IL-1ra In Patients Research Articles

P-48 EVALUATION OF IL-1β AND IL-1RA IN PATIENTS WITH CHRONIC LIVER DISEASES

P-48 EVALUATION OF IL-1β AND IL-1RA IN PATIENTS WITH CHRONIC LIVER DISEASES

Serum determination of IL-1β and IL-1RA in patients with chronic liver diseases

Serum determination of IL-1β and IL-1RA in patients with chronic liver diseases

MO10-4 Novel non-invasive biomarkers for the detection of myelofibrosis in patients with myeloproliferative neoplasms

Myeloproliferative neoplasms (MPN) are a group of blood cancers whose progression results in myelofibrosis (MF). Patients with MPN having MF develop severe anemia, splenomegaly, and occasionally acute leukemia. Thus, early detection of MF is crucial for predicting the prognosis of MPN. Previous studies have reported increased circulating CD34+ cells and serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-8, and IL-1ra in patients with MPN having MF. In the present study, we evaluated the efficacies of these parameters as non-invasive markers of MF progression.

In vivo study of pro-inflammatory cytokine changes in serum and synovial fluid during treatment with celecoxib and etoricoxib and correlation with VAS pain change and synovial membrane penetration index in patients with inflammatory arthritis.

ObjectivesTo determine the impact of celecoxib and etoricoxib therapy on serum and synovial fluid levels of IL-1β, IL-6, TNF-α, sTNFR1, sTNFR2 and IL-1Ra in patients with inflammatory arthritis. To determine the correlation between cytokine changes and synovial membrane penetration index of the study drugs, and pain VAS change.MethodsFifty-one patients with inflammatory synovial fluid accumulation in a knee joint (33 women), randomized on 3 groups of 17 each: 100 mg b.i.d. celecoxib treated group, 90 mg o.d. etoricoxib treated group, and the control group with no NSAID treatment. Cytokines serum and synovial fluid levels as well as membrane penetration index were assessed prior and after treatment.ResultsCelecoxib led to decrease of both synovial fluid and serum levels of IL-6 (p=0.017 and p=0.003, respectively). In the etoricoxib treated group synovial fluid IL-6 concentration was significantly decreased after treatment (p=0.019). Correlating the study drugs penetration index with the change of cytokines and their receptors levels, positive correlation was found with the reduction of synovial fluid IL-1β for the celecoxib (p=0.032) and with the increase of synovial fluid sTNFR1 for the etoricoxib group (p=0.028). Pain VAS reduction was positively correlated with decrease of synovial fluid IL-1β (p=0.041) and IL-6 levels (p<0.005) and negative with synovial fluid sTNFR1 changes (p=0.045) in celecoxib group, and negative with serum TNF-α decrease (p=0.044) in the etoricoxib group.ConclusionOur results suggest that celecoxib and etoricoxib inhibit the inflammatory cytokines, mostly in synovial fluid but also in serum, causing through this mechanism, decrease of inflammation, irrespective to COX-2 inhibition.

IL-1Ra (recombinant human IL-1 receptor antagonist) in the treatment of rheumatoid arthritis: the efficacy

Interleukin 1 receptor antagonist (IL-1Ra) is a naturally occurring IL-1 inhibitor, acting as a "receptor antagonist", which blocks IL-1 mediated signal transduction. In 1990 IL-1Ra was cloned and later on, a large numbers of studies led to disclosure of the crucial importance of the imbalance between IL-1 and IL-1Ra in the pathogenesis of rheumatoid arthritis (RA). In 1991, almost 8 years after the initial isolation of IL-1, recombinant IL-1Ra (IL-1ra, Kineret) was introduced in clinical trials involving patients with RA. Between 2001 and 2002 IL-1ra was approved by the US Food and Drug Administration and by the European Agency for the Evaluation of the Medicinal Products and in 2003 it was registered in Italy, too. In RA recombinant IL-1ra has been evaluated in 5 randomized, placebo-controlled clinical trials involving more than 2900 patients. Two of the trials involved the use of IL-1ra as monotherapy versus placebo and two trials in combination with methotrexate (MTX); the last trial explored the use of a fixed 100 mg/day IL-1ra dosage in a RA patient population including a wide array of co-morbid conditions as well as concomitant medications. The studies confirmed both the efficacy and the safety of IL-1ra in patients with active and severe RA. 43% of patients receiving 150 mg/day IL-1ra achieved a 20% response according to the American College of Rheumatology criteria (ACR20), compared to 27% in the placebo group. In the MTX combination therapy study, 42% of the patients receiving 1 mg/Kg/day of IL-1ra achieved an ACR20, 24% an ACR50 and 10% an ACR70. In each study, significant improvements in the Health Assessment Questionnaire scores (HAQ) were observed. There were rapid gains in the number of days at work or domestic activity in the treated patients, and the increases in productivity were dose related. At early 24 weeks, there was significant reduction of both the score for progression of joint space narrowing (JSN) and the Total modified Sharp-Genant score (a combination of erosion and JSN) in all treatment groups (30,75 and 150mg/day). The clinical benefits of treatment with daily subcutaneous injections of IL-1ra in active RA patients were maintained for up to 48 weeks. IL-1ra, a selective inhibitor of the IL-1 pathway, represents an important new biologic approach to treating patients with RA, that significantly reduces clinical signs and symptoms of the disease and joint destruction and has proved safe and well tolerated also in combination with other DMARDs and concomitant medications.

Modulation of Cytokine and Cytokine Receptor/Antagonist by Treatment with Doxycycline and Tetracycline in Patients with Dengue Fever

Dengue virus infection can lead to dengue fever (DF) or dengue hemorrhagic fever (DHF). Disease severity has been linked to an increase in various cytokine levels. In this study, we evaluated the effectiveness of doxycycline and tetracycline to modulate serum levels of IL-6, IL-1B, and TNF and cytokine receptor/receptor antagonist TNF-R1 and IL-1RA in patients with DF or DHF. Hospitalized patients were randomized to receive standard supportive care or supportive care combined with doxycycline or tetracycline therapy. Serum cytokine and cytokine receptor/antagonist levels were determined at the onset of therapy and after 3 and 7 days. Cytokine and cytokine receptor/antagonist levels were substantially elevated at day 0. IL-6, IL-1β, and TNF remained at or above day 0 levels throughout the study period in untreated patients. Treatment with tetracycline or doxycycline resulted in a significant decline in cytokine levels. Similarly, IL-1RA and TNF-R1 serum concentrations were elevated at baseline and showed a moderate increase among untreated patients. Both drugs resulted in a significant rise in IL-1Ra levels by day 3 in patients. In contrast, treatment did not affect a similar result for TNF-R1. When compared to the control group, however, a significant rise post-treatment was seen upon intragroup analysis. Further analysis demonstrated that doxycycline was significantly more effective at modulating cytokine and cytokine receptor/antagonist levels than tetracycline.

20th National Meeting of the British Neuroscience Association

20th National Meeting of the British Neuroscience Association

Polymorphism in the IFN-γ Gene Is Associated with Severe Acute Graft Versus Host Disease in β Thalassemia Major Patients Undergoing Matched Related Hematopoietic Stem Cell Transplantation (HSCT).

Acute graft versus host disease (aGVHD) is a major cause for morbidity and mortality following allogeneic HSCT (alloHSCT). Polymorphisms in Th2 cytokine genes such as IL-10 have been shown to modulate GVHD. Th1 cytokines, IFN-γ, TNF-α and IL-1β have been implicated in the pathogenesis of aGVHD in mouse models but there is limited data in human HSCT. We have evaluated the prevalence of the following functional polymorphisms in Th1 cytokines (IFN-γ +874, TNF-α −308, IL-1β −511 and +3953), Th2 cytokines (IL-10, IL-6), TGF-β and IL-1Ra in patients with β thalassemia major undergoing matched related alloHSCT and correlated them with the incidence of aGVHD. A total of 129 patients were evaluated. Patients who expired before day 15 (n=9) and for whom appropriate DNA samples were not available (n=18) were excluded. Of the 102 patients who were assessable, 72 (72%) patients received conditioning with Bu (16mg/kg) / Cy (200mg/kg) with anti-thymocyte globulin (ATG) while 30 (28%) patients received Bu (600mg/m2) / Cy (200mg/kg) without ATG. All patients received unmanipulated bone marrow and standard cyclosporine / short-course methotrexate towards prophylaxis against GVHD. Patients who died after HSCT without achieving ANC >500/mm3 were not assessed for aGVHD (n=6). Of the remaining 96 patients, 54 (53%) had aGVHD, 13 (24%) of which were grade III–IV. Apart from the immunogenetic markers mentioned above, the impact of other risk factors for aGVHD such as recipient and donor age, sex mismatch, conditioning regimen, cell dose, ABO compatibility and thalassaemia risk class were also analyzed. Of these, recipient age >10 years and female to male sex-mismatched transplants were found to increase the risk of developing severe aGVHD (grade III–IV). Among the cytokine polymorphisms evaluated, donor IFN-γ (dIFN-γ) +874 T/T genotype, associated with higher levels, was found to significantly increase the risk of developing severe aGVHD (RR= 4.9; p= 0.013; 95% CI 1.39–17.08). These results were also found to be consistent on forward stepwise multivariate analysis. No correlation was found between severe aGVHD and TNF-α, IFN-γ, IL 10 polymorphisms of recipients and IL-1Ra polymorphisms of donor. IFN-γ may facilitate antigen presentation and effector cell recruitment as elucidated in various experimental studies. Therefore, it is possible that dIFN-γ +874 T/T genotype might contribute to increased incidence of severe aGVHD since the effector T cells mediating aGVHD are of donor origin after transplant. Our data shows for the first time that development of severe aGVHD in patients with β thalassemia major undergoing matched related alloHSCT is affected by immunogenetic factors other than HLA.Risk factorsRelative risk [95% CI] *P-value *Relative risk [95% CI] ♠P-value ♠Recipient age >103.1 [1.05–9.34]0.0404.3 [1.36–13.33]0.012< 101.01.0Sex mismatched Transplant - Yes4.7 [1.05–21.32]0.043NSNo1.0Female to Male Transplant Yes3.5 [1.15–10.74]0.0285.3 [1.59–17.49]0.006No1.01.0IFN- γ +874 TT3.3 [1.00–10.59]0.0504.9 [1.39–17.08]0.013TA+AA1.01.0* - Univariate analysis, ♠- Multivariate analysis

Decreased levels of peritoneal interleukin-1 receptor antagonist in patients with endometriosis and disease-related dysmenorrhea

To determine the level of interleukin-1 receptor antagonist (IL-1ra) in peritoneal fluid (PF) and serum in patients with endometriosis. A prospective analytical study. University-affiliated obstetrics and gynecology academic training hospital. One hundred eighteen patients underwent laparoscopy for benign gynecologic diseases. Peripheral blood and PF were obtained before and during surgical procedures, and the levels of IL-1ra were measured. The concentrations of IL-1ra in PF and serum were correlated with the presence of endometriosis, disease stage, and the phase of menstrual cycle. Peritoneal fluid IL-1ra concentrations were significantly lower in patients with endometriosis than in patients without endometriosis. Peritoneal fluid IL-1ra concentrations decreased with the increased severity of endometriosis and also decreased in disease-related dysmenorrhea; serum IL-1ra levels showed no significant difference between the patients with and without endometriosis. The concentrations of IL-1ra in PF and serum were not correlated with the phase of menstrual cycle. Our results suggested that decreased levels of PF IL-1ra in patients with endometriosis and disease-related dysmenorrhea may play an important role in the pathogenesis of this disease.

Association of interleukin-1Ra gene polymorphism in patients with bladder cancer: Case control study from North India

Objectives To evaluate whether polymorphism of interleukin (IL)-1β gene (exon 5 and promoter region) and IL-1 receptor antagonist (Ra), 86-bp variable number tandem repeat, are associated with transitional cell carcinoma of the urinary bladder, because cytokines have been hypothesized to be important in cancer development. Methods The study included 120 patients with bladder cancer (age range 32 to 69 years) and 150 age-matched controls (age range 25 to 62 years). The polymorphisms were identified by polymerase chain reaction/restriction fragment length polymorphism method and IL-1Ra polymorphism by variable number of identical tandem repeat analysis. Genotype distribution and allelic frequencies between patients and controls were compared. Results A significant difference was found in the frequency distribution of the IL-1Ra gene polymorphism in patients with bladder cancer compared with the normal control group ( P <0.001), but no difference was found in the frequencies of the IL-1β promoter region and exon 5 genotypes between patients with bladder cancer and controls ( P = 0.112 and P = 0.953, respectively). Conclusions This is perhaps the first report on polymorphic changes in gene encoding IL-1Ra in patients with bladder cancer from India. Our data suggest that IL-1Ra intron 2 polymorphism seems to play a prominent role among the IL-1 gene cluster with respect to bladder cancer, and the association studies appear to be plausible in determining the cancer susceptibility and risk.

Interleukin-1 receptor antagonist genotype is associated with coronary atherosclerosis in patients with type 2 diabetes.

Recently, inflammation has received considerable attention in the pathogenesis of both type 2 diabetes and atherosclerosis. The interleukin-1 receptor antagonist (IL-1ra) is a major modulator of the interleukin-1 pro-inflammatory pathway. We studied the relationship between a variable number tandem repeat (VNTR) polymorphism in intron 2 of the IL-1ra gene (IL1RN) and coronary artery disease (CAD) in patients with and without type 2 diabetes, following 787 consecutive patients admitted for suspected CAD. According to the current criteria of the American Diabetes Association, 250 patients had type 2 diabetes. In this group of patients, allele 2 carriers (n = 108) had an increased prevalence of CAD compared with noncarriers (85.2 vs. 73.2%), a difference that remained significant in a multivariate logistic regression model (odds ratio 2.2, 95% CI 1.1-4.3, P = 0.02). No association of CAD with allele 2 carrier status was present among nondiabetic patients (n = 537). Enzyme-linked immunosorbent assays showed decreased baseline plasma levels of IL-1ra in patients with type 2 diabetes, which may in part explain the role of the IL1RN VNTR in these patients.

Association of Interleukin-1 Receptor Antagonist Gene Polymorphism with IgA Nephropathy

It is evident that cytokines play an important role in the pathogenesis as well as disease progression of IgA nephropathy (IgAN). Several gene polymorphisms of the pertinent cytokines have an influence on the level of cytokine production. Interleukin-1 receptor antagonist (IL-1ra) gene polymorphism has been found to affect disease susceptibility and activity in several inflammatory diseases. In the present study, we analyzed polymorphism of the variable number tandem repeat (VNTR) of IL-1ra in patients diagnosed as having IgAN (n = 106) and normal controls (n = 74). The allele frequency of IL-1ra polymorphism in IgAN patients was not statistically different from that of the control group. There was no significant difference in the carriage rate of the two-repeat allele (IL1RN*2) between IgAN patients and the control group (8.5 vs. 6.8%). The carriage rate of IL1RN*2 was significantly higher in IgAN patients with severe proteinuria (≧1.6 g/day) or increased serum creatinine level (≧2.0 mg/dl; p < 0.05). Furthermore, the carriage rate of IL1RN*2 was significantly higher in patients with severe mesangial cell proliferation (p < 0.01). Our results suggest that IL-1ra polymorphisms are not associated with the development of IgAN in Japanese patients but the presence of IL1RN*2 may be associated with increased disease activity.

Interleukin-1 receptor antagonist treatment of rheumatoid arthritis patients: Radiologic progression and correlation of Genant/Sharp and Larsen scoring methods

Objective: The Genant/Sharp scoring method is a validated radiologic scoring system useful for diagnosing, classifying, and defining specific clinical problems associated with rheumatoid arthritis (RA). The Genant/Sharp scoring method is described, and its level of correlation with the Larsen scoring method is discussed. Method: The Genant/Sharp scoring system evaluates erosion, joint space narrowing (JSN), and a combination of erosion and JSN referred to as the total score. This method was used to determine change in radiographic progression during 2 consecutive 6-month intervals within a multicenter, double-blind, placebo-controlled study of recombinant human interleukin-1 receptor antagonist (IL-1ra) in patients with RA. These results were compared with the results obtained through the Larsen scoring method to determine their correlation. Results: The Genant/Sharp scoring method showed a moderate correlation with the Larsen scoring method, particularly at baseline, and showed similar treatment trends in a study of IL-1ra in patients with RA. Conclusion: The Genant/Sharp scoring method provides an alternative to the Sharp and Larsen approaches for radiographic assessment in RA. Semin Arthritis Rheum 30:26-32 (Suppl 2). Copyright © 2001 by W.B. Saunders Company

Five genetic markers in the interleukin 1 family in relation to inflammatory bowel disease

Background—An imbalance between the proinflammatory cytokine interleukin 1β (IL-1β) and the anti-inflammatory cytokine IL-1 receptor antagonist (IL-1ra) has been postulated as a pathogenic factor in inflammatory bowel disease (IBD).Aims—To study...

CIRCULATING SERUM LEVELS OF IL-1ra IN PATIENTS WITH RELAPSING REMITTING MULTIPLE SCLEROSIS ARE NORMAL DURING REMISSION PHASES BUT SIGNIFICANTLY INCREASED EITHER DURING EXACERBATIONS OR IN RESPONSE TO IFN-β TREATMENT

Interleukin (IL)-1 receptor antagonist (IL-1ra) is a naturally occurring inhibitor of IL-1 which binds to IL-1 receptors without generating immunologic responses. Evidence has recently been provided that the balance between the production of IL-1 and IL-1ra might influence the course of immunoinflammatory diseases such as inflammatory bowel diseases, rheumatoid arthritis (RA) and Lyme arthritis. To assess whether endogenous IL-1ra may also have a role on the course of multiple sclerosis (MS) we presently studied the fluctuation of the serum levels of IL-1ra in patients with relapsing remitting (RR) MS either during remission or exacerbation. Moreover, to evaluate whether the beneficial effect of IFN-β on the course of MS might also be mediated by an increased production of IL-1ra, we measured the levels of circulating IL-1ra in MS patients prior to and after 6 months of continuous treatment with natural human IFN-β (6 000 000 IU three times a week for 6 months). Our results demonstrated that, relative to control subjects, IL-1ra serum levels are ‘normal’ during remitting phases of RR MS but significantly elevated either during exacerbations or in response to IFN-β treatment.

Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: A randomized, open-label, placebocontrolled multicenter trial

To evaluate the safety, pharmacokinetics, and efficacy of human recombinant interleukin-1 receptor antagonist (IL-1ra) in the treatment of patients with sepsis syndrome. Prospective, open-label, placebo-controlled, phase II, multicenter clinical trial using three different doses of human recombinant IL-1ra. Twelve academic medical center intensive care units in the United States. Ninety-nine patients with sepsis syndrome or septic shock who received standard supportive care and antimicrobial therapy, in addition to infusion with escalating doses of IL-1ra or placebo. Patients received an intravenous loading dose of either human recombinant IL-1ra (100 mg) or placebo, followed by a 72-hr intravenous infusion of either one of three doses of IL-1ra (17, 67, or 133 mg/hr) or placebo. All patients were evaluated for 28-day, all-cause mortality. A dose-dependent, 28-day survival benefit was associated with IL-1ra treatment (p = .015), as indicated by the following mortality rates: 11 (44%) deaths among 25 placebo patients; eight (32%) deaths among 25 patients receiving IL-1ra 17 mg/hr; six (25%) deaths among 24 patients receiving IL-1ra 67 mg/hr; and four (16%) deaths among 25 patients receiving IL-1ra 133 mg/hr. A dose-related survival benefit was observed with infusion of IL-1ra in patients with septic shock at study entry (n = 65; p = .002) and in patients with Gram-negative infection (n = 45; p = .04). Patients with an increased circulating interleukin-6 (IL-6) concentration of > 100 pg/mL at study entry demonstrated a dose-related survival benefit with IL-1ra treatment (p = .009). In patients with an increased IL-6 concentration at study entry, the magnitude of the decrease in IL-6 concentration 24 hrs after the initiation of therapy was correlated with increasing the IL-1ra treatment dose (p = .052). A significant dose-related reduction in the Acute Physiology and Chronic Health Evaluation (APACHE II) score was achieved by the end of infusion (p = .038). A renal elimination mechanism for IL-1ra was suggested by the positive correlation between IL-1ra plasma clearance and estimated creatinine clearance (p = .001; r2 = .51). Human recombinant IL-1ra was well tolerated. This initial evaluation suggests that human recombinant IL-1ra is safe and may provide a dose-related survival advantage to patients with sepsis syndrome. A larger, definitive clinical trial is needed to confirm these findings.