoid synovium was not determined.     

Relationship between urinary sialylated saccharides, serum amyloid A protein, and C-reactive protein in rheumatoid arthritis and systemic lupus erythematosus.

The urinary excretion of sialic-acid-containing oligosaccharides, total sialic acid, serum amyloid A protein (SAA), and C-reactive protein (CRP) has been studied in 48 patients with rheumatoid arthritis (RA) and in 17 patients with systemic lupus erythematosus (SLE). Linear regression analysis revealed a close positive correlation between serum SAA and CRP levels in both RA (r = 0.71, p less than 0.001) and SLE (r = 0.86, p less than 0.001). The urinary excretion of sialyl lactose showed a positive correlation with the serum levels of SAA and CRP in RA (r = 0.45 and r = 0.45, respectively, p less than 0.01) but not in SLE (r = 0.05 and r = 0.10 respectively). Changes in serum total sialic acid levels paralleled those in CRP and SAA in RA as well as in SLE. Patients with very active RA had higher urinary sialyl oligosaccharide excretion (p less than 0.001), higher CRP levels (p less than 0.01), and higher SAA levels ( p less than 0.05) than those with moderately active disease.     

Monitoring C-reactive protein levels to predict favourable clinical outcomes from tocilizumab treatment in patients with rheumatoid arthritis

Objectives

The inflammatory cytokine interleukin-6 (IL-6) directly stimulates C-reactive protein (CRP) expression. The present study aimed to examine how clinical treatment outcomes of rheumatoid arthritis (RA) with tocilizumab (TCZ), a humanised monoclonal anti-IL-6 receptor antibody, are related to CRP levels monitored for 52 weeks.

Methods

One hundred and twenty-two RA patients who underwent TCZ treatment between May 2008 and September 2009 were registered in the Tsurumai Biologics Communication Registry. Data were collected at initiation of treatment (baseline) and over 52 weeks for Disease Activity Score 28-ESR (DAS28-ESR), Boolean core measurements, serum CRP levels and matrix metalloproteinase-3 levels. To compare clinical results, patients were divided into three groups based on treatment time required to achieve normal CRP levels.

Results

Multivariate analysis using the Cox proportional-hazards regression model found that higher CRP levels at baseline was a significant and independent factor in predicting normal CRP levels over 52 weeks (hazard ratio 0.86 per 1 mg/dL). In contrast, disease duration, concomitant methotrexate use and previous tumour necrosis factor inhibitor failure were not significant factors. Patients with normal CRP levels at 12 weeks of TCZ treatment achieved better clinical outcomes, including remission based on DAS28-ESR criteria, compared to patients with elevated CRP levels at 12 weeks.

Conclusions

Adequate suppression of pathological IL-6 signalling during TCZ treatment improves clinical outcomes and can be monitored with serum CRP levels, a readily available biomarker in clinical practice.     

C-reactive protein and coronary artery calcium in asymptomatic women with systemic lupus erythematosus or rheumatoid arthritis

Patients with systemic lupus erythematosus (SLE) and those with rheumatoid arthritis (RA) have increased risk for atherosclerotic cardiovascular disease. The aims of this study were to compare the presence of coronary artery calcium (CAC) in age- and race-matched women with SLE, those with RA, and healthy controls without diabetes mellitus or history of myocardial infarction, angina pectoris, or stroke and to investigate its relation with traditional risk factors, inflammation, and endothelial activation. Study subjects completed cardiovascular risk factor assessment and electron-beam computed tomography that measured CAC. The 2 patient groups had similar prevalence and extent of CAC as well as significantly increased odds of having any CAC (odds ratio 1.87, 95% confidence interval 1.09 to 3.21) and more extensive CAC (odds ratio 4.04, 95% confidence interval 1.42 to 11.56 for CAC score >100) compared with healthy controls. After controlling for differences in cardiovascular risk factors, including insulin resistance and hypertension, the results remained statistically significant. After adjustment for differences in levels of C-reactive protein and/or soluble intercellular adhesion molecule-1, however, women with chronic inflammatory diseases no longer had significantly increased odds of having any CAC or more extensive CAC compared with controls. In conclusion, asymptomatic and nondiabetic women with chronic inflammatory diseases had significantly increased odds of having CAC and more extensive CAC compared with age- and race-matched healthy controls. The increased odds for CAC may in part result from higher levels of inflammation and endothelial activation in these patients.     

Does C-reactive protein modulate T-lymphocyte function in methotrexate-treated rheumatoid arthritis patients?

Thirty-four patients with rheumatoid arthritis were treated with oral methotrexate for 6 months. Methotrexate was given as a single weekly dose of 7.5-10 mg. A correlation between serum concentration of CRP and proportion of CD8+ lymphocytes in peripheral blood was found in this group of patients. This correlation can be described by a linear regression equation. According to the results obtained, CRP suppresses lymphocyte function in patients with RA. This is the consequence of the stimulating effect on suppressor mechanisms.     

C-reactive protein and implications in rheumatoid arthritis and associated comorbidities

C-reactive protein (CRP) is routinely assessed as a marker of systemic inflammation in rheumatoid arthritis (RA). However, it is also an immune regulator that plays an important role in inflammatory pathways associated with RA and promotes atherogenic effects. Comorbidities linked to systemic inflammation are common in RA, and CRP has been associated with the risk for cardiovascular disease, diabetes, metabolic syndrome, pulmonary diseases, and depression. The relationship between systemic inflammation, CRP, and comorbidities in RA is complex, and it is challenging to determine how changing CRP levels may affect the risk or progression of these comorbidities. We review the biological role of CRP in RA and its implications for disease activity and treatment response. We also discuss the impact of treatment on CRP levels and whether reducing systemic inflammation and inhibiting CRP-mediated inflammatory pathways may have an impact on conditions commonly comorbid with RA.