Use Of TNF-α Antagonists Research Articles

Effect of Thiopurine on Potential Surgical Intervention in Crohn’s Disease in Korea: Results from the CONNECT Study

Objectives: The incidence of Crohn’s disease and the number of associated surgeries are increasing in Korea. This study investigated the effect of azathioprine/6-mercaptopurine (6-MP) and TNF-α antagonists on abdominal and perianal surgery in Korean patients with Crohn’s disease. Design: A retrospective cohort study. Setting: Data from the Crohn’s Disease Clinical Network and Cohort (CONNECT) were used. Patients with confirmed Crohn’s disease between 1982 and 2008 from 32 hospitals in the Republic of Korea were enrolled. The effect of azathioprine/6-MP on abdominal and perianal surgery was analysed using logistic regression analysis adjusting for age and sex. Participants: In total, 1161 Crohn’s disease patients were included in the Republic of Korea in the surgery (n = 462, male = 339, female = 123) and control groups (n = 699, male = 484, female = 215). Results: In total, 1161 patients were selected, with 462 patients who underwent abdominal (n = 245) or perianal surgery (n = 217). The preoperative usage rates of azathioprine/6-MP were 18.8% and 65.1% (p < 0.0001) in the surgery and control groups, respectively. The preoperative usage rates of TNF-α antagonists were 7.1% and 23.3% (p < 0.0001) in the surgery and control groups, respectively. A multivariate analysis revealed that the preoperative use of azathioprine/6-MP had an odds ratio of 0.094 for all surgeries (95% confidence interval [CI]: 0.070–0.127, p < 0.0001), 0.131 for abdominal surgery (95% CI: 397–1.599, p < 0.0001), and 0.059 for perianal surgery (95% CI: 0.038–0.091, p < 0.0001). The preoperative use of TNF-α antagonists had an odds ratio of 0.225 for all surgeries (95% CI: 0.151–0.335, p < 0.0001), 0.403 for abdominal surgery (95% CI: 0.261–0.623, p < 0.0001), and 0.064 for perianal surgery (95% CI: 0.026–0.160, p < 0.001). Strengths of this study: The study presents new evidence of the reduced risk of surgery following azathioprine use in Crohn’s disease patients. Limitations of this study (1) This was not a controlled prospective study. (2) There was a selection bias specific to the CONNECT cohort. (3) The combination or sequential use of azathioprine/6-MP and TNF-α antagonists was not excluded. Conclusion: Azathioprine/6-MP is significantly associated with a reduced risk of abdominal and perianal surgery in Korean patients with Crohn’s disease.

Evidence‐based consensus on opportunistic infections in inflammatory bowel disease

Evidence‐based consensus on opportunistic infections in inflammatory bowel disease

A Review of the Clinical Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Vedolizumab.

Vedolizumab is a humanized anti-α4β7 integrin monoclonal antibody that selectively blocks trafficking of memory T cells to inflamed gut tissue by inhibiting the α4β7-mucosal addressin cell adhesion molecule-1 (MAdCAM-1) interaction. Approved for treating patients with moderately to severely active ulcerative colitis (UC) or Crohn’s disease (CD), vedolizumab is administered as a 300 mg intravenous infusion. Vedolizumab undergoes a rapid, saturable, non-linear, target-mediated elimination process at low concentrations and a slower, linear, non-specific elimination process at higher concentrations. At therapeutic concentrations, vedolizumab primarily undergoes linear elimination. From population pharmacokinetic modeling, the vedolizumab terminal elimination half-life (t ½ β) was estimated to be 25.5 days; linear clearance (CLL) was similar for patients with UC (0.159 L/day) and CD (0.155 L/day). Extreme low albumin concentrations and extreme high body weight values were potentially clinically important predictors of vedolizumab CLL. Other factors, including concomitant therapy use (methotrexate, azathioprine, mercaptopurine, or aminosalicylates) or prior tumor necrosis factor-α (TNF-α) antagonist use, had no clinically relevant effects on CLL. A positive exposure–efficacy relationship for clinical remission and clinical response was apparent for vedolizumab induction therapy in patients with UC or CD. On average, patients with higher albumin, lower fecal calprotectin (UC only), lower C-reactive protein (CD only), and no prior TNF-α antagonist use had a higher probability of remission. Off drug, 10% of patients with UC or CD were positive for anti-drug antibodies. This article provides a comprehensive review of the clinical pharmacokinetics, pharmacodynamics, exposure–efficacy relationships, and immunogenicity of vedolizumab.

Exposure-efficacy Relationships for Vedolizumab Induction Therapy in Patients with Ulcerative Colitis or Crohn's Disease.

A positive relationship between vedolizumab trough serum concentrations and clinical outcomes in patients with ulcerative colitis [UC] or Crohn's disease [CD] has been reported. Here we further explore exposure-efficacy relationships for vedolizumab induction therapy in post hoc analyses of GEMINI study data. Vedolizumab trough concentrations at Week 6 or 10 were grouped in quartiles and clinical outcome rates calculated. Exposure-efficacy relationships at Week 6 and potential baseline covariate effects were explored using logistic regression and individual predicted cumulative average concentration through Week 6 [Caverage] as exposure measure. Higher vedolizumab concentrations were associated with higher clinical remission rates; the exposure-efficacy relationship was steeper for UC than CD. Unadjusted analyses overestimated the relationship, more so for CD. From covariate-adjusted models, average probability of remission at Week 6 increased by approximately 15% for UC and 10% for CD between Caverage values of 35 and 84 µg/ml [5th and 95th percentiles, respectively]. On average, patients with higher albumin, lower faecal calprotectin [UC only], lower C-reactive protein [CD only], and no previous tumour necrosis factor-α [TNFα] antagonist use had a higher remission probability. Previous TNFα antagonist use had the greatest impact; remission probability was approximately 10% higher in treatment-naïve patients. Higher vedolizumab serum concentrations were associated with higher remission rates after induction therapy in patients with moderately to severely active UC or CD. This relationship is affected by several factors, including previous TNFα antagonist use. Prospective studies are needed to assess vedolizumab dose individualisation and optimisation.

TNF-α antagonist may not be suitable for severe rituximab-induced interstitial lung disease.

Rituximab-induced interstitial lung disease (R-ILD) has aroused more concern in recent years. Anti-TNF-α treatment has been suggested for the treatment of severe R-ILD, due to the plausible suggestion that its pathogenesis is related to TNF-α. This commentary aimed to comment on the role of TNF-α antagonists in R-ILD. Although most R-ILD patients respond well to glucocorticoids, other treatment options are needed for patients who are refractory to conventional treatment. Contrary to expectations, the TNF-α antagonist etanercept brought no benefit in R-ILD. Moreover, TNF-α-targeted therapies were reported to induce or exacerbate interstitial lung disease. The role of TNF-α in the pathogenesis of R-ILD is still unclear due to limited studies on its aetiology. Use of TNF-α antagonists in R-ILD is still speculative, as clinical trials do not support its efficacy. What's more, TNF-α antagonists may themselves induce interstitial lung disease with poor prognosis.

Autoimmunogenicity during anti-TNF therapy in patients with psoriasis and psoriatic arthritis.

IntroductionThe tumor necrosis factor (TNF-α) was initially described as lymphotoxin or cachectin. The discovery of therapies blocking the action of TNF-α, in 1988, started a new era in the therapy. One of often reported adverse effects related to the use of TNF-α antagonists is induction of the formation of autologous antibodies and antibodies neutralizing anti-TNF drugs. The development of anti-TNF-induced lupus or classical drug-induced lupus is more rarely reported.AimTo evaluate the presence and the level of anti-nuclear antibodies in patients with psoriasis and psoriatic arthritis and the influence of anti-TNF therapy used on the concentration of antinuclear antibody (ANA).Material and methodsA total of 28 subjects were included in the study. 71.4% of subjects were diagnosed with psoriatic arthritis and 28.6% with plaque psoriasis.ResultsAmong the patients with plaque psoriasis, the antinuclear antibodies were found in 25% of subjects and in 80% of patients with psoriatic arthritis. After the treatment an increase in the titer or appearance of antibodies was found in 66.7% in the infliximab group, 18.2% in the etanercept group and 54.7% in the adalimumab group. No subjects developed symptoms of drug-induced systemic lupus.ConclusionsOur findings have shown that all anti-TNF therapies induced ANA in psoriatic arthritis and psoriatic patients. Considering a mild course of lupus induced by anti-TNF treatment and, usually intrinsic, resolution of symptoms, the biological therapy still appears as a safe treatment for patients.

Anti-TNFα therapies are safe during pregnancy in women with inflammatory bowel disease: a systematic review and meta-analysis.

The use of TNFα antagonists is well described for inflammatory bowel disease (IBD), but their safety profile during pregnancy is yet to be fully elucidated. A systematic review and meta-analysis were performed to identify studies that explored the safety of anti-TNFα therapy during pregnancy in patients with IBD. A systematic literature search was conducted to identify studies that investigated the pregnancy outcomes among women with IBD on anti-TNFα therapy. The primary outcome was the overall rate of unfavourable pregnancy-related outcomes among women with IBD on anti-TNFα therapy. Secondary outcomes included rates of abortions (spontaneous or elective), preterm delivery, low birth weight, and congenital malformations. Odds ratios (OR) with 95% confidence interval (CI) are reported. Eligible studies used an observational or interventional design, enrolled subjects with IBD on anti-TNFα therapy for at least 1 trimester and compared outcomes with appropriately matched controls. Overall, 5 studies with a total of 1216 participants were eligible for inclusion in the meta-analysis. There was no significant difference in the rates of total unfavourable pregnancy outcomes between pregnant women with IBD who were on anti-TNFα therapy and controls not on anti-TNFα therapy (OR, 1.00 [95% CI, 0.72-1.41]). Similarly, there were no statistically significant differences in the rates of abortion (OR, 1.53 [95% CI, 0.97-2.41]), preterm birth (OR, 1.00 [95% CI, 0.62-1.62]), low birth weight (OR, 1.05 [95% CI, 0.62-1.78]), or congenital malformation (OR, 1.10 [95% CI, 0.58-2.09]). The use of anti-TNFα therapy does not seem to increase the risk of unfavorable pregnancy outcomes among women with IBD, although the optimal timing of therapy through pregnancy and the postpartum period was not assessed in this analysis. These data can help counsel patients around family planning and perinatal management.

Early Tumor Necrosis Factor α Antagonist Therapy in Everyday Practice for Inflammatory Back Pain Suggesting Axial Spondyloarthritis: Results From a Prospective Multicenter French Cohort

To determine the frequency of and factors associated with early tumor necrosis factor α (TNFα) antagonist therapy in everyday clinical practice in patients with suspected axial spondyloarthropathy (SpA). We used data from the prospective observational study in the French Devenir des Spondylarthropathies Indifférenciées Récentes (DESIR; Outcome of Recent Undifferentiated Spondylarthropathies) cohort of 708 patients with recent-onset (<3 years) inflammatory back pain (IBP) suggesting axial SpA. TNFα antagonist use was recorded at months 6 and 12 and factors independently associated with TNFα antagonist therapy were identified by multivariate logistic regression. Among the 708 patients (mean age 33.8 years, 46.2% men), 166 (23.4%) patients received TNFα antagonist therapy by month 12, including 120 (73.6%) patients who fulfilled Assessment of SpondyloArthritis international Society (ASAS) axial criteria and 157 (94.6%) who fulfilled at least 1 SpA criteria set; 109 (65.6%) had no sacroiliitis. Factors independently associated with early TNFα antagonist therapy were high Ankylosing Spondylitis Disease Activity Score using the C-reactive protein level (odds ratio [OR]1-point increase 1.60, 95% confidence interval [95% CI] 1.25-2.03, P < 0.001), high physician's global disease activity score (OR 1.37, 95% CI 1.21-1.54, P < 0.001), ASAS nonsteroidal antiinflammatory drug score >50 (OR 1.88, 95% CI 1.24-2.87, P = 0.003), current or past disease-modifying antirheumatic drug use (OR 2.09, 95% CI 1.22-3.59, P = 0.008), systemic corticosteroid use (OR 2.48, 95% CI 1.43-4.34, P = 0.002), and mild to severe radiographic hip abnormalities (OR 9.43, 95% CI 2.11-42.09, P = 0.003). After adjustment on these factors, Achilles enthesis hypervascularization by power Doppler and number of work days missed were associated with TNFα antagonist therapy. In the DESIR cohort, approximately one-fourth of patients with recent IBP suggestive of axial SpA were under anti-TNFα therapy after 1 year of followup. All factors associated with this early initiation reflected higher disease activity, refractoriness, or severity, which suggests compliance of French rheumatologists with current treatment guidelines.

What is the Important Issue to Prevent the Postoperative Crohn's Disease?

Crohn's disease (CD) is a chronic inflammatory disease that affects the entire gastrointestinal tract. Complications caused by CD, including strictures, perforations, and fistulas, often lead patients to undergo surgery, including intestinal resection. Several studies have reported that 50-80% of CD patients undergo the surgery during their lifetime.1 In Korea, Ye et al. reported that the cumulative probability of intestinal resection at 1, 5, and 10-15 years after a diagnosis of CD was 15.5%, 25.0%, and 32.8%, respectively.2 In a more extensive study by Park et al., the cumulative probability of intestinal resection at 10, 20, and 30 years after a diagnosis of CD was 43.5%, 70.0%, and 76.1%, respectively.3 These data suggest that the intestinal resection rate of Korean CD patients is not lower than that of Western patients and that Korean CD patients may, in fact, have a similar clinical course to Western CD patients. However, intestinal resection does not cure CD, and many patients suffer from postoperative recurrences of the disease. The recurrence of disease necessitates repeated intestinal resection, with up to 50% of patients undergoing additional surgery after 20 years.4 Ye et al. also reported that 30.8% of the patients who received an intestinal operation required a repeat operation after 10 years.2 Postoperative recurrence can be defined as clinical recurrence or endoscopic recurrence. Postoperative endoscopic recurrence (PER), which is usually quantified using a Rutgeerts scoring system,5 typically precedes clinical recurrence and PER was reported to occur in almost 58% of CD patients within 1 year of intestinal resection.6 In this issue, Lee et al. conducted a retrospective study to evaluate the factors influencing and recurrence rates of postoperative CD.7 Thirty-four patients who were regularly followed-up for at least 1 year after intestinal resection were analyzed. The mean follow-up period after intestinal resection was 65.4 months and their results showed a cumulative clinical recurrence rate of 8.8%, 12.5%, and 33.5% at 1, 2, and 4 years, respectively. Among 21 patients who had received colonoscopy after their intestinal resection, the cumulative PER was 42.9% and 66.1% at 1 and 2 years, respectively. Therefore, 27 out of 34 patients (79.1%) showed clinical or endoscopic recurrence after intestinal resection. Although the sample size in this study was small, and the duration of follow-up was relatively short, these results are comparable with data from Western countries. Given the increased incidence of CD in Korea and the resulting increase in intestinal resection, the prevention and management of postoperative recurrence is an important issue for Korean clinicians. As such, Lee et al.'s study-which is the first to report the recurrence rate and risk factors for CD after intestinal resection in Korea-is of particular relevance.7 A risk-stratified strategy involving tailored therapy according to high/low risk patient groups in order to prevent postoperative recurrence of CD was recently proposed. This postoperative management strategy included determining the risk factors of patients, identifying PER by performing colonoscopy 6-12 months after surgery, and promptly introducing preventive medications in order to reduce the recurrence rate. High-risk factors included smoking, perforating behavior, perianal disease, young age, repetitive surgery, and extensive bowel disease.8 In contrast, low-risk factors included the stricture behavior and old age at diagnosis. Until now, 5-aminosalicylates (5-ASA) and probiotics have not been proven to be effective in preventing postoperative recurrence of CD, whilst metronidazole has shown short-term benefits (3 months). Azathioprine/6-mercaptopurine (AZT/6-MP) has been proven to be effective and combined therapy with metronidazole and AZT/6-MP was more effective than metronidazole alone. In this issue, Lee et al. also demonstrated that patients who took immunomodulators to prevent postoperative recurrence had significantly lower recurrence rates than the 5-ASA group (P=0.042).7 These results are comparable with the large scale study by Park et al. in which early use of AZT was associated with a significantly delayed requirement for intestinal resection (hazard ratio: 0.63, 95% confidence interval: 0.46-0.85).3 Recent studies have also focused on the effectiveness of tumor necrosis factor (TNF)-α antagonists in treating and preventing PER, especially in high-risk patients. TNF-α antagonist therapy (including infliximab and adalimumab) seemed more effective than AZT in preventing and treating PER in many studies.9,10 Despite these studies being performed with few patients and without long-term follow-up, and although safety and cost issues should also be considered, the use of TNF-α antagonists is currently recommended as appropriate treatment in the high-risk patient group. In Korea, the efficacy of TNF-α antagonists in preventing the postoperative recurrence of CD has not yet been reported. Therefore, prospective large-scale studies are needed to clarify the burden of postoperative recurrence of CD and to determine the high-risk factors of recurrence in Korean CD patients. Furthermore, the efficacy of TNF-α antagonists in improving the long-term prognosis and quality of life of high-risk patients should be further investigated.

Tuberculosis Screening Before and During Treatment with Tumor Necrosis Factor Antagonists: Something Old, Something New

The increased risk of tuberculosis (TB) with tumor necrosis factor (TNF-α) antagonist treatment is well recognized1. The risk seems to parallel the background risk of TB. In Spain, where the incidence in the general population is 23/100,000, the incidence risk ratio of TB was 4.13 (95% CI 2.59–6.83) in patients with rheumatoid arthritis (RA) compared to the general population and 19.9 (95% CI 16.2–24.8) in patients with RA who were exposed to TNF-α antagonists compared to those who were not. In Sweden, where the incidence is 5/100,000, the incidence risk ratio was 2.0 (95% CI 1.2–3.4) in patients with RA and 4.0 (95% CI 1.3–12) in patients with RA using TNF-α antagonists1,2. In more than half of the patients, TB during TNF-α antagonist use is extrapulmonary and/or disseminated1. There seems to be a bimodal pattern with reactivation of latent TB early during the treatment course, with primary active TB usually developing later in the course. After the implementation of routine screening programs, with increased awareness of the clinical and radiological clues along with use of the tuberculin skin test (TST) and interferon-γ (IFN-γ) release assays (IGRA), a significant decrease in TB reactivation was observed among patients using TNF-α antagonists3. However, there is still no consensus on whether TST or IGRA should be preferred for screening in these patients, who are usually immunocompromised because of the character of their diseases and the immunosuppressives they use. In this issue of The Journal , Costantino, et al 4 report the results of TST and T-SPOT.TB assay in a large cohort of patients who are candidates for TNF-α antagonist therapy. The TST is a time-honored method of showing that one has been exposed to mycobacteria. Its potential shortcomings are giving false-positive results because of … Address correspondence to Dr. G. Hatemi, Associate Professor, Istanbul University, Cerrahpasa Medical School, Department of Internal Medicine, Division of Rheumatology, Istanbul 34300, Turkey. E-mail: gulenhatemi{at}yahoo.com

Recommendations for using TNFα antagonists and French Clinical Practice Guidelines endorsed by the French National Authority for Health

The use of TNFα antagonists must follow specific guidelines to ensure optimal effectiveness and safety. The French Society for Rheumatology (SFR) and Task Force on Inflammatory Joint Diseases (CRI), in partnership with several French learned societies, asked the French National Authority for Health (HAS) to develop and endorse good practice guidelines for the prescription and monitoring of TNFα antagonist therapy by physicians belonging to various specialties. These guidelines were developed, then, validated by two multidisciplinary panels of experts based on an exhaustive review of the recent literature and in compliance with the methodological rules set forth by the HAS. They pertain to the initial prescription of TNFα antagonists and to a variety of clinical situations that can arise during the follow-up of patients receiving TNFα antagonists (infections, malignancies, pregnancy, vaccination, paradoxical adverse events, surgery, use in older patients, and vasculitides).

Meta‐analysis: peri‐operative anti‐TNFα treatment and post‐operative complications in patients with inflammatory bowel disease

The impact of peri-operative use of TNFα antagonists on post-operative complications such as infection and wound healing is controversial. To conduct a systematic review and meta-analysis to assess the impact of peri-operative use of TNFα antagonists on post-operative complications such as infection and wound healing in patients with inflammatory bowel disease (IBD). A literature search identified studies that investigated post-operative outcomes in patients with IBD using TNFα antagonists. The primary outcome was the rate of post-operative infectious complications. Secondary outcomes included the rates of non-infectious complications and total complications. Odds ratios (OR) with 95% confidence intervals (CI) are reported. Overall, 18 studies with 4659 participants were eligible for inclusion. Patients with IBD using preoperative anti-TNFα therapies had significant increases in post-operative infectious [OR 1.56 (95% CI, 1.09-2.24)], non-infectious [OR 1.57 (95% CI, 1.14-2.17)] and total complications [OR 1.73 (95% CI, 1.23-2.43)]. Studies limited to patients with Crohn's disease demonstrated a statistically significant increase in infectious (OR 1.93, 95% CI 1.28-2.89) and total (OR 2.19, 95% CI 1.69-2.84) complications, and a trend towards increase in non-infectious complications (OR 1.73, 95% CI 0.94-3.17). Studies of patients with ulcerative colitis did not demonstrate significant increases in infectious (OR 1.39, 95% CI 0.56-3.45), non-infectious (OR 1.40, 95% CI 0.68-2.85), or total complications (OR 1.10, 95% CI 0.81-1.47). Anti-TNFα therapies appear to increase the risk of post-operative complications. The increase in risk is small, and may well reflect residual confounding rather than a true biological effect. Nevertheless, physicians should exercise caution when continuing biological therapies during the peri-operative period.

Liver Injury From Tumor Necrosis Factor-α Antagonists: Analysis of Thirty-four Cases

Tumor necrosis factor (TNF)-α antagonists have been associated with drug-induced liver injury (DILI). We reviewed cases of DILI in the United States to identify those associated with use of TNF-α antagonists. We searched the U.S. DILI Network (DILIN) database, from 2003 to 2011, for cases associated with TNF-α antagonists. Mean Roussel-Uclaf Causality Assessment Method scores were calculated. A DILIN severity score was assigned according to a previously published scale, and we identified 6 subjects likely to have DILI associated with use of TNF-α antagonists. We also searched PubMed for articles that reported hepatotoxicity from TNF-α antagonists, identifying 28 additional cases suitable for analysis. The drugs presumed to have caused DILI were infliximab (n = 26), etanercept (n = 4), and adalimumab (n = 4). The anti-TNF-α agent was the probable cause of 12 cases of DILI (35%), a very likely cause for 21 (62%), and a definite cause for 1 (3%). Median latency was 13 weeks (range, 2-104); however, 7 cases (20%) had latency periods longer than 24 weeks. Twenty-two of 33 subjects who underwent serologic analysis (67%) tested positive for anti-nuclear and/or smooth muscle antibodies. Of these 22, 17 underwent liver biopsy; 15 subjects had clear features of autoimmunity. The 22 subjects with autoimmune features had longer median latency (16 vs 10 weeks) and higher peak levels of alanine aminotransferase (784 vs 528 U/L) than the 12 without such features. There was 1 case of severe cholestasis. All but one subject improved after discontinuation of the implicated drug; 12 subjects received corticosteroid therapy. No deaths were attributed to liver injury, although one patient with preexistent cirrhosis required liver transplantation. Acute liver injury caused by TNF-α antagonists may be a class effect because multiple agents in this category have been implicated. The most common presentation is an autoimmune phenotype with marked hepatocellular injury, but a mixed non-autoimmune pattern or predominant cholestasis also occurs. The prognosis is usually good after drug discontinuation, although some patients may benefit from a course of corticosteroids. ClinicalTrials.gov: Number, NCT00345930.

A Case of Etanercept Induced Palmoplantar Pustular Psoriasis

Observations: Etanercept is a human recombinant soluble tumor necrosis factor  (TNF-α) receptor fusion protein. Etanercept has been used successfully to treat a wide range of inflammatory disorders including psoriasis and psoriatic arthritis resistant to classical disease-modifying treatments. The widespread use of TNF-α antagonists led to the recognition of adverse effects. Herein, we report a case of palmoplantar pustular psoriasis in a 37-year-old man during the etanercept therapy.

Complications of TNF-α antagonists and iron homeostasis

TNF-α is a central regulator of inflammation and its blockade downregulates other pro-inflammatory cytokines, chemokines, and growth factors. Subsequently, TNF-α antagonists are currently used in treatment regimens directed toward several inflammatory diseases. Despite a beneficial effect, the use of TNF-α antagonists is associated with an increased risk for infections and neoplasms; the basis for these complications is unclear. This cytokine also participates in iron homeostasis and the sequestration of this metal, mediated by TNF-α, is considered protective. We hypothesize that treatment with TNF-α antagonists predisposes the patient to infections and neoplasms by reversing the sequestration of host iron mediated by the cytokine and increasing available concentrations of this metal. It is recommended that patients who are to receive TNF-α antagonists be tested for iron overload and the use of these agents in those individuals with excess iron should be reconsidered. Furthermore, it is predicted that alternative attempts to treat inflammatory diseases by blocking other pivotal cytokines that also participate in iron homeostasis (e.g. IFN-γ, IL-1, and IL-6) will similarly be associated with infections and neoplastic complications.

Leishmaniasis in rheumatoid arthritis

Leishmaniasis represents a complex of diseases with an important clinical and epidemiological diversity. Visceral leishmaniasis is of higher priority than cutaneous leishmaniasis as it is a fatal disease in the absence of treatment. The clinical spectrum of leishmaniasis and control of the infection are influenced by the parasite-host relationship. The role of cellular immune responses of the Th1 type in the protection against disease in experimental and human leishmaniasis is well established. TNF-alpha has been implicated in cytokine-induced macrophage activation and tissue granuloma formation, two activities linked to control of intracellular visceral infection caused by Leishmania donovani. Anti-tumor necrosis factor-alpha (TNF-alpha) strategies have had a marked and substantial impact in the treatment of rheumatoid arthritis, however the clinical use of TNF-alpha antagonists has been accompanied by increased reporting of infections. Here we report the first case of visceral leishmaniasis in a patient treated for a long period of time with human anti TNF-alpha monoclonal antibody, adalimumab. Due to the low incidence rate of Mediterranean visceral leishmaniasis, a systematic screening for leishmaniasis in all patients treated with biologics may be not recommended. However, for those patients living at high risk of leishmaniasis exposure, a periodical serological monitoring should be performed during therapy with anti-TNF monoclonal antibodies.

S08 * ESBRA-NIAAA JOINT SYMPOSIUM ALCOHOLIC LIVER DISEASE: FROM PATHOGENESIS TO TREATMENT * S08.1 * INCREASING BURDEN OF ALCOHOLIC LIVER DISEASE 2011

S08 * ESBRA-NIAAA JOINT SYMPOSIUM ALCOHOLIC LIVER DISEASE: FROM PATHOGENESIS TO TREATMENT * S08.1 * INCREASING BURDEN OF ALCOHOLIC LIVER DISEASE 2011

Does Anti-Tumor Necrosis Factor-α Therapy Affect Risk of Serious Infection and Cancer in Patients with Rheumatoid Arthritis?: A Review of Longterm Data

Given the important role tumor necrosis factor-α (TNF-α) antagonists play in managing rheumatoid arthritis and the concern for safety during longterm therapy, we reviewed the latest evidence regarding longterm risk of infection and malignancy with TNF-α antagonists. Our objective was to provide clinicians with information that can be used to counsel and monitor patients who may be candidates for biologic therapy for rheumatoid arthritis (RA). Risk is examined in the context of background infection and malignancy rates in RA. Randomized controlled trial (RCT) data and observational studies summarizing the risk of infection and/or malignancy in RA and specific risks associated with the use of anti-TNF-α biologic agents (adalimumab, infliximab, and etanercept) were identified through a PubMed search. Overall, patients with RA appear to have an approximately 2-fold increased risk of serious infection compared to the general population and non-RA controls, irrespective of TNF-α antagonist use. Although data on infection rates with TNF-α antagonist use are contradictory, caution is merited. Recent analyses suggest that the risk of infection is highest within the first year. Regarding malignancy risk, RCT and observational data are also conflicting; how ever, caution is warranted regarding lymphoproliferative cancers in children and adolescents.

Diabetes mellitus and insulin resistance in patients with rheumatoid arthritis: Risk reduction in a chronic inflammatory disease

To perform a systematic literature review of the potential association among molecular markers of inflammation, alterations in body composition, and insulin resistance (IR), a precursor to type 2 diabetes mellitus (DM), in rheumatoid arthritis (RA) patients. To determine the impact of tumor necrosis factor α (TNFα) as a pivotal proinflammatory cytokine in the pathophysiology of type 2 DM and RA, and the effect of antirheumatic drugs on glycemic control. We performed a search of PubMed to identify articles on IR and body habitus in patients with RA. Patients with RA had characteristics placing them at high risk for IR and type 2 DM. The incidence and prevalence of type 2 DM in RA was not clearly increased compared with the general population; however, studies suggested that patients with RA are likely to have IR and have increased risk of cardiovascular disease (CVD). The prevalence of type 2 DM and IR could be estimated from reports of risk factors for CVD in RA patients. The TNFα antagonists provided rapid and effective control of RA-related inflammation. Evidence indicated that extended use of TNFα antagonists in RA may provide the additional benefit of improving insulin sensitivity. These treatment-related changes may contribute to an overall reduction in the risk of type 2 DM and CVD in RA patients. Controlling inflammation may improve insulin sensitivity and subsequently reduce the risk of developing type 2 DM in RA patients. This may also reduce the risk of CVD in this high-risk group. Future studies are required to elucidate the relationships between inflammation, body composition, IR, TNFα antagonist use, and the risk of developing type 2 DM in RA patients.

Efficacy of tumour necrosis factor‐α antagonists in aphthous ulceration: review of published individual patient data

Severe aphthous ulceration may require systemic immunosuppressive or immunomodulatory therapy, but a small subset of patients remains resistant to or intolerant of these agents. Although use of TNF-α antagonists in aphthous ulceration is increasingly reported, the current evidence base for use is weak and evaluation of individual cases may provide the best available data to support such use. The aim of this study was to review all published data on the use of TNF-α antagonists in patients with severe aphthous ulceration refractory to systemic agents and discusses this in the context of any possible benefits that may guide any future use. A comprehensive search on MEDLINE and EMBASE from 1995 to 2010 was performed using pre-defined search terms, with articles included if they met specific criteria. Sixteen cases from individual case reports or small case-series in which use of TNF-α antagonists in aphthous ulceration were identified in which details of previous systemic therapy and use of subsequent adjunctive therapy were available. Agents with reported success in resolving active ulceration and reducing ulcer recurrence were infliximab, etanercept and adalimumab. Evidence for efficacy of TNF-α antagonists in aphthous ulceration infection is limited. Such data suggest that in patients with severe aphthous ulceration TNF-α antagonists have some efficacy in inducing ulcer resolution and reducing recurrence. These agents may represent an option in severe refractory aphthosis, although in the absence of controlled studies, caution is advocated if use is to be considered.