Tuberculosis infection in patients with rheumatoid arthritis and the effect of infliximab therapy

OBJECTIVE: According to the Centers for Disease Control and Prevention, the 1999 and 2000 incidence rates for tuberculosis (TB) in the US population were 6.4 and 5.8, respectively, per 100,000 persons. Recently, reports of TB following infliximab administration have raised questions regarding the rate of TB in patients with rheumatoid arthritis (RA) generally and in those treated with infliximab in clinical practice. We undertook this study to determine the baseline rate of TB in RA prior to the introduction of infliximab and to determine the rate of TB among those currently receiving infliximab. METHODS: We surveyed patients with questionnaires, followed by detailed validation from medical records and physician reports. In study 1, we evaluated 10,782 RA patients in 1998-1999 prior to the widespread use of infliximab. In study 2, we evaluated 6,460 infliximab-treated patients in 2000-2002. RESULTS: In study 1, the lifetime rate of TB was 696 per 100,000 patients (95% confidence interval [95% CI] 547-872). Of these cases, 76.8% occurred prior to the onset of RA. During the period of prospective followup, 1 case of TB developed during 16,173 patient-years of followup, yielding a rate of 6.2 cases (95% CI 1.6-34.4) per 100,000 patients. In study 2, the TB incidence rate among infliximab-treated patients was 52.5 cases (95% CI 14.3-134.4) per 100,000 patient-years of exposure. Three of the 4 cases occurred in patients with a history of TB exposure, and no cases occurred in persons with recent TB skin tests or prophylaxis. CONCLUSION: The rate of TB is not increased in RA patients generally. Among infliximab-treated patients, the rate is 52.5 cases (95% CI 14.3-134.4) per 100,000 patient-years of exposure. A thorough medical history regarding TB, as well as tuberculin testing and radiographic examination (if indicated), should be an essential component of anti-tumor necrosis factor therapy.     

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.     

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.

     

Significant risk and associated factors of active tuberculosis infection in Korean patients with inflammatory bowel disease using anti-TNF agents

AIM:To evaluate the incidence and risk factors of Korean tuberculosis(TB) infection in patients with inflammatory bowel disease(IBD) undergoing anti-TNF treatment.METHODS:The data of IBD patients treated with anti-TNFs in 13 tertiary referral hospitals located in the southeastern region of Korea were collected retrospectively.They failed to show response or were intolerant to conventional treatments,including steroids or immunomodulators.Screening measures for latent TB infection(LTBI)and the incidence and risk factors ofactive TB infection after treatment with anti-TNFs were identified.RESULTS:Overall,376 IBD patients treated with antiTNF agents were recruited(male 255,mean age of anti-TNF therapy 32.5±13.0 years);277 had Crohn’s disease,99 had ulcerative colitis,294 used infliximab,and 82 used adalimumab.Before anti-TNF treatment,screening tests for LTBI including an interferon gamma release assay or a tuberculin skin test were performed in 82.2%of patients.Thirty patients(8%)had LTBI.Sixteen cases of active TB infection including one TB-related mortality occurred during 801 personyears(PY)follow-up(1997.4 cases per 100000 PY)after anti-TNF treatment.LTBI(OR=5.76,95%CI:1.57-21.20,P=0.008)and WBC count5000 mm3(OR=4.5,95%CI:1.51-13.44,P=0.007)during follow-up were identified as independently associated risk factors.CONCLUSION:Anti-TNFs significantly increase the risk of TB infection in Korean patients with IBD.The considerable burden of TB and marked immunosuppression might be attributed to this risk.     

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.     

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.     

Time‐dependent increased risk for serious infection from continuous use of tumor necrosis factor antagonists over three years in patients with rheumatoid arthritis

Objective

To investigate associations between continuous treatments with tumor necrosis factor (TNF) antagonists and risk for developing serious infections (SIs) over 3 years in Japanese patients with rheumatoid arthritis (RA) enrolled in the Registry of Japanese RA Patients for Long‐Term Safety (REAL) database.

Methods

We analyzed 727 RA patients who had started either infliximab or etanercept (the anti‐TNF group; 1,480.1 patient‐years [PY]) and 571 RA patients who had started conventional nonbiologic disease‐modifying antirheumatic drugs (the unexposed group; 1,104.1 PY) at the time of enrollment in the REAL. We assessed the occurrence of SIs within a 3‐year observation period, including the period after switching to other TNF antagonists, and all SIs, unlimited to the first one in each patient as reported in other studies, to evaluate the real safety of TNF antagonists in daily practice.

Results

The incidence rate of SIs per 100 PY was 5.54 (95% confidence interval [95% CI] 4.44–6.84) in the anti‐TNF group and 2.72 (95% CI 1.87–3.83) in the unexposed group. Poisson regression analysis revealed that the relative risk (RR) of continuous use of TNF antagonists for SIs after adjusting for baseline and time‐dependent covariates was significantly elevated both overall (1.97, 95% CI 1.25–3.19) and for the first year (2.40, 95% CI 1.20–5.03), but not for the second and third years combined (1.38, 95% CI 0.80–2.43). The adjusted RR for SIs of etanercept compared to infliximab was not significantly elevated.

Conclusion

Continuous anti‐TNF therapy was significantly associated with increased risks for developing SIs during, but not after, the first year.     

Effectiveness of recommendations to prevent reactivation of latent tuberculosis infection in patients treated with tumor necrosis factor antagonists

OBJECTIVE: To investigate the impact of official recommendations regarding the management of latent tuberculosis (TB) infection on the rate of active TB in patients receiving treatment with tumor necrosis factor (TNF) antagonists. METHODS: Data on active TB rates and on screening and treatment of latent TB infection were extracted from the BIOBADASER (Spanish Society of Rheumatology Database on Biologic Products), a registry of patients with rheumatic conditions treated with TNF antagonists. The rates of active TB among the BIOBADASER patients were compared with those in the background Spanish population, and BIOBADASER patients with rheumatoid arthritis (RA) were compared with a cohort of RA patients from the EMECAR (Morbidity and Clinical Expression of Rheumatoid Arthritis) study who were not treated with TNF antagonists and were followed up for 5 years. RESULTS: Active TB developed in 34 patients, of whom 32 started taking TNF antagonists prior to the official recommendations on latent TB infection (pre-OR) and 2 began treatment after the recommendations were issued (post-OR). All cases of TB occurred during treatment with infliximab, and 28 of these patients had RA. Pre-OR, the active TB rate in BIOBADASER patients was 20.9-fold higher than in the background Spanish population, while RA patients in the BIOBADASER had rates 22.6- and 6.2-fold higher than the background and EMECAR populations, respectively. Post-OR, 324 patients with a tuberculin skin test result > or =5 mm and/or chest radiograph findings suggestive of past TB were treated for 9 months with isoniazid (INH). Post-OR, active TB rates among the BIOBADASER patients decreased by 78% (incidence risk ratio [IRR] 0.22, 95% confidence interval [95% CI] 0.03-0.88; P = 0.008), while among RA patients in the BIOBADASER, the rate dropped by 83% and reached the EMECAR rate (IRR 1.0, 95% CI 0.02-8.2). There were no INH treatment-related hospitalizations or deaths. CONCLUSION: Strategies to treat latent TB infection that are tailored to the at-risk population can effectively and safely lessen the likelihood of active TB in patients treated with TNF antagonists.     

Influence of methotrexate, TNF blockers and prednisolone on antibody responses to pneumococcal polysaccharide vaccine in patients with rheumatoid arthritis

OBJECTIVE: To compare antibody responses to 23-valent pneumococcal vaccine (Pneumovax) in controls and patients with established rheumatoid arthritis (RA) treated with TNF blockers, methotrexate (MTX) or a combination of both. METHODS: Patients with RA (n = 149) and healthy controls (n = 47) were vaccinated. Treatment with TNF blockers (etanercept or infliximab) and MTX was given to 50 patients, and 62 patients were treated with TNF blockers alone or with other DMARDs. MTX alone was given to 37 patients. Concentrations of immunoglobulin G (IgG) antibodies against pneumococcal capsular polysaccharides 23F and 6B were measured by enzyme-linked immunoassay before and 4-6 weeks after vaccination. An immune response was defined as a twofold or higher increase in antibody concentration following vaccination. RESULTS: Prevaccination antibody levels for both 23F and 6B were similar in the patient groups. Antibody concentrations after vaccination increased significantly in all groups. Patients treated with TNF blockers without MTX showed better immune responses than those treated with TNF blockers in combination with MTX (P = 0.037 for 23F and P = 0.004 for 6B) or MTX alone (P<0.001 for both 23F and 6B). RA patients given MTX alone had the lowest immune responses. Prednisolone treatment did not influence the responses. CONCLUSIONS: Patients treated with TNF blockers and controls showed similar responses to vaccination. In contrast, patients treated with MTX had reduced responses regardless of anti-TNF treatment. The findings do not argue against the use of pneumococcal vaccination in RA patients undergoing treatment with TNF blockers.     

<Emphasis Type="Italic">Listeria</Emphasis> infections associated with infliximab: case reports

Infliximab is a human-murine chimeric monoclonal antibody directed against tumor necrosis factor α (TNFα). Infliximab and other TNF blockers are used to treat inflammatory diseases such as rheumatoid arthritis (RA). TNF blockers are suspected to play a key role in some infections. We report here two cases of Listeria monocytogenes sepsis associated with infliximab treatment for RA. The first patient developed a terminal ileitis and a bacteraemia after three doses of infliximab; the second RA patient presented a bacteraemia associated with a prosthetic joint arthritis of the left hip, both related to Listeria. Those two cases occurred in a population of 518 patients treated with TNF blockers in our hospitals since the year 2000. Those events are of particular interest because of the severity of the infection, because the treatment differs from other infections, and because that, in the rheumatology unit, septic arthritis can mimic RA symptoms. They enhance the likelihood for this drug to increase the risk for infections with germs like Listeria.     

Risk of tuberculosis is higher with anti–tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: The three‐year prospective french research axed on tolerance of biotherapies registry

Objective

Tuberculosis (TB) is associated with anti–tumor necrosis factor (anti‐TNF) monoclonal antibody (mAb) therapy, but whether this association is drug‐specific remains a concern. Our objective was to describe cases of TB associated with anti‐TNF mAb therapy, identify risk factors, and estimate the incidence.

Methods

We conducted an incidence study and a case–control analysis to investigate the risk of newly diagnosed TB associated with the use of anti‐TNF agents. As part of the French Research Axed on Tolerance of Biotherapies (RATIO) registry, for 3 years we collected cases of TB among French patients receiving anti‐TNF mAb therapy for any indication; for each case, 2 patients treated with anti‐TNF agents served as control subjects.

Results

We collected 69 cases of TB in patients treated for rheumatoid arthritis (n = 40), spondylarthritides (n = 18), inflammatory colitis (n = 9), psoriasis (n = 1) and Behçet's disease (n = 1) with infliximab (n = 36), adalimumab (n = 28), and etanercept (n = 5). None of the patients had received correct chemoprophylactic treatment. The sex‐ and age‐adjusted incidence rate of TB was 116.7 per 100,000 patient‐years. The standardized incidence ratio (SIR) was 12.2 (95% confidence interval [95% CI] 9.7–15.5) and was higher for therapy with infliximab and adalimumab than for therapy with etanercept (SIR 18.6 [95% CI 13.4–25.8] and SIR 29.3 [95% CI 20.3–42.4] versus SIR 1.8 [95% CI 0.7–4.3], respectively). In the case–control analysis, exposure to infliximab or adalimumab versus etanercept was an independent risk factor for TB (odds ratio [OR] 13.3 [95% CI 2.6–69.0] and OR 17.1 [95% CI 3.6–80.6], respectively). Other risk factors were age, the first year of anti‐TNF mAb treatment, and being born in an endemic area.

Conclusion

The risk of TB is higher for patients receiving anti‐TNF mAb therapy than for those receiving soluble TNF receptor therapy. The increased risk with early anti‐TNF treatment and the absence of correct chemoprophylactic treatment favor the reactivation of latent TB.

     

Influenza vaccination as model for testing immune modulation induced by anti-TNF and methotrexate therapy in rheumatoid arthritis patients

OBJECTIVES: To compare serological response to influenza vaccine in patients with long-standing rheumatoid arthritis (RA) treated with tumour necrosis factor (TNF) blockers and/or methotrexate (MTX) and controls. METHODS: Altogether, 149 patients with RA and 18 healthy subjects were vaccinated. Fifty patients were treated with TNF blockers (etanercept or infliximab) in combination with MTX (TNF blockers + MTX), while 62 patients received TNF blockers alone or with other disease-modifying anti-rheumatic drugs (DMARDs) (TNF blockers without MTX). Thirty-seven patients were treated with MTX without TNF blockers (MTX). Vaccination was performed with trivalent vaccine (Influvax or Vaxigrip) both containing 15 microg haemagglutination inhibition (HI) of each of two A strains (H1N1 and H3N2) and one of B strains (B1 or B2). Serum samples were collected prior to and 4-6 weeks after vaccination and titrated against all four strains using HI assay. A positive immune response was defined as > or =4-fold increase compared with pre-vaccination titre levels. A titre > or =40 was considered protective. Pre- and post-vaccination geometric mean titres (GMT) were compared. RESULTS: Post-vaccination titre levels increased significantly in all groups, also reflected by high frequencies of positive immune responders. A positive immune response to combinations of all strains was significantly better for the MTX group. Individuals with protective levels before vaccination responded less well as a group. CONCLUSIONS: RA patients treated with MTX without TNF blockers had significantly better serological response to influenza vaccination compared with those receiving TNF blockers alone or in combination with MTX and/or other DMARDs. However, the immune response is sufficiently large to warrant influenza vaccination to all RA patients regardless of treatment.     

Drug retention rates and relevant risk factors for drug discontinuation due to adverse events in rheumatoid arthritis patients receiving anticytokine therapy with different target molecules

OBJECTIVE: To compare reasons for discontinuation and drug retention rates per reason among anticytokine therapies, infliximab, etanercept and tocilizumab, and the risk of discontinuation of biological agents due to adverse events (AE) in patients with rheumatoid arthritis (RA). METHOD: This prospective cohort study included Japanese RA patients who started infliximab (n=412, 636.0 patient-years (PY)), etanercept (n=442, 765.3 PY), or tocilizumab (n=168, 206.5 PY) as the first biological therapy after their enrolment in the Registry of Japanese Rheumatoid Arthritis Patients for Long-term Safety (REAL) database. Drug retention rates were calculated using the Kaplan-Meier method. To compare risks of drug discontinuation due to AE for patients treated with these biological agents, the Cox proportional hazard model was applied. RESULTS: The authors found significant differences among the three therapeutic groups in demography, clinical status, comorbidities and usage of concomitant drugs. Development of AE was the most frequent reason for discontinuation of biological agents in the etanercept and tocilizumab groups, and the second most frequent reason in the infliximab group. Discontinuation due to good control was observed most frequently in the infliximab group. Compared with etanercept, the use of infliximab (HR 1.69; 95% CI 1.14 to 2.51) and tocilizumab (HR 1.98; 95% CI 1.04 to 3.76) was significantly associated with a higher risk of discontinuation of biological agents due to AE. CONCLUSIONS: Reasons for discontinuation are significantly different among biological agents. The use of infliximab and tocilizumab was significantly associated with treatment discontinuation due to AE compared with etanercept.     

TNF blockers and tuberculosis: an Indian concern

Reactivation of latent tuberculosis (TB) with TNF blockers is a cause of concern particularly in developing countries like India, which has a high burden of TB infection. Although etanercept and infliximab are available in India, published data on Indian experience are scant. Limited data indicate that risk of reactivation of TB is substantially increased. With the growing use of these agents in India inspired by encouraging results in various rheumatic conditions a rise in cases of TB is expected. At present, no guidelines exist in India with regard to treatment of latent TB. Indian rheumatologists must adopt a rational approach when treating rheumatic diseases with TNF blockers.     

The infectious profiles of anti‐tumor necrosis factor agents in a Thai population: a retrospective study a the university‐based hospital

Aims: Anti‐tumour necrosis factor‐α (anti‐TNF) agents represented treatment advances in a number of rheumatologic diseases. However, adverse effects of anti‐TNF agents have been identified through both clinical trials and post‐marketing surveillance, especially an increased risk of serious infections. This study firstly described the infectious profiles of anti‐TNF agents in a Thai population. Methods: We retrospectively reviewed all infectious incidences from 100 consecutive medical records of patients who were treated with either etanercept or infliximab for any rheumatologic and non‐rheumatologic conditions. Results: Indications for anti TNF‐α agents were mainly rheumatoid arthritis (46%) and spondyloarthropathy (SpA) (41%). Seventy‐seven patients were treated with etanercept and 23 with infliximab. For those whose initial treatment was etanercept, there were two events of suspected active pulmonary tuberculosis (TB) and suspected hepatitis‐B virus (HBV) reactivation. Two out of 23 patients (8.7%) who were firstly treated with infliximab had herpes zoster skin infection. Incidence of overall infection before anti‐TNF treatment were significantly higher in patient who started with etanercept (0.065 vs. 0.019 cases per person‐years in etanercept and infliximab respectively, P < 0.0001). Incidence of overall infection post‐anti‐TNF treatment were 0.122 and 0.201 cases per person‐years in patients who started with etanercept and infliximab with no significant difference (P > 0.05). The overall infection rates were significantly increased after infliximab treatment (P < 0.0001). Conclusion: Even thought there were two new events of TB and HBV reactivation after etanercept treatment, incidence of overall infection seemed to be increased after infliximab treatment. The infectious screening and monitoring with high index of suspicion as well as the pre‐emptive treatment are still important whenever either etanercept or infliximab is started.     

Increased risk of tuberculosis in patients with rheumatoid arthritis

OBJECTIVE: To quantify the risk of tuberculosis (TB) in an unselected sample of patients with rheumatoid arthritis (RA) compared to the risk in the general population. METHODS: The incidence of TB in the general population of Spain was obtained from the National Network of Epidemiological Surveillance reports. The incidence of TB was ascertained from a cohort of 788 patients with RA selected randomly from the registries of 34 participating centers throughout Spain. A patient was considered a TB case only if information about disease symptoms, microorganism identification, and TB treatment were confirmed in the clinical records. The relative risk of TB in RA was calculated by dividing the standardized mean incidence of TB from 1990 to 2000 in the RA cohort by the mean incidence of TB in Spain during the same years. RESULTS: The mean incidence of TB in the general population of Spain from 1990 to 2000 was 23 cases per 100,000. Seven cases of TB were identified in the RA cohort, yielding a mean annual incidence (1990-2000) of 134/100,000 patients. The incidence risk ratio of pulmonary TB in patients with RA compared to the general population is 3.68 (95% CI 2.36-5.92). CONCLUSION: We found a 4-fold increased risk of TB infection in patients diagnosed with RA. These results might help to interpret the magnitude of the problem attributable to the introduction of new therapies in RA.     

Anti-nuclear antibodies, anti-DNA and C4 complement evolution in rheumatoid arthritis and ankylosing spondylitis treated with TNF-alpha blockers

OBJECTIVE: To investigate autoantibody induction in rheumatoid arthritis (RA) and ankylosing spondylitis (AS) in a cohort of French patients treated with TNF-alpha blockers. METHODS: We tested the serum of patients for antinuclear antibodies (ANA), anti-DNA antibodies and C4 complement at baseline, and for each infusion for infliximab, and at month 3, 6 and 12 for etanercept. We looked for all signs suggesting a drug-induced lupus. We tried to correlate ANA and anti-DNA development with various clinical data, especially the response to treatment. RESULTS: 229 patients were included in the study. 159 were treated with infliximab (98 RA and 61 AS) and 125 with etanercept (116 RA and 9 AS). In the infliximab group, 43.6% of RA patients and 27.1% of AS had significant levels of ANA at baseline. This proportion increased during the follow up to 73% in RA patients and 52% in AS patients. The proportion of patients positive for anti-DNA antibodies increased from 0% to 9.5% in RA group, and from 0% to 2% in AS group. In the etanercept group, 58.5% of these patients had significant levels of ANA at baseline; this proportion raised to 63.3% in patients previously treated with infliximab, and fell to 20.6% in the patients who never received TNF-alpha blockers. No significant variation of ANA, anti-DNA and C4 levels was observed in the etanercept group. Only three patients developed clinical manifestations (chilblain lupus) possibly related to these auto-antibodies, two with infliximab and one with etanercept. CONCLUSION: The ANA induction was only observed under infliximab therapy. Thus, ANA induction seems not to be a therapeutic class effect. This difference between infliximab and etanercept treatment may be the consequence of differential capacity of a monoclonal antibody and a soluble receptor in inducing apoptotic cell death of the cells expressing TNF on their membrane.     

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.     

Tumour necrosis factor blockers do not increase overall tumour risk in patients with rheumatoid arthritis, but may be associated with an increased risk of lymphomas

OBJECTIVE: To determine whether TNF blockers increase tumour risk in patients with RA. MATERIALS AND METHODS: The South Swedish Arthritis Treatment Group register (SSATG) comprises over 90% of anti-TNF treated patients with RA in the area. 757 patients treated with etanercept or infliximab included between 1 February 1999 and 31 December 2002 were identified. 800 patients with conventional antirheumatic treatment in a community based cohort served as a comparison cohort. Tumours and deaths were identified in the cancer registry and population census registers. Patients were followed up from initiation of anti-TNF treatment or 1 July 1997 for the comparison group, until death or 31 December 2002. RESULTS: In the anti-TNF group, 16 tumours (5 lymphomas) were identified in 1603 person-years at risk, and in the comparison group 69 tumours (2 lymphomas) in 3948 person-years. Standardised incidence ratios (SIRs) for total tumour relative risk for the anti-TNF group and the comparison group were 1.1 (95% confidence interval (CI) 0.6 to 1.8) and 1.4 (95% CI 1.1 to 1.8), respectively. The lymphoma relative risk (RR) was 11.5 (95% CI 3.7 to 26.9) and 1.3 (95% CI 0.2 to 4.5), respectively The total tumour RR excluding lymphoma was 0.79 (95% CI 0.4 to 1.42) and 1.39 (95% CI 1.08 to 1.76), respectively. Proportional hazard analysis for lymphomas yielded RR 4.9 (95% CI 0.9 to 26.2) in anti-TNF treated versus untreated patients. CONCLUSION: Community based patients with RA treated conventionally had an increased overall tumour risk compared with the background population. A possible additional increased risk for lymphoma associated with TNF blockers was based on few cases and needs confirmation.     

Etanercept,infliximab, and leflunomide in established rheumatoid arthritis: clinical experience using a structured follow up programme in southern Sweden

OBJECTIVE: To explore the feasibility of prospectively monitoring treatment efficacy and tolerability of infliximab, etanercept, and leflunomide over a two year period in patients with established rheumatoid arthritis (RA) in clinical practice using a structured protocol. METHODS: All patients with RA at seven centres in southern Sweden, for whom at least two disease modifying antirheumatic drugs, including methotrexate, had failed or not been tolerated, who started treatment with either infliximab, etanercept, or leflunomide were included. They were evaluated at predefined times using a standardised protocol including items required for evaluating response to the American College of Rheumatology (ACR) or EULAR criteria. All adverse events were recorded using World Health Organisation terminology. Concomitant treatment and survival while receiving a drug were recorded. RESULTS: During the study 166 patients were treated with etanercept, 135 with infliximab, and 103 with leflunomide. Treatment response as determined by the ACR and EULAR response criteria was similar for the tumour necrosis factor (TNF) blockers. The TNF blockers performed significantly better than leflunomide both as determined by the response criteria and by survival on drug analysis. Thus 79% and 75% continued to receive etanercept or infliximab compared with 22% of patients who started leflunomide after 20 months. The spectrum of side effects did not differ from those previously reported in the clinical trials. The initial two year experience of a protocol for postmarketing surveillance of etanercept, infliximab, and leflunomide shows that a structured protocol with central data handling can be used in clinical practice for documenting the performance of newly introduced drugs. CONCLUSIONS: Efficacy data for the TNF blockers comply with results in clinical trials, whereas leflunomide appeared to perform worse than in clinical trials. Prolonged monitoring is required to identify possible rare side effects.