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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

Background  Anti-TNF agents are now widely used in Crohn’s disease (CD), and in ulcerative colitis (UC).

Aim  To review the safety profile of anti-TNF agents in all patients treated with infliximab in Edinburgh from 1999 to 2007.

Methods  Complete data were available on 202/207 patients comprising 157 CD, 42 UC and three coeliac disease. Median follow-up was 2.4 years (1.0–4.9) with a total of 620 patient-years follow-up. About 19.1% of CD patients were subsequently treated with adalimumab.

Results  Seven deaths (3.3%) occurred in follow-up; only one death was <1 year post-infliximab (at day 72, from lung cancer). A total of six malignancies (three haematological, three bronchogenic) and six cases of suspected demyelination (three with confirmed neurological disease) were reported. In the 90 days following infliximab, 95 adverse events (36 serious) occurred in 58/202 (28.7%) patients. In all, 42/202 (20.8%) had an infectious event (22 serious) and 27/202 (13.4%) of patients had an infusion reaction: 19 acute (four serious) and eight delayed (three serious).

Conclusions  Serious infections, malignancies and neurological disease complicate anti-TNF use in clinical practice. Although evidence for causality is unclear, potential mechanisms and predisposing factors need to be explored. In individual patients, the risk/benefit analysis needs to be carefully assessed and discussed prior to commencement of therapy.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

The efficacy of anti-TNF antibodies in Crohn’s disease (CD) is well established with infliximab, adalimumab and certolizumab pegol (North America only) presently licensed for luminal and fistulizing disease.1–8 Infliximab is also licensed for moderate ulcerative colitis (UC) based on data from ACT1/2 trials9 and has become an alternative to ciclosporine as rescue therapy in acute severe UC failing first-line medical therapy.10, 11 Infliximab is the only anti-TNF antibody licensed for paediatric use in North America and Europe.12 In CD, most current guidelines recommend that these agents are reserved for those patients refractory to standard medical therapy, thus maximizing the relative benefit in any particular patient. Recently, attention has turned to top–down treatment algorithms with combined early immunosuppression.13 In this strategy, more patients will potentially be exposed and in some, where the disease could not have been predicted to follow a more benign course will have been unnecessarily exposed to potentially toxic therapy.14 Therefore, continued monitoring of known adverse events (AEs) and vigilance for new safety signals in long-term follow-up data are critical.

The most common reported side effects are acute infusion reactions (IRs), delayed hypersensitivity reactions and infections.15, 16 In particular, anti-TNF therapy has been shown to be associated with tuberculosis17 and opportunistic infections.18, 19 While concomitant immunosuppression has been shown to decrease formation of antibodies to infliximab and hence the likelihood of IRs,20, 21 it has also been shown to increase the likelihood of opportunistic infections.18 Anti-TNF therapy has also been associated with drug-induced lupus and demyelinating complications. Most recently, a series of eight cases of hepatosplenic T-cell lymphoma (HSTCL) were reported in young CD patients concomitantly treated with infliximab and a thiopurine;22 this had risen to 13 in predominantly paediatric IBD with such concomitant treatment by November 2007 (letter from Schering-Plough, Welwyn Garden City, UK). The aggressive and near universal fatality of these lymphomas has coloured physicians’ approach to maintenance therapy with both agents in this patient group.

The aim of this retrospective study was to evaluate the short- and long-term safety of anti-TNF therapy in a Scottish tertiary referral centre cohort of IBD childhood and adult patients treated in the past 8 years. All of the patients in this cohort were initially treated with infliximab, with 15% subsequently treated with adalimumab.

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

Study population and data collection

This was a retrospective study designed to analyse the safety profile of anti-TNF therapy in all patients treated in the Gastroenterology Unit at the Western General Hospital (WGH), Edinburgh, and the Department of Paediatric Gastroenterology and Nutrition at the Royal Hospital for Sick Children (RHSC), Edinburgh, between 1999 and 2007. These are the major centres for adult and paediatric IBD in Edinburgh, although a few patients have been treated with anti-TNF therapy at other hospitals in the referral area. Patients were identified from hospital pharmacy and nurse-practitioner held records, ensuring 100% capture of all treated patients and infusions in these 2 units. All patients were screened for tuberculosis by chest radiograph, reported by an experienced consultant radiologist prior to first infusion. In cases where this was inconclusive or there was a clinical history suspicious of previous tuberculosis exposure, patients were referred to a consultant respiratory physician with expertise in mycobacterial infections. Patients were treated either in dedicated day case units or as in-patients at both sites. Until 2005, all infusions of infliximab were given over 2 h; after this date, infusion duration was decreased to 1 h in patients on maintenance therapy after the third dose. All patients after 2003 were given preinfusion hydrocortisone (100 mg i.v. in some younger patients, 200 mg i.v. in all others). All out-patients were asked about symptoms of infection prior to infusion. All in-patients on i.v. corticosteroids were rigorously assessed for clinical and laboratory signs of infection prior to therapy. In all cases where there was suspicion of infection, anti-TNF therapy was delayed to await results of microbiological analysis and subsequent antimicrobial therapy where indicated. At both sites, anti-TNF therapy is not given to females who are pregnant. The risks and benefits were discussed with all patients prior to the commencement of anti-TNF therapy. The induction regime and subsequent dosing were otherwise entirely at the discretion of the individual consulting physician.

Data were collected retrospectively by case-note review on a standardized data collection form and subsequently entered into a Microsoft Access database (Seattle, WA, USA). Parameters recorded for every patient were: age, gender, ethnicity, diagnosis (Lennard–Jones criteria), date of diagnosis, medical history, detailed smoking history, disease location and behaviour (Montreal classification), extra-intestinal manifestations, indication for infliximab, date of first and all subsequent infliximab infusions, infliximab infusion strategy (induction only, induction plus episodic or induction plus maintenance), concomitant medical therapy [including oral and i.v. corticosteroids, 5-ASA, azathioprine (AZA), mercaptopurine, methotrexate], weight and body mass index (at first infliximab and 1 year later), blood parameters at first infliximab infusion and 6 weeks afterwards, number of hospital admissions (year prior to and year following start of infliximab therapy), surgery, death, acute and delayed IRs, infections (bacterial, viral and fungal infections including the skin/soft tissue infections, abscesses, gastroenteritis, septicaemia, i.v. line infections, pneumonia, upper respiratory tract infections, urinary tract infections), malignancy, drug-induced lupus, demyelination/multiple sclerosis. For those patients subsequently treated with adalimumab, additional data were recorded, including date treatment commenced, induction regime, dates of all subsequent adalimumab injections, AEs whilst on adalimumab therapy.

Two hundred and seven patients with IBD who were treated with infliximab at were included in this study. All but two patients remained under close follow-up, with transition of the childhood (<18 years) cases from RHSC to WGH, when appropriate. Two patients were followed up elsewhere; three patients had their case-notes destroyed. Sufficient data were therefore collected on 202 patients for full analysis.

Study outcomes and analysis

Primary outcomes were number of AEs occurring in the 90 days following infliximab infusion or adalimumab injection and death. Malignancies, deaths and autoimmune diseases from commencing infliximab to the date of most recent follow-up were also recorded. Serious AEs (SAEs) were defined as fatal or life-threatening events, those leading to or prolonging hospitalization or those that resulted in significant disability. Acute IRs were any significant AEs occurring during or within 1 h post-infliximab infusion. Serum sickness-like reactions were defined as ≥1 of the following symptoms occurring 1–14 days after infliximab re-infusion: myalgia, arthralgia, fever, rash.

Descriptive data were displayed with median values and inter-quartile ranges (IQRs) if continuous and as number (%), if categorical. In the analysis of serum-sickness like reactions, Mann–Whitney U-test was used for analysis of median longest time between previous infusions, receiver operator curves (ROC) used to generate likelihood ratios plus sensitivity and specificity values and Fisher’s exact test for analysis of drug holidays > or <12 months. Analysis of infectious events and concomitant immunosuppression was made by chi-squared testing. P-values of <0.05 were considered significant and odds ratios (ORs) were given with 95% confidence intervals (CI) and two-sided P-values. All data analyses were performed and graphs created using GraphPad Prism (version 4.00 for Windows; Graphpad Software, San Diego, CA, USA).

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

Patient characteristics

The study population consisted of 157 (77.7%) patients with CD, 42 (20.8%) with UC and three (1.5%) with coeliac disease (Table 1). The median age at first infliximab therapy was 30.8 years (IQR 22.0–42.9) with 13.5% of patients under the age of 18 at treatment, 55.6% aged 18–39, 23.7% 41–64 and 7.7%≥65 years of age. The median follow-up was 2.4 years (IQR 1.0–4.9); 2.5% and 8.7% of patients had <28 and <90 days follow-up respectively. Fifty-two patients were followed up for 0–1 year, 39 for 1–2 years, 22 for 2–3 years, 21 for 3–4 years, 24 for 4–5 years and 48 for ≥5 years. Twenty patients (50.0% female) were treated at RHSC, consisting 16 CD and four UC and with median age at diagnosis 12.3 years (IQR 9.2–13.0) and median age at first infusion 15.0 years (IQR 13.5–16.0).

Table 1.   Demographics and phenotype of study population
  1. IQR, inter-quartile range; CD, Crohn’s disease; UC, ulcerative colitis; pts, patients.

Gender99 Male; 103 female
Median age at diagnosis (IQR)23.8 years (15.9–34.2)
Median age at first infusion (IQR)30.8 years (22.0–42.9)
Median duration diagnosis to first infliximab infusion (IQR)4.9 years (1.2–11.0)
Location of first infusion
 Western General Hospital, Edinburgh, UK182
 Royal Hospital for Sick Children, Edinburgh20
Median follow-up time (IQR)2.4 years (1.0–4.9)
Indication for infliximab treatment
 CD157 (77.7%)
  Luminal CD118 (75.2%)
  Fistulizing CD36 (22.9%)
  Oral CD1 (0.6%)
  Penile CD1 (0.6%)
  Pyoderma gangrenosum1 (0.6%)
 UC42 (20.8%)
  Acute severe UC27 (64.3%)
  Chronic active UC11 (26.2%)
  Pouchitis4 (9.5%)
 Coeliac disease3 (1.5%)
Disease extent at diagnosis
 CD (unavailable 5 pts)
  L1 (terminal ileum)23 (15.1%)
  L2 (colon)62 (40.8%)
  L3 (ileocolon)42 (27.6%)
  L4 (upper GI disease)6 (3.9%)
  L1 + L4 (terminal ileum + upper GI disease)5 (3.3%)
  L2 + L4 (colon + upper GI disease)14 (9.2%)
 UC (unavailable 7 pts)
  E1 (proctitis)3 (7.1%)
  E2 (left-sided colitis)15 (35.7%)
  E3 (extensive colitis)17 (40.5%)
Infliximab treatment regime
 Single dose/induction only120 (59.4%)
 Single dose/induction + on-demand episodic 42 (20.7%)
 Single dose/induction + maintenance 40 (19.8%)
Adalimumab treatment (n = 30)
 Gender 11 Male; 19 Female
 Age at therapy32.3 years (19.5–41.6)
 Median duration of follow-up0.92 years (0.37–1.84)
Reason for adalimumab treatment
 Loss of infliximab efficacy6 (20.0%)
 Previous infliximab reaction7 (23.3%)
 No response to infliximab11 (36.7%)
 Long infliximab holiday6 (20.0%)
Adalimumab dose escalation to 40 mg once weekly 16 (53.3%)
 Duration to dose escalation0.55 years (0.15–1.49)

In all, 30/157 (19.1%) patients with CD were subsequently treated with adalimumab. This cohort comprised 19 (63.3%) females with a median age at treatment of 32.3 years (IQR 19.5–41.6 years) (Table 1). The median duration of follow-up from initiation of adalimumab was 0.92 years (IQR 0.37–1.84).

Patients had a mean ± s.d. of 1.39 ± 1.38 hospital admissions in the year prior to starting infliximab including 0.58 ± 0.82 for an acute disease flare-up. At the time of first infliximab infusion, the median weight and body mass index were 62.8 kg (IQR 52.8–74.0) and 20.8 (IQR 17.5–24.6) respectively. Peripheral blood inflammatory markers, CRP and ESR, were elevated at baseline with median levels of 18 mg/L (IQR 9–37) and 28 mm/hr (IQR 12–50) respectively (Supporting information Table S1).

In the cohort of patients with CD, 102/157 (65.0%) were on concomitant immunosuppression with AZA, mercaptopurine or methotrexate at the time of first infliximab infusion (Table 2). In addition, 72/157 (45.9%) had documented prior intolerance to one or more of these drugs. In all, 85/157 (54.1%) of patients were on concomitant corticosteroids with 13/157 (8.3%) with prior corticosteroid intolerance and 82/157 (52.2%) had surgery prior to anti-TNF therapy, of which 81.2% was resectional. In CD patients with a minimum of 1 year follow-up, there were mean ± s.d. of 1.44 ± 1.55 and 1.21 ± 1.97 (P = 0.028) hospital admissions in the year prior to and the year following commencement of infliximab respectively.

Table 2.   Concomitant immunosuppression at time of first infliximab infusion
DiagnosisCDUCCO
  1. Details are presented for concomitant immunosuppressants: AZA, azathioprine; MP, mercaptopurine; MTX, methotrexate and corticosteroids (oral prednisolone, oral budesonide, intravenous methylprednisolone and intravenous hydrocortisone). The first row details the number of patients treated with AZA, MP or MTX only, corticosteroids only or a combination of the two. The remaining rows detail total numbers treated with each individual therapy.

  2. IQR, inter-quartile range; CD, Crohn’s disease; UC, ulcerative colitis; CO, coeliac disease; pts, patients.

AZA/MP/MTX only51 (32.5%)2 (4.8%)
Corticosteroids only32 (20.4%)24 (57.1%)2 (66.7%)
AZA/MP/MTX plus corticosteroids55 (35.0%)15 (35.7%)
AZA79 (50.3%)12 pts (28.6%)0 pts (0%)
 Median dose (IQR) (unavailable 10 pts)1.6 mg/kg (1.0–2.0)1.5 mg/kg (0.8–2.0)
 Median duration (IQR) (unavailable 11 pts)10.5 months (1.6–39.5)23.8 months (0.7–39.4)
 Number with previous AZA intolerance46 pts (29.3%)13 (31.0%)1 pt (33.3%)
MP6 (3.8%)3 pts (7.1%)0 pts (0%)
 Median dose (IQR)0.9 mg/kg (0.8–1.0)1.1 mg/kg (0.9–1.5)
 Median duration (IQR)3.7 months (1.7–6.6)3.9 months (2.2–15.1)
 Number with previous MP intolerance10 pts (6.4%)3 (7.1%)0 (0%)
MTX17 (10.8%)1 pt (2.4%)0 pts (0%)
 Median dose (IQR)20 mg (20–25)10 mg
 Median duration (IQR)13.1 months (5.1–18.5)1.0 months
 Number with previous MTX intolerance16 pts (10.2%)1 (2.4%)0 (0%)
Oral prednisolone70 (44.6%)12 pts (28.6%)2 pts (66.7%)
 Median dose (IQR) (unavailable 1 pt)15 mg (15–40)30 mg (18.8–35)11.5 mg (9.8–13.3)
 Median duration (IQR) (unavailable 15 pts)4.3 months (1.0–12.2)1.0 months (0.2–5.1)5.5 months
 Number with previous corticosteroid intolerance13 pts (8.3%)0 (0%)0 (0%)
Budesonide8 (5.1%)2 pts (4.8%)0 pts (0%)
 Median dose (IQR)9 mg (5.3–9.0)6 mg (4.5–7.5)
 Median duration (IQR) (unavailable 3 pts)1.1 months (1.0–13.4)0.1 months
Intravenous corticosteroid7 (4.5%)23 (54.8%)0 pts (0%)
 Median dose methylprednisolone (IQR)60 mg (50–60)60 mg (40–60); n = 20
 Median dose hydrocortisone (IQR)200 mg (200–300); n = 3
 Median duration (IQR) (unavailable 2 pts)0.2 months (0.1–0.3)0.2 months (0.2–0.3)
Surgery prior to first infliximab therapy
 ≥1 surgical procedure82 pts (52.2%)4 pts (9.5%)0 pts (0%)
 Resection67 pts (42.7%)4 pts (9.5%)

Anti-TNF therapy

All infliximab infusions, except four, were of 5 mg/kg (four infusions of 10 mg/kg infliximab: two in two UC patients in an infliximab trial; two in a CD patient with severe refractory orofacial and fistulizing disease). The total number of infusions received by patients was 718, with a steady increase year-on-year of number of patients treated and number of infusions per annum (Figure 1). Each patient with CD received a median of 3 infusions (IQR 1–4), whilst those with UC had a median of 1 infusion (IQR 1–2.5). Three patients were treated for refractory coeliac disease with single infusions of infliximab. The indications for anti-TNF therapy and the infliximab treatment regimes are detailed in Table 1.

image

Figure 1.  Infliximab (IFX) usage in Edinburgh at the Western General Hospital and the Royal Hospital for Sick Children showing year-on-year number of infusions (dashed line) and number of treated patients (continuous line). The data for 2007 were collected up to September and are therefore incomplete.

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The indication for subsequent adalimumab therapy was loss of infliximab efficacy in six of 30 (20.0%), previous infliximab reaction in seven of 30 (23.3%), no response to infliximab in 11/30 (36.7%) and long infliximab holiday in six of 30 (20.0%). All adalimumab-treated patients received an induction dose of 80 mg followed by 40 mg every other week by subcutaneous injection. About 16/30 (53.3%) of patients required dose escalation to 40 mg once weekly at a median of 0.55 years (IQR 0.15–1.49 years) following adalimumab induction.

Summary of AEs

In total, 95 AEs occurred within 90 days of infliximab in 58 of 202 patients (28.7%; Table 3). Thirty-six SAEs occurred within 90 days of infliximab in 30 of 202 patients (14.9%). There were a total of 21 AEs during adalimumab therapy in 12/30 (40.0%) patients including four SAEs. In total, to the end of follow-up, there were 49 SAEs including seven deaths, six malignancies, four acute IRs, three serum sickness-like reactions (SSLRs) and 24 infectious events.

Table 3.   Summary of adverse events
Type of AENumber of AEs within 90 days of IFX (total to end of follow-up)Number of SAEs within 90 days of IFX (total to end of follow-up)
  1. Events are divided into number of adverse events (AEs) and serious adverse events (SAEs) within 90 days of infliximab (IFX), plus the total number to the end of follow-up presented in brackets.

Total95 (111)36 (49)
Deaths1 (7)1 (7)
Malignancies2 (6)2 (6)
Acute infusion reaction20 (20)4 (4)
Serum sickness-like reaction8 (8)3 (3)
Infections60 (60)24 (24)
Suspected demyelination2 (6)2 (3)
Confirmed demyelination0 (1)0 (1)
Drug-induced lupus0 (1)0 (1)
Other AE2 (2)0 (0)

Mortality

A total of seven deaths (3.5%) were observed (Table 4), a median of 52.3 months post-infliximab (IQR 19.4–52.6; range 2.3–56.5). The median age at death was 74.0 years (IQR 52.6–76.2; range 38.5–85.0). Six deaths occurred greater than a year after infliximab treatment and were considered unrelated (three pneumonias, one lung cancer, one T-cell lymphoma, one cryptogenic cirrhosis). The other death occurred 72 days after a CD patient’s third infliximab infusion; this was a male smoker with lung cancer, described below. Four deaths occurred in patients diagnosed with malignancy post-infliximab (two lung cancers, one lymphoma, one myelodysplasia). There was no mortality in the group of patients subsequently treated with adalimumab.

Table 4.   Summary of deaths occurring in total follow-up period of cohort
Gender/ age (year)/ diagnosisYear of diagnosisYear of deathPrior infliximab infusions (n)Time since last infusion (months)Associated treatment (duration)Cause
  1. Age is documented as age at death in years.

  2. CD, Crohn’s disease; UC, ulcerative colitis; CO, coeliac disease.

M/66/CD1994200232.3UnavailableLung cancer
M/76/CO19862006152.3NilLung cancer, refractory coeliac disease
F/73/CD19792006352.55-ASA 2 g (4 m)Pneumonia on background of myelodysplasia
M/52/CO19882005152.6NilPeripheral T-cell lymphoma
M/38/CD20042004419.4NilBronchopneumonia, severe peripheral vascular disease and CD
F/84/CD19582005428.3NilFrailty; cryptogenic cirrhosis
F/75/CD19482005156.5Prednisolone 22.5 mg (5 year continued steroid therapy)Multiple falls, pneumonia, bacterial meningitis

Acute IRs

Twenty acute IRs to infliximab were recorded in 19 of 202 patients (9.4%) (full details in Supporting information Table S2). The infusion was discontinued in 11 cases (55% of IRs). Four IRs were serious: one anaphylaxis requiring adrenaline; three others requiring hospital admission. Median number of prior infusions was 3.5 (IQR 2.0–6.5). Two IRs occurred after first infliximab infusion; for the remainder, median time since last infusion was 63.0 days (IQR 37.0–156.5). IRs occurred in the presence of concomitant immunosuppression in 16 of 17 cases (concomitant treatment details unavailable in three nonserious cases). All patients received preinfusion hydrocortisone; two patients also received preinfusion chlorpheniramine. Five patients were successfully reinfused with infliximab, one with preinfusion chlorpheniramine. One patient experienced a mild IR on reinfusion. One patient developed an SSLR 4 days post-IR. There was no adalimumab-mediated hypersensitivity in this cohort. However, one patient had to discontinue therapy because of localized discomfort at the injection site.

Serum sickness-like reactions

In all, eight SSLRs occurred in eight of 202 patients (4.0%; Supporting information Table 3). Of these, three SSLRs were serious, requiring hospital admission and i.v. corticosteroids. Of note, all three serious episodes were characterized by severe jaw pain as an early feature. One of these patients (F/33/CD) had had an IR, also serious, during her most recent infliximab infusion. All eight patients were on concomitant immunosuppression, although one patient who had a serious SSLR had been on immunosuppression for less than a month. Only two patients were subsequently reinfused: one successfully; one unsuccessfully, experiencing an IR requiring discontinuation of infusion.

Six of eight SSLRs occurred after second infusion; the remaining two SSLRs after three and six infusions respectively. Median time between last infusion and SSLR onset was 8 days (IQR 7.0–9.5; range 4–10). The median longest time between previous infusions was 895.0 days (IQR 107.0–1838.0) vs. 70.5 days (IQR 28.0–209.5) in those who did not have SSLR (P = 0.016) (Figure 2). ROC analysis revealed an area under the curve of 0.76 (95% CI: 0.54–1.01; P = 0.015) with maximum likelihood ratio of 4.07 at 106 days. However, in two of eight patients, the SSLR occurred without a significant ‘drug holiday’ (21 and 107 days respectively). In the six of eight patients with a significant drug holiday, the shortest interval resulting in SSLR was 462 days. We therefore compared SSLR occurrence using a 12-month drug holiday as a clinically relevant cut-off. Six of 27 (22.2%) patients with a drug holiday of >12 months had an SSLR compared with two of 103 (1.9%) <12 months (P = 0.001; OR: 14.4; 95% CI: 2.72–76.5) (Figure 2).

image

Figure 2.  Serum-sickness like reactions (SSLRs). The longest duration between previous infliximab infusions (infliximab ‘drug holiday’) is plotted for those patients with and without SSLR with median values represented by horizontal straight line (top panel). P-value given is based on Mann–Whitney U-test. Number of patients experiencing SSLR is plotted by ‘drug holiday’ of > or <1 year (bottom panel). Analysis based on chi-squared statistic with odds ratio (OR) and 95% confidence intervals (CI) given.

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Infections

In all, 42 of 202 patients (20.8%) had a total of 60 infectious events within 90 days of infliximab infusion (Supporting information Table S4). Concomitant therapy at the time of each infectious event (unavailable in four cases) was: 24/56 on AZA (median dose 100 mg, IQR 75–150; median duration 365 days, IQR 60–1095), eight of 56 on mercaptopurine (median dose 50 mg, IQR 25–75; median duration 365 days, IQR 60–730), six of 56 on methotrexate (median dose 22.5 mg, IQR 15.0–25.0; median duration 225 days, IQR 180–913), 20/56 on prednisolone (median dose 17.5 mg, IQR 6.5–35.0, including three patients on high-dose i.v. methylprednisolone), one of 56 on budesonide, eight of 56 on 5-ASA, and 13/56 on combination of a thiopurine or methotrexate and prednisolone. There was no difference in concomitant immunosuppression (corticosteroids, thiopurines/methotrexate or combination) at start of infliximab therapy between those patients who had an infectious event 90 days after infliximab and those who did not have (Figure 3). Median number of infusions prior to infection was 2 (IQR 1–5); median time since last infusion was 28.0 days (IQR 13.0–47.0).

image

Figure 3.  Occurrence of infectious event stratified by concomitant immunosuppression at the time of first infliximab infusion. CS, corticosteroids; AZA, azathioprine; MP, mercaptopurine; MTX, methotrexate.

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In total, 24 serious infectious events occurred in 20 of 202 patients (9.9%). The patient was on concomitant AZA, mercaptopurine or methotrexate in 16/24 episodes, prednisolone in seven of 24 and a combination of immunosuppressants and corticosteroids in five of 24. Of these serious cases, 13 required treatment with i.v. antibiotics and two with i.v. anti-virals. Six infectious events occurred post-operatively; four of these were considered serious.

Two sepsis-related complications (colonic perforation and facial cellulites) occurred within the adalimumab-treated patients, both previously described.23, 24 Further 10 cases of minor infections (chest infections, tonsillitis and fevers) in seven individuals who required temporary discontinuation of adalimumab therapy (all <3 weeks) were reported.

Malignancies

Six of 202 patients (3.0%) were diagnosed with malignancy post-treatment (Table 5). Of these, three were haematological malignancies. A 47-year-old female CD patient was diagnosed with a small bowel lymphoma (non-Hodgkin’s, B-cell) 23 days after her ninth infliximab infusion. The mass was found during a surgical procedure. A 73-year-old female CD patient was diagnosed with myelodysplasia 48 months after her third infliximab infusion. A 52-year-old male coeliac disease patient was diagnosed with a cutaneous T-cell lymphoma, 20 months after one infliximab infusion.

Table 5.   Summary of malignancies. Age is documented as age at diagnosis of malignancy in years
Gender/ age (year)/ diagnosisYear of malignancy diagnosisPrior infliximab infusions (n)Time since last infusion (months)Associated treatment (duration)Clinical presentationOutcome
  1. CD, Crohn’s disease; UC, ulcerative colitis; CO, coeliac disease; AZA, azathioprine; MTX, methotrexate.

F/47/CD20059<1AZA 150 mg (11 year)Small bowel lymphoma (non-Hodgkin’s, B-cell)Remission
F/70/CD2006627MTX 15 mg (4 year) Adalimumab (2 year)Lung cancer (nonsmall cell)Remission
M/66/CD200232UnavailableLung cancerFatal
M/76/CO2006151NilLung cancerFatal
F/73/CD2006348AZA 75 mg (4 year)MyelodysplasiaFatal
M/52/CO2002120NilCutaneous T-cell lymphomaFatal

There were three cases of lung cancer in our cohort. Three of 13 (23.1%) patients >65 years of age and with a significant smoking history developed lung cancer. Two of these cases were probably related to anti-TNF therapy given their temporal association. One of these patients, a 70-year-old female ex-smoker (34.5 pack-years) with CD, developed histologically proven, locally advanced nonsmall cell lung cancer (TNF-R1 and -R2 positive on immunohistochemistry) whilst on maintenance adalimumab (2.1 years, 40 mg every other week) only to enter sustained clinical remission (20 months to date) on drug withdrawal only and no specific anti-tumour therapy. We have previously reported the full details of this case.25 The second case was a 66-year-old male smoker (20/day) with CD, diagnosed with lung cancer 2 months after his third infusion; his preinfliximab CXR showed possible pathological change on review, but he was asymptomatic at this time. Thirdly, a 76-year-old male smoker (15/day) with coeliac disease was diagnosed with a lung cancer 62 months after one infliximab infusion.

Drug-induced lupus and other autoimmune diseases

A 15-year-old male CD patient developed drug-induced lupus. This occurred 132 days after his fourth infliximab infusion. He was on concomitant immunosuppression at the time of infusion and drug-induced lupus (AZA 100 mg, 2 years duration). He presented with unremitting pyrexia despite negative cultures, thrombocytopenia, anaemia, suspected vasculitis and raised titres of antinuclear antibodies and IgG. He was an in-patient for 56 days and required treatment with platelets, vitamin K and intravenous corticosteroids.

Six patients presented with suspected demyelinating disease post-infliximab [two within 90 days of infusion (both SAEs) and one on maintenance adalimumab], although only three had evidence of definite neurological abnormality following detailed assessment. A 34-year-old female with small bowel CD developed extensive central demyelination on adalimumab responding partially to drug withdrawal, high-dose prednisolone and plasma exchange. A 74-year-old female CD patient had nerve conduction studies showing severe axonal sensorimotor polyneuropathy, 4 years after her only infliximab infusion. A 48-year-old male with coeliac disease had nerve conduction studies and an electromyogram showing severe demyelinating neuropathy, 1.5 years after his only infliximab infusion; however, his symptoms of progressive sensory disturbance began prior to his infliximab infusion and his disorder was thought to be secondary to malnutrition. A 38-year-old female CD patient was found to have oligoclonal CSF bands approximately 4 years after infliximab infusion, during which time she had been treated with maintenance natalizumab. A 61-year-old male CD patient was investigated for neuropathy, after developing myalgia and fatigue 88 days after his 10th infliximab infusion. A 47-year-old male CD patient presented with numbness and tingling of his hands, 55 days after his third infliximab infusion. However, neurological review and detailed investigation showed no significant evidence of abnormality in these latter three patients.

Other AEs

A 65-year-old CD patient developed alopecia, 39 days after first infliximab infusion. A 21-year-old UC patient developed asymptomatic elevated serum aminotransferase levels, 12 days after first infliximab infusion; however, her AZA and corticosteroid doses had recently been increased. She received three further infliximab infusions with no liver function test abnormalities.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

The safety profile of anti-TNF drugs in inflammatory bowel disease was initially established in a series of placebo-controlled clinical trials up to 1 year. As these drugs have become more widely used and surveillance has continued, additional safety signals have emerged. In the initial period of postmarketing surveillance, the increased risk of reactivating latent TB was identified17 and additional signals have subsequently emerged, most notably the concerns regarding HSTCL in young patients22 and regarding bronchogenic carcinomas in heavy smokers.25, 26 However, these smaller and delayed safety signals are, by their very nature, much harder to detect.

We have demonstrated a broadly comparable AE profile to other tertiary referral populations world-wide15, 16, but our data highlight some worrying issues – the high incidence of lung cancer in older patients who smoke and the unresolved concerns regarding neurological complications including demyelination. Both lung cancer and demyelination are high-incident diseases in Scotland as a result of genetic (demyelination) or environmental factors (smoking and lung cancer); the present data may reflect an accelerated course in susceptible individuals after anti-TNF exposure.

The overall mortality rate in our cohort at 3.5% compares with rates of 2.8% and 2.0% reported in retrospective series from Scandinavia and the Mayo group respectively.15, 16 In the latter, Colombel and colleagues quote a 1.0% mortality ‘possibly’ related to infliximab.15 In our dataset, only one of the seven deaths occurred within a year of anti-TNF exposure; causality is much harder to determine for the others. Treatment-associated mortality needs to be interpreted in light of the documented underlying mortality of IBD. In Stockholm County, the standardized mortality ratio has been calculated at 1.51 in CD and 1.37 in UC.27

Three lung cancers and three haematological malignancies were seen in this study and, of these, one resulted in death only 72 days after infliximab treatment. Malignancies have been reported in the major clinical trials of anti-TNF antibodies in CD – eight with infliximab (ACCENT I and II),2, 5 two with adalimumab (CLASSIC I and II and CHARM),1, 3, 4 and four with certolizumab pegol (PRECiSE I and II).6, 8 In the recently reported Leuven cohort of 148 adalimumab-treated patients, there were seven cancers in five patients.28 In the North American TREAT registry with 15 000 patient-years’ follow-up on 6273 patients, there was no increase in the rates of malignancy in patients receiving infliximab (incidence per 100 patient-years of 0.58) compared with those not receiving infliximab (0.53; relative risk: 1.1; 95% CI: 0.71–1.63).29 However, interpretation of these data is limited by potential selection bias. Moreover, the data in rheumatoid arthritis are less reassuring than published data in IBD. In a systematic review of data from nine clinical trials (3493 patients treated with infliximab or adalimumab; 1512 placebo treated controls), Bongartz et al.30 reported an increased risk of malignancy in anti-TNF treated patients (pooled OR: 3.3; 95% CI: 1.2–9.1). Of note, whilst 11 of the reported 35 malignancies in anti-TNF patients were lymphomas or leukaemias, 14 were solid organ cancers. In a trial of the anti-TNF agent etanercept in Wegener granulomatosis, there were six solid cancers in 89 patients treated etanercept plus cyclophosphamide compared with none out of 91 treated with cyclophosphamide alone.31

Most pertinent to the present data are recent reports that suggest an increased risk of lung cancer in heavy smokers treated with anti-TNF therapy. In the Mayo Clinic series of 500 CD patients, two lung cancers, both thought ‘possibly related’ to infliximab were reported in elderly smokers.15 A recent 24-week trial of infliximab in COPD was notable for the high malignancy rate in 157 infliximab treated patients (nine malignancies including four lung cancers plus two additional lung cancers after study completion vs. one of 77 in placebo group).26 Of great interest, a biological explanation for this risk is perhaps evident in a landmark paper by Koebel et al.32 in a murine model of metastatic cancer induced by 3′-methylcholanthrene, a carcinogen in cigarette smoke. In this established model, a first wave of metastatic tumours kills a majority of mice. The survivors remain healthy but critically, this is dependent on intact adaptive immunity. Experimental depletion of T cells or blockade of IL-12 or IFN-γ in vivo resulted in tumour growth and spread with resulting fatality. These TNF-dependent mechanisms appear critical in maintaining tumour dormancy.

Six patients in our study were investigated for suspected demyelination. In three patients, definite neurological abnormality was detected, but in only one was anti-TNF therapy directly implicated in a potentially causal manner. On the basis of the present published literature, it remains difficult to establish a clear-cut relationship between anti-TNF therapy and demyelination especially in light of the documented increased background risk in patients with IBD33 and the high incidence of multiple sclerosis in Scotland and the rest of the UK.34 For example, in the recent early combined immunosuppression trial in CD, of 65 patients in the ‘top–down’ group (infliximab plus AZA), a 25-year-old developed confirmed demyelination, resolving with withdrawal of anti-TNF therapy.13 In the ACT studies in UC, there were three cases of demyelination in those treated with infliximab compared with none in the placebo groups.9 Furthermore, we are aware of two further cases of severe demyelination, temporally related to anti-TNF therapy in Scotland. We would advise that use of these agents is withheld in patients with any history of demelination or optic neuritis and re-considered if a strong family history is present. The drug needs to be withdrawn immediately if neurological symptoms develop.

Our local protocol has included pre-treatment of all patients with intravenous hydrocortisone since 2003 and this may have contributed to the relatively low number of acute IRs in our population. The long duration of our study (8 years compared with 4 and 2 years in the Mayo15 and Stockholm16 cohorts respectively) and long follow-up (620 patient-years), combined with the predominantly episodic use of infliximab, has allowed us to analyse the effect of ‘drug holiday’ on immunogenicity. Our analysis indicated that a long interval between previous infusions is indeed a significant factor in the development of SSLRs with all significant drug holidays >1 year. However, it is noteworthy that 77.8% of patients with a drug holiday over 1 year tolerated infliximab re-infusion with no clinical evidence of immunogenicity. Moreover, all of our patients developing delayed reactions were on thiopurine or methotrexate immunosuppression.

Infection was the most common AE in this and the other published studies. We did not detect any confirmed cases of opportunistic infection. In addition, there were no cases of tuberculosis, probably due in part to both implementation of screening and the relatively low prevalence in our population. A majority of infectious events occurred in the presence of concomitant immunosuppression, but in contrast to other reports,18, 29 we did not see any increased risk of infection in patients on thiopurines or corticosteroids. In our practice, we are stringent at withholding scheduled anti-TNF therapy, if there is clinical suspicion of infection to allow for a period of assessment and treatment.

Important AEs occur with anti-TNF therapy. As experience increases, some of these are predictable or treatable and preventable, but others are incurable conditions occurring in an apparently idiosyncratic manner. Thus, risks need to be balanced with the potential benefits on an individual level and discussed with patients in detail prior to initiation of therapy. In Edinburgh, current practice is to discuss the risks of infusion reaction, infection, demyelination, lymphoma (including hepatosplenic T-cell lymphoma) and other malignancy. The potential association with lung cancer identified in our study is of concern in light of other reports in infliximab-treated patients and we feel that the potential for carcinogenesis is an area requiring special vigilance. Our experience leads us to caution against the use of anti-TNF agents in older patients with significant smoking histories or underlying lung disease and to avoid these agents in any patients with a history suggestive of demyelination. We feel that there is a compelling case for continuing vigilance in the use of these agents and to this end, strongly support the establishment of independent registries to assess drug use, efficacy and safety objectively and accurately.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

Declaration of personal interests: None. Declaration of funding interests: CWL, GH and IDRA have received financial sponsorship (for educational and travel grants, and advisory fees) from Schering-Plough, Shire Pharmaceuticals, Abbott Pharmaceuticals, Ferring, Proctor and Gamble, and UCB. DCW has served as a consultant to Schering-Plough. JXXS has received research support from Schering-Plough, Abbott, UCB and Elan Pharmaceuticals and acted as a consultant for Schering-Plough, Abbott, Ferring and UCB.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

Supporting Information

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

Table S1. Peripheral blood markers at time of firstinfliximab infusion and subsequently at around 6 weeks post-infliximab.

Table S2. Details of all acute infusion reactions toinfliximab.

Table S3. Details of all serum sickness-likereactions with infliximab.

Table S4. Details of all infectious events ininfliximab-treated patients.

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Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.