Serum Interleukin 6 Before and After Therapy with Tocilizumab Is a Principal Biomarker in Patients with Rheumatoid Arthritis

Objective.Biologic treatments including the humanized anti-interleukin 6 (anti-IL-6) receptor antibody tocilizumab (TCZ) provide therapeutic options for patients with rheumatoid arthritis (RA). We investigated useful biomarkers to predict the responsiveness to TCZ by measurement of serum proinflammatory cytokine concentrations.Methods.Serum samples were collected from 61 patients with RA before biologic treatment and at 4 weeks after initial administration of either TCZ (n = 32) or infliximab (IFX; n = 29) and from 13 healthy serum donor controls. Disease Activity Score of 28 joints (DAS28) was determined at baseline and after treatment.Results.Although IL-1β, IL-2, IL-6, IL-17A, IL-17F, interferon-α, and tumor necrosis factor-α (TNF-α) were all increased in sera from patients with RA compared with controls, only the IL-6 level was significantly correlated with DAS28 before treatment. The IL-6 level before treatment was positively correlated with DAS28 after TCZ treatment, and was significantly lower in TCZ-responsive patients (as judged by a post-treatment DAS28 < 3.2) than in TCZ-resistant patients (post-treatment DAS28 ≥ 3.2). DAS28 after TCZ was significantly lower than after administration of IFX in patients with low pretreatment IL-6 (< 51.5 pg/ml, the mean baseline value of IL-6 in all RA patients), but not in those with high pretreatment IL-6. These results indicate that low serum IL-6 is associated with a favorable response to TCZ.Conclusion.Although both TNF-α and IL-6 are major targets of therapeutic intervention in RA, baseline serum IL-6 but not baseline TNF-α level is a potential biomarker reflecting disease activity. Measurement of serum IL-6 in RA before treatment may be useful to estimate residual disease activity after TCZ treatment and to predict responsiveness to TCZ treatment.

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Infliximab Treatment Increases Left Ventricular Ejection Fraction in Patients with Rheumatoid Arthritis: Assessment of Heart Function by Echocardiography, Endothelin 1, Interleukin 6, and NT-pro Brain Natriuretic Peptide

The Journal of Rheumatology ◽

10.3899/jrheum.110751 ◽

2012 ◽

Vol 39 (4) ◽

pp. 701-706 ◽

Cited By ~ 35

Author(s):

PRZEMYSLAW J. KOTYLA ◽

ALEKSANDER OWCZAREK ◽

JAROSLAW RAKOCZY ◽

MACIEJ LEWICKI ◽

EUGENE J. KUCHARZ ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Left Ventricular Ejection Fraction ◽

Ejection Fraction ◽

Brain Natriuretic Peptide ◽

Disease Activity ◽

Interleukin 6 ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Ventricular Ejection Fraction ◽

Tnf Α

Objective.To study the influence of anti-tumor necrosis factor-α (TNF-α) treatment on echocardiographic measures and concentrations of endothelin 1 (ET-1), interleukin 6 (IL-6), and amino-terminal fragment of pro-brain natriuretic peptide (NT-proBNP) in a cohort of 23 female patients with rheumatoid arthritis (RA).Methods.We recruited 23 patients (mean age 51.3 ± 1.55 yrs) with RA resistant to treatment with disease-modifying antirheumatic drugs and average disease duration of 7.1 ± 1.0 years who had been selected to start treatment with the anti-TNF-α antagonist infliximab. Transthoracic echocardiographic examinations were performed before the first infusion and repeated after 1 year of treatment. Data for age, sex, RA disease activity by Disease Activity Score (DAS28) and echocardiographic data, NT-proBNP, IL-6, ET-1, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and other routine laboratory data were collected before treatment and after 1 year.Results.Twelve months of treatment with infliximab resulted in reduction of RA activity (i.e., reduction of DAS and acute-phase reactants). There was increased left ventricle ejection fraction, from 58.5% before treatment to 63% after. Treatment with infliximab also resulted in significant reduction of ET-1 (1.26 fmol/ml before treatment vs 0.43 fmol/ml after), IL-6 (58.46 pg/ml vs 3.46 pg/ml), and NT-proBNP (43.06 fmol/ml vs 14.78 fmol/ml). These reductions were observed after just 4 months of treatment and remained significant until the termination of the study.Conclusion.In patients with RA, treatment with infliximab contributed significantly to increase in left ventricular ejection fraction. Improvement of cardiac function was shown by conventional echocardiography; there was reduction of biochemical markers of heart failure.

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Evaluating the efficacy of intra-articular injections of platelet rich plasma (PRP) in rheumatoid arthritis patients and its impact on inflammatory cytokines, disease activity and quality of life.

Current Rheumatology Reviews ◽

10.2174/1573397116666201113090629 ◽

2020 ◽

Vol 16 ◽

Author(s):

Dalia S. Saif ◽

Nagwa N. Hegazy ◽

Enas S. Zahran

Keyword(s):

Quality Of Life ◽

Rheumatoid Arthritis ◽

Disease Activity ◽

Inflammatory Cytokines ◽

Platelet Rich Plasma ◽

Joint Inflammation ◽

Monthly Interval ◽

Post Injection ◽

Tnf Α

Background: Among rheumatoid arthritis patients (RA), general disease activity is well regulated by diseasemodifying anti-rheumatic medications (DMARDS), but sometimes local inflammation still persists among a few joints. Adjuvant modern molecular interventions as Platelet Rich Plasma (PRP) with a suggested down regulating effect on inflammatory mediators has a proven effect in management of RA. We aim to evaluate the therapeutic effect of intra-articular PRP versus steroid in RA patients and their impact on inflammatory cytokines IL1B , TNF α, local joint inflammation, disease activity and quality of life (QL). Methods: Open labeled parallel randomized control clinical trial was carried out on 60 RA patients randomly divided into 2 groups, Group 1: included 30 patients received 3 intra-articular injections of PRP at monthly interval, Group 2: included 30 patients received single intra-articular injection of steroid. They were subjected to clinical, laboratory, serum IL1B and TNF α assessment at baseline and at 3, 6 months post injection. Results: Patients of both groups showed improvements in their scores of evaluating tools at 3months post injection and this improvement was persistent in the PRP group up to 6 months post injection while it was continued only for 3 months in the steroid group. Conclusions: PRP is a safe, effective and useful therapy in treating RA patients who had insufficient response and persistent pain and inflammation in just one or two joints through its down regulating effect on inflammatory cytokines IL1B, TNF α with subsequent improvement of local joint inflammation, disease activity and QL.

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Serum IL-35 is decreased in overweight patients with rheumatoid arthritis: its correlation with Th1/Th2/Th17-related cytokines

BMC Immunology ◽

10.1186/s12865-021-00431-x ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Yuxuan Li ◽

Yang Jie ◽

Xiaofei Wang ◽

Jing Lu

Keyword(s):

Rheumatoid Arthritis ◽

Medical Records ◽

Clinical Information ◽

Serum Cytokines ◽

Healthy Donors ◽

Potential Biomarker ◽

Tnf Α ◽

Ifn Γ ◽

Quantitative Changes ◽

Anti Inflammatory Cytokine

Abstract Background Obesity is correlated with worse drug responses and high disease activity in patients with rheumatoid arthritis (RA). Interleukin (IL)-35 is a novel anti-inflammatory cytokine that mainly produced by regulatory T (Treg). This study was performed to analyze whether IL-35 was correlated with obesity in RA and investigate the correlation between other Th1/Th2/Th17-related cytokines and obesity in RA. Results The serum IL-35 level was analyzed in RA (n = 81) and healthy donors (n = 53) by ELISA assay, and was compared between three groups (body mass index (BMI) < 18.5,≥18.5 to 25, > 25). Serum cytokines including IL-2, IL-4, IL-10, IL-17, INF-γ, TNF-α levels were measured using Flowcytometry assay. Clinical information was extracted from medical records. Serum IL-35 level in overweight patients were significantly decreased than those in lean patients. Furthermore, Th1/Th2/Th17-related cytokines from overweight patients with RA showed the characteristic immunological features. Serum IL-6, IL-17 and TNF-α levels were positively correlated with BMI. However, serum IL-2, IL-4, IL-10 and IFN-γ concentrations were not correlated with BMI. Conclusions Quantitative changes in serum IL-35 level were characteristic in overweight patients with RA. These findings indicate that IL-35 plays an important role in the development of RA and may prove to be a potential biomarker of active RA.

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SAT0111 THE RELATIONSHIP BETWEEN THE ADMINISTRATION OF IL-6 INHIBITORS AND INSULIN RESISTANCE IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.6509 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 989.3-989

Author(s):

A. Jitaru ◽

C. Pomirleanu ◽

M. M. Leon-Constantin ◽

F. Mitu ◽

C. Ancuta

Keyword(s):

Rheumatoid Arthritis ◽

Insulin Resistance ◽

Insulin Sensitivity ◽

Beneficial Effect ◽

Disease Activity ◽

Interleukin 6 ◽

Normal Weight ◽

Diabetic Patients ◽

Model Assessment ◽

Inflammatory Status

Background:Rheumatoid arthritis (RA) is associated with an increased cardiovascular (CV) risk, due not only to the traditional risk factors (hypertension, insulin resistance/diabetes, obesity, smoking), but to the inflammatory status as well. The blockade of interleukin-6 (IL-6) can regulate the glucose metabolism, reducing the glucose level and insulin resistance (IR). This beneficial effect is seen more in patients with normal values of body mass index (BMI), compared to the obese population.Objectives:Given the mentioned existing data, we aim to demonstrate the positive effect of IL-6 inhibitors in active RA patients with normal or increased BMI.Methods:We recruited 56 consecutive patients with definite and active RA, non-responders/partial responders to conventional synthetic Drug Modifying Anti-Rheumatic Drugs (csDMARDs)/biological therapy. For a period of 52 weeks, patients received subcutaneous Tocilizumab (TCZ) in a dose of 162mg once a week, according to European League Anti Rheumatism (EULAR) recommendation and National Protocol. We assessed demographics, RA-related parameters (clinical, inflammatory and immune) and metabolic markers, as well as the peripheral response to insulin, quantified by Homeostasis Model Assessment for insulin resistance (HOMA-IR) and the Quantitative Insulin Sensitivity Check Index (QUICKI). We did not include in the study the patients known with diabetes mellitus (DM) and those undergoing glucocorticoids.Results:After 52 weeks of treatment, most of the patients showed a statistically significant reduction of HOMA-IR (3.61 ± 1.21 at the onset vs. 2.45 ± 1.46 at the end of the study, p<0.001), while QUICKI registered a slight increase (0.32 ± 0.01 at the onset vs. 0.33 ± 0.01 at the end of the study, p<0.001). Also, the decrease in insulin and glucose levels were more obvious in patients with normal BMI, strictly related to disease activity.Conclusion:Long-term administration of TCZ in active RA is associated with a significant reduction of disease activity and IR, especially in normal weight patients. This confirms that obesity, as a CV risk factor, represents one of the main causes of IR.References:[1]Castañeda S, Remuzgo-Martínez S, López-Mejías R et al. Rapid beneficial effect of the IL-6 receptor blockade on insulin resistance and insulin sensitivity in non-diabetic patients with rheumatoid arthritis.Clin Exp Rheumatol. 2019; 37(3):465-473.[2]Lehrskov LL, Christensen RH. The role of interleukin-6 in glucose homeostasis and lipid metabolism.Semin Immunopathol. 2019; 41(4):491-499.[3]Ursini F, Russo E, Ruscitti P, Giacomelli R, De Sarro G. The effect of non-TNF-targeted biologics and small molecules on insulin resistance in inflammatory arthritis.Autoimmun Rev. 2018 Apr;17(4):399-404.Disclosure of Interests:Alexandra Jitaru: None declared, Cristina Pomirleanu: None declared, Maria-Magdalena Leon-Constantin: None declared, Florin Mitu: None declared, CODRINA ANCUTA Consultant of: AbbVie, Pfizer, Roche, Novartis, UCB, Ewopharma, Merck Sharpe and Dohme, and Eli Lilly, Speakers bureau: AbbVie, Pfizer, Roche, Novartis, UCB, Ewopharma, Merck Sharpe and Dohme, and Eli Lilly

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The Correlation between Increased Serum Concentrations of Interleukin-6 Family Cytokines and Disease Activity in Rheumatoid Arthritis Patients

Yonsei Medical Journal ◽

10.3349/ymj.2011.52.1.113 ◽

2011 ◽

Vol 52 (1) ◽

pp. 113 ◽

Cited By ~ 38

Author(s):

Soo-Jin Chung ◽

Yong-Jin Kwon ◽

Min-Chan Park ◽

Yong-Beom Park ◽

Soo-Kon Lee

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Interleukin 6 ◽

Serum Concentrations

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Association of RETN and TNFRSF1B polymorphisms with TNF-α inhibitor response in rheumatoid arthritis patients

10.21203/rs.2.24442/v1 ◽

2020 ◽

Author(s):

Nga Thi Trinh ◽

Hyun Jeong Kim ◽

Woorim Kim ◽

Sang Oh Kang ◽

Kyung Hyun Min ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Statistical Significance ◽

Univariate Analysis ◽

Multivariable Logistic Regression Analysis ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Final Model ◽

Asian Populations ◽

Tnf Α

Abstract Background: Despite the improvement from the introduction of tumor necrosis factor inhibitors (TNFi) in the rheumatoid arthritis (RA), TNFi therapy fails for more than 30% or results in a partial response. Thus, we aimed to explore treatment marker by examining the association of single nucleotide polymorphisms (SNPs) with response to TNFi therapy.Method: Genes associated with RA or RA treatment were reviewed and fourteen SNPs with minor allele frequency ≥ 20% in the East Asian populations were selected and analyzed. Data were collected from 105 RA patients. Our primary endpoint was the disease activity score using 28-joint count after six months of treatment (DAS28-6month). The secondary outcomes were the subcomponents of DAS28.Results: A total of 88 patients were included in the final analyses. Among the 14 SNPs analyzed, one SNP showed statistical significance in DAS28-6month: patients with the GG allele of RETN rs1862513 had a 4.7 times higher chance of low disease activity at 6-months than GC or CC-carriers (p = 0.033), as indicated by multivariable logistic regression analysis. Rs3397 was marginally significant in univariate analysis (p=0.059), but was significant in the multivariable model (p=0.041). The final model explained 24.5% (Nagelkerke R2) of the variance in DAS28-6month.Conclusion: Our results demonstrated that, among the genes related to RA, SNPs in RETN and TNFRSF1B were associated with the response of TNFi treatment.

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Levels of CXCL13 and sICAM-1 correlate with disease activity score in patients with rheumatoid arthritis treated with tocilizumab

Advances in Rheumatology ◽

10.1186/s42358-019-0097-1 ◽

2019 ◽

Vol 59 (1) ◽

Cited By ~ 1

Author(s):

Katie Tuckwell ◽

Cem Gabay ◽

Thierry Sornasse ◽

Ruediger Paul Laubender ◽

Jianmei Wang ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Disease Activity Score ◽

Serum Levels ◽

Activity Score ◽

Intercellular Adhesion Molecule ◽

Inadequate Response ◽

Intercellular Adhesion Molecule 1 ◽

Baseline Serum ◽

Early Ra

Abstract Background Tocilizumab (TCZ), a humanized monoclonal antibody against the interleukin-6 receptor, has been proven to be a safe and effective treatment for rheumatoid arthritis (RA). Because RA is a heterogenous disease and patient response to treatments can vary, identifying characteristics that predict which patients are more likely to respond to TCZ is important for optimal patient care. Serum levels of C-X-C motif chemokine ligand 13 (CXCL13) and soluble intercellular adhesion molecule-1 (sICAM-1) have been associated with response to TCZ in patients with RA. Objectives To evaluate the association of CXCL13 and sICAM-1 with disease activity and response to TCZ in patients with early RA and those with inadequate response to disease-modifying antirheumatic drugs (DMARD-IR). Methods Baseline and week 24 serum CXCL13 and sICAM-1 levels were measured using available patient samples from the FUNCTION (early RA) and LITHE (DMARD-IR) trials. Correlations between CXCL13 and sICAM-1 levels and Disease Activity Score in 28 joints calculated with erythrocyte sedimentation rate (DAS28-ESR) at baseline and between change in CXCL13 and sICAM-1 and change in DAS28-ESR at week 24 were estimated. CXCL13 and sICAM-1 changes from baseline to week 24 were compared between treatment arms. The effects of TCZ treatment and baseline DAS28-ESR, CXCL13 and sICAM-1 levels on DAS28-ESR remission and 50% improvement per the American College of Rheumatology (ACR50) response at week 24 were determined. Results Overall, 458 patients from FUNCTION and 287 patients from LITHE were included. Correlation of baseline serum CXCL13 and sICAM-1 levels with DAS28-ESR was weak to moderate. CXCL13 and sICAM-1 levels decreased significantly at week 24 in TCZ-treated patients in both the early-RA and DMARD-IR populations. CXCL13 and sICAM-1 changes correlated moderately to weakly with DAS28-ESR changes at week 24 in both populations. The treatment regimen, but not baseline CXCL13 and sICAM-1 levels, had a significant effect on the likelihood of DAS28-ESR remission and ACR50 response. Conclusions Although CXCL13 and sICAM-1 are modestly associated with RA disease activity, they do not predict response to TCZ in all RA populations.

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Sustained discontinuation of infliximab with a raising-dose strategy after obtaining remission in patients with rheumatoid arthritis: the RRRR study, a randomised controlled trial

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2019-216169 ◽

2019 ◽

Vol 79 (1) ◽

pp. 94-102

Author(s):

Yoshiya Tanaka ◽

Koji Oba ◽

Takao Koike ◽

Nobuyuki Miyasaka ◽

Tsuneyo Mimori ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Treatment Group ◽

Treatment Strategy ◽

Activity Index ◽

Randomised Trial ◽

Standard Group ◽

Sustained Remission ◽

Inadequate Response ◽

Baseline Serum ◽

Tnf Α

ObjectivesThe aim of this study is to determine whether the ‘programmed’ infliximab (IFX) treatment strategy (for which the dose of IFX was adjusted based on the baseline serum tumour necrosis factor α (TNF-α)) is beneficial to induction of clinical remission after 54 weeks and sustained discontinuation of IFX for 1 year.MethodsIn this multicentre randomised trial, patients with IFX-naïve rheumatoid arthritis with inadequate response to methotrexate were randomised to two groups; patients in programmed treatment group received 3 mg/kg IFX until week 6 and after 14 weeks the dose of IFX was adjusted based on the baseline levels of serum TNF-α until week 54; patients in the standard treatment group received 3 mg/kg of IFX. Patients who achieved a simplified disease activity index (SDAI) ≤3.3 at week 54 discontinued IFX. The primary endpoint was the proportion of patients who sustained discontinuation of IFX at week 106.ResultsA total of 337 patients were randomised. At week 54, 39.4% (67/170) in the programmed group and 32.3% (54/167) in the standard group attained remission (SDAI ≤3.3). At week 106, the 1-year sustained discontinuation rate was not significantly different between two groups; the programmed group 23.5% (40/170) and the standard group 21.6% (36/167), respectively (2.2% difference, 95% CI −6.6% to 11.0%; p=0.631). Baseline SDAI <26.0 was a statistically significant predictor of the successfully sustained discontinuation of IFX at week 106.ConclusionProgrammed treatment strategy did not statistically increase the sustained remission rate after 1 year discontinuation of IFX treatment.

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Levels of Plasma-soluble Triggering Receptor Expressed on Myeloid Cells-1 (sTREM-1) Are Correlated with Disease Activity in Rheumatoid Arthritis

The Journal of Rheumatology ◽

10.3899/jrheum.111218 ◽

2012 ◽

Vol 39 (5) ◽

pp. 933-938 ◽

Cited By ~ 11

Author(s):

SANG TAE CHOI ◽

EUN-JIN KANG ◽

YOU JUNG HA ◽

JUNG-SOO SONG

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Myeloid Cells ◽

Disease Status ◽

Joint Disease ◽

Healthy Controls ◽

Cell Counts ◽

Tnf Α ◽

White Blood Cell Counts ◽

Factor Α

Objective.To determine whether levels of plasma-soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) are elevated in patients with rheumatoid arthritis (RA) and whether levels are correlated with disease activity and other variables.Methods.Our study included 71 patients with RA and 50 age- and sex-matched healthy controls. Clinical characteristics and laboratory measures, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and 28-joint Disease Activity Score (DAS28) were assessed. Plasma levels of sTREM-1 and tumor necrosis factor-α (TNF-α) were measured by ELISA.Results.Patients with RA had significantly higher plasma sTREM-1 levels than healthy controls (170.10 ± 84.71 pg/ml vs 97.41 ± 40.64 pg/ml; p < 0.001). In patients with RA, plasma sTREM-1 levels were found to be correlated with DAS28, ESR, CRP, white blood cell counts, neutrophil counts, and plasma TNF-α levels (r = 0.329, p = 0.005; r = 0.241, p = 0.043; r = 0.314, p < 0.001; r = 0.261, p = 0.028; r = 0.278, p = 0.019; and r = 0.313, p = 0.009, respectively). Plasma sTREM-1 levels in patients with active disease status (DAS28 > 3.2) were significantly higher than in those with low disease status (DAS28 ≤ 3.2; 208.89 ± 100.14 pg/ml vs 150.29 ± 68.70 pg/ml; p = 0.005).Conclusion.Patients with RA had higher plasma sTREM-1 levels than healthy controls, and plasma sTREM-1 levels were correlated with disease activity measures, suggesting that plasma sTREM-1 could play a role in the inflammatory process associated with TNF-α, and that it may be a useful disease activity marker in RA.

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