We review the global experience of infections in patients treated with tumour necrosis factor (TNF)-α inhibitors, which shows that the overall incidence of severe infections is at least doubled. In particular, this is true regarding tuberculosis. Screening and prophylactic measures have substantially reduced but not eliminated the risk. Recent improvements in immunologic testing for non-Bacillus Calmette–Guerin (BCG)-related antigens allow more sensitive identification of latent tuberculosis and wider use of such methods holds promise as pre-treatment screening instruments.
Tumour necrosis factor alpha (TNF-α), synthesised by macrophages in response to pro-inflammatory stimuli, acts as a central mediator of inflammation and immune regulation and it is also an important mediator of sepsis . Its role in rheumatoid arthritis (RA) pathogenesis has been largely demonstrated .
The introduction of anti-TNF-α treatment more than 10 years ago has significantly improved the treatment of inflammatory joint diseases, such as RA, ankylosing spondylitis (AS) and psoriatic arthritis (PsA) .
The efficacy of anti-TNF-α treatment was confirmed in several clinical trials on either inflammation or joint bone damage.
Despite the satisfactory efficacy, there have always been concerns about the safety of biological drugs. In the long-term surveillance of TNF-α inhibitors, serious adverse events (SAEs), particularly due to intracellular organism infections (tuberculosis (TB) and other granulomatous infections), were observed .
Epidemiologic studies have shown that RA patients have an increased risk of bacterial infection compared with the general population . Some studies have also shown that methotrexate (MTX) is associated with an increased incidence of infection .
In clinical practice, it is sometimes difficult to separate the risk deriving from the use of anti-TNF-α treatment from other possible causes.
Most frequent infections in different therapies
A number of bacterial, viral and fungal infections occurred in patients with rheumatic diseases treated with anti-TNF-α . the risk of infection is higher early after initiating treatment and decreases with prolonged exposure to anti-TNF-α treatment .
Listing et al. followed up for 3 years about 1000 RA patients and 601 control patients treated with TNF-α (512 patients receiving etanercept and 346 patients receiving infliximab) and anakinra (70 patients). The total number of adverse events per 100 patient-years was 22.6 (95% confidence interval (95% CI) 18.7–27.2) among patients receiving etanercept, 28.3 (95% CI 23.1–34.7) among patients receiving infliximab and 6.8 (95% CI 5.0–9.4) among controls ( P < 0.0001) .
By contrast, meta-analyses of RA and in PsA studies did not evidence an increased risk of infections with any of the three biologic agents. The meta-analytic and exposure-adjusted pooled analyses in randomised controlled trials, involving 18 randomised trials with about 8808 patients treated over an average of 0.8 years, did not identify an increased risk of SAEs with recommended doses .
Infliximab
In 2001, in infliximab-treated patients, Keane reported about 190 cases of TB and Wallis et al. observed 335 cases up to September 2002 . Most of these patients were a progression or reactivation of latent TB infection (TBLI) and the median time to diagnosis after initiation of TNF blockers was 12 weeks. A large part of patients developed extrapulmonary TB, and disseminated disease was very frequent .
The analysis of incidence rates in USA of RA with infliximab showed that, in untreated patients, the rate was 6.2 TB cases per 100,000 patient-years versus 52.2 cases of infliximab-treated patients . This datum was confirmed in another study , which found a rate of TB in infliximab-treated patients as 54 per 100,000 patients.
Further, histoplasmosis reactivation was reported in Ref. : listeriosis and coccidioidomycosis were found in infliximab-treated patients .
The Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis (ATTRACT) study reported a similar incidence of serious infections in patients receiving MTX alone or in combination with infliximab, in different doses (3 or 10 mg kg −1 every 4 or 8 weeks) after 1 and 2 years of follow-up. The most common serious infections were pneumonia, TB, sepsis, bronchitis and septic bursitis. None occurred in patients treated with MTX alone.
In the early RA receiving MTX alone or in combination with infliximab, in two different doses 3 and 6 mg kg −1 every 8 weeks Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset (ASPIRE) study, serious infections were significantly more common in patients treated with MTX and infliximab, than with only MTX .
Etanercept
From November 1998 to March 2002, a total of 25 reports of TB associated with etanercept therapy has been reported to the Food and Drug Administration (FDA): 17 cases were from USA, seven from Europe and one from India .
In a 2-year study comparing etanercept versus MTX, a similar incidence of SAEs was reported: 4%, 2% and 3% for MTX, etanercept 10 and 25 mg, respectively in Ref. . In addition in the first year of the Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes (TEMPO) trial, which analysed the safety of etanercept alone or in combination with MTX , the incidence of infections and serious infections were similar, also during the 2-year follow-up: no TB infections were registered but a case of bronchopulmonary aspergillosis was observed.
In the Add Enbrel or Replace Methotrexate (ADORE) study , only two severe infections were observed in the etanercept monotherapy and one in the combination group.
In RA patients without concomitant disease-modifying antirheumatic drug (DMARD) therapy, etanercept showed a favourable safety profile and consistent efficacy throughout the 5-year study duration. No reports of demyelinating disease, serious blood dyscrasias or opportunistic infections were reported. Rates of serious infections decreased over the 5-year period and only one case of suspected TB was reported in Ref. .
Adalimumab
The first studies with adalimumab have shown a low incidence of serious infections . In the Anti-TNF Research Study Program of the Monoclonal Antibody D2E7 in Patients with Rheumatoid Arthritis (ARMADA) trial, one serious infection was observed during the first year. Rate of infection was similar in the adalimumab and in MTX monotherapy arm , such as in the Safety Trial of Adalimumab in Rheumatoid arthritis (STAR) study, combining adalimumab 40 mg to traditional therapy . In the following 4-year open-label extension of the ARMADA study, the most common serious infections were pneumonia, urinary tract infections and septic arthritis, but no cases of TB or opportunistic infections were reported in Ref. . In the 26 weeks’ study, the incidence of serious infections was higher in the adalimumab group, but in the following 1-year study , serious infections were associated mainly to the combination therapy.
The analysis of controlled and open-label trials with adalimumab identified a rate of serious infections of 5.1 in 100 patient-years of exposure .
Certolizumab
In the RAPID 1 study, mild/moderate adverse events occurred in 52.8%, 56.0% and 50.8% of patients in the placebo, certolizumab pegol 200 mg and 400 mg groups, respectively. The most frequently reported adverse events included urinary tract infection, upper respiratory tract infection and headache for certolizumab pegol 200 mg . Serious infections occurred in 3.2% and 2.4% certolizumab pegol 200 mg and 400 mg, respectively. Serious infections on certolizumab pegol 200 mg included one case each of erysipelas, disseminated TB, peritoneal and pulmonary TB, gastroenteritis, postoperative wound infection, tooth abscess and urosepsis. Certolizumab pegol 400 mg was associated with one case of erysipelas, pneumonia and upper respiratory tract infection and two cases of sinusitis and TB . Five patients in the certolizumab pegol arms developed TB: at screening, two of these five patients had purified protein derivative (PPD) reactions of 4–5 mm with normal chest X-ray findings and one patient with a PPD reaction (6 mm) had also an abnormal chest X-ray . These data were confirmed in the following study, RAPID 2 .
Golimumab
In the first study on efficacy and safety of golimumab in RA, the overall rate of infections in each of the active drug groups was no greater than in the placebo group. During the follow-up of 52 weeks, three cases of pneumonia ( Haemophilus influenzae , Streptococcus pneumoniae and Legionella ) were reported in the golimumab-treated patients .
In a 24-week study, to assess the safety and the efficacy of golimumab in MTX-naïve patients with active RA , the incidence of serious infections was similar across treatment groups. A case of TB of the spine was diagnosed in a patient 33 days after she received golimumab treatment at week 8.
In the GO-FORWARD study, serious infections were greater in patients treated with golimumab and MTX than with golimumab and with MTX alone. A patient died due to sepsis after an ileus and aspiration pneumonia. No cases of TB or opportunistic infections were observed .
In the golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor α inhibitors GO-AFTER study, 460 RA patients discontinued at least one anti-TNF-α and were treated with a stable dose of DMARDs (MTX, sulphasalazine, hydroxycholoquine, steroids and non-steroidal anti-inflammatory drugs (NSAIDs)). For weeks 1–24, occurrence of infections was similar in the three arms of treatments and serious infections were uncommon. No patient developed TB or opportunistic infections .
In a 48 weeks’ study, RA patients on intravenous golimumab alone or in combination with MTX were assessed.43 During the first 16 weeks’ placebo-controlled period, adverse event rates were slightly higher in patients receiving golimumab plus MTX than in patients receiving golimumab monotherapy. Higher proportions of all golimumab-treated patients than MTX-treated patients had SAEs through week 16. No cases of TB or opportunistic infections were reported. Through 48 weeks in the golimumab group, 82% of infections were observed and 72% infections in the MTX group. In golimumab-treated patients, the most frequent adverse events were: upper respiratory infections (12% in the golimumab group vs. 9% in the placebo-MTX group), bronchitis (7% vs. 5%); nasopharyngitis (6% vs. 5%); urinary tract infections (6% vs. 2%); and sinusitis (5% for both) .
Data from registries
Clinical trials and post-marketing analysis are fundamental to monitor the safety profile of biologic therapies. Other good instruments are the national or local registries. The data are extrapolated from the real-world setting and are not biased on inclusion/exclusion criteria, mandatory for the clinical trials.
The ‘RA observation of Biologic Therapies’ (RABBIT) German registry evidenced a significant difference between patients treated with infliximab or etanercept and patients with only DMARDs therapy. On these three regimens, higher incidence of infections (28.3, 22.6 and 6.8/100,000 patients/year, respectively) and serious infections were observed .
In the Swedish registry, an increased risk of hospitalisation due to infections was observed during the first year of treatment and decreased with the prolongation of treatment .
No increase of overall risk of serious infection was observed in British patients treated with anti-TNF-α and those treated with DMARDs only, except for serious skin and soft-tissue infections. These had a significantly greater incidence in anti-TNF-α patients than in DMARDs patients. Similar data were observed also for serious intracellular infections ( Mycobacterium , Legionella pneumophila , Listeria monocytogenes or Salmonella ) . No differences were recorded between etanercept, adalimumab and infliximab.
In France, the ‘Recherche Axée sur la Tolérance des Biothérapies’ (RATIO) registry collected data on opportunistic and severe infections occurring in patients treated on anti-TNF-α. The registry recorded an increased risk of Legionella pneumonia (10 cases in 1 year) (six cases treated with adalimumab, two treated with etanercept and two treated with infliximab).
The Spanish registry ‘BIOBADASER’ followed about 7000 treated patients. Through the period 2000–2006, 907 episodes of infection were observed and the incidence was 53.09 cases per 1000 patient-years (CI 95% 49.69–56.66). The most frequent infections were cutaneous (12.18 cases/1000 patient-years), pneumonia (5.97 cases/1000 patient-years), cystitis (3.92 cases/1000 patient-years), TB (3.51 cases/1000 patient-years) and arthritis (3.76 cases/1000 patient-years). The most common pathogens were Staphylococcus aureus , Staphylococcus. epidermidis , Escherichia coli , Pseudomonas aeruginosa and Salmonella . In RA, the estimated incidence of TB associated with infliximab was 1893 per 100,000 in the year 2000 and 1113 per 100,000 in the year 2001 .
Data from the ‘Dutch Rheumatoid Arthritis Monitoring’ (DREAM) register analysed about 1560 RA patients through 5 years of follow-up. The incidence rates of serious infections and malignancies were 2.9 per 100 patient-years .
Data from registries
Clinical trials and post-marketing analysis are fundamental to monitor the safety profile of biologic therapies. Other good instruments are the national or local registries. The data are extrapolated from the real-world setting and are not biased on inclusion/exclusion criteria, mandatory for the clinical trials.
The ‘RA observation of Biologic Therapies’ (RABBIT) German registry evidenced a significant difference between patients treated with infliximab or etanercept and patients with only DMARDs therapy. On these three regimens, higher incidence of infections (28.3, 22.6 and 6.8/100,000 patients/year, respectively) and serious infections were observed .
In the Swedish registry, an increased risk of hospitalisation due to infections was observed during the first year of treatment and decreased with the prolongation of treatment .
No increase of overall risk of serious infection was observed in British patients treated with anti-TNF-α and those treated with DMARDs only, except for serious skin and soft-tissue infections. These had a significantly greater incidence in anti-TNF-α patients than in DMARDs patients. Similar data were observed also for serious intracellular infections ( Mycobacterium , Legionella pneumophila , Listeria monocytogenes or Salmonella ) . No differences were recorded between etanercept, adalimumab and infliximab.
In France, the ‘Recherche Axée sur la Tolérance des Biothérapies’ (RATIO) registry collected data on opportunistic and severe infections occurring in patients treated on anti-TNF-α. The registry recorded an increased risk of Legionella pneumonia (10 cases in 1 year) (six cases treated with adalimumab, two treated with etanercept and two treated with infliximab).
The Spanish registry ‘BIOBADASER’ followed about 7000 treated patients. Through the period 2000–2006, 907 episodes of infection were observed and the incidence was 53.09 cases per 1000 patient-years (CI 95% 49.69–56.66). The most frequent infections were cutaneous (12.18 cases/1000 patient-years), pneumonia (5.97 cases/1000 patient-years), cystitis (3.92 cases/1000 patient-years), TB (3.51 cases/1000 patient-years) and arthritis (3.76 cases/1000 patient-years). The most common pathogens were Staphylococcus aureus , Staphylococcus. epidermidis , Escherichia coli , Pseudomonas aeruginosa and Salmonella . In RA, the estimated incidence of TB associated with infliximab was 1893 per 100,000 in the year 2000 and 1113 per 100,000 in the year 2001 .
Data from the ‘Dutch Rheumatoid Arthritis Monitoring’ (DREAM) register analysed about 1560 RA patients through 5 years of follow-up. The incidence rates of serious infections and malignancies were 2.9 per 100 patient-years .
TB
Even in the 21st century, TB kills more people than any other infective agent . Mycobacterium tuberculosis can persist within the human host for years or even for life without causing disease, in a syndrome known as latent tuberculosis infection (LTBI) . In 2008, World Health Organization (WHO) reported that about one-third of the world’s population is believed to harbour LTBI and approximately 10% of immunocompetent persons with LTBI will develop active TB , eluding immune surveillance and respond to triggers that stimulate reactivation.
TNF plays a major role in defence against infection and in the formation and maintenance of granulomas and, therefore, anti-TNF-α treatments are recognised as a risk factor for reactivation of LTBI .
Clinical trials performed with anti-TNF-α in several auto-immune diseases did not report an increased susceptibility to typical or opportunistic infections. However, post-marketing analysis has clearly demonstrated an increased susceptibility to infections, in particular those caused by M. tuberculosis , atypical mycobacteria and other organisms .
Ageing of the population and immunosuppressive treatments are risk factors for progression to active TB . However, accurate surveillance and prophylaxis reduced the risk of TB reactivation .
Spontaneous pharmacovigilance studies have also confirmed that anti-TNF-α increased the risk of TB and that infliximab and adalimumab carry a higher risk than etanercept .
The RATIO registry listed 69 cases of TB in patients treated respectively for RA ( n = 40), spondylarthritides ( n = 18), inflammatory colitis ( n = 9), psoriasis ( n = 1) and Behçet’s disease ( n = 1). The standardised 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 British Society for Rheumatology Biologics Register (BSRBR), incidence rate ratios of TB for infliximab and adalimumab compared with etanercept were 2.8 (95% CI 1.2, 7.1) and 3.8 (95% CI 1.6, 9.1), respectively .
These differences could be explained, in part, to differences in mechanism of action, biology and kinetics between the drugs .
From 1998 to 2002, incidence of granulomatous infections were reported as 239 per 100,000 cases on infliximab versus 74 per 100,000 cases on etanercept . Rate of Mycobacterium TB was 5 times greater for infliximab than for etanercept. These data were subsequently revised and the rate reduced to 54 per 100,000 with infliximab and 28 per 100,000 with etanercept .
Clinical manifestations of active TB in patients treated with anti-TNF-α are atypical, miliar or extrapulmonary presentation, similar to reports on immunodeficient patients .
In 2002, Carmona et al. showed a 4-fold increased risk of TB infection in RA patients versus general population (134/100,000 patients vs. 23 cases per 100 000) and showed also that this risk was further increased with the use of infliximab . One of the first screening programmes was adopted in Spain after the analysis of the increased risk of TB in RA patients. The estimated incidence of TB associated with infliximab in RA patients was 1893 per 100,000 in 2000 and 1113 per 100,000 in 2001, compared with a background incidence of TB in Spain in 2000 of 21 cases/100,000 patients. After official guidelines were established for TB prevention in patients treated with biologic agents, the incidence dropped to 172 cases/100,000 patients .
After 2 years from the introduction of LTBI recommendation, 34 cases (28 RA patients) of active TB were found, of whom 32 started anti-TNF-α prior to the official recommendation on LTBI (pre-OR) and two began treatment after the recommendations were issued (post-OR). All TB cases occurred during treatment with infliximab. Post-OR, active TB rates among the BIOBADASER patients decreased by 78% (incidence risk ratio (IRR) 0.22, 95% CI 0.03–0.88; P = 0.008), while among RA patients in the BIOBADASER, the rate dropped by 83% .
A remarkable difference between the incidence of TB before and after introduction of infliximab was observed also in two large USA studies . Before infliximab, the incidence of TB was comparable to that in the general population (6.2/100,000 patients) but after its introduction, it increased to 52/100,000 patients. No cases were recorded in patients who underwent TB screening or prophylaxis. Three of the four cases of TB during therapy with infliximab occurred in patients with a history of exposure to TB .
Fewer cases of serious infections occurred in adalimumab-treated patients in a controlled and open-label study: 34 cases of TB (0.27/100 patient-years) and four cases of histoplasmosis (0.03/100 patient-years) . During the post-marketing analysis, 17 cases of TB (0.02/100 patient-years) and 46 cases of other opportunistic infections (0.06/100 patient-years) were recorded .
One of the most recent reports on TB comes from the French RATIO register and lists 69 cases of TB in patients treated with anti-TNF-α. The sex- and age-adjusted incidence rate of TB was 116.7/100 000 patient-years, 12.2 times that of the general population . Thirty-six cases were recorded with infliximab, 28 with adalimumab and five with etanercept, confirming several earlier reports.
Recommendations
Several recommendations for detecting LTBI have been proposed in different countries .
In 2002, the RATIO study group established new recommendations in France . Patients were considered to have LTBI when chest X-rays showed present residual nodular lesions larger than 1 cm 3 or old lesions, or when a skin reaction larger than 10 mm induration at tuberculin skin test (TST) is found. Treatment lasting at least 6 months, including at least 2 months with combination rifampicin–pyrazinamide, was suggested. After July 2005, TST value was then decreased to 5 mm, in almost all countries .
The Portuguese Societies of Rheumatology and Pneumonology have proposed TB screening mandatory before starting an anti-TNF-α therapy .
In cases of suspected active lesions on TST, LTBI should be excluded/confirmed and adequate therapy initiated.
Screening for LTBI
Screening for active TB or LTBI is mandatory prior to the initiation of anti-TNF-α therapy , to reduce the risk of LTBI reactivation . At present, TST remains the most used to detect LTBI , together with chest X-ray and a complete family and personal history.
The TST is usually performed in several countries but it has numerous drawbacks. In fact, it has a poor specificity as previous Bacillus Calmette–Guerin (BCG) vaccinations and environmental mycobacterium exposure may result in a false positive . Conversely, TST in IMID may often give more negative reaction than in the general population with a subsequent risk of TB reactivation with anti-TNF-α therapy . The false-negative TST can occur in immune suppression (276 consensus) but may also be false positive due to previous BCG vaccination .
In the mycobacterium TB genome, the observation of genes that are absent in BCG offered the opportunity to develop more specific tests to investigate mycobacterium TB infection, especially in LTBI . Recently, two new interferon (IFN)γ-based ex vivo assays, involving 10-kDa culture filtrate protein (CFP-10) and 6-kDa early secretory antigenic target (ESAT-6) have been developed to identify LTBI and active TB: T-SPOT®. TB , a new tipe of test ELISPOT (enzyme-linked immunospot) and QuantiFERON TB Gold in-tube (QFT-GIT) . QuantiFERON TB Gold (QFT-G) is not affected by prior BCG vaccination , and it is less influenced by previous TB infection with non-TB mycobacteria
In a Japanese study, in 216 BCG-vaccinated nursing students, a specificity of 98.1% was recorded and in 118 patients with cultured-confirmed TB, was also found a sensitivity of 89% was also found .
On about 100 healthy, BCG-vaccinated students, similar results were observed: the specificity of QFT-G was 96% compared with 49% for the TST. Among 54 patients affected by TB, the sensitivity of the QFT-G was 81% compared with 78% for the TST .
The feasibility of QFT-GIT tests for the diagnosis of LTBI was evaluated in 393 subjects for both the TST and QFT-GIT tests. A total of 52 were positive for the QFT-GIT tests and 74 were positive for TST, resulting in an overall concordance of 87.8% .
Also in a comparison study of in vitro -specific blood tests with TB-specific antigens (CFP-10 andESAT-6) and TST to detect LTBI, the tests showed higher positive results in patients with than without LTBI ( P < 0.005). Among 13 patients with LTBI, five had a negative TST (38.5%), but all had positive blood results, and only two showed a negative blood assay result (15.4%) .
QFT-GIT and enzyme-linked immunosorbent spot (ELISPOT) showed a high specificity of 97.7% (95% CI, 96–99%) and 92.5% (CI, 86–99%), respectively. Both assays were more specific than TST, and they were not correlated to BCG vaccination .
These new tests have greater specificity for LTBI than TST, but it should be noted that false-negative results and indeterminate results occur also with the interferon (IFN)-γ release assay .
The new tests gave good results and confirmed that QFT-GIT could be used for the screening of LTBI and active TB. The current data do not support the UK national guidelines on TB, suggesting the use of IFN-γ release assays (IGRAs) as confirmation test in TST-positive subject .
The recent consensus on biologic agents suggested to evaluate every patient candidate to anti-TNF-α therapy for LTBI, including history of prior exposure, prior drug addiction and acute drug addition, Human Immunodeficiency Virus (HIV) infection, birth and living in an area with high risk of TB infections and working or living in high-risk TB settings . Moreover, physical examination, TST and chest X-ray are fundamental before anti-TNF-α treatment.
In conclusion, the screening for TB or LTBI is mandatory prior to the initiation of anti-TNF-α therapies to reduce the risk of LTBI reactivation .
TB prophylaxis
A chemoprophylaxis regimen is required when evidence of LTBI, not previously treated, is demonstrated.
From the British Thoracic Society (BTS) recommendations, there are two principal chemoprophylaxis regimens: isoniazid for 6–9 months or rifampicin plus isoniazid for 2–3 months. The use of rifampicin and pyrazinamide, mainly used in USA , showed a high risk for hepatic failure and fatal hepatitis .
Chemoprophylaxis is highly efficient: 60% have been reported for the isoniazid regimen and 50% for the combination therapy. The necessary time between the onset of chemoprophylaxis and the start of biological therapy is not fully understood, but some observational data suggest waiting at least 1 month after the beginning of prophylaxis, before starting TNF-blocking therapy .
Resistant TB cases are precisely defined by the recommendations of the World Health Organization as primary, initial, acquired multidrug resistant and extensively drug-resistant TB. Resistant TB may result from the administration of monotherapy or inadequate combinations of anti-TB drugs .
Other opportunistic infections (OIs)
Many infectious adverse events have been reported and the most common pathogens were granulomatous infection , aspergillosis , Listeria monocitogenes and Salmonella .
Other opportunistic infections (OIs), such as hystoplasmosis , coccidiomycosis pneumocystosis and other fungal or viral infections have been described in patients on anti-TNF-α blockers.
Significant differences in the rate of serious bacterial infections (which required intravenous antibiotic therapy) were also observed between patients treated with TNF inhibitors or with DMARDs .
A total of 24 530 RA patients were compared with a random sample of non-RA patients ( n = 500 000) to evaluate the rate of hospitalisation. The rate of first hospitalised infections was higher in the RA cohort (2.03; 95% CI, 1.93–2.13). In the case-control analysis, the current use of biological DMARDs was associated with slightly increased risk of hospitalised infection (rate ratio (RR) = 1.21; 95% CI 1.02–1.43).
In the ‘Lombardy Rheumatology Network’ (LORHEN) registry , 1064 patients with long-standing RA (519 treated with infliximab, 303 with adalimumab and 242 with etanercept) were followed. Seventy-three patients (6.9%) experienced a total of 74 with serious infections. The incidence rate for all treatment courses was 35.9/1000 patient-years (95%, CI: 27.66–44.13). Most of the cases were lower respiratory tract (34.2%) or skin and soft-tissue infections (20.5%) .
A higher infection risk in ankylosing spondylitis cases receiving anti-TNF-α was also evident .
Systematic retrospective study of all 709 patients receiving at least one anti-TNF-α therapy (between 1997 and December 2004) showed a total of 275 infectious events in 245 patients (34.5%) and 6.2% fulfilled the definition of serious infections. The incidence rate of serious infections was 3.4 ± 38.7 per 100 patient-years before anti-TNF-α therapy versus 10.5 ± 86.9 during the first TNF-α blocker course ( P = 0.03) .
The ‘Consortium of Rheumatology Researchers of North America’ (CORRONA) registry included 7971 RA patients treated with MTX, TNF antagonists or other DMARDs.
The adjusted rate of infections per 100 person-years was increased among users of MTX (30.9, 95% CI 29.2–32.7), TNF antagonists (40.1, 95% CI 37.0–43.4) and a combination of MTX and TNF antagonists (37.1, 95% CI 34.9–39.3) compared with users of other non-biological DMARDs (24.5, 95% CI 21.8–27.5).
Anti-TNF-α use was associated with an increased risk of opportunistic infections (IRR 1.67, 95% CI 0.95–2.94) .
Elderly patients had also a higher risk of opportunistic infections associated with the use of steroids , with increased acute-phase reactants and with high disease activity .
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