All-cause and cause-specific mortality in rheumatoid arthritis are not greater than expected when treated with tumour necrosis factor antagonists

BACKGROUND: Mortality is increased in rheumatoid arthritis (RA), mainly because of cardiovascular (CV) events, cancer and infections. Recent data suggest that treatment with tumour necrosis factor (TNF) antagonists may affect this trend. OBJECTIVE: To assess whether treatment with TNF antagonists is associated with reduction in CV events, cancer and infection rates, and in mortality in patients with RA treated and not treated with TNF antagonists. METHODS: BIOBADASER is a registry for active long-term follow-up of safety of biological treatments in patients with RA. It includes 4459 patients with RA treated with TNF antagonists. EMECAR is an external RA cohort (n = 789) established to define the characteristics of the disease in Spain and to assess comorbidity. The incidence density (ischaemic heart disease) of CV events, cancer and infections was estimated and compared. The standardised mortality ratio was compared with the rate in the general population. A propensity score was used to match cohorts by the probability of being treated. RESULTS: Rates of CV and cancer events are significantly higher in EMECAR than in BIOBADASER (RR 5-7 for different CV events, and RR 2.9 for cancer), whereas the rate of serious infections is significantly higher in BIOBADASER (RR 1.6). Mortality ratio of BIOBADASER by EMECAR is 0.32 (0.20-0.53) for all causes of death, 0.58 (0.24-1.41) for CV events, 0.52 (0.21-1.29) for infection and 0.36 (0.10-1.30) for cancer-related deaths. CONCLUSION: Morbidity, other than infection, and mortality are not higher than expected in patients with RA treated with TNF antagonists.     

Risk of tuberculosis in patients treated with tumor necrosis factor antagonists due to incomplete prevention of reactivation of latent infection

OBJECTIVE: To evaluate the causes of new cases of active tuberculosis (ATB) in patients treated with tumor necrosis factor (TNF) antagonists included in the national registry BIOBADASER (Base de Datos de Productos Biológicos de la Sociedad Espa?ola de Reumatología) after the dissemination of recommendations to prevent reactivation of latent tuberculosis infection (LTBI). METHODS: Incidence rate of ATB per 100,000 patient-years and 95% confidence intervals (95% CIs) were calculated in patients entering BIOBADASER after March 2002 and were stratified by compliance with recommendations (complete or incomplete). ATB rates in BIOBADASER were compared with the background rate and the rate in the rheumatoid arthritis cohort EMECAR (Estudio de la Morbilidad y Expresión Clínica de la Artritis Reumatoide) not treated with TNF antagonists. In addition, rates of ATB among patients treated with adalimumab, etanercept, and infliximab were estimated and compared only for treatments started after September 2003, when all 3 drugs became fully available. RESULTS: Following March 2002, a total of 5,198 patients treated with a TNF antagonist were registered in BIOBADASER. Fifteen ATB cases were noted (rate 172 per 100,000 patient-years, 95% CI 103-285). Recommendations were fully followed in 2,655 treatments. The probability of developing ATB was 7 times higher when recommendations were not followed (incidence rate ratio 7.09, 95% CI 1.60-64.69). Two-step tuberculosis skin test for LTBI was the major failure in complying with recommendations. CONCLUSION: New cases of ATB still occur in patients treated with all available TNF antagonists due to lack of compliance with recommendations to prevent reactivation of LTBI. Continuous evaluation of recommendations is required to improve clinical practice.     

Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: A multicenter active‐surveillance report

Objective

The long‐term safety of therapeutic agents that neutralize tumor necrosis factor (TNF) is uncertain. Recent evidence based on spontaneous reporting shows an association with active tuberculosis (TB). We undertook this study to determine and describe the long‐term safety of 2 of these agents, infliximab and etanercept, in rheumatic diseases based on a national active‐surveillance system following the commercialization of the drugs.

Methods

We analyzed the safety data actively collected in the BIOBADASER (Base de Datos de Productos Biológicos de la Sociedad Española de Reumatología) database, which was launched in February 2000 by the Spanish Society of Rheumatology. For the estimation of TB risk, the annual incidence rate in patients treated with these agents was compared with the background rate and with the rate in a cohort of patients with rheumatoid arthritis (RA) assembled before the era of anti‐TNF treatment.

Results

Seventy‐one participating centers sent data on 1,578 treatments with infliximab (86%) or etanercept (14%) in 1,540 patients. Drug survival rates (reported as the cumulative percentage of patients still receiving medication) for infliximab and etanercept pooled together were 85% and 81% at 1 year and 2 years, respectively. Instances of discontinuation were essentially due to adverse events. Seventeen cases of TB were found in patients treated with infliximab. The estimated incidence of TB associated with infliximab in RA patients was 1,893 per 100,000 in the year 2000 and 1,113 per 100,000 in the year 2001. These findings represent a significant increased risk compared with background rates. In the first 5 months of 2002, after official guidelines were established for TB prevention in patients treated with biologics, only 1 new TB case was registered (in January).

Conclusion

Therapy with infliximab is associated with an increased risk of active TB. Proper measures are needed to prevent and manage this adverse event.

     

Metronidazole prevents reactivation of latent Mycobacterium tuberculosis infection in macaques

Targeting Mycobacterium tuberculosis bacilli in low-oxygen microenvironments, such as caseous granulomas, has been hypothesized to have the potential to shorten therapy for active tuberculosis (TB) and prevent reactivation of latent infection. We previously reported that upon low-dose M. tuberculosis infection, equal proportions of cynomolgus macaques develop active disease or latent infection and that latently infected animals reactivated upon neutralization of TNF. Using this model we now show that chemoprophylaxis of latently infected cynomolgus macaques with 6 mo of isoniazid (INH) effectively prevented anti-TNF antibody-induced reactivation. Similarly, 2-mo treatment of latent animals with a combination of INH and rifampicin (RIF) was highly effective at preventing reactivation disease in this model. Metronidazole (MTZ), which has activity only against anaerobic, nonreplicating bacteria, was as effective as either of these treatments in preventing reactivation of latent infection. Because hypoxic lesions also occur during active TB, we further showed that addition of MTZ to INH/RIF effectively treated animals with active TB within 2 mo. Healing lesions were associated with distinct changes in cellular pathology, with a shift toward increasingly fibrotic and calcified lesions. Our data in the nonhuman primate model of active and latent TB supports targeting bacteria in hypoxic environments for preventing reactivation of latent infection and possibly shortening the duration of therapy in active TB.     

Comprehensive tuberculosis screening program in patients with inflammatory arthritides treated with golimumab,a human anti–tumor necrosis factor antibody,in Phase III clinical trials

Objective

Reactivation of Mycobacterium tuberculosis infection is a major complication in patients treated with anti–tumor necrosis factor (anti‐TNF) agents. We report on the 5 cases of active tuberculosis (TB) that developed in the Golimumab Phase III Program (3 with rheumatoid arthritis, 1 with psoriatic arthritis, and 1 with ankylosing spondylitis) through 1 year among 2,210 patients receiving golimumab.

Methods

Data from global studies were used for an in‐depth evaluation of the 5 cases of TB through week 52. Integrated safety data were evaluated for potential hepatotoxicity in patients treated with anti‐TB therapy.

Results

No active TB developed among 317 patients receiving golimumab and treated for latent TB with isoniazid. Active TB occurred in 5 patients not treated with isoniazid by week 52 (in 2 patients by week 24); all of the patients had negative TB screening tests (per the local guidelines) and resided in countries with high background rates of TB. No deaths were due to TB. Across all of the groups (placebo and golimumab), alanine aminotransferase and aspartate aminotransferase elevations occurred in greater proportions of patients treated for latent TB infection versus not treated; elevations were largely mild (<3 times the upper limit of normal).

Conclusion

Comprehensive TB screening kept the number of active TB cases relatively low despite conducting the studies in TB‐endemic regions. Treatment for latent TB infection appeared effective, since no patients treated for latent TB had TB reactivation. Concurrent treatment with golimumab and anti‐TB medication was generally well tolerated. Clinicians should remain vigilant for development of active TB after initiation of TNF inhibitors, since prompt diagnosis and treatment can improve outcomes.     

Rates of serious infection,including site‐specific and bacterial intracellular infection,in rheumatoid arthritis patients receiving anti–tumor necrosis factor therapy: Results from the British Society for Rheumatology Biologics Register

Objective

To determine whether the rate of serious infection is higher in anti–tumor necrosis factor (anti‐TNF)–treated rheumatoid arthritis (RA) patients compared with RA patients treated with traditional disease‐modifying antirheumatic drugs (DMARDs).

Methods

This was a national prospective observational study of 7,664 anti‐TNF–treated and 1,354 DMARD‐treated patients with severe RA from the British Society for Rheumatology Biologics Register. All serious infections, stratified by site and organism, were included in the analysis.

Results

Between December 2001 and September 2005, there were 525 serious infections in the anti‐TNF–treated cohort and 56 in the comparison cohort (9,868 and 1,352 person‐years of followup, respectively). The incidence rate ratio (IRR), adjusted for baseline risk, for the anti‐TNF–treated cohort compared with the comparison cohort was 1.03 (95% confidence interval 0.68–1.57). However, the frequency of serious skin and soft tissue infections was increased in anti‐TNF–treated patients, with an adjusted IRR of 4.28 (95% confidence interval 1.06–17.17). There was no difference in infection risk between the 3 main anti‐TNF drugs. Nineteen serious bacterial intracellular infections occurred, exclusively in patients in the anti‐TNF–treated cohort.

Conclusion

In patients with active RA, anti‐TNF therapy was not associated with increased risk of overall serious infection compared with DMARD treatment, after adjustment for baseline risk. In contrast, the rate of serious skin and soft tissue infections was increased, suggesting an important physiologic role of TNF in host defense in the skin and soft tissues beyond that in other tissues.

     

Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report

OBJECTIVE: The long-term safety of therapeutic agents that neutralize tumor necrosis factor (TNF) is uncertain. Recent evidence based on spontaneous reporting shows an association with active tuberculosis (TB). We undertook this study to determine and describe the long-term safety of 2 of these agents, infliximab and etanercept, in rheumatic diseases based on a national active-surveillance system following the commercialization of the drugs. METHODS: We analyzed the safety data actively collected in the BIOBADASER (Base de Datos de Productos Biológicos de la Sociedad Espa?ola de Reumatología) database, which was launched in February 2000 by the Spanish Society of Rheumatology. For the estimation of TB risk, the annual incidence rate in patients treated with these agents was compared with the background rate and with the rate in a cohort of patients with rheumatoid arthritis (RA) assembled before the era of anti-TNF treatment. RESULTS: Seventy-one participating centers sent data on 1,578 treatments with infliximab (86%) or etanercept (14%) in 1,540 patients. Drug survival rates (reported as the cumulative percentage of patients still receiving medication) for infliximab and etanercept pooled together were 85% and 81% at 1 year and 2 years, respectively. Instances of discontinuation were essentially due to adverse events. Seventeen cases of TB were found in patients treated with infliximab. The estimated incidence of TB associated with infliximab in RA patients was 1,893 per 100,000 in the year 2000 and 1,113 per 100,000 in the year 2001. These findings represent a significant increased risk compared with background rates. In the first 5 months of 2002, after official guidelines were established for TB prevention in patients treated with biologics, only 1 new TB case was registered (in January). CONCLUSION: Therapy with infliximab is associated with an increased risk of active TB. Proper measures are needed to prevent and manage this adverse event.     

Mycobacterial Infections in Patients Treated with Tumor Necrosis Factor Antagonists in South Korea

Background

The aims of this study were to determine the incidence of tuberculosis (TB) and nontuberculous mycobacteria (NTM) lung disease in patients who were treated with tumor necrosis factor (TNF) antagonists in South Korea and to evaluate their clinical characteristics.

Methods

We surveyed all patients (N = 509) who were treated with TNF antagonists at Severance Hospital, South Korea, between January 2002 and December 2011. We reviewed the patients’ medical records and collected microbiological, radiographic, and clinical data, including the type of TNF blocker(s) used and the results of tuberculin skin tests and interferon-gamma release assays.

Results

Rheumatoid arthritis (43.6 %) and ankylosing spondylitis (27.9 %) were the most common diseases in the patients treated with TNF antagonists. Patients received etanercept (33.4 %), infliximab (23.4 %), or adalimumab (13.2 %). The remaining patients received two or more TNF antagonists (30 %). Nine patients developed TB, and four patients developed NTM lung disease. After adjustment for age and sex, the standardized TB incidence ratio was 6.4 [95 % CI 3.1–11.7] compared with the general population. The estimated NTM incidence rate was 230.7 per 100,000 patients per year.

Conclusions

Our results show that mycobacterial infections increase in patients treated with TNF antagonists. The identification of additional predictors of TB for the treatment of latent tuberculosis infection and the careful monitoring and timely diagnosis of NTM-related lung disease are needed for patients who receive long-term therapy with TNF antagonists.     

Asian Organization for Crohn's and Colitis and Asia Pacific Association of Gastroenterology consensus on tuberculosis infection in patients with inflammatory bowel disease receiving anti‐tumor necrosis factor treatment. Part 2: Management

Because anti‐tumor necrosis factor (anti‐TNF) therapy has become increasingly popular in many Asian countries, the risk of developing active tuberculosis (TB) among anti‐TNF users may raise serious health problems in this region. Thus, the Asian Organization for Crohn's and Colitis and the Asia Pacific Association of Gastroenterology have developed a set of consensus statements about risk assessment, detection and prevention of latent TB infection, and management of active TB infection in patients with inflammatory bowel disease (IBD) receiving anti‐TNF treatment. Twenty‐three consensus statements were initially drafted and then discussed by the committee members. The quality of evidence and the strength of recommendations were assessed by using the Grading of Recommendations Assessment, Development, and Evaluation methodology. Web‐based consensus voting was performed by 211 IBD specialists from nine Asian countries concerning each statement. A consensus statement was accepted if at least 75% of the participants agreed. Part 2 of the statements comprised three parts: (3) management of latent TB in preparation for anti‐TNF therapy, (4) monitoring during anti‐TNF therapy, and (5) management of an active TB infection after anti‐TNF therapy. These consensus statements will help clinicians optimize patient outcomes by reducing the morbidity and mortality related to TB infections in patients with IBD receiving anti‐TNF treatment.     

Serious infections in patients with rheumatoid arthritis and other immune-mediated connective tissue diseases exposed to anti-TNF or rituximab: data from the Spanish registry BIOBADASER 2.0

Data on infections in patients exposed to biologic therapies are mainly focused on rheumatoid arthritis (RA). Little is known about the safety profile in other immune-mediated connective tissue diseases (ICTD). The purpose of this study was to describe and to compare the risk of serious infections (SI) in patients with RA and other ICTD on anti-TNF or rituximab and to identify predictors of SI. We analyzed RA or other ICTD patients on anti-TNF or rituximab included in the Spanish registry BIOBADASER 2.0 (2000–2011). For each disease group, incidence rate (IR), mortality rate (MR) and IR ratio (IRR) of SI with 95 % CI were estimated. Risks were then standardized by age and sex to the general population. Risk factors for SI were assessed by Poisson regression models. A total of 3,301 patients on anti-TNF (n = 3,166) or rituximab (n = 135), of which 176 (5 %) had ICTD other than RA, were analyzed. IR of SI was higher in non-RA ICTD than in RA, with an IRR of 3.15 (95 % CI 1.86, 5.31) before adjustment and 1.96 (95 % CI 1.06, 3.65) after adjustment for age, comorbidity and corticoid use. Mortality due to infections was higher in ICTD although it did not reach statistical significance. Age, disease duration, comorbidities, corticosteroids and ICTD different to RA were all independently associated with SI. Patients with ICTD other than RA are at a high risk of SI when prescribed anti-TNF or rituximab, partly due to the excess comorbidity and immunosuppressive co-treatment, but also to the inflammatory disease. When evaluating the risk/benefit ratio of off-label medications in ICTD patients, age, comorbidities and corticoid use should carefully be taken into account, applying adequate preventive measures.     

我国部分地区肿瘤坏死因子拮抗剂使用人群的结核病预防性治疗情况分析

目的 了解中国部分地区应用肿瘤坏死因子(tumor necrosis factor,TNF)拮抗剂治疗的患者结核病预防性治疗情况。方法 搜集2014年3月至2016年2月中国东、中、西部13家三级甲等综合医院接诊的应用依那西普或英夫利西单抗治疗的类风湿关节炎(rheumatoid arthritis,RA)或强直性脊柱炎(ankylosing spondylitis,AS)患者作为研究对象,共981例。收集研究对象的性别、年龄、激素和免疫抑制剂使用情况、并发基础疾病情况、结核病既往史、结核分枝杆菌潜伏感染(LTBI)筛查情况、胸部X线摄片(简称“胸片”)或胸部CT扫描结果、结核病预防性治疗情况。分析应用TNF拮抗剂的RA或AS患者筛查LTBI和非活动性肺结核的比例,进行结核病预防性治疗的比例以及采用的治疗方案。结果 981例研究对象中应用依那西普者779例(79.4%),应用英夫利西单抗者202例(20.6%)。仅有25.7%(252/981)的研究对象进行LTBI筛查,阳性率为18.3%(46/252)。2.8%(27/981)的研究对象诊断为非活动性肺结核,其中,有结核病既往史者19例。712例(72.6%)研究对象进行了胸片检查和(或)胸部CT扫描,报告非活动性肺结核者13例(1.8%)。共15例研究对象进行了结核病预防性治疗;并发LTBI者中有6例(13.0%,6/46)进行结核病预防性治疗;诊断为非活动性肺结核者均未进行结核病预防性治疗。进行结核病预防性治疗者中,应用异烟肼单药预防方案者9例(60.0%,9/15),疗程1~18个月不等。结论 中国部分地区目前应用TNF拮抗剂治疗的RA或AS患者的LTBI筛查比例低,进行结核病预防性治疗比例低,预防对象选择标准不一且预防方案不规范。     

Asian Organization for Crohn's and Colitis and Asian Pacific Association of Gastroenterology consensus on tuberculosis infection in patients with inflammatory bowel disease receiving anti‐tumor necrosis factor treatment. Part 1: Risk assessment

Because anti‐tumor necrosis factor (anti‐TNF) therapy has become increasingly popular in many Asian countries, the risk of developing active tuberculosis (TB) among anti‐TNF users may raise serious health problems in this region. Thus, the Asian Organization for Crohn's and Colitis and the Asian Pacific Association of Gastroenterology have developed a set of consensus statements about risk assessment, detection, and prevention of latent TB infection and management of active TB infection in patients with inflammatory bowel disease (IBD) receiving anti‐TNF treatment. Twenty‐three consensus statements were initially drafted and then discussed by the committee members. The quality of evidence and the strength of recommendations were assessed by using the Grading of Recommendations Assessment, Development, and Evaluation methodology. Web‐based consensus voting was performed by 211 IBD specialists from nine Asian countries concerning each statement. A consensus statement was accepted if at least 75% of the participants agreed. Part 1 of the statements comprised two parts: (i) risk of TB infection during anti‐TNF therapy and (ii) screening for TB infection prior to commencing anti‐TNF therapy. These consensus statements will help clinicians optimize patient outcomes by reducing the morbidity and mortality related to TB infections in patients with IBD receiving anti‐TNF treatment.     

Risk of serious bacterial infections among rheumatoid arthritis patients exposed to tumor necrosis factor α antagonists

Objective

To evaluate the risk of serious bacterial infections associated with tumor necrosis factor α (TNFα) antagonists among rheumatoid arthritis (RA) patients.

Methods

A retrospective cohort study of US RA patients enrolled in a large health care organization identified patients who received either TNFα antagonists or methotrexate (MTX). Administrative data were used to identify hospitalizations with possible bacterial infections; corresponding medical records were abstracted and reviewed by infectious disease specialists for evidence of definite infections. Proportional hazards models evaluated time‐dependent infection risks associated with TNFα antagonists.

Results

Hospital medical records with claims‐identified suspected bacterial infections were abstracted (n = 187) among RA patients who received TNFα antagonists (n = 2,393; observation time 3,894 person‐years) or MTX (n = 2,933; 4,846 person‐years). Over a median followup time of 17 months, the rate of hospitalization with a confirmed bacterial infection was 2.7% among the patients treated with TNFα antagonists compared with 2.0% among the patients treated with MTX only. The multivariable‐adjusted hazard ratio (HR) of infection among the patients who received TNFα antagonists was 1.9 (95% confidence interval [95% CI] 1.3–2.8) compared with patients who received MTX only. The incidence of infections was highest within 6 months after initiating TNFα antagonist therapy (2.9 versus 1.4 infections per 100 person‐years; multivariable‐adjusted HR 4.2, 95% CI 2.0–8.8).

Conclusion

The multivariable‐adjusted risk of hospitalization with a physician‐confirmed definite bacterial infection was ∼2‐fold higher overall and 4‐fold higher in the first 6 months among patients receiving TNFα antagonists versus those receiving MTX alone. RA patients were at increased risk of serious infections, irrespective of the method used to define an infectious outcome. Patients and physicians should vigilantly monitor for signs of infection when using TNFα antagonists, particularly shortly after treatment initiation.

     

Risk of tuberculosis in a Chinese registry of rheumatoid arthritis and ankylosing spondylitis for tumour necrosis factor‐α antagonists

Aim: To understand the risk of tuberculosis (TB) infection in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS) who required tumour necrosis factor‐α (TNF‐α) antagonist treatment. Methods: Patients with RA and AS who were screened for infliximab and etanercept treatment for up to 6 months were entered in a registry between 2003 and 2005. The purified protein derivative (PPD) test and chest anteroposterior and lateral view X‐ray were performed at screening. The risk of TB infection in theses patients was observed during follow up. Results: Among 67 RA patients screened, a positive PPD reaction was found in one patient. Of the 169 AS patients screened, 23 were positive for the PPD reaction, two had pulmonary TB calcinosis and two were diagnosed as having pulmonary TB. The incidence of PPD positive reaction and pulmonary TB calcinosis or active TB in our screened RA and AS patients was significantly lower than that reported in the recent fourth national TB infection rates and prevalence (P < 0.01). Only one patient with RA developed neck lymph node TB 6 months after completion of infliximab infusion. Conclusion: Patients with AS and RA are not at an increased risk of TB infection if screened properly before short course treatment with anti‐TNF‐α agents.     

Safety of tumor necrosis factor inhibitors use for rheumatoid arthritis and ankylosing spondylitis in Africa, the Middle East, and Asia: focus on severe infections and tuberculosis

Multiple studies of patients in Western countries with rheumatoid arthritis (RA) and ankylosing spondylitis (AS) have indicated increased risk for active tuberculosis (TB) and other infections among these individuals. It has also been consistently reported that patients receiving tumor necrosis factor (TNF) inhibitors for these conditions have higher rates of active TB and other infections than RA or AS patients not receiving these medications. These issues have been studied less extensively in the Asia and Africa–Middle East regions, and information from these regions is important because of higher rates of TB in the general population. This paper reviews studies of RA and AS patients from Asia, Africa, and the Middle East who received TNF inhibitors. A literature search was conducted using http://www.ncbi.nlm.nih.gov/pubmed to collect and report these data. The years included in the PubMed literature search ranged from January 2000 to October 2011. Additionally, information from the China Hospital Knowledge Database was used to report data from Chinese patients with RA and AS treated with TNF inhibitors. Results from these studies indicate that the risk for active TB and other infections in AS and RA patients from Asia, Africa, and the Middle East are increased in patients receiving TNF inhibitors and that the risk is higher among those treated with monoclonal antibodies versus soluble TNF receptor.     

Incidence of tuberculosis in Korean patients with rheumatoid arthritis (RA): effects of RA itself and of tumor necrosis factor blockers

OBJECTIVE: To elucidate the incidence rate and relative risk of tuberculosis (TB) in patients with rheumatoid arthritis (RA) and in patients with RA treated with tumor-necrosis-factor (TNF) blockers in Korea. METHODS: Using data from the Korean National Tuberculosis Association (KNTA) as a control and data from a single-center cohort of patients with RA, we conducted an evaluation of 1285 patients with RA not exposed to TNF blockers and reviewed medical records of 90 and 103 patients with RA treated with infliximab and etanercept, respectively, between 2001 and 2005. RESULTS: The mean incidence rate of TB, reported by the KNTA, was 67.2 per 100,000 person years (PY) from 2001 to 2004. In the TNF-blocker-na?ve RA cohort, 9 cases of TB developed during 3497 PY of followup (257 per 100,000). In the infliximab-treated RA group, 2 cases of TB developed during 78.17 PY of followup (2558 per 100,000 PY), and there was no case of TB during 73.67 PY of followup in the etanercept-treated RA group. The risk of TB was higher in RA patients not treated with TNF blockers (sex- and age-adjusted risk ratio 8.9; 95% confidence interval 4.6-17.2), and in those treated with infliximab (sex- and age-adjusted risk ratio, 30.1; 95% confidence interval, 7.4-122.3) compared with the general Korean population. CONCLUSION: The risk of TB infection is 8.9-fold higher in Korean patients with RA and 30.1-fold higher in RA patients treated with infliximab, compared with the general Korean population.     

Comparison of tuberculosis incidence in ankylosing spondylitis and rheumatoid arthritis during tumor necrosis factor inhibitor treatment in an intermediate burden area

Clinical characteristics of antitumor necrosis factor (TNF) agents-related tuberculosis (TB) in ankylosing spondylitis (AS) are not well described. The aim was to compare the incidences and the characteristics of TB in AS and rheumatoid arthritis (RA) during TNF inhibitor treatment. AS (n?=?1,322) and RA (n?=?3,154) patients who received medical care between January 2001 and August 2011 were enrolled. The incidence of TB in patients treated, or not, with TNF inhibitors and the clinical features associated with TB were explored. Seven patients with AS and seven with RA developed TB while receiving TNF inhibitor therapy, resulting in an incidence rate of 600.2/100,000 person-years (PYs) (95 % confidence interval (CI), 241.3–1236.3) for those with AS and 771.6/100,000 PYs (95 % CI, 310.2–1589.9) for those with RA. Incidence rate ratios for TNF inhibitor-treated vs. untreated patients were 4.87 for AS (95 % CI, 1.50–15.39; p?p?p?=?0.002). Extrapulmonary TB was predominant at 85.7 % during TNF inhibitor treatment. Three (42.8 %) of the AS patients, but none of the RA patients, developed TB with concomitant isoniazid. All AS patients recovered from TB whereas two of seven RA patients died. Treatment with TNF inhibitors significantly increases the risk of extrapulmonary TB in AS. Symptoms of infection should warrant clinicians to evaluate for TB during TNF inhibitor therapy in AS patients.     

Effectiveness of the combination of a whole-blood interferon-gamma assay and the tuberculin skin test in detecting latent tuberculosis infection in rheumatoid arthritis patients receiving adalimumab therapy

OBJECTIVE: To investigate QuantiFERON-tuberculosis Gold (QFT-G) assay and tuberculin skin test (TST) for latent tuberculosis (TB) infection (LTBI) in patients with rheumatoid arthritis (RA) treated with adalimumab. METHODS: We prospectively followed up 43 RA patients who received adalimumab therapy and underwent serial TSTs and QFT-G assays. TST was performed using Mantoux method and QFT-G assay was examined by measuring interferon-gamma levels in whole blood samples that were incubated with early secretary antigenic target-6 and culture filtrate protein 10. RESULTS: Before starting adalimumab therapy, 8 RA patients (18.6%) had positive and 35 (81.4%) had negative TST results. All 8 RA patients with positive TST results were diagnosed as LTBI and received isoniazid prophylaxis (INHP) 1 month before starting adalimumab therapy. None of these 8 RA patients developed active TB 2 years after completing INHP. A high rate (10 [37.0%] patients) of TST conversion was observed among 27 patients who had completed 12-month adalimumab therapy. Of these 10 patients with TST conversion, 2 patients had positive QFT-G results and 1 developed active TB disease. Among 17 RA patients who did not have TST conversion after 12-month adalimumab therapy, 1 patient who had a positive QFT-G result developed active TB disease. Of all 43 RA patients who received adalimumab therapy, 4 (9.3%) developed active TB after starting adalimumab therapy. CONCLUSION: The application of TST for detecting LTBI is limited in RA patients by the frequent presence of anergy. Combined QFT-G assay and TST can aid in detecting LTBI in RA patients receiving adalimumab therapy.     

Tuberkulose im Kindesalter

The prevention, diagnosis and treatment of childhood tuberculosis (TB) remain a challenge. As a result of an increased risk of disease progression after infection in children <?5 years of age, prophylactic treatment with isoniazide (INH) for 3 months is indicated after contact with infected TB patients. For patients with (asymptomatic) latent TB, treatment with INH for 9 months or INH and rifampicine (RMP) for 3 months is indicated for all children and adolescents. Uncomplicated active TB in children can most commonly be treated with a combination of RMP, INH and pyrazinamide (PZA) during the first 2 months followed by a combination of RMP and PZA for the following 4 months. Especially in young children, rapid diagnosis and treatment is crucial because of an increased risk of disseminated life-threatening tuberculosis. The worldwide increase in drug-resistant TB is challenging and children and adolescents should be managed out in specialist centers.     

Tuberculosis infection in rheumatic patients with infliximab therapy: experience with 157 patients

It is recommended to evaluate the presence of latent tuberculosis infection (LTBI) prior to the use of antitumor necrosis factor α. The aim of this study is to assess the presence of LTBI in patients with rheumatic diseases undergoing treatment with infliximab in an endemic area for tuberculosis (TB). LTBI was searched through the contact history, chest X-ray and tuberculin skin test with purified protein derivative (PPD) ≥5 mm. We studied 157 patients in the period from May 2005 to October 2008, 99 (63.1%) were women with average age of 49 years and 58 (36.9%) were men with average age of 41 years. The group comprising 90 patients (57.3%) with rheumatoid arthritis (RA), 54 (34.4%) with ankylosing spondylitis (AS) and 13 (8.3%) with psoriatic arthritis (PsA) had PPD reactor 13.4% (21/157), being prevented by isoniazid (INH) in these patients. There are dissimilar responsiveness to the PPD between the three pathologies, and the reactivity was lower in RA (RA × AS: χ(2) = 12; P = 0.0004; and RA × PsA: χ(2) with Yates' correction = 3.6; P = 0.05). No significant difference between the reactivity of the PPD and the use of immunosuppressive drugs (P = 0.81) is observed. The immunoprophylaxis with INH showed an efficacy of 95% (20/21); three (1.9%) patients developed active TB (spondylodiscitis, meningitis and lymphadenopathy) after the use of infliximab, reaffirming extrapulmonary involvement. These results suggest that PPD has a low sensitivity for detection of LTBI in RA and that the previous use of immunosuppressive drugs does not affect the response to PPD.